FINAL Pathology topics SEM 2 Flashcards
Skin tumors of epithelial origin (epidermis, hair follicle, sebaceous and sweat gland tumors).
Morphology – Usually are less than 1 cm in diameter, brown or red in color, and rough.
BENIGN AND PREMALIGNANT EPITHELIAL LESIONS
# Benign epithelial neoplasms are very common properly develop from stem cells reside in the
epidermis and hair follicles.
# They grow to a limited size and generally do not undergo malignant transformation.
SEBORRHEIC KERATOSIS
# Presents as raised round, discolored plaques on the extremities or face made of proliferating
basal epidermal cells Characterized by keratin pseudocysts on epidermis see also sometimes
hyperkeratosis
# common tumor in the elderly Usually these lesions are of little clinical importance. In rare cases
see abundant such as lesions may appear as a paraneoplastic syndrome most common are the GI
tract carcinoma association which produce GF that stimulate epidermal proliferation.
# Pathogenesis – activating mutations in Fibroblast Growth Factor receptor .
ACTINIC KERATOSIS
# This lison usually a result of chronic exposure to sunlight, and is associated with hyperkeratosis
hence actinic keratosis.
# Pathogenesis –. Mostly associated with TP53 mutation age fair skin n sun exposure (inducing
tp53 mutation). has the potential to become malignant (SSC) therefore must be removed .
Epidermis – show cytological atypia in lower part of epidermis; parakeratosis of stratum corneum
can also be seen .Dermis – actinic elastosis. Instead of collagen see elastic fibers become
homogenous appearance on HE …
SEBACEOUS ADENOMA
# Rear benign, self-limited growth, that appear in the head and neck region of older individuals.
Present as flesh-colored papules-elevated less than 5 mm lesion.
# Pathophys Association with Muir-Torre syndrome, a rare autosomal dominant cancer syndrome,
and with internal malignancy, mainly colon carcinoma. Both cases are considered subtypes of
hereditary nonpolyposis colorectal carcinoma syndrome, characterized by loss of a DNA
mismatch repair protein.
expansion of germinative basaloid cell layers at periphery
MALIGNANT EPIDERMAL TUMORS
SQUAMOUS CELL CARCINOMA
# Malignant proliferation of squamous cells. Presents as an red scaling may ulcerate , nodular
mass, usually appear on sun-exposed sites in older people typically the face (classically
involving the lower lip) With higher incidence in men than in women.
risk factors include immunosuppressive therapy, toxin exposure - arsenic exposure, and chronic
inflammation (e.g., scar from burn, chronic ulcers etc..)
# Pathogenesis – Exposure to UV light Causes mutation in TP53, HRAS and loss of function in
Notch receptors, which regulates differentiation of normal squamous epithelia. Also has
Immunosuppressive effect on skin by impairing antigen presentation by Langerhans cells.
defined by penetration of the basement membrane. Show variable degrees of differentiation,
ranging from tumors with cells arranged in orderly lobules that exhibit extensive keratinization
to neoplasms consisting of highly anaplastic cells with foci of necrosis and only abortive, singlecell
keratinization (dyskeratosis). See inflammatory reaction aroun nodules in dermis
related to the thickness of the lesion and degree of invasion into the sub cutis. Mucosal
squamous cell carcinoma (oral, pulmonary, esophageal) are much more aggressive
BASAL CELL CARCINOMA
# Malignant proliferation of the basal cells of the epidermis Most common cutaneous malignancyA
slow-growing tumor that Rarely metastasize
tumor suppressor mutation that regulates the Hedgehog pathway, causes familial basal cell
carcinoma and also in sporadic see mutations in hedgehok path. Mutations in p53 are also
common in familial or sporadic carcinomas.
dilated (telangiectasia) vessels ‘pink, pearl-like papule’ Classic location is the upper lip.
Tumor cells resemble the epidermal basal cells from which they originate. On histo see horizontal
growth along-epithelodermaljunction and vertical growth into dermis crate island of malignant
cells may be bordered by palisading, around it see inflammation and it destroy surrounding
dermis as it replace it…
sinuses may occur.
Actinic keratosis is a precursor lesion of squamous cell carcinoma and presents as a
hyperkeratotic, scaly plaque, often on the face, back, or neck.
Keratoacanthoma is well-differentiated squamous cell carcinoma that develops
rapidly and regresses spontaneously; presents as a cup-shaped tumor filled with
keratin debris
Melanocytic tumors of the skin.
Initially composed of oval cells that grow in nests along the dermoepidermal junction
Melanocytes are responsible for skin pigmentation and are present in the basal layer
of the epidermis.Derived from the neural crest. Synthesize melanin in melanosomes
using tyrosine as a precursor molecule Pass melanosomes to keratinocytes
Melanocytic nevus is the benign tumor of melanocytes Nevus = congenital.Malignant
melanoma is a malignant tumor of melanocytes
MELANOCYTIC NEVI
# A brown, uniformly pigmented, small (<5mm), solid regions of elevated skin (papules)
with well defined, rounded borders.
=> JUNCTIONAL NEVI
# Most junctional nevi grow into the underlying dermis as nests or cords of cells =>
COMPOUND NEVI
# In older lesions, the epidermal nests may be lost completely to leave pure
INTRADERMAL NEVI.
# The majority of benign nevi show an activating mutation in BRAF, or less commonly
in RAS. BRAF – a gene encoding Ser/Thr kinase which is involved in directing cell
growth.
# changes of morphology of cells as evidence of cellular senescence Superficial nevus
cells – larger and less mature, tend to produce melanin and grow in nests. Deeper nevus
cells – smaller and more mature, produce little to no pigment and grow in cords or
single cells; the deepest nevus cells grow n fascicles.
DYSPLASTIC NEVUS
# Dysplastic nevi consist mainly of compound nevi and Marked by Cytological atypia
(consisting of irregular nuclei and hyperchromasia)
# result from BRAF or RAS mutations May occur sporadically or in a familial form
(autosomal dominant inheritance).appearance of dysplastic nevi mainly Familial are
considered as markers for risk to develop melanoma .
# Morphology – Larger than most acquired nevi (>5mm), may occur in large numbers
come as flat macules to slightly raised plaques, show variable pigmentation and
irregular borders.accure on sun expose n non expose surfaces
Nevus cell nests within the epidermis may be enlarged and fusion with adjacent
nests.As a result, the nevus cells begin to replace the normal basal cells at the
dermoepidermal junction- lentiginous pattern
Dermal changes as host respond see Lymphocytic infiltration into the superficial
dermis. melanin phagocytosis by dermal macrophages Linear fibrosis surrounding
epidermal nests of melanocytes.
MELANOMA
# Malignant neoplasm of melanocytes; most common cause of death from skin cancer
# Pathogenesis – Sunlight exposure plays the important role - Most melanomas occur
sporadically also hereditary predisposition – dysplastic nevus syndrome (autosomal dominant
disorder characterized by formation of dysplastic nevi that may progress to melanoma).
Mutations in the gene of p16 gene that encodes a cyclin-dependent kinase inhibitor regulating
the G1-S transition; this mutation id found in 40% of familial melanomas and less commonly in
sporadic cases the gene is silenced by methylation. Somatic activating mutations in the protooncoggenes BRAF and NRAS are common in melanomas of bout kinds
the epidermis (in situ) and superficial dermal layers => during this stage no metastasizes, and do
not induce angiogenesis. Vertical growth: the melanoma grows into the deeper dermal layers,
lacking cell maturation- with greater metastatic potential => metastases involves regional lymph
nodes, liver, lungs, brain etc.
# Morphology –show large variation of pigmentation (black, brown, red etc..) The borders are
irregular and notched.
Malignant cells grow in poorly-formed nests or ad individual cells at all levels of the epidermis
Melanoma cells are larger than nevus cells, containing large nuclei with chromatin clumped at
the periphery of the nucleus, with prominent eosinophilic nucleoli (described as “cherry
red”).Superficial spreading melanomas are associated with lymphocytic infiltrate.
surfaces, esophagus, meninges, and the eye.
Signs of melanoma – ABCs of melanoma – Asymmetry, Border, Color, Diameter, Evolution
(change of an existing nevus).
Probability of metastasis is predicted by measuring the depth of invasion in mm of the vertical
growth phase nodule from the top of the granular call layer of the epidermis (Breslow thickness)
Classification and grading of soft tissue tumors. Tumors of adipose tissue. Tumors and tumorlike
lesions of fibrous tissue.
Sarcoma vs. Carcinoma : carcinoma easily will be separated into parenchyma &
CLASSIFICATION AND GRADING OF SOFT TISSUE TUMORS
Soft tissue – The bulk of the body is composed of the cells forming tissues that are
considered “soft” tissues or connective tissues.
(Any non-epithelial tissue except bone, cartilage, CNS, hematopoietic and lymphoid tissues).These embryological derived from the mesoderm. Hence, they are often called me-senchymal tissues.
Classification of soft tissue tumors:
stroma. In sarcoma both paranchyma & stroma are derived from the same origin =
cannot be separated.
neuroectoderm!
not from malignant transformation of adult tissue cells .
MSCs, are multipotent stromal cells that can differentiate into a variety of cell types creating mesenchymal tissue MSCs
do not differentiate into hematopoietic cells got self-renewing asymmetric division and
found in body : placenta umbilical cord blood, adipose tissue, adult muscle, corneal
stroma or the dental pulp of deciduous baby teeth, but do not have the capacity to
reconstitute an entire organ.
Metaplasia is common in soft tissue tumors
malignancies), but they cause 2% of all cancer deaths, reflecting their lethal nature.
with irradiation and systemic therapy reserved for large high-grade tumors.
Diagnostic classification- histology, immunohistochemistry, electron microscopy,
cytogenetics and molecular genetics are important in assigning the correct diagnosis.
Keeping in mind the high metaplastic appearance…
Histological diagnosis = pattern recognition help in estimate tumer type patterns apper
chrecteristicly with different tumers
Spindle cell/epitheloid/pleiomorphic/small blue cell /biphasic
Grading Differentiation! How well it resembles the origin cell. Staging = the stage!
Location.
# Staging- use TNM system as size and depth of invesion looked in T the N for nodal
involvement and the M for metastasis With tumors larger than 20 cm, metastases
develop in 80% of cases; by contrast, for tumors 5 cm or smaller, metastases occur in
only 30% of cases. It is rare for adult sarcomas to metastasize to lymph nodes.
Note that in STT the dipper ones more aggressive then superficial..
the mitotic activity and of the extent of necrosis.
- Differentiation (1-3 score) less diffrant. Higher score
- Mitotic count (1-3 score)
- Necrosis (1-3 score) higher score more necrosis
Total sum = from 1-3 by addition of scores in each category as 3 grade got higst summed up
score Grade help to indicate the probability of distant metastases and reaction to treatment…
TUMORS OF ADIPOSE TISSUE
LIPOMA
# Most lipomas are solitary lesions, mobile, slowly enlarging, painless masses (
Multiple lipomas may suggest the presence of rare heredity syndromes).
» Conventional lipoma- (the most common subtype) are soft, yellow, wellencapsulated
masses of mature adipocytes; they can vary considerably in
size and no pleomorphism.
» Myolipoma – a benign tumor that consists of fat cells with variable
number of muscle cells.
» Spindle cell lipoma – slow-growing subcutaneous tumors, mainly in the
back, neck and sholders of older men.
» Myelolipoma – a benign tumor composed of mature adipocytes and
hematopoietic cells.
» Pleomorphic lipoma – characterized by giant cells that resemble small
flowers, with overlapping nuclei.
» Angiolipoma – subcutaneous nodule with vascular structure; they are
commonly painful.
LIPOSARCOMA
liposarcomas arise in deep soft tissues or in the retroperitoneum.
» Well-differentiated liposarcoma – malignant lesions that arise in the
retroperitoneum, commonly associated with amplification of a region in
the long arm of chromosome 121
.
» Dedifferentiated liposarcoma – consists of a well-differentiated
liposarcoma adjacent to a more poorly differentiated tumor.
» Myxoid (round cell) liposarcoma – associated with translocation between
chromosomes 12 and 16, which affects the transcription factor that plays a
role in normal adipocyte differentiation. More aggressive pleomorphic
variant, which tend to recur after excision and metastasize to lungs.
» Myxoid liposarcoma characterized by abundant, mucoid
extracellular matrix.
» Lipoblasts are present indicative of fatty differentiation.
They have cytoplasmic lipid vacuoles that scallop (צדפה (the nucleus
TUMORS AND TUMOR-LIKE LESIONS OF FIBROUS TISSUE
I. REACTIVE PROLIFERATIONS
# Nodular fasciitis –rapidly growing reactive lesion of self-limited fibroblastic
proliferation that probably resulted from trauma(Rarely recurs after excision)
and is superficial
» Morphology – Tightly woven uniform spindle cells and collagen are seen
(=stroiform arrangement) A few lymphocytes & vascular channels are
present.
» Can be up to several cm in diameter and appears nodular Typically occurs
in adults on the volar aspect of the forearm, chest or back
» Distinguished from other types of fibroblastic proliferations by the
presence of metaplastic bone.
» Characterized by the ossification of muscle. Develops in the proximal
muscles of the extremities in athletic adolescents and young adults after
trauma.
» Initially, the involved area is swollen and painful, and eventually develops
into a hard, painless, well-demarcated mass. Critical to distinguish from
extra skeletal osteosarcoma.
II. FIBROMATOSES
# Benign soft tissue tumors the lesions are locally aggressive, but DO NOT metastasizes.
Many cases recur after surgical removal.
» Superficial fibromatoses – arise in the superficial fascia2
, can be associated with
trisomy 3 & 8, but usually are harmless.
» Deep fibromatoses – include the desmoid tumor that arise in the abdominal wall and
mesentery, and muscles of the trunk and extremities, as isolated lesions or as a
component of Gardner syndrome3
; tend to grow in a locally aggressive manner,
» The tumors are gray-white, firm to rubbery, poorly demarcated, infiltrative masses (1-
15cm).
» histology consistent with : contain abundant dense collagen. with low cellularity , a
proliferation of well-differentiated fibroblasts that tend to grow in an infiltrative fashion
III. FIBROSARCOMA
# Malignant neoplasms composed of fibroblasts. Tend to grow slowly And Typically
found in the deep tissues of the thigh, knee and retroperitoneal area. Recur locally after
excision. (in 50% of cases) Can metastasize, usually to the lungs.
hemorrhage and necrosis. Histologic examination discloses all degree of
differentiation.
Tumors of skeletal muscle, smooth muscle, peripheral nerve and synovial origin.
Skeletal muscle neoplasms are almost all malignant.rheabdomyoma is rear bingeing skeletal
SKELETAL MUSCLE TUMORS
.m. tumor most often found in heart.
RHABDOMYOMA
# rear benign hamartomatous tumor of striated muscle. Can be cardiac or extra cardiac most
often found in the heart. Can be classified as adult type, fetal type and genital type. Very rear but
Most frequent primary tumor of the heart in infants and children
RHABDOMYOSARCOMA
# Skeletal muscle malignant neoplasm Usually appears in children and adolescents.
Occur most commonly in the head and neck region or the urogenital tract .
# often chromosomal translocation are found, mainly t(2,13)4
.
# Morphology – Can be sub classified into morphological types embryonal, alveolar and
pleomorphic variants.
Tumors that arise next to the bladder or vagina are soft, gelatinous, grape-like masses (sarcoma
botryoides); in other cases the tumor is poorly defined.
Rhabdomyoblast is the cell that appears in all types, and exhibits granular, eosinophilic
cytoplasm rich in thick and thin filaments. These cells can be round or elongated2 IHC: desmin,
aktin
Clink.: aggressive; chemotherapy often effective, especially in children (cure)
SMOOTH MUSCLE TUMORS
LEIOMYOMA
the uterus.
chromosomes 6 and 12
intramural (within the myometrium), submucosal (directly beneath the endometrium), or
subserosal5 (directly beneath the serosa).
Large neoplasms may develop ischemic necrosis with areas of hemorrhage and cystic
softening; after menopause, they may become collagenous and even calcified.
LEIOMYOSARCOMA
in postmenopausal women (in contradiction to leiomyoma)
Present as firm, painless masses. Common sites of development are skin, deep soft tissues of the
extremities and retroperitoneum. Metastasize typically to the lungs.
myometrium, and NOT from pre-existing leiomyomas.
arranged in interwoven fascicles. Present cytological atypia and mitotic activity. Present a wide
range of cell differentiation, from close resemblance to leiomyoma to anaplastic tumors.
PERIPHERAL NERVE TUMORS
# In most tumors, the neoplastic cells show evidence of Schwann cell differentiation.
These tumpors usually occur in adults.They are frequently associated with familial tumor
syndromes neurofibromatosis type 1 (NF1) and type 2 (NF2)
SCHWANNOMA AND NEUROFIBROMATOSIS TYPE 2
# Schwannomas are benign encapsulated tumor composed of Schwann cells that may occur in
soft tissues, internal organs or spinal nerve roots
.Causing local compression of the involved
nerve, or the compression of adjacent structures
.The presence of bilateral vestibular Schwannomas is the hallmark of NF2.
Affected patients carry a dominant loss-of-function mutation of the merlin8 gene on chromosome 22
Schwannomatosis is a familial condition associated with multiple Schwannomas in which
vestibular nerve is absent
can be separated from it.
Histo-Biphasic tumor: Antoni A – dense areas; bland spindle cells arranged into intersecting
fascicles.Often align to produce nuclear palisading, resulting in alteration bands of nuclear and a
nuclear areas called Verocay bodies. Antoni B – loose meshwork of cells and stroma
Thick-walled hyalinized vessels often are present
NEUROFIBROMA
# Benign peripheral nerve sheath tumors.
# Subdivided into 3 types:
» Localized cutaneous neurofibroma – arise as superficial nodular or polypoid tumor. These occur
either as solitary sporadic lesions or as multiple lesions in the context of NF1
» Plexiform neurofibroma – grow diffusely within a nerve or a nerve plexus; associated with type 1
neurofobromatosis (NF1); may evolve to a malignant tumor; involve multiple fascicles of
individual affected nerves, residual axons are found embedded within the diffuse neoplastic
Schwann cell proliferation
» Diffuse neurofibromas – infiltrative proliferation; large subcutaneous masses. Often associated
with NF1; often found in the dermis and subcutis of the skin.
cutaneous neurofibroma) or diffuse.
In contrast with Schwannomas, neoplastic Schwann cells are mixed with other cell types (mast cells,
fibroblast-like cells and perineurial-like cells).
Stroma contains loose wavy collagen bundles/dense collagen
MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
# Highly malignant sarcomas, which are locally invasive.
# Seen in adults, typically show evidence of Schwann cell derivation and sometimes arise from
transformation of a plexiform neurofibroma (50% arise from NF1)
» Large, poorly defined tumor masses.
» Tumors are highly cellular, exhibiting malignancy properties (anaplasia, necrosis, infiltrative
growth pattern, pleomorphism, high proliferative activity)
» Low power magnification shows alternating areas of high and low cellularity marble-like
appearance
NEUROFIBROMATOSIS TYPE 1
# Autosomal dominant disorder caused by mutation in the tumor suppressor neurofibromin found of
chromosome 17.
# Neurofibromin is a negative regulator of Ras.
arterial stenoses, pigmented nodules of the iris (Lisch nodules), pigmented skin lesions.
SYNOVIAL SARCOMA
synovium; less than 10% are intra-articular.
# Usually develop in deep soft tissues around the large joints of the extremities, mainly the knee
joint.
# Most synovial sarcomas show t(X, 18)9
.
# Morphology –
» The tumor can be monophasic (only one cell type – spindle cell), or biphasic (both cell types).
» Nonophasic tumors may be mistaken with fibrosarcomas or malignant peripheral nerve sheath
tumor, differential diagnosis is done by immunohistochemistry showing a positive test result
for keratin and epithelial membrane antigen.
» Tumor cells can be of two types:
1) Spindle cell (fibrous type cell) – arranged in cellular fascicles that surround the epithelial cells.
2) Epithelial-like cell – cuboidal to columnar, form glands or grow in solid cords or aggregates.
» Common metastatic site are the lungs, bones and regional lymph node
Tumors of skeletal muscle, smooth muscle, peripheral nerve and synovial origin.
Skeletal muscle neoplasms are almost all malignant.rheabdomyoma is rear bingeing skeletal
SKELETAL MUSCLE TUMORS
.m. tumor most often found in heart.
RHABDOMYOMA
# rear benign hamartomatous tumor of striated muscle. Can be cardiac or extra cardiac most
often found in the heart. Can be classified as adult type, fetal type and genital type. Very rear but
Most frequent primary tumor of the heart in infants and children
RHABDOMYOSARCOMA
# Skeletal muscle malignant neoplasm Usually appears in children and adolescents.
Occur most commonly in the head and neck region or the urogenital tract .
# often chromosomal translocation are found, mainly t(2,13)4
.
# Morphology – Can be sub classified into morphological types embryonal, alveolar and
pleomorphic variants.
Tumors that arise next to the bladder or vagina are soft, gelatinous, grape-like masses (sarcoma
botryoides); in other cases the tumor is poorly defined.
Rhabdomyoblast is the cell that appears in all types, and exhibits granular, eosinophilic
cytoplasm rich in thick and thin filaments. These cells can be round or elongated2 IHC: desmin,
aktin
Clink.: aggressive; chemotherapy often effective, especially in children (cure)
SMOOTH MUSCLE TUMORS
LEIOMYOMA
the uterus.
chromosomes 6 and 12
intramural (within the myometrium), submucosal (directly beneath the endometrium), or
subserosal5 (directly beneath the serosa).
Large neoplasms may develop ischemic necrosis with areas of hemorrhage and cystic
softening; after menopause, they may become collagenous and even calcified.
LEIOMYOSARCOMA
in postmenopausal women (in contradiction to leiomyoma)
Present as firm, painless masses. Common sites of development are skin, deep soft tissues of the
extremities and retroperitoneum. Metastasize typically to the lungs.
myometrium, and NOT from pre-existing leiomyomas.
arranged in interwoven fascicles. Present cytological atypia and mitotic activity. Present a wide
range of cell differentiation, from close resemblance to leiomyoma to anaplastic tumors.
PERIPHERAL NERVE TUMORS
# In most tumors, the neoplastic cells show evidence of Schwann cell differentiation.
These tumpors usually occur in adults.They are frequently associated with familial tumor
syndromes neurofibromatosis type 1 (NF1) and type 2 (NF2)
SCHWANNOMA AND NEUROFIBROMATOSIS TYPE 2
# Schwannomas are benign encapsulated tumor composed of Schwann cells that may occur in
soft tissues, internal organs or spinal nerve roots
.Causing local compression of the involved
nerve, or the compression of adjacent structures
.The presence of bilateral vestibular Schwannomas is the hallmark of NF2.
Affected patients carry a dominant loss-of-function mutation of the merlin8 gene on chromosome 22
Schwannomatosis is a familial condition associated with multiple Schwannomas in which
vestibular nerve is absent
can be separated from it.
Histo-Biphasic tumor: Antoni A – dense areas; bland spindle cells arranged into intersecting
fascicles.Often align to produce nuclear palisading, resulting in alteration bands of nuclear and a
nuclear areas called Verocay bodies. Antoni B – loose meshwork of cells and stroma
Thick-walled hyalinized vessels often are present
NEUROFIBROMA
# Benign peripheral nerve sheath tumors.
# Subdivided into 3 types:
» Localized cutaneous neurofibroma – arise as superficial nodular or polypoid tumor. These occur
either as solitary sporadic lesions or as multiple lesions in the context of NF1
» Plexiform neurofibroma – grow diffusely within a nerve or a nerve plexus; associated with type 1
neurofobromatosis (NF1); may evolve to a malignant tumor; involve multiple fascicles of
individual affected nerves, residual axons are found embedded within the diffuse neoplastic
Schwann cell proliferation
» Diffuse neurofibromas – infiltrative proliferation; large subcutaneous masses. Often associated
with NF1; often found in the dermis and subcutis of the skin.
cutaneous neurofibroma) or diffuse.
In contrast with Schwannomas, neoplastic Schwann cells are mixed with other cell types (mast cells,
fibroblast-like cells and perineurial-like cells).
Stroma contains loose wavy collagen bundles/dense collagen
MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
# Highly malignant sarcomas, which are locally invasive.
# Seen in adults, typically show evidence of Schwann cell derivation and sometimes arise from
transformation of a plexiform neurofibroma (50% arise from NF1)
» Large, poorly defined tumor masses.
» Tumors are highly cellular, exhibiting malignancy properties (anaplasia, necrosis, infiltrative
growth pattern, pleomorphism, high proliferative activity)
» Low power magnification shows alternating areas of high and low cellularity marble-like
appearance
NEUROFIBROMATOSIS TYPE 1
# Autosomal dominant disorder caused by mutation in the tumor suppressor neurofibromin found of
chromosome 17.
# Neurofibromin is a negative regulator of Ras.
arterial stenoses, pigmented nodules of the iris (Lisch nodules), pigmented skin lesions.
SYNOVIAL SARCOMA
synovium; less than 10% are intra-articular.
# Usually develop in deep soft tissues around the large joints of the extremities, mainly the knee
joint.
# Most synovial sarcomas show t(X, 18)9
.
# Morphology –
» The tumor can be monophasic (only one cell type – spindle cell), or biphasic (both cell types).
» Nonophasic tumors may be mistaken with fibrosarcomas or malignant peripheral nerve sheath
tumor, differential diagnosis is done by immunohistochemistry showing a positive test result
for keratin and epithelial membrane antigen.
» Tumor cells can be of two types:
1) Spindle cell (fibrous type cell) – arranged in cellular fascicles that surround the epithelial cells.
2) Epithelial-like cell – cuboidal to columnar, form glands or grow in solid cords or aggregates.
» Common metastatic site are the lungs, bones and regional lymph node
The patomechanism of glomerular kidney diseases.
The functional unit of the kidney is the nephron, which is composed of the glomerulus and a
STRUCTURE OF THE NEPHRON
tubular system, in which the filtered fluid is converted into urine.
1) Fenestrated endothelium – each pore is 70-100nm in diameter.
2) Glomerular basement membrane – consists of 3 sub layers => lamina rara interna and lamina
rara externa10, between them is the lamina densa
3) Visceral epithelium – composed of podocytes that possess interdigitating processes adherent to
the lamina rara externa create by their processes 20-30nm wide filtration slits that are covered
by a slit membrane. Podocyte slit diaphragm are an important diffusion barrier for plasma
proteins and synthesis of the GBM components.
have contractile, proliferative abilities, laying down CT and secretion of active mediators.
# The selective permeability depends on the size of the molecule, the charge (cationic are more
permeable) of molecule
CLINICAL MANIFESTATION OF RENAL DISEASE
can be grouped into reasonably well-defined syndromes
Azotemia is an elevation of blood urea nitrogen and creatinine levels reflects a decreased
glomerular filtration rate (GFR) Prerenal azotemia is seen when there’s hypo perfusion of the
kidney -decrease in GFR Post renal azotemia – urine flow is obstructed below the level of the
kidney
Uremia when azotemia gives rise to clinical manifestations metabolic and endocrine alterations
incident to renal damage
Major syndromes:
• Nephritic syndrome: due to glomerular injury (most common - post streptococcal
glomerulonephritis); visible/microscopic hematuria, some level of oligouria and azotemia and
hypertension.
• Nephrotic syndrome: heavy proteinuria (>3.5g/day), hypoalbunemia, severe edema,
hyperlipidemia and lipiduria.
• Asymptomatic hematuria: non-nephrotic proteinuria, usually due to mild glomerular
abnormalities.
• Rapidly progressive glomerulonephritis: nephritic synd that progress to rena failure in weeks
to months
• Acute kidney injury: dominated by acute oliguria or anuria and azotemia. May result from
glomerular injury, intestinal injury, vascular injury or acute tubular injury.
• Chronic kidney disease: prolonged symptoms and signs of uremia, due to progressive
scarring in the kidney.
Urinary tract infection: characterized by bacteriuria and pyuria. May be symptomatic or
asymptomatic, may affect the kidney (pyelonephritis) or the bladder (cystitis) only.
• Nephrolithiasis (renal stones): manifested by renal colic-cherecter abd. Pain , hematuria
(without casts) and recurrent stone formation.
MECHANISM OF GLOMERULAR INJURY
change GN). In Secondary glomerular diseases- injury is caused by a systemic disease
(SLE, hypertension, diabetes mellitus, Alport syndrome).
Most types of primary glomerular diseases, and many of the secondary diseases, are caused by immune
reactions. Which come in 2 types :
1.antibody-associated
# Circulating immune complexes Injury resulting from deposition of soluble circulating
antigen-antibody complexes in the glomerulus.
Complexes are formed due to exposure to antigens that DO NOT originate in the
glomerulus. The deposition of these complexes produces injury through the activation of
the complement system and recruitment of leukocytes.
The glomerular lesions usually consist of leukocytes infiltration into glomeruli, and proliferation of endothelial,
mesangial and epithelial cells.
either with glomerular antigens or with molecules planted within the glomerulus.
The antibodies react directly with antigens fixed or planted in the glomerulus.
Planted antigens include nucleosomal complexes in patients with SLE, bacterial products egendostroptosin
expressed by group A streptococci, IgG which tend to deposit in the
mesangium and the immune complexes themselves.
in most cases planted antigens induce a granular pattern under immunofluorescence microscopy.
membrane (GBM) glomerulonephritis, autoantibodies are produced against the
GBM14.Deposition of anti-GBM antibodies appears linear in immunoplerescence.
The GBM antigen responsible for the production of these antibodies is a domain in collagen
type IV of the GBM.
Constitute less than 1% of glomerulonephritis cases, its results include severe glomerular damage- with necrosis, crescents and rapidly progressive.
Anti-GBM may cross react with the basement membrane of the alveoli resulting in both
kidney and alveoli lesions known as Goodpasture syndrome.
2.cell-mediated Glomerular injury is caused by sensitized T cells, and may explain
incidents in which there were no deposits of antibodies or immune complexes.Even so, it
has been difficult to establish the exact role of T cells or cell-mediated immune response
in any form of glomerulonephritis.
Mediators of immune injury
# Complement-leukocyte mediated injury – activation of complement generates
chemotactic agents (mainly C5a) that help recruit neutrophils; the neutrophils
release proteases, oxygen-derived free radicals that cause cell damage and
arachidonic acid metabolites which contribute to reduction in GFR.
Complement dependent injury (when there are no neutrophils) – activation of the
membrane attack complex (C5-C9), which causes the creation of pores in the
GBM. And up-regulates TGF-β receptors on podocytes (stimulates synthesis of
ECM).
response and release a vast number of biologically active molecules.
# Platelets – aggregate in the glomerulus during the immune response and release
prostaglandins and GF.
# Resident glomerular cells(mesangial,epithelial, endothelial) – can be stimulated
to secrete mediators
# thrombin – produces as a consequence of intraglomerular thrombosis cause
leukocytes infiltration and glomerular cell proliferation.
OTHER THEN IMMUNE MECHANISMS:
1) Podocyte injury:
# reflected by morphologic changes including; effacement of foot processes,
vacuolization, retraction ad detachment of cells from the GBM.
2) Nephron loss:
# maladaption occurs in the remaining nephrons, for example: hypertrophy causig
an increase in the single nephron GFR, and capillary hypertention.
The remaining nephrons become maladaptive which leads to further endothelial
lesions and podocyte inury, increase in protein permeability and accumulation of
proteins and lipids in the mesangial matrix.
glomeruli.
Diseases causing nephrotic syndrome
Characterize by proteinuria lead to hypoalbuminemia and edema. Glomerular disorders(in BM or
THE NEPHROTIC SYNDROME
podocyte) characterized by increased permeability to plasma proteins (mainly albumin)-
proteinuria (> 3.5 g/day) resulting in cherecter clinical manifestations:
1) Massive proteinuria – daily protein loss in the urine of 3.5g or more.
2) Hypoalbuminemia – serum albumin concentration of less than 3g/100 ml.
3) Generalized edema – also called anasarca, results from decreased plasma oncotic pressure.
Usually starts with periorbital edema, the edema is an character clinical manifestation
4) Hyperlipidemia and lipiduria – caused by increased hepatic lipoprotein synthesis. may be due to
hypoalbuminemia that triggers synthesis of lipoprotein or massive proteinuria causes loss of an
inhibitor of their synthesis.
5) Hypercoagulable state—due to loss of antithrombin III
Derangement of the capillary wall increased permeability leakage of plasma proteins into
filtrate proteinuria serum albumin hypoalbuminemia plasma ocnotic pressure
secretion of rennin by the renal juxtamedullary cells (due to decrease in intravascular volume)
angiotensin-aldosterone axis stimulation retention of salt & water by the kidney edema
# In children, nephritic syndrome is usually the primary illness , while in adults it is usually a
secondary manifestation to a systemic disease
MINIMAL-CHANGE DISEASE (lipoid nephrosis)
# Seen mainly in young children (also may be in adult) Most common cause of nephrotic syndrome
in children usually idiopathic (may be associated with Hodgkin lymphoma)
to proteinuria the damage caused by T-cell derived cytokines that damages the podocyte foot
processes.
show disappearance of podocytes foot processes (in electron microscopy) No immune complex
deposits; negative immunofluorescence.
The cells of the proximal convoluted tubules are heavily laden with protein droplets and lipids. The cytoplasm of the podocytes appears flattened; the
epithelial cells undergo vacuolization and occasional focal detachment.
function is preserved. Protein loss is usually confined to smaller proteins- selective proteinuria
(albumin); response to steroid therapy -corticosteroid treatment is used.
MEMBRANOUS NEPHROPATHY (membranous glomerulonephritis)
of sub epithelial immune complexes deposits along GBM in early stages, the glomeruli appear
normal, but later the show diffuse thickening of the capillary wall.
Can be secondary to: Infections (chronic hepatitis B/C, syphilis). Solid Malignant tumors, mainly
melanoma, and carcinoma of lungs and colon. SLE and autoimmune conditions.
Drugs (penicilamine, non-steroidal anti-inflammatory agents).
reacting with intrinsic or planted glomerular antigens; a podocyte antigen, the phospholipase A2
receptor, is the antigen that is most often recognized by the antibodies.
resulting in thickening of the GBM H&E- LM. Due to immune complex sub epithelial deposition
along GBM see granular appearance in IF. in EM sub epithelial deposits, spike and dome pattern
the podocytes show effacement of foot processes
proteinuria)
Only 40% suffering from progressive disease will have renal failure after 2-20
years. Poor response to steroids
FOCAL & SEGMENTAL GLOMERULOSCLEROSIS
involving only segments of each affected glomerulus (segmental involvement).
secondary to:
1) May be associated with HIV, heroin use, and sickle cell disease
2) As a maladaptation after nephron loss.
3) In inherited or congenital forms resulting from mutations affecting cytoskeletal or related proteins
expressed in podocytes (podocin).
minimal-change disease ,Injury to the podocytes is thought to be the initiating event of primary
FSGS. Deposition of hyaline masses in the glomeruli entrapment of plasma proteins and lipids
in foci of injury where sclerosis has developed.
» Light microscopy The affected glomeruli exhibit segmental increased mesangial matrix,
obliterated capillary lumens, and deposition of hyaline masses (hylinosis) and lipid droplets.
» Florescence No immune complex deposits but Nonspecific trapping of immunoglobulins, mainly
IgM, and complement proteins C3 in areas of hylinosis.
» Podocytes exhibit disappearance - effacement of foot processes.
» Progression of the disease leads to global sclerosis of the glomeruli with tubular atrophy and
interstitial fibrosis. Collapsing glomerulopathy – collapse of the entire glomerular tuft and
podocyte hyperplasia. May be in primary cases, or associated with HIV.
response to corticosteroids therapy, development of end-stage renal failure (in 50% of the cases).
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
cells. Patient may exhibit nephrotic or nephritic picture. Or sub nephrotic proteinuria
# Pathogenesis – There are two major types of MPGN (MPGN type 1 & Dense deposit disease
{once called type 2}), with type I more common (80%).
» Type I – sub endothelial deposit associated with HBV and HCV
» Type II – Type II (dense deposit disease)—intra membra no us; associated with C3 nephritic
Factor (autoantibody that stabilizes C3 convertase, leading to over activation of
Complement, inflammation, and low levels of circulating C3)
» Large glomeruli with lobular appearance. Proliferation of mesangial and endothelial cells. GBM
is thickened and glomerular capillary wall has a “tram track” appearance, this “splitting” of the
GBM is due to extension of processes of mesangial and inflammatory cells into the GBM and
deposition of mesangial matrix.
Type I more prominent train trak appearance then type 2
# Clinical features – Poor response to steroids; progresses to chronic renal failure
# Note membranous GN is the cause when you see lupus patient with nephrotic synd. but most
common lupus kidney is the membranous glomeruloproliferative nephritis comes with
nephritic synd.
Diseases causing nephritic syndrome.
Glomerular disorders cherectrize by glomerular inflamtion (damaging
THE NEPHRITIC SYNDROME
endothelium-GBM-mesangial cells) Main feature of syndrome include hematuria
oliguria & azotemia and hypertension
# Clinical manifestations include acute onset of:
1) Hematuria – with dysmorphic red cells and red cell casts in the urine This
inflammatory reaction injures the capillary walls permitting blood to pass into the
urine
2) some degree of oliguria and azotemia Oliguria (low output of urine).Azotemia
(high levels of nitrogen containing compounds). As result of reduced GFR
3) Hypertension result from fluid retention & sum release of renin from ischemic
kidneys.
4) +/- not severe proteinuria/edema(periorbital)
# Histologically
1. Proliferation of the cells within the glomeruli
2. Inflammatory leukocytes infiltrate
ACUTE POSTINFACTIOUS (POSTSTREPTOCOCCAL) GLOMERULONEPHRITIS
develops following a streptococcal infection (beta-hemolytic, group A –nephritogenic strain
carry M protein).although may develop following other infections
failure.Some adults (25%) develop rapidly progressive glomerulonephritis (RPGN).
infection (localized to the pharynx or skin) see m Prot.
Molc mimicry result in autoreactive AB against glomerular components as GBM . glomerular deposition of immune complexes with activate the alternative complement pathway lead to infiltration of leukocytes (C5a attract
neutrophils etc.…) resulting in proliferation of and damage to glomerular cells pathogenesis
include streptococcal exotoxin B (Spe B) SpeB may induce immune-complex-mediated
glomerulonephritis as SpeB deposits colocalizes with complement and IgG and is present in the
sub epithelial humps that are the hallmark lesion of PSGN Nephritogenicity may be related to its
plasmin-binding activity of bough that would induce inflammatory reactivity and glomerular
basement membrane (GBM) degradation as, plasmin receptor of strep. co-localizes in
glomeruli mesangial cells with plasmin, but not with IgG or complement .bout SPEB70,
71 and
NAPlr72 are capable of inducing chemotactic (monocyte chemoattractant protein 1) and IL-6
moieties in mesangial cells
LM- diffuse increased cellularity - proliferation and swelling of endothelial and mesangial cells plus infiltrating
neutrophils and monocytes. sometimes there is necrosis of endothel cell and mass named crescents is visable in
part of glomeruli
IF -Granular IgG and C3c within the capillary walls +/- mesangial deposition
EM -Intramembranous or most often, subepithelial “humps”
and hypertension, BUT with gross hematuria cola urine color .Serum complement levels are low, streprococcal
antibodies may be detected.
IgA NEPHROPATHY
microscopic/ gross hematuria appearance.
within 1-2 days of a nonspecific upper respiratory tract infection.
IgA production21, some of which is abnormal, and deposition of IgA or IgA-containing immune
complexes in the mesangium activate complement (alternative) cause glomerular injury.
Also in liver disease defect in hepatobiliary clearance on IgA complexes (secondary IgA
nephropathy).
LM: vary considerably may see focal proliferative GN /mesangioproliferative GN /crescentic
GN
IF: mesangial deposition of IgA, often with C3
EM: electron-dense deposits in the mesangium
# Clinical- most often affects children and young adults50% present with gross hematuria after an
infection of the respiratory tract hematuria typically lasts for several days in recurrent episodes
over very long period of time there is risk to develop chronic renal failure -in 25% to 50% of
cases over a period of 20 years
HEREDITARY NEPHRITIS
proteins.
loss and eye disorders22
α3, α4, α5 chains. Mutation in one of the α chains (crucial for lens, cochlea and glomerulus) will
cause Alport syndrome.
occur. In some cases, interstitial cells appear foamy as a result of accumulation of fats and
mucopolysaccharides (foam cells) as a reaction to proteinuria.
With progression, glomerulosclerosis; vascular sclerosis; tubuar atrophy and interstitial fibrosis are
typical changes.
GBM is thin at first, and late in course the GBM develops irregular foci of thickening with pronounced
splitting and lamination of the lamina densa basketweave appearance
# Clinical course – most common form of inheritance is X-linked (mutation in α5 chain) males are
affected more frequently and sevearly female carrier asymptomatic rarely, inheritance may be autosomal recessive/dominant (defects in α3/4 chains). At age of 5 to 20 see gross or microscopic hematuria and proteinuria renal failure develops between 20 and 50 years of age
Rapidly progressive glomerulonephritis.
Glomerulum-capillary network, glomeruli-corpuscle
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS
A clinical syndrome leading to renal failure in short time ~weeks and may arise from different types of
glomerulonephritis.
Characterized by:
» Progressive loss of renal function with Severe oliguria and azotemia
» Laboratory findings of nephritic syndrome
» Histologically, formations of crescents are seen between Bowman’s capsule and the glomerular capillary
network, due to proliferation of parietal epithelial cells
Etiology may be learned from immunofluorescence pattern:
ANTI-GLOMERULAR BASEMENT MEMBRANE CRESCENTIC GLOMERULONEPHRITIS
Characterized by linear deposits in immunofluorescent of IgG and C3 on the GBM.
May be idiopathic but in some cases see AB deposits on BM of alveolar capillaries if such as patient with
hematuria and hemoptysis its Goodpasture syndrome24. Classic seen in young adult male.
Morphology: Kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surface.
Glomeruli show segmental necrosis and crescents appearance In time, may undergo scarring
glomerulosclerosis develops
IMMUNECOMPLEX MEDIATED CRESCENTIC GLOMERULONEPHRITIS
Granular pattern of staining is characteristic finding in immunofluorescent
Rapid progressive GN with Crescents may be the complication of any immune-complex nephritides
most common associated with post streptococcal GN, diffused proliferative GN such as most common
SLE-kidney , IgA nephropathy and Henoch-Schonlein purpura
Morphology: Segmental necrosis and crescents are present. In contrast with Anti-GBM Crescentic
Glomerulonephritis, segments of glomeruli without necrosis show the underlying immune complex GN.
PAUCI-IMMUNE CRESCENTIC GLOMERULONEPHRITIS
Defined as no anti-GBM antibodies / immune complex deposition are detected not in IF nor EM.
Although Segmental necrosis and crescents are seen.
In many cases, the condition is limited to the kidney and is therefore called idiopathic.
Antineutrophil cytoplasmic antibodies (ANCA) typically are found in the serum in some cases crescentic GN is a
component of systemic vasculitis (e.g. microscopic polyagniitis pANCA or Wegener granulomatosiscANCA)
Chug Strauss got eosinophilia and asthma and granulomatous inflammation that polyangitis don’t have
even both come with pANCA
Acute and chronic pyelonephritis.
A purulent inflammation of the kidney and renal pelvis, caused by bacterial infection may origin
A group of inflammatory diseases that primarily involve the tubules and interstitium. The
glomeruli may be spared or affected only late in course.
» Pyelonephritis as you talk on bacterial infection of upper urinary tract prominently involving
The renal pelvis25 , most common form of TIN. The term interstitial nephritis relating to TIN
nonbacterial origin mostly results from drugs, metabolic disorders (hypokalemia), viral infection
and immune reaction.
ACUTE PYELONEPHRITIS
from lower part of UT or from blood hematogenous less common -molnar
Pathogenesis – Principal causative agents are enteric G(-) rods, mainly E.coli, but also Klebsiella,
Enterococcus faecalis. With outflow obstruction26 , bladder dysfunction- vesicoureteral reflux 3
,
catheter see infection may ascend…
# Morphology – Abscess with pus may be seen on cut surface, histo see mix inflammatory infiltrate
marked by neutrophils in tubular sys. Interstitum and b.v. -glomeruli are spared the affected areas
show abscess loss of parenchymal structures note it isn’t diffused .one complication is papillary
necrosis(ischemic and supportive); there are 3 predisposing conditions for this: diabetes, urinary
tract obstruction and analgesic abuse
Clinical features – Presents with fever, flank pain, and leukocytosis in addition to symptoms of
cystitis urgent frequent small amount of urine
CHRONIC PYELONEPHRITIS
In case of recurrent injury see morphology of chronic inflammation including scarring and
deformities of pelvic calycal system uneven interstitial fibrosis Chronic inflammatory infiltrate of
lymphocytes, plasma cells, and neutrophils. Dilation/contraction of tubules, with atrophy of the
lining epithelium. Dilated tubules contain colloid casts similar to thyroid appearance thyroidization.
#Can be divided into two forms:
1) Chronic obstructive pyelonephritis – recurrent infections superimposed on obstruction lesions,
leading to recurrent renal inflammation scarring, eventually causing chronic pyelonephritis.
2) Chronic reflux-associated pyelonephritis (reflux nephropathy) – results from superimposition of
UTI on congenital vesico-urethral reflux and intrarenal reflux.
The damage may cause
scarring/atrophy unilaterally or bilaterally
Clinical features – hypertension, asymmetrical contraction of the kidneys, polyuria eventually,
secondary glomerulosclerosis (with proteinuria)
UROCYSTITIS
Infection of the bladder Presents as dysuria(burning sensation), urinary frequency, urgency, and
suprapubic pain; systemic signs (e.g., fever) are usually absent.
Patho mechanisems:
o infections Principal causative agents are enteric G(-) rods, mainly E.coli, but also Klebsiella,
Staphylococcus saprophytics—increased incidence in young, sexually active women Proteus
mirabilis—alkaline urine with ammonia scent Enterococcus faecalis. Types may be : Acute
Chronic Granulomatous
o Vesico-ureteral reflux
o Urinary outflow disability- Causes include prostatic hyperplasia; bladder stones; tumors
neurologic disease, diabetic bladder
Fistula formation- Abnormal connection formed between the bladder and the surrounding
organs may create from Malignant tumors Postirradiating necrosis Crohn dissease Cervical
carcinoma /Rectum carcinoma
Laboratory findings1Urinalysis—cloudy
urine with pyuria > 10 WBCs/high power field (hpf)
2Dipstick—Positive leukocyte esterase (due to pyuria) and nitrites (bacteria convert nitrates to
nitrites)
- Culture—greater than 100,000 colony forming units (gold standard)
Note! Sterile pyuria is the presence of pyuria (> 10 WBCs/hpf and leukocyte esterase) with
negative urine culture.
Suggests urethritis due to Chlamydia trachomatis or Neisseria
gonorrhoeae (dominant presenting sign of urethritis is dysuria)
Tubulointerstitial nephritis. Acute tubular injury. Diffuse cortical necrosis.
DRUG-INDUCED INTERSTITIAL NEPHRITIS
# Acute drug-induced interstitial nephritis is associated with the usage of drugs: synthetic
penicillin’s (methicillin, ampicillin), synthetic antibiotics (rifampin), diuretics (thiazides), nonsteroidal anti-inflammatory agents –analgesic use etc.
Pathogenesis:
» The onset of the nephropathy is NOT dose-dependent; the drug induces an immune reaction.
» The drug acts as an hapten, during secretion by the tubules it covalently bunds to a tubular cell
component and becomes immunogenic IgE and cell mediated immune response damage the
tubules.
» IgE levels are elevated, suggesting type I hypersensitivity, and mononuclear or granulomatous
infiltrate suggests a T-cell mediated, type IV hypersensitivity.
Morphology – the interstitium shows profound edema and infiltration by eosinophils and also
lymphocytes and macrophages seen –interstitial inflammation; Glomeruli are normal, except in
cases caused by non-steroidal anti-inflammatory agents in which hypersensitivity leads to
podocyte foot disappearance nephritic syndrome.
Clinical features – the disease begins 2-40 days after exposure to the drug, characterized by
fever, eosinophilia, a rash in some cases, and renal finding that include hematuria, minimal
proteinuria, and leukocyturia.
In 50% of cases – increase in serum creatinine, oliguria(less than
400 ml/day) may develop into renal failure if remove drug see recovery although it may take
several months
ACUTE TUBULAR INJURY
Most common cause for acute renal injury characterized by destruction of tubular epithelial
cells, followed by acute renal failure (oliguria, proteinuria, blood retention of urea and
creatinine)
Cuases for acute renal injury range from: ischemic injury, glomerular rapid progress-acute
tubular injury –interstitial nephritis like drug induced…
Pathogenesis – result from ischemia/nephrotoxic to renal tubols
» toxic acute tubular necrosis-after ingestion or inhalation of toxic substance ethylene glycol,
mercury, lead, carbon tetrachloride, methyl alcohol, nephrotoxic drugs greatest characterized by
proximal tubular epithelium necrosis due to interference of ingested toxic agents (poisons,
organic solvents, drugs, heavy metals) with epithelial cell metabolism.
Necrotic cells fall into the tubule lumen, obliterating it, and determining acute renal failure (oligo-anuria).
Basement membrane is intact, so the tubular epithelium regeneration is possible
» ischemic acute tubular necrosis- also called acute vasomotor nephropathy; due to inadequate
renal blood flow, often from marked hypotension and shock (acute pancreatitis, severe trauma);
ischemia causes vasoconstriction, which leads to reduced glomerular filtration rate and oliguria
Intrarenal vasoconstriction - mediated by sublethal endothelial injury - release of endothelin
(vasoconstrictor), decreased production of NO and prostaglandins - reduced glomerular plasma
flow, and blood supply to tubular sys.
Tubular cells: Ischemic tubular cells express chemokines, cytokines promoting interstitial
inflammation. Ischemia change cell express of pumps na not absorbed and
tubologlomerular feedbeck n vasoconstriction ischemia damage also BM so cell detachment n
debris obligating tubular system more breakdown of tubule lead to beck leak of filtrate to
interstitium…
Morphology –
ischemic ATI varies from cell swelling to focal tubular epithelial necrosis and apoptosis
mainly in the straight proximal tubule and the ascending thick limb.
Tubular injuries show
thinning or loss of proximal tubule brush border, vacuolization of cells, sloughing of tubular
cells into the urine.
Proteinaceous casts are found in distal tubules and collecting duct along with hemoglobin.
Edema is seen in the intestitium along with inflammatory infiltrates (PMN leukocytes,
lymphocytes and plasma cells).
Later - epithelial regeneration (flattened epithelium, dilated tubular Lumina, large nuclei with
prominent nucleoli and mitotic activity)
Toxic acute tubular necrosis is characterized by proximal tubular epithelium necrosis (no
nuclei, intense eosinophilic homogenous cytoplasm, but preserved shape) Basement membrane
is intact,
The interstitium and glomeruli are not affected
Clinical course –patient suffers from oliguria/anuria and decreased GFR; electrolyte
abnormalities; acidosis; uremia
DIFFUSE CORTICAL NECROSIS
The pathological progression of ATN, resulting from diminished renal arterial perfusion due to
vascular spasm, microvascular injury or DIC.
Can occur as a result of:
» In adults => pregnancy, HIV, shock, trauma, SLE, sickle cell anemia.
» In neonates => congenital heart disease, anemia, placental hemorrhage.
DCN can be classified into 5 forms:
1) Focal => the kidneys show focal necrosis of glomeruli without thrombosis, and patchy necrosis
of tubules.
2) Minor => larger areas of necrosis are evident with vascular and glomerular thrombosis.
3) Patchy => patches of necrosis occupy 2/3 of the cortex.
4) Gross => almost the entire cortex is involved; thrombosis of the arteries is more widespread.
5) Confluent => the kidneys show widespread glomerular and tubular necrosis with no arterial
involvement.
Morphology –
» Grossly, the kidney appears red (congested) with yellowish-white spots (infarcts).
» Microscopically, one can see ischemic necrosis, massive leukocytes infiltration in deeper areas
(in contact with the medulla), and thrombosis (intravascular and intraglomerular).
Congenital and cystic kidney diseases.
Pathogenesis –Even with complete obstruction, glomerular filtration persists for some time because
CYSTIC DISEASE OF THE KIDNEY
SIMPLE CYST
Generally non harmful lesions that occur in multiple or single cystic commonly, they are 1-5cm
in diameter, usually confined to the cortex.
# The main importance of cysts is their differentiation from kidney tumors. In contrast to renal
tumors, the cysts have smooth contours, are almost always avascular and produce fluid rather
than solid tissue under ultrasonography.
Dialysis- associated acquired renal cysts are present in both cortex and medulla and occur in
kidneys of patients with end-stage kidney diseases who have undergone prolonged dialysis-see
shrunk kidney with cyst unlike polycystic diseas …. Those patient at highr risk to develop renal
cell carcinoma at the effected kidney
AUTOSOMAL DOMINANT (ADULT) POLYCYSTIC KIDNEY DISEASE
Characterized by multiple expanding cysts on both kidneys that eventually destroy the
parenchyma.
Caused by heterogeneous28 inheritance of:
» PKD1 – the defective gene in 85%-90% of the cases, encodes for Polycysticn-1 (a cell
membrane protein) is involved in cell-cell or cell-matrix interactions
» PKD2 – the defective gene in 10%-15% of the cases and encodes for ycystin-2 functions as a
Ca2+ membrane channel.
Both polycystin molecules are believed to act together by forming a heterodimer, thus mutation
in either of the genes gives rise to the same phenotype. Although Patients with PDK2 mutations
have a slower rate of disease progression.
Morphology –
» The kidneys may reach an enormous size-palpable abdominally as masses extending into the
pelvis.
» with numerous dilated cysts.The pressure of the expanding cyst leads to ischemic atrophy of
renal substance.
» The cysts may arise at any level of the nephron; tubules, collecting ducts and occasionally
Bowman’s capsule.
» Clinical features – usually does not produce symptoms until the age of 40; symptoms include
flank pain, hematuria, hypertension and urinary infection; Asymptomatic liver cysts occur in
one third of patients.
Aneurysms in circle of Willis, with resultant subarachnoid hemorrhage,
may be associated with this disease.
AUTOSOMAL RECESSIVE (CHILDHOOD) POLYCYSTIC DISEASE
Rear AR inherited form of polycystic disease accruing in childhood with different genetic
background Characterized by multiple closed cysts that are NOT in continuity with the
collecting system.
This disease results from mutations in PKHD1 gene found on chromosome 6, encodes for
fibrocysin. A receptor-like protein that may be involved in tubulogenesis and/or in the
maintenance of duct-lumen architecture.
Morphology –bilateral numerous small cysts in both the cortex and medulla, giving the kidney
a sponge-like appearance. The cysts are lined with cuboidal cells, reflecting their origin from
the collecting tubules.
In most cases, the disease is associated with epithelium-lined cysts in the liver, and
proliferation of portal bile ducts. Perinatal, neonatal, infantile and juvenile subtypes
have been defined, depending on the time of presentation and the presence of associated
hepatic lesions.
Clinical features – most common forms are perinatal and neonatal; manifestations usually
present at birth, and new-born babies die quickly of hepatic or renal failure, while patients who
survive develop liver cirrhosis (congenital hepatic fibrosis).
MEDULLARY CYSTIC DISEASE
There are 2 types:
1) Medullary sponge kidney
Characterized by cystic dilatation of the collecting tubules in one or both kidneys. Relatively
common innocuous condition occasionally associated with nephrolithiasis (formation of kidney
stone).
2) Nephronophthisis medullary cystic disease complex
Group of autosomal recessive disorders resulting in chronic renal disease beginning in childhood
almost always associated with renal dysfunction. Characterized by corticomedullary cysts, atrophy
and interstitial fibrosis “Phthisis” (Greek): dwindling or wasting away
Pathogenesis – associated with several mutations in different genes -NPHP genes produce
nephrocystins in cilia / basal body structures
Morphology – small contracted kidneys. Numerous small cysts, lined by cuboidal epithelium, are
found mainly in the cortico-medullary junction. Other less specific pathologic changes are chronic
tubulointerstitial nephritis with tubular atrophy and progressive interstitial fibrosis.
Clinical features – initial manifestations are polyuria and polydipsia (excessive thirst), a
consequence of diminished tubular function; diagnosis is difficult since there are no serologic
markers, and the cysts are too small to recognize in radiologic imaging.
The 2nd type has 4 variants, based on the time of onset: infantile, juvenile (most common),
adolescent and adult. Usually associated with extra-renal manifestations, most often appear as
retinal abnormalities; retinitis pigmentosa and early onset of blindness in the most severe form.
HYDRONEPHROSIS
The dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma,
caused by obstruction to the outflow of urine-may occur at any level of the urinary tract; from the
urethra to the pelvis.
The most common causes of obstruction are:
» Congenital – atresia33 of the urethra, valve formations in either ureter or urethra, renal artery
compressing the ureter, renal ptosis with torsion, bending of the ureter.
» Acquired – foreign bodies (stone). Tumors; benign prostatic hyperplasia/ carcinoma, bladder
tumors (papilloma and carcinoma), inflammation (of the prostate, ureter, urethra). Neurogenic
spinal cord damage with paralysis of the bladder. Pregnancy.
of continued filtration, the affected calyces and pelvis become dilated.
Initial functional disturbances are manifested by impaired concentration ability, and later glomerular filtration starts to diminish.
The obstruction leads to increased pressure in the tubular system, and the filtrate subsequently
diffuses back into the interstitium and perirenal spaces and from there it returns to the lymphatic
and venous system the high pressure generated causes the compression of the renal vasculature,
resulting in arterial insufficiency and venous stasis.
The obstruction also triggers an interstitial
inflammatory reaction, eventually leading to interstitial fibrosis.
Morphology – display morphologic changes that vary with the speed and degree of obstruction
1) Partial (temporary) obstruction – the kidney may be massively enlarged (up to 20cm), the renal
parenchyma atrophied with obliteration of the papillae and flattening of the pyramids.
2) Complete obstruction – glomerular filtration is compromised at an early stage, so renal function
may cease even when dilation is relatively slight; in severe cases, coagulative necrosis of the renal
papillae may occur.
epithelium. With sudden and complete obstruction there may be coagulative necrosis of the renal
papillae. In severe cases, the glomeruli also become atrophic and disappear converting the entire
kidney into a thin shell of fibrous tissue.
Clinical features – bilateral and complete obstruction produces anuria (if it’s below the bladder the
main symptom is bladder distention); incomplete bilateral obstruction causes polyuria rather than
oliguria due to defects in tubular concentrating mechanisms.
Unilateral obstruction may be silent
for a long period unless the other kidney for some reason is not functioning.
NEPHROLITHIASIS (kidney stones)
kidney.
low urine Volume as Precipitation of a urinary solute may accrue as a stone
Clinical features – Presents as colicky pain with hematuria and unilateral flank tenderness Stone is
usually passed within hours; if not, surgical intervention may be required.
Large stones can be present in the renal pelvis without producing any symptoms, but small stones
may pass into the ureter and produce typical intense pain that often radiates to the groin=> renal
colic often by this time there is gross hematuria.
1.Calcium oxalate and/ or calcium phosphate composition- Most common type; usually seen in adults.
The cause of stone formation is often obscure the most common cause of stone formation is
increased urine concentration of the constituents of the stone, so it exceeds their solubility in the
urine (supersaturation). In this case most patient present idiopathic hypercalciuria which is not
associated with hypercalcemia. Although hypercalcemia and its related causes must be excluded.
Also seen with Crohn disease-oxalate increase from resorption of intestine…
Treatment is hydrochlorothiazide (calcium-sparing diuretic).
2.Ammonium magnesium phosphate/ Struvite stones - Second common type, common cause is
infection with urease-positive organisms (proteus vulgaris or Klebsiella bacteria’s) alkaline urine
leads to formation of stone.
Classically, results in staghorn calculi in renal calyces Treatment involves surgical removal of
stone (due to size) and eradication of pathogen (to prevent recurrence).
3.Uric acid stones- Third most common stone (5%) and the only radiolucent (invisible in imaging),
Risk factors include hot climates leading to low urine volume, and acidic pH patients exhibit low
ph. urine which favors the formation of the uric acid stones without neither hyperuricemia nor
increased urine urate.. seen in patients with gout-hyperuricemia or disease with increase cellular
turnover n uric acid production such as leukemia or myeloproliferative disorders patient are at
increases risk.
Treatment involves hydration and alkalization of urine (potassium bicarbonate); allopurinol is also
administered in patients with gout.
4.Cysteine stones- Rare cause of nephrolithiasis; usually seen in children associated with genetical
defects the renal transport of certain amino acids (including cysteine) results in decreased tubules
reabsorption of cysteine- cystinuria.
May form staghorn calculi; treatment involves hydration and alkalization of urine.
Urolithiasis, hydronephrosis and obstructive uropathy
Pathogenesis –Even with complete obstruction, glomerular filtration persists for some time because
HYDRONEPHROSIS
The dilation of the renal pelvis and calyces, with accompanying atrophy of the parenchyma,
caused by obstruction to the outflow of urine-may occur at any level of the urinary tract; from the
urethra to the pelvis.
The most common causes of obstruction are:
» Congenital – atresia33 of the urethra, valve formations in either ureter or urethra, renal artery
compressing the ureter, renal ptosis34 with torsion, bending of the ureter.
» Acquired – foreign bodies (stone). Tumors; benign prostatic hyperplasia/ carcinoma, bladder
tumors (papilloma and carcinoma), inflammation (of the prostate, ureter, urethra). Neurogenic
spinal cord damage with paralysis of the bladder.
Pregnancy.
of continued filtration, the affected calyces and pelvis become dilated. Initial functional
disturbances are manifested by impaired concentration ability, and later glomerular filtration starts to diminish.
The obstruction leads to increased pressure in the tubular system, and the filtrate subsequently
diffuses back into the interstitium and perirenal spaces and from there it returns to the lymphatic
and venous system the high pressure generated causes the compression of the renal vasculature,
resulting in arterial insufficiency and venous stasis.
The obstruction also triggers an interstitial
inflammatory reaction, eventually leading to interstitial fibrosis.
Morphology – display morphologic changes that vary with the speed and degree of obstruction:
1) Partial (temporary) obstruction – the kidney may be massively enlarged (up to 20cm), the renal
parenchyma atrophied with obliteration of the papillae and flattening of the pyramids.
2) Complete obstruction – glomerular filtration is compromised at an early stage, so renal function
may cease even when dilation is relatively slight; in severe cases, coagulative necrosis of the renal
papillae may occur.
epithelium. With sudden and complete obstruction there may be coagulative necrosis of the renal
papillae. In severe cases, the glomeruli also become atrophic and disappear converting the entire
kidney into a thin shell of fibrous tissue.
Clinical features – bilateral and complete obstruction produces anuria (if it’s below the bladder the
main symptom is bladder distention); incomplete bilateral obstruction causes polyuria rather than
oliguria due to defects in tubular concentrating mechanisms. Unilateral obstruction may be silent
for a long period unless the other kidney for some reason is not functioning.
(cont, there is more need to check more)
Kidney and urinary collecting system neoplasias
NEOPLASIA OF THE KIDNEY
Benign tumors, such as small(less then 0.5cm) cortical papillary adenomas are common and
have no clinical significance.
# Most common malignant tumor of the kidney is renal cell carcinoma althow tumors of lower
urinary tract are even more common
RENAL CELL CARCINOMA
# Malignant tumor Derived from renal tubular epithelium, thus these tumors are located mainly
in the cortex. the most common metastasis are to the lungs and bone.
Represent 80%-85% of all primary malignant tumors of the kidney, occur most commonly at
the age of 60-70. Men are more commonly affected than women.
Risk factors: smoking, obesity, hypertension, exposure to cadmium and persons who acquire
polycystic disease as a complication of chronic dialysis.
Clinical features – The clinical triad of renal cell carcinomas; painless hematuria, palpable
abdominal mass if large enough, dull flank pain. Extra-renal manifestations Fever, weight loss,
or paraneoplastic syndrome e.g., polycythemia (due to increased amount of erythropoietin
secreted by the tumor) renin or ACT H may also be present.
Involvement of the left renal vein
by carcinoma blocks drainage of the left spermatic vein leading to varicocele. Right spermatic
vein drains directly into the IVC; hence, right-sided varicocele is not seen.
Staging:T—based on size and involvement of the renal vein (occurs commonly and Increases
risk of hematogenous spread to the lungs and bone) N—spread to retroperitoneal lymph nodes
The 3 most common forms are; clear cell carcinoma, papillary renal cell carcinoma and
chromophobe renal carcinoma.
CLEAR CELL CARCINOMAS
Most common type (70%-80% of cases).Derived from the proximal convoluted tubule. Located
predominantly in cortex
Morphology –
» Gross appearance – Gross exam reveals a solitary large spherical yellow mass with areas of
cystic softening or hemorrhage.
» The tumor may invade into the renal vein and grows as a solid column within it and may extend
all the way to the inferior vena cava or right atrium.
» Microscopically – tumor cells appear with clear cytoplasm demarcated by their cell membrane
(vacuolated-lipid Leiden accumulate glycogen and lipids). With small round, uniform nuclei.
Majority of the cases arise sporadically (non-inheritant), but may arise in familiar forms.bouth
associated with loss of VHl (3chromosome) tumor suppressor gene, which leads to increased
IGF-l (promotes growth) and increased HIF(hypoxia-induced transcription factor) (increases
VF.GF and PDGF).
» Hereditary tumors arise in younger adults and are often bilateral, von Hippel-Lindau disease is
an autosomal dominant disorder associated with inactivation of the VHL gene leading to
increased risk tor hemangioblastoma of the cerebellum and renal cell carcinoma.
» Sporadic associated with cigarette smoking
PAPILLARY RENAL CELL CARCINOMAS
# Comprises 10%-15% of renal cancers.
Derived from the proximal convoluted tubule. Show
papillary growth pattern, and are frequently multifocal and bilateral.
Papillary renal cell carcinoma can be sporadic or familial:
Familial form – characterized by increased dosage of the MET gene35, located on chromosome 7
(due to trisomy or tetrasomy), along with activating mutations of the MET gene.
» Sporadic form – characterized by larger amount of chromosome 7, resulting in increased dosage
of the product of MET gene, but it lacks the mutations in the gene itself.
Morphology: Unlike clear cell carcinomas, papillary carcinomas are frequently multifocal in
origin and less yellow no lipid accumulation.. Consists of papillae covered by eosinophilic
cells arranged in an irregular, pseudostratified manner and fibromuscular core .
CHROMOPHOBE RENAL CARCINOMAS
# Least common type, represent 5% of renal carcinomas.Arise from intercalated cells of the
collecting ducts.
Characterized by having multiple losses of complete chromosomes, mainly 1, 2, 6, 10, 13, 17
and 21 => hypo ploidy.
Gross appearance tends to be tan-brown. The tumor cells have abundant eosinophilic cytoplasm
with a distinct cell membrane. The nuclei are surrounded by halos of clear cytoplasm.
WILMS TUMOR (nephroblastoma)
Wilms’ tumor (nephroblastoma) is a malignant mixed tumor containing metanephric blastema36,
stromal and epithelial derivatives. It is the most frequent renal tumor in children before age of 5
years (peak of incidence at age of 2 )
Etiology of Wilms’ tumor (nephroblastoma):
mutations of WT1 gene on chromosome 11 and
nephroblastematosis (persistence of renal blastema in kidney tissue).
show association 2 syndromes:
WAGR syndrome—Wilms tumor, Aniridia, Genital abnormalities, and mental and motor
Retardation. Beckwith-Wiedemann syndrome—Wilms tumor, neonatal hypoglycemia,
Muscular hemi hypertrophy, and organomegaly (including tongue)
Morphology: In most cases, it is unilateral. The tumor tends to be encapsulated and
vascularized. The tumor consists in tumor epithelial component (abortive tubules and glomeruli)
surrounded by metanephric blastema and tumor immature spindled cell stroma. The stroma may
include differentiated (muscle, cartilage, bone, fat tissue, fibrous tissue) or anaplastic elements.
The tumor compresses the normal kidney parenchyma and may metastasize to the lungs.
TUMORS OF URINARY COLLECTING SYSTEM
UROTHELIAL (TRANSITIONALCELL) CARCINOMA
# urinary collecting system from renal pelvis to urethra is lined with transitional epithelium
Malignant tumor arising from the transitional epithelium
Most common type of lower urinary tract cancer; usually arises in the bladder Tumors are often
multifocal and recur
Generally seen in older adults; affect men about three times as frequently as women
# classically presents with painless hematuria
Major risk factor is exposure to β-naphthylamine, cigarette smoking, chronic cystitis,
schistosomiasis, cyclophosphamide
# tumors are classified
papillary urothelial neoplasms of low malignant potential (PUNLMP)
Low grade urothelial carcinoma (papillary/flat; invasiv /non invasiv)
High grade urothelial carcinoma (papillary/flat; invasiv /non invasiv)
Arises via two distinct pathways
» Flat—develops as a high-grade flat tumor and then invades; associated with early
P53 mutations
» Papillary—develops as a low-grade papillary tumor that progresses to a high-grade
Papillary tumor and then invades; not associated with early p53 mutations
SQUAMOUS CELL CARCINOMA
Malignant proliferation of squamous cells, usually involving the bladder Arises in a background
of squamous metaplasia (normal bladder surface is not lined by squamous epithelium)
Risk factors include chronic cystitis (older woman). Schistosoma hematobium
Infection (Middle East male), and long-standing nephrolithiasis.
ADENOCARCINOMA
Malignant proliferation of glands, usually involving bladder
Arises from a urachal remnant connection of fetal bladder to yolk sack (tumor develops at the
dome of the bladder), cystitis glandularis-columnar metaplasia in respond to chronic
inflammation , or exstrophy (congenital failure to form the caudal portion of the anterior
abdominal and bladder walls open bladder to world )
Diseases involving renal vessels, diabetic nephropathy
Atherosclerosis. (forms, risk factors, pathogenesis).
one of the three subtypes of arteriosclerosis-thickening of arteries patho gr. (which are
atherosclerosis, Monckeberg’s arteriosclerosis and arteriolosclerosis).
1) Arteriolosclerosis –intima involve affects small arteries and arterioles, got
2 types hyaline thickening or proliferative (hyperplastic) changes;
usually associated with hypertension or diabetes mellitus.
2) Mönckeberg medical calcific sclerosis – calcific deposits that involve the
tunica media of medium-sized muscular arteries, but does not affect the
blood flow since it does not involve the tunica intima.
3) Atherosclerosis – the thickening and hardening of large to medium size
arteries as a result of the accumulation of fatty material (cholesterol, TAGs).
ATHEROSCLEROSIS
Involves large- and medium-sized arteries; abdominal aorta, coronary artery,
Popliteal artery, and internal carotid artery are commonly alfected.
An atherosclerotic plaque/atheroma is a Intimal plaque that obstructs blood
flow Consists of a necrotic lipid core (mostly cholesterol) with a
fibromuscular cap often undergoes dystrophic calcification
The atherosclerotic plaques obstruct the blood flow, as well as weakening the
underlying media-impaired blood diffusion . These plaques can also rupture,
causing acute thrombosis-reveling lipid negative charged core
RISK FACTORS FOR ATHEROSCLEROSIS
# Nonmodifiable:
- Age – the accumulation of atherosclerotic plaques progresses with age,
but becomes clinically manifest in middle age or later. - Gender – premenopausal women are relatively protected against
atherosclerosis; after menopause, the incidence of atherosclerosis-related
diseases increases with age. - Genetics – familial predisposition to atherosclerosis and ischemic heart
disease (IHD) is multifactorial, and related to hypertension, diabetes
mellitus, and familial hypercholesterolemia.
Modifiable:
- Hyperlipidemia – the major component associated with increased risk is LDL
cholesterol, which delivers cholesterol to peripheral tissues; in contrast, HDL
mobilizes cholesterol from tissues, as well as developing and existing
atheroma’s, back to the liver for excretion in the bile => higher LDL levels,
together with decreased HDL, constitute a risk factor for formation of
atheroma’s; - Hypertension – both systolic and diastolic levels are important contributors to
premature atherosclerosis. - Cigarette smoking – increase the incidence and severity of atherosclerosis =>
prolonged smoking of 1 pack daily increases the death rate from IHD by
200%. - Diabetes mellitus – induces hypercholesterolemia.
- Lipoprotein A – altered form of LDL that contains the apolipoprotein B100
link to apolipoprotein A => high levels are associated with higher risk of
coronary and cerebrovascular diseases, independent of cholesterol or LDL
levels. - Other factors – lack of exercise, stressful lifestyle, and obesity.
Hyperhomocystinemia –are caused by low folate and vitamin B intake.
PATHOGENESIS
Response-to-injury hypothesis – atherosclerosis is a chronic inflammatory
response of the arterial wall to endothelial injury. consists of a raised lesion with
a soft, yellow core of lipids (mainly cholesterol and cholesteryl esters), covered
by a firm, white fibrous cap-fibromuscular cap
Lesion progression occurs by: Process start as early as teenage years with fatty
stripes formation created from Damage to endothelium allows lipids to leak into
the intima. Accumulation of lipoproteins, mainly LDL, on the vessel wall just
under endothel in intimal level. Lipids are oxidized and then consumed by
macrophages via scavenger receptors, resulting in foam cells.
Monocyte from blood are origin of MFactor release from activated platelets, macrophages and
vascular wall cells, denoting processes of Inflammation and healing leads to
deposition of’extracellular matrix and proliferation of smooth muscle.
Pathogenesis and morphology of atherogenesis
the formation of atherosclerotic intimal plaques. atherosclerosis is the result of response to
endothelial injury with chronic inflammation (lymphocytes and macrophages) ,fibro
proliferative process- recruited and proliferating smooth muscle cells which has become
excessive and in its excess this protective response has become the disease stat
At early stage, the intimal plaque includes aggregates of foam cells (macrophages
accumulating lipids)and not so elevated- Fatty streaks; with progression to fibrofatty pluqe see
the atheroma modifies collagen synthesized by smooth muscle cells producing a fibrous cap,
but retain the lipid-laden core which may become dystrophically calcified over time. Next
such as advanced pluqe may :
Rupture- surface of the atheroma exposes the blood stream to highly thrombogenic substances,
inducing thrombus formation that can partially or completely occlude the lumen => the
thrombi may become organized and incorporated into the growing plaque.
Atheroembolism – plaque rupture releases debris into the blood stream, producing microemboli.
Aneurysm formation – atherosclerotic-induced pressure, and loss of elasticity, causes
weakness of the vessel wall and development of aneurysms.
Grow till create critical stenosis - ischemic injury to organs
PATHOGENESIS OF ATHEROGENESIS
ENDOTHELIAL INJURY
Early lesions begin at the site of intact but dysfunctional endothelium, there is increased
endothelial permeability, enhanced leukocyte adhesion and altered gene expression.
# Endothelial dysfunction can be caused by :
1) Toxins from cigarette smoke, homocysteine and infectious agents.
2) Hemodynamic disturbance-Atherogenesis occurs at the openings of existing vessels, branch
points, as along the posterior wall of the abdominal aorta => where there are disturbed flow
patterns .Laminar flow leads to the induction of genes whose products (antioxidant
superoxide dismutase) actually protect against atherosclerosis.
3) Lipids (hypercholesterolemia- The dominant lipids in atheromas are cholesterol and
cholesteryl ester)Lipoprotein abnormalities increase the risk of atherosclerosis, and include
increased LDL level, decreased HDL level increased level of abnormal lipoprotein A,may be
Genetic defects39 or Acquired disorders that cause hypercholesterolemia, such as diabetes
mellitus and hyperthyroidism.
Accumulation of lipoproteins within the intima, which are then oxidized through the action
of oxygen free radicals => oxidized LDL40 is ingested by macrophages through a scavenger
receptor, leading to foam cells formation.
4) Inflammation
a. Endothelial cells express adhesion molecules that encourage leukocyte adhesion => VCAM-1
binds monocytes and T cells.
b. Monocytes transform into macrophages and engulf lipoproteins, including oxidized LDL (foam
cells) => progressive accumulation of lipids results in activation of macrophages and production
of cytokines that increases leukocyte adhesion
c. T cells that are recruited to the intima interact with macrophages and generate inflammation.As
a result of the chronic inflammatory state, activated leukocytes and vascular wall cells release
GFs that promote smooth muscle proliferation and ECM synthesis.
SMOOTH MUSCLE PROLIFERATION
# Smooth muscle proliferation and ECM deposition convert the fatty streak into a mature
atheroma. The smooth muscle cells produce ECM, mainly collagen, which stabilizes the
atherosclerotic plaque.
Smooth muscle cells derived from the intima, as well as recruited from circulating precursors.
Several GFs take part in the proliferation of the smooth muscle cells: platelet-derived growth
factor (PDGF) fibroblast growth factor (FGF), and transforming growth factor alpha (TGFα).
MORPHOLOGY OF ATHEROSCLEROSIS
Fatty streaks – composed of lipid-filled macrophages (foam cells), but they are not
significantly raised
Atherosclerotic plaque –Atheromatous plaques appear white-yellow may be hard n calcified .
vessels more prone to plaque formation are abdominal aorta, coronary arteries, popliteal
arteries, internal carotid arteries, and the vessels of circle of Willis.
An eccentric lesion under microscope composed of
The fibrous cap is composed of smooth
muscle cells and dense collagen; in shoulder of cap there is a more cellular area (containing
macrophages, T cells and smooth muscle cells), and deep to the fibrous cap is a necrotic core
(containing Intracellular and extracellular lipids,
debris from dead cells, foam cells and plasma
proteins).The cholesterol content of the plaque is usually present as crystalline aggregates =>
washed out during normal tissue processing => empty “clefts” are left => neovascularization
(proliferating small blood vessels) seen in periphery of plaque
The pathogenesis of hypertension. Hypertensive vascular disease.
The blood pressure depends on the regulation of cardiac output-systolic (p) and total peripheral
HYPERTENSION
Hypertension – Increased blood pressure; may involve pulmonary or systemic circulation
,Systemic HTN is defined as pressure over 140/90 mm Hg (normal < 120/80 mm Hg) and its
Divided into primary or secondary types based on etiology
resistance-diastolicb.p. (regulated by arterioles ) hence Contributors to hypertension:
1) Reduced renal Na+ excretion – causes an obligatory increase in fluid volume and increased
cardiac output, resulting in elevated blood pressure.
2) Vascular change – vasoconstriction or structural changes in the vascular wall that result in
increased resistance( Aortic rigidity)
PATHOGENESIS OF HYPERTENSION
Primary (essential) hypertension- HTN of unknown etiology accunts for about 95% of cases,
although viewed as multifactorial condition involving inheritance and environment:
1) Risk factors include age, race (increased risk in African Americans, decreased risk in Asians)
2) Genetic factors – defects in the genes encoding components of RAS, familial history of
hypertensive disease .
3) Environmental factors – stress, obesity, smoking, physical inactivity and heavy consumption
of salt
# Secondary hypertension-It is secondary to a known underlying cause.
» Renal artery stenosis is a common cause, Stenosis decreases blood flow to glomerulus.
Responds by secreting renin, which converts Angiotensinogen to angiotensin .Angiotensin I is
converted to angiotensin 11 (ATII) by angiotensin converting enzyme ATII raises blood
pressure by (I) contracting arteriolar smooth muscle,increasing total peripheral resistance and
(2) promoting adrenal release of aldosterone, which increases resorption of sodium in the distal
convoluted tubule (expanding plasma volume).
Leads to HTN with increased plasma renin and
unilateral atrophy (due to low blood flow) of the affected kidney important causes of stenosis
include atherosclerosis (elderly males) and fibromuscular dysplasia (young females)
» Adrenals or other endocrine organ disorders:
1) Conn syndrome (primary hyperaldosteronism) – the overproduction of aldosterone, mainly due
to adrenal adenoma.
2) Cushing syndrome – excess production of cortisol that enhances the vasoconstrictive effect of
epinephrine.,hyperthyroidesiem
3) Diabetes mellitus – when complicated by diabetic glomerulonephritis
HYPERTENSIVE VASCULAR DISEASE
# Hypertension can cause cardiac hypertrophy and heart failure (hypertensive heart disease), aortic
dissection, renal failure and cerebrovascular hemorrhages-strokes. Hypertensive vascular disease,
induced by hypertension:
» In large to medium size .a. see increased tendency to atherogenesis plus risk to develop aortic
dissection and cerebrovascular hemorrhages
There are 2 form of small b.v. hypertension related diseases
» Hyaline arteriolosclerosis – homogenous, pink proteinaceous thickening of the walls of arterioles
with loss of underlying structural detail and narrowing of the lumen => plasma components leak
across the vascular endothelium,. Also seen in diabetic both lead to nephrosclerosis glomerular
scarring… link to bening HT
» Hyperplastic arteriolosclerosis – related to more acute blood pressure elevations, associated with
“onionskin”, concentric, laminated41 thickening of the walls of arterioles with luminal narrowing
=> the hyperplastic changes are accompanied by fibrinoid deposits and vessel wall necrosis.
Complications of hypertension
Progressive heart failure = left ventricular hypertrophy adaptation to pressure overload (left
ventricule) ↓ concentric (compensated) ↓ dilatative (decompensated)
Cerebrovascular stroke - atherosclerosis - reversible ischemic attack - haemorrhagic infarction
(encephalomalacia) - apoplexia (Pathology) sudden loss of consciousness, often followed by
paralysis, caused by rupture or occlusion of a blood vessel in the brain (primary hemorrhage)
Charcot–Bouchard aneurysms (also known as miliary aneurysms or microaneurysms) are
aneurysms of the brain vasculature which occur in small blood vessels (less than 300 micrometre
diameter).
Charcot–Bouchard aneurysms are most often located in the lenticulostriate vessels of
the basal ganglia and are associated with chronic hypertension.
Charcot–Bouchard aneurysms are a common cause of cerebral hemorrhage. cerebral haemorrhage and subarachnoid
haemorrhage due to ruptured berry aneurysms Berry aneurysm: A small aneurysm that looks like
a berry and classically occurs at the point at which a cerebral artery departs from the circular
artery (the circle of Willis) at the base of the brain. Berry aneurysms frequently rupture and bleed.
in patients with benign hypertension
Renal demage - nephrosclerosis - Hyperplastic arteriolosclerosis
Arterial aneurysms. Dissections of the aorta
Localized abnormal ballon like dilation of a blood vessel or the heart,anyrisem complication pockets of
ANEURYSMS
stasis lead to subsequent thrombosis, embolization and also potential to rupture :
» True aneurysm – when an aneurysm involves all 3 layers of the arterial wall (atherosclerotic, syphilitic
and congenital aneurysms, and ventricular aneurysms).
» False aneurysm (pseudoaneurysm) – a breach in the vascular wall leading to an extravascular hematoma
that freely communicates with the intravascular space – pulsating hematoma. E.g. ventricular ruptures
after MI, contained by a pericardial adhesion.
#shape and size:
» Saccular aneurysm – a spherical outpouching, involving only a portion of the vessel wall, which vary
from 5-20cm in diameter and usually contain thrombi.
» Fusiform aneurysm – a circumferential dilation up to 20cm dimeter, commonly seen involve extensive
portions of the aortic arch, abdominal aorta, and the iliac artery.
» Mycotic aneurysm – as result of endocarditis embolization of septic embolus nearby supportive process
etc. …caused by infection that weakens the wall of the artery, with rupture and thrombosis as major
complications.
The etiology of depends on the site of its occurrence
in the aorta. Causes of aortic aneurysm include:
» inherited syndromes- lead to abnormal c.t.
synthasis such as Marfan syndrome, EhlersDanlos syndrome type 4.usually appear in the
root of ascending aorta
» non- inflammatory aneurysms are associated with congenital conditions (bicuspid aortic valveroot of aorta) and acquired conditions (hypertension- ascending aortic aneurysm). the
pathogenesis of the aneurysms is due to medial degeneration of the elastic aortic wall may
demonstrate degrees of cystic, medial degeneration
» inflammatory destruction:
a) Secondary to syphilis/bacterial infection - Characteristic of the tertiary stage of syphilis see in the
ascending aorta. Inflammation Involves small vessels all over the body, particularly the vasa
vasorum => Hyperplastic thickening of vasa vasorum => reduced blood flow to aorta =>
ischemic medial injury => aneurysm.
The involved vessels develop obliterative endarteritis => luminal narrowing and obliteration, scarring of
the vessel wall, and a dense surrounding rim of lymphocytes and plasma cells that may extend into the
media (syphilitic aortitis). Major complication is dilation of the aortic valve root, resulting in aortic valve
Insufficiency, other complications include compression of mediastinal structures (e.g., airway
or esophagus) and thrombosis/embolism.
b) noninfectious aortitis as Atherosclerosis –dominant factor for abdominal aortic aneurysm. As
Severe atherosclerosis lead to destruction and thinning of the aortic media, compromise nutrient and
waste diffusion from the vascular lumen into the wall => degeneration and necrosis of media =>
dilation of the vessel. More see occurs due to an altered balance of collagen degeneration and
synthesis mediated by local inflammatory infiltrates and their proteolytic enzymes.e.g Elevated
matrix metalloproteinases (MMPs) levels, together with decreased levels of tissue inhibitor of
metalloproteinases (TIMPs).
There are 2 important variants of AAA:
1) Inflammatory AAA – characterized by dense periaortic fibrosis, containing lymphocytes and
macrophages infiltrate.
2) Mycotic AAA – atherosclerotic lesions infected by circulating organisms due to bacteremia.
Clinical Presentation as pulsatile abdominal mass that grows with time complication:
Rupture into the peritoneal cavity with massive hemorrhage.
Embolism from the atheroma or mural thrombus lead to Obstruction of a branch vessel, resulting in
downstream tissue ischemia (for example, obstruction of the iliac arteries can cause ischemic damage to the legs).
Compression of local structures (e.g., ureter)
AORTIC DISSECTION
Occurs when there is a tear in intima allow blood to penetrate through the wall of the aorta may
completely rapture the aorta as deadly hemorrhage or propagate within media as blood filled channel –
intramural hematoma .
For this development must have 2 factors the very high pressure flow –hence accurse in proximal 10
cm of aorta and preexisting weakness of media layer, Aortic dissection is not necessarily associated
with aortic dilation.
Pathogenesis – Aortic dissection occurs in 2 groups:
» About 90% of cases Men aged 40-60 with the existence of hypertension. Hypertension is the
major risk factor => hypertrophy of the media => ECM degeneration and loss of smooth muscle
cells. More aorta is very large and thick b.v. must use vasa vasurum for nutrients vasa vasurum
hyaline arteriolosclerosis impaired blood supply and weakens wall
» Younger patients with systemic or localized abnormalities of c. tissue (for example, Marfan
/ehaler danols synd.4).
Inherited or acquired c. tissue disorders abnormal ECM, such as Marfan syndrome (most
common) no fibrillin no elastic weak media, Ehlers-danlos syndrome, vitamin C deficiency,
copper metabolic defects.
Morphology –The tear is usually found in the ascending aorta within 10cm of the aortic valve. in a few
cases, the channel origin in intimal lesion free area ruptures back into the lumen of the aorta in origin of
atherosclerotic plaque , creating a “double-barreled aorta”.
Histologically the dissecting intramural hematoma spreads along the laminar planes between the middle
and outer thirds of media, pre-existing lesion to wall not identified in most cases but cystic medial
degeneration (CMD) separation of the elastic and smooth muscle cell elements of the media by cystic
spaces filled with proteoglycan-rich ECM.
Clinical features –
» Aortic dissections can be classified as:
1) Proximal lesions (type A dissections) – involve the ascending aorta (DeBakey type I),
2) Distal lesions (type B dissections) – usually begin distal to the subclavian artery (DeBakey type III).
» Aortic dissections are characterized by the sudden onset of excruciating pain, beginning in the anterior
chest, radiating to the back between the scapula’s, and moving downwards as the dissecting progresses.
» complications
1. Cardiac tamponade (hemorrhage into the pericardial sac). Most common cause of death
- Extension of the dissection and compression of the outlets to the great arteries of the neck, renal,
mesenteric or iliac arteries impairing their blood flow. - The channel can rupture through the adventitia and into mediastinum, causing a massive fetal
hemorrhage
Venous disorders (dilation, inflammation and obstruction). Vascular neoplasias.
Vascular neoplasms can be derived from endothelial cells, or from cells that surround and/or support the
VENOUS DISORDERS
VARICOSE VEINS
# Abnormally dilated and tortuous (twisted) veins, produced by prolonged increase in intramural pressure and
loss of vessel wall support.
The superficial veins of upper and lower leg are usually involved.with about 20%of man and 1/3 of woman
will develop it
# Morphology –
» Wall thinning at the points of maximal dilation with smooth muscle hypertrophy and intimal fibrosis.Elastic
tissue degeneration.
» Spotty medial calcifications (phlebosclerosis).
» Venous valve deformities (rolling and shortening).
Clinical features –
» Venous valves become incompetent upon widening, leading to stasis and edema causing pain and
thrombosis
» Persistent edema => secondary ischemic skin changes the skin is pale and often hairless, cool, thickened
nail => stasis dermatitis of skin reddish purple and scaleded venus stasis result in increase pressure in
microcirculation and ulcerations.Poor wound healing + superimposed infections = chronic varicose ulcers.
Esophageal varices –
» Occurs due to portal vein hypertension, usually due to cirrhosis, but also because of portal vein obstruction
or hepatic vein thrombosis.
» Liver cirrhosis => portal vein hypertension => opening of porto-systemic shunts => increased blood flow to
veins of the gastro-esophageal veins (esophageal varices), to the veins of the rectum (hemorrhoids), and to
the periumbilical veins (caput medusa).
» The rupture of the esophageal varices can lead to massive upper GI hemorrhage that can be fatal.
# Hemorrhoids – Varicose dilation of the hemorrhoidal venous plexus at the anorectal junction. Can be caused
by pregnancy, chronic constipation or strain of defecation.
THROMBOPHLEBITIS AND PHLEBOTHROMBOSIS
Definitions –
» Thrombophlebitis – an inflammation of the veins caused by a blood clot.
» Phlebothrombosis – blood clots formed in the veins.
In most cases (>90%), these conditions involves the deep veins of the leg, but they can also appear in
the periprostatic veins (in males), the pelvic venous plexus (in females), the large veins in the skull and
the dural sinuses.
deep venous thrombosis is caused by :stasis e.g. bad care patient ,procoagulative state –contraceptives,
vascular wall injury such in venipuncture or infection Virchow’s triad, Peritoneal infections can lead to
portal vein thrombosis.
Thrombi in the leg tend to produce few, if any, symptoms => local manifestations (Distal edema,
cyanosis, superficial vein dilation, and pain- homans test: foot dorsiflexion cuff .m. compress vain and
cause pain) can be entirely absent.
Thromboembolisem-95%of pulmo. Embolism are result of DVT risk to complication…
SUPERIOR & INFERIOR VENA CAVAL SYNDROMES
SVC syndrome –commonly caused by certain neoplasms (Bronchogenic carcinoma, mediastinal
lymphoma.)Which their location compress or invade the SVC.
The resulting obstruction produces marked dilation of the veins of the head, neck and arms,
accompanied by cyanosis. Pulmonary vessels can also become compressed, resulting in respiration
distress.
IVC syndrome – Caused by : Certain neoplasms, such as hepatocellular carcinoma and renal cell
carcinoma, show tendency to grow within veins or by thrombus from the hepatic(Budd–Chiari
syndrome), renal, or lower extremity veins or other tumors compressing IVC..
The obstruction of IVC induces marked lower extremity edema, distension of the superficial collateral
veins of the lower abdomen, and in case of renal vein involvement, massive proteinuria.
VASCULAR TUMORS
blood vessels. Vascular tumors can be either benign hemangiomas, intermediate lesions that are locally
aggressive, or highly malignant angiosarcomas.
#General distinction between benign and malignant tumors:
» Benign tumors – produce obvious vascular channels filled with blood cells, lined by a monolayer of normal
endothelial cells (without atypia).
» Malignant tumors – cellular with cytological anaplasia (including mitotic figures), and usually do NOT form
well-organized vessels
BENIGN TUMORS AND TUMOR LIKE CONDITIONS
Hemangioma -A common benign tumor of infancy and childhood characterized by increase number of
normal or abnormal vessels filled with blood. Usually spontantusly regress with age .
» Cherectarly appear as localize lesion in head and neck skin or oral mucosa/tongue but may appear
internally if so ~ 1/3 of it seen in the liver .When involving large portions of the body-more extensive
lesions named => angiomatosis.
» Clinical variants:
1) Capillary hemangioma – most common consists of closely packed thin capillaries and scant stroma
lined by flattened one layer endothelium; can occur in the skin, subcutaneous tissues, mucous
membranes of the oral cavity and lips, liver, spleen and kidneys.
2) Cavernous hemangioma – characterized by large vascular channels, separated by c. tissue stroma, and
most frequently involves deep structures (liver, pancreas, spleen and brain); they appear as red-blue soft
masses, 1-2cm in diameter.
Glomus tumor (glomangioma) - Benign painful tumor Arises from modified smooth muscle cells of
glomus body, a specialized arteriovenous anastomosis involved in thermoregulation .
» Most commonly found in the distal portions of the digits, especially under the fingernails.
» The tumors are round, slightly elevated, red-blue, firm nodules, consist of masses of glomus
specialized tissue. Histologically resemble cavernous hemangiomas branching vascular channels
separated by stroma containing glomus cells in nests, aggregates Glomus cells are arranged around
vessels.
Vascular ectasias -Local dilation of preexisting vessels:
» Telangiectasia – permanent dilation of preformed small blood vessels ( capillaries, venules or
arterioles) not a tumor just structure abnormality.
Hereditary hemorrhagic telangiectasia – an autosomal dominant disorder that creates telangiectasia malformations present at birth usually distributed over the
skin and mucous membranes their rupture can cause nosebleeds epistaxis , GI bleeding and hematuria.
» Nevus flammeus – the ordinary birth mark, flat lesion ranging in color from light pink to deep purple.
May regress with time Port wine stain is a special form of nevus flammeus that tends to grow with the
child, thickens the skin surface and has no tendency to fade.
» Spider telangiectasia – a non-neoplastic vascular lesion consists of a radial array of subcutaneous
arteries or arterioles, surrounding a central core; associated with hyper estrogenic states such as
pregnancy or cirrhosis.
Bacillary angiomatosis -Reactive vascular proliferation due to opportunistic infection by Bartonella family of gram( – ) bacteria’s . Most commonly affects immunocompromised individuals (especially those with HIV)
» Can occur in any cutaneous site as red papules and nodules which are widely distributed Rarely occurs
in mucosa or internal organs e.g. bone and brain.
» Histologically, there is capillary proliferation with epithelioid endothelial cells showing nuclear atypia
and mitoses; the lesions contain stromal neutrophils, nuclear dust and purplish granular material
(representing the causal bacteria).
INTERMEDIATE-GRADE TUMORS
Kaposi sarcoma (KS) -Vascular neoplasm that develops from the cells lining the lymph vessels or
blood vessels, and appears as tumors on the skin or on mucosal surfaces (for example, inside the
mouth). Strong association to AIDS
» Pathogenesis – the tumor is caused by infection with human herpes virus 8 (HHV-8), which is also
called KS-associated herpesvirus (KSHV). Virus synth homologue prot to cyc. D and suppress P53
induction of apoptosis
» Types of KS:
1) Chronic KS – also called classic KS
Mostly affects older men of eastern European or Mediterranean origin, not associated with HIV. It is
characterized by red to purple nodules, usually on distal lower extremities, and is typically
asymptomatic and localized.
2) Lymphadenopathy KS – also called African or endemic KS
Most common in people living in equatorial Africa, and is also not associated with HIV.
Patients present with lymphadenopathy, which occasionally involves the viscera, and is extremely
aggressive.
3) Transplant-associated KS
Occurs in transplant patients whose immune system have been suppressed to avoid organ rejection. It
tends to be aggressive with nodal, mucosal and visceral involvement.
4) AIDS-associated (epidemic) KS
Can involve lymph nodes and viscera, and is considered an “AIDS defining” illness => when a person
infected with HIV develops KS, that person officially has AIDS.
» Morphology – consist of 3 stages of progression :
Patches – solitary or multiple red-purple macules, confined to the distal lower
extremities, with irregular dilated b.v. and chronic inflammatory infiltrate in-between b.v.
Plaques – larger and raised, composed of dermal accumulation of vascular channels
lined by spindle cells, with RBCs, hemosiderin-filled macrophages, lymphocytes and
plasma cells scattered among them.
Nodules– the lesions become nodular and more distinctly neoplastic, composed of
sheets of proliferating spindle cells in the dermis or subcutaneous tissue, with marked
hemorrhage, hemosiderin and lymphocytes.
MALIGNANT TUMORS
Angiosarcoma
» Malignant endothelial neoplasm, varying from highly differentiated to anaplastic tumors.
» Usually involves the skin, soft tissue, breast and liver.
» Hepatic angiosarcoma is associated with carcinogen exposure, especially arsenic, thorium
dioxide (thorotrast), and polyvinyl chloride.
» Lymph angiosarcoma arises from lymphatic vessels.
» Morphology –
Begin as small, sharply demarcated, red nodules.
Become large masses of red-tan to white-gray tissue.
» Clinical features – they are locally invasive and can metastasize.
Hemangiopericytome
» Rare tumors derived from pericytes.
» Occur as slowly enlarging, painless masses.
» Most common on lower extremities.
» Consist of numerous branching capillary channels and gaping sinusoidal spaces, enclosed within
nests of spindle shaped cells.
Disorders of lymphatic vessels.
LYMPHANGITIS
Lymphangitis, bacterial infection of the lymphatic vessels. Acute inflammation
elicited by bacterial infections that spread into and throughout the lymphatics.
Main causative agents are group A, β-hemolytic streptococci. The condition is most
commonly caused by streptococcus or staphylococcus organisms
The affected lymphatics are dilated, and filled with exudate of neutrophils and
monocytes.
Lymphangitis most commonly develops after cutaneous inoculation of
microorganisms that invade the lymphatic vessels and spread toward the regional
lymph nodes.
The inflamed lymph vessels are visible as red streaks under the skin that extend from
the site of infection to the groin or armpit with painful enlargement of the draining
lymph nodes (acute lymphangitis).
If the bacteria are not contained within the lymph nodes, they may pass into the
venous circulation, resulting in bacteremia or sepsis.
Reminder: The major function of the lymphatic system is to resorb fluid and protein
from tissues and extravascular spaces.
The absence of a basement membrane beneath
lymphatic endothelial cells affords the lymphatic channels a unique permeability,
allowing resorption of proteins that are too large to be resorbed by venules.
Lymphatic channels are situated in the deep dermis and subdermal tissues parallel to
the veins and have a series of valves to ensure one-way flow. Lymph drains via
afferent lymphatics to regional lymph nodes and then by efferent lymphatics to the
cisterna chyli and the thoracic duct into the subclavian vein and venous circulation
LYMPHEDEMA
Edema upon impaired lymphatic dranage , Lymphedema is traditionally classified
into two forms: primary, which is genetic, and secondary caused by an acquired
defect in the lymphatic system
Primary lymphedema – occurs as isolated congenital defect, or as the familiar Milroy
disease A familial, autosomal-dominant disorder, it is often caused by anaplastic
lymphatic channels. The disorder manifests at birth or later, up to age 1 year.,
resulting from lymphatic agenesis or hypoplasia.
Secondary (obstructive) lymphedema – accumulation of interstitial fluid due to
blockage of normal lymph vessels; the obstruction can be the result of malignant
tumors, therapeutic or post-inflammatory thrombosis and scarring.
Commonly associated with obesity, infection, neoplasm, trauma, and therapeutic
modality:
I. Filariasis-The most common cause of secondary lymphedema worldwide is filariasis,
a disease caused by the parasite Wucheria bancrofti which are widely distributed in
tropical and subtropical regions of the world and are transmitted to man by
mosquitoes infecting lymphnodes and may result in some of the untreated cases in
the condition known as elephantiasis, which is typically associated with the gross
expansion of the tissues of the legs and scrotum.
II. Malignancy and cancer treatment- In the industrialized world, the most common
causes of secondary lymphedema are malignancy and its treatment.
This means that the disease can arise from obstruction from metastatic cancer or primary lymphoma or
can be secondary to radical lymph node dissection and post-irradiation fibrosis
Commonly affected area is the axillary region after mastectomy and radical dissection
for breast cancer.
III. Other causes- Morbid obesity frequently causes impairment of lymphatic return and
commonly results in lymphedema.
# Lymphedema increases the hydrostatic pressure in the lymph vessels, causing
accumulation of lymph fluid in various spaces => chyloud ascites (abdomen),
chylothorax, and chylopericardium.
Ischemic heart failure. Left-sided and right-sided heart failure.
HEART FAILURE
Occurs when the heart is unable to pump blood at the rate necessary to supply the
requirements of the metabolizing tissues
Forward failure, and inadequate cardiac output, is almost always accompanied by
backward failure, an increased congestion of the venous circulation => the failing
ventricle is unable to eject the blood delivered to it, resulting in increased EDV,
leading to increased diastolic pressure and elevated venous pressure.
The cardiovascular system can adapt to reduced myocardial contractility in a few
ways:
1) Activation of neurohumoral systems – release of epinephrine to increase
heart rate and contractility, activation of rennin-angiotensin system, and
release of atrial natriuretic peptide (ANP) that causes vasodilation,
natriuresis and dieresis to relieve pressure overload states.
2) The Frank-Starling mechanism – increase of EDV causes stretch of
cardiac muscle fibers and dilation of the ventricle, and results in more
forceful contraction to elevate cardiac output
3) Myocardial structural changes – including hypertrophy to increase the
mass of the contractile tissue (adult cardiac myocytes are unable to
proliferate) => the capillary bed does not always increase with
coordination to the increased oxygen demands of the hypertrophic cells,
causing an ischemic injury
LEFT-SIDED HEART FAILURE
Usually occurs due to ischemic heart disease (IHD), systemic hypertension,
mitral or aortic valve disease, and primary diseases of the myocardium.
The result is damming of blood within the pulmonary circulation, and diminished
peripheral blood pressure and flow.
Morphology –
» The left ventricle is usually hypertrophied and dilated.
» Secondary enlargement of the left atrium can reduce stroke volume, and
lead to stasis and thrombus formation.
» Rising pressure in the pulmonary veins results in pulmonary congestion
and edema. Histologically => interstitial transudate alveolar septal edema,
and intra-alveolar edema.
Capillary leakage hemoglobin is converted to
hemosiderin => heart failure cells (macrophages containing hemosiderin).
Clinical features – breathlessness (dyspnea), cough, orthopnea in later stages
(dyspnea when lying down), enlarged heart, tachycardia, a 3rd heart sound (S3),
mitral regurgitation and systolic murmur (due to displacement of the papillary
muscle laterally).
RIGHT-SIDED HEART FAILURE
Usually the consequence of left-sided heart failure; Pressure increase in the
pulmonary circulation => increase burden on the right side of the heart.
Isolated right-sided heart failure occurs in case of:
1) Patients with intrinsic disease of lung parenchyma and/or pulmonary
vasculature that result in chronic pulmonary hypertension => COR
PULMONALE
2) Patients with pulmonic or tricuspid valve disease.
Isolated right-sided heart failure is characterized by
» Liver –congestion (nutmeg liver) => centrilobular necrosis and more
peripheral yet reversible fatty change ,upon chronic injury risk to develop
cardiac cirrhosis => the central areas become fibrotic.
» Portal system elevated pressure also result in congested enlarged spleen
may see more brown color again view hemosiderin accumulation.
» Pleural and pericardial spaces – accumulation of fluid (effusion) in the
pleural and pericardial spaces.
» Subcutaneous tissue – peripheral edema pitting edema symmetric both
lower extremities.
Angina pectoris. Acute coronary syndrome.
ISCHEMIC HEART DISEASE
A group of related syndromes resulting from myocardial ischemia, most common cause for the
reduction in coronary blood flow is atherosclerotic disease. Hence risk to develop IHD are same as ones
of develop AS (age, gender, metabolic state, smoking etc.)
IDH can also be the result of increased demand (increased heart rate, hypertension), or of diminished
oxygen-carrying capacity (anemia, CO poisoning).
The clinical manifestations of IDH are angina pectoris, acute myocardial infarction, chronic IHD and
sudden cardiac death.
ANGINA PECTORIS
It is a periodic chest pain caused by reversible myocardial ischemia. Pressing retrosternal pain not
related to breading, no elevation in myocardial enzymes opposing to MI, character ECG changes may
seen (coronary/hyper acute t waves or ST alteration or both) and relief upon nitroglycerin
administration…
There are 3 variants of AP:
1) Typical (stable) AP
Episodic chest pain50 result of reversible injury to myocyte (swelling hallmark) associated with
increased myocardial oxygen demand (tachycardia, hypertension =exertion/emotional stress etc.)
Usually occurs due to fixed atherosclerotic narrowing (>70%) of one or more coronary arteries =>
myocardial oxygen supply is sufficient no stress , but cannot be increased to meet the adequate
demand.
Can be relieved by drugs that cause peripheral vasodilation, as nitroglycerin administration lead to
immediate relief- vasodilation of mainly veins as reduced preload thus o2 demand …
2) Prinzmetal (variant) AP
Episodic-less then 20 min chest pain unrelated to exertion, occurring at rest due to Short term
complete occlusion of blood supply like in coronary artery spasms/repeated complete obstructive
thrombus who partially lysed and reformed, usually take place near an existing atherosclerotic plaque,
although normal vessels can also be affected.
Can be relieved by vasodilators such as nitroglycerin and Ca2+ channel blockers. ECG ST elevation
transmural ischemia ,deadly may lead to arrhythmia and cardiac arrest. Main patient present it are
male smoker
3) Unstable AP (crescendo angina)
AP show also at rest from incomplete occlusion of coronary, It is associated with
atherosclerosis/plaque disruption and superimposed thrombosis, embolization… risk to progress to
potentially irreversible injury ischemia.- It is called pre-infarction angina
Characterized by increasing frequency of pain => episodes tend to be more intense and long lasting
than stable AP.
ACUTE CORONARY SYNDROME
Refers to any of the 3 catastrophic outcomes of IHD see picture upon coronary atherosclerosis and
typical AP may develop chronic ischemic heart diseas or progress to acute coronary syndrome.
- Unstable AP
- Acute MI-previously non major occlusive plaque build thrombose and see acute unset sever ischemia
- Sudden cardiac death-usually refer to sudden collapse of circulation as from arrhythmia without
prominent myocardial damage
Associated with coronary thrombosis/embolisem-acute pluqe changes,vasoconstriction such upon
agonist of epi ,platelet local realis, endothelin other vasoconstrictor realis upon endothelial imbalance
ext. endothelin and cocaine usage.
Symptoms include angina pectoris but sever, shortness of breath, nausea and sweating and sympathetic
dominance .
The etiology, pathogenesis and morphology of myocardial infarction.
ETIOLOGY OF MYOCARDIAL INFARCTION
MI, or common name heart attack, is necrosis of heart muscle resulting from ischemia.
The major underlying cause is atherosclerosis (as see disruption of plaque and thrombogenesis);
therefore the frequency of MI rises progressively with age and occurrence of risk factors to
atherosclerosis; women are protected against MI during their reproductive years.
Other risk factors that contribute to MI are hypertension, smoking, diabetes mellitus, gender (men are more affected).
PATHOGENESIS
Most MIs are caused by acute coronary artery thrombosis, resulting from disruption of an
atherosclerotic plague and formation of thrombus. In limit to sub endocardial infarctions, the cause is
usually increase in demand such as arrhythmia/hypertension under settings of diffused coronary
atherosclerosis ischemic necrosis of the myocardium ,most distal to the epicardial vessels
Occurrence of MI without occlusive atherosclerotic disease(~10% of MI ) include Vasospasms
(prinzmetal AP , elevated catecholamine or exogenous cocaine),mural thrombose/ valve vegetation
leading to thromboembolism in coronaries
Ischemia without atherosclerosis or thromboembolic disease can be caused by disorder of small
intramyocardial arterioles, including vasculitis (Kawasaki diseas a vasculitis in small children
preferentially involving coronaries), amyloid deposition or stasis (e.g. sickle cell disease).
Sequence of events in coronary artery occlusion:
» Atheromatous plaque is disrupted -> sub endothelial collagen and necrotic plaque are exposed
to the blood
» Platelets aggregate and activated -> release of thromboxane A2, ADP and serotonin ->
vasospasm, Coagulation begins with exposure of TF and platelet surface…
» Thrombus evolves to completely occlude vessel
# Myocardial response to ischemia –
» aerobic glycolysis ceases -> inadequate production of ATP, and accumulation of toxic products
(lactic acid) loss of contractility, myofibrillar relaxation, glycogen depletion, cellular and
mitochondrial swelling. These changes are REVERSIBLE
» severe prologue ischemia ( more then 20-40 minutes) causes irreversible injury and death of
myocytes as coagulation necrosis , irreversible injury usually appear initially in the sub
endocardial zone since it’s the last area to receive blood from the epicardial vessels and it has a
high intramural pressure -> Infract usually achieves its full extent within 3-6 hours (transmural
infract)
MORPHOLOGY
Patterns of infraction – location , size and morphology depend on the size and duration of involved
vessel; rate of development; metabolic demands of the myocardium. Usually in MI atria’s are
speared
Epicardial vessels are interconnected by collateral circulation; in case of epicardial occlusion,
collateral dilation can provide adequate perfusion.
Microscopic infract – small vessel occlusion, no changes on ECG. Occurs in vasculitis,
embolization/ mural thrombi, vessel spasm …
In most patients, the distribution of infarcts is as follows:
» Left anterior descending (LAD) artery (most common 40%) infarct involves the anterior left
ventricle, anterior 2/3 of septum and the apex. Left coronary occlusion is typically fatal (“widow
maker”).
» Right coronary artery (RCA) 2nd common infarct involves the posterior left ventricle,
posterior septum and right ventricle. RV papillary .m.
» Left circumflex artery (LCX) -> infarct involves the lateral left ventricle.
Myocardial necrosis eventually proceeds to scar formation without any significant regeneration. The
gross and microscopic appearance of MI depends on the interval of time since the original injury
(coagulative necrosis -> acute & chronic inflammation -> fibrosis :
- In 1st day- initial 1st min come with loss of function no visible change may end as
arrhythmia/cardiogenic shock if large effected area, next 4-24 hr. development of coagulative
necrosis lose nuclei look dark on macro due to stagnated trapped blood again danger of
necrosis conductive sys. And arrhythmia. - In first week- events of inflammation take place ,initial 3 days neutrophils infiltrate if transmural
infract may involve epicardium as fibrinous pericarditis, following days till full week past see
macrophages come to clean inflammatory debris n initiate granulation tissue formation so this
stage myocardium most weak and danger of rapture as complication papillary .m. rapture=mitral
insufficiency/vent. Wall rapture and cardiac tamponade !macro appearance in 1st week as yellow
pallor appearance micro see inflamtory infiltrate inbt necrotic myocytes - Till end of month follow infarction-from 1-3 week see granulation tissue micro fibroblast
depositing collagen and new blood vessels leading to red border around infract macro
morphology as new blood vessel formed from preexisting ones on edges of necrotic tissue ,till
end of month scar (main collagen 1) replace the myocardium risk for anyurisem and turbulencestasis-new thrombose etc.…
Infracts older than 3 hours can be stained by a substrate51 for LDH – leaks from cell at the area of
necrosis. The infracted area is pale
CLINICAL FEATURES
Severe chest pain radiating to neck, jaw, left arm, lasts a few minutes-hours (in contrast with angina
pectoris); pain isn’t relieved by nitroglycerin or rest. Pulse is rapid and weak; patients are nauseated,
Dyspnea is common due to impaired contractile ability -pulmonary congestion and edema,SNS sings
In severe MI cardiogenic shock develops
# Lab findings – leaked enzymes – myoglobin, cardiac troponin may raise 5 fold almost absolute for
MI less other stuff as inflammation but if absent for sure this isn’t MI raise after 4 hr. from event peak in 24 hr and fall after about a week , creatine kinase useful for detection of 2ndery event as take ~6hr to raise
and peak in 24 and fall in about 72 hr. , LDH
# Reperfusion injury- Reperfusion when injury is still reversible can preserve cell viability. Perfused
myocardium appear hemorrhagic and show an eosinophilic contraction band necrosis.
» Return of blood means return of oxygen and inflammatory cells lead to Free radicals which far
more injure myocytes
» Myocardial ischemia contributes to arrhythmias by causing electrical instability of ischemic
regions of the heart -> ventricular fibrillation -> sudden death. During ischemia IC Ca levels are
significantly increased, after reperfusion more ca but no pump capacity , contraction of
myofibrils is uncontrolled -> cell death see contraction band necrosis pattern
CONSEQUENCES OF MYOCARDIAL INFARCTS
Contractile dysfunction – resulting in hypotension, pulmonary vascular congestion, and pulmonary
transudation into the pulmonary interstitial and alveolar spaces.
Arrhythmias – sinus bradycardia, heart block, tachycardia, ventricular premature contractions, and
ventricular fibrillation.
Myocardial rupture – complications include rupture of the wall with hemopericardium and cardiac
tamponade; rupture of the septum with left to right shunt; and papillary muscle rupture resulting in
mitral regurgitation.
Pericarditis – develops within 2-3 days after MI and usually spontaneously resolves. Dressier
syndrome rear AI pericarditis appearing about 6 week follow transmural infarction as result of
exposure of pericards AG to immune system
Infarct expansion Chamber dilation – wakening of necrotic muscle results in its thinning and dilation
of the infarct region.
Mural thrombus – local loss of contractility, causing stasis, with endocardial damage, causing
thrombogenic surface; can result in the formation of mural thrombus and thromboembolism.
Ventricular aneurysm – usually results from anterolateral infarction with the formation of thin scar
tissue, may lead to mural thrombus, arrhythmias and heart failure.
Papillary muscle dysfunction
Hypertension. Cor pulmonale.
HYPERTENSION (topic 80)
Hypertension – a chronic medical condition in which the blood pressure in the arteries is
elevated, requiring the heart to work harder than normal to circulate the blood through the
vasculature.
Regulation of blood pressure depends on the regulation of cardiac output (affected by blood
volume), and total peripheral resistance (regulated by arterioles via neurological and
hormonal inputs).
The kidneys, and to some extent the adrenal glands, are responsible for blood pressure
regulation, mainly by the rennin-angiotensin system (RAS).
Hypertension can cause cardiac hypertrophy and heart failure (hypertensive heart disease),
aortic dissection, and renal failure.
CARDIAC HYPERTENSION
Cardiac myocytes are terminally differentiated cells, which lack the capacity to divide ->
hyperplasia CANNOT occur.
Instead, increased work will induce an increased mass and heart size -> hypertrophy
The pattern of the hypertrophy reflects the initiating stimulus:
» Concentric hypertrophy – develops due to pressure-overloaded ventricles (in hypertension or
aortic valve stenosis), with an increased wall thickness that can reduce the volume of the
ventricle.
» Eccentric hypertrophy – develops due to volume overload (in aortic valve insufficiency), and
is characterized by ventricular dilation associated with muscle mass increase.
Prolonged hypertrophy can eventually result in myocyte contractile failure, cardiac dilation,
CHF and sudden death.
Although hypertensive heart disease mostly affect the lecft side of the heart secondary to
systemic hypertension, pulmonary hypertension also can cause right-sided hypertensice
changes – cor pulmonale
SYSTEMIC HYPERTENSION
Systemic hypertension occurs when there’s left ventricular hypertrophy without other
cardiovascular pathology (valvular stenosis); and evidence of hyertension
Morphology – left ventricular hypertrophy, without ventricular dilation (until very late in the
process). Heart weight ~500gr, wall thickness >2cm, causing stiffness that impairs diastolic
filling; microscopically, there is nuclear enlargement and hyperchromasia, and interstitial fibrosis
PULMONARY HYPERTENSION
Usually low pressure in pulmonary circulation about 25/10 mmHg and Venus pressure 2-5
mmhg if raise above 25mmhg its an pulmonary hypertension
Characterized by atherosclerosis of the pulmonary trunk, smooth muscle hypertrophy of
pulmonary arteries, and intimal fibrosis; plexiform lesions–endothelial prolifartion and
occlusion of small .a. lumen are seen With severe, long-standing disease
Sub classified as primary or secondary based on etiology
A. primary-Classically seen in young adult females, Etiology is unknown; some rear familial
forms are related to inactivating mutations of BA1PR2, leading to proliferation of vascular
smooth muscle. Rare, autosomal dominant with incomplete penetrance Mutations in bone morph
genic protein receptor 2 signaling pathway (BMPR2)
B. secondary - Due to hypoxemia (e.g., COPD and interstitial lung disease) or increased volume
in the pulmonary circuit (e.g., congenital heart disease); may also arise with recurrent
pulmonary embolism
COR PULMONALE
pulmonary hypertensive heart disease- is the enlargement and failure of the right ventricle of the
heart as a response to increased vascular resistance (such as from pulmonic stenosis) or high
blood pressure in the lungs. Presents with exertional dyspnea or right-sided heart failure
# Consists of right ventricular hypertrophy and dilation – frequently accompanied by right heart
failure - due to pulmonary hypertension, caused by primary disorders of the lung parenchyma or
pulmonary vasculature.
Can be either acute or chronic:
» Acute – follows massive pulmonary embolism with obstruction of >50% of the pulmonary
vascular bed. Thromboembolic obstruction of proximal pulmonary arteries
» Chronic – occurs secondary to prolonged pressure overload, caused by obstruction of the
pulmonary vasculature, or compression/obliteration of septal capillaries (resulting from
emphysema, interstitial pulmonary fibrosis, or primary pulmonary hypertension).
Morphology –
» In acute cor pulmonale – the right ventricle is dilated, but does not show hypertrophy.
» In chronic cor pulmonale – right ventricle hypertrophy. When ventricular failyre develops,
ventricle and right atrium are dilated; pulmonary arteries often contain atheromatous plaque
Rheumatic fever. Rheumatic heart disease
RHEUMATIC FEVER
An immunologically-mediated, systemic disease that occurs after group A, β-hemolytic streptococcus
pharyngitis about 2-3 weeks after pharyngitis.
# Most often affects children 5-15 years old. In only about 3% of infected individuals hence genetic
susceptibility is likely to influence (due to the small minority of infected people). Can be prevented by
AB penicillin treatment to strep throat infection preventing complications such as scarring of mitral
valve which may lead to need in surgery for valve replacement.
Pathogenesis – it is a hypersensitivity reaction induced by host antibodies against group A streptococci
=> some M proteins induce antibodies that cross-react with glycoproteins in the heart and joints, this
cross-reactivity is a type II hypersensitivity reaction and is termed molecular mimicry. This
Autoimmune attack manifested as systemic disease affecting the connective tissue around arterioles,
heart and joints, producing the symptoms of rheumatic fever.
Morphology – the classic lesion of rheumatic fever histologic characteristic appearance of Aschoff
body => an area of focal interstitial inflammation that is characterized by fragmented collagen and
fibrinoid material, by activated macrophages with slander wavy nucleus (Anitschkow cells), and by
occasional giant cells .
Manifestations of rheumatic fever As jones criteria an diagnostic system in it the Major criteria
represent manifestations:
Polyarthritis- A temporary migrating inflammation of the large Joints, usually starting in the legs and
migrating upwards.
Pancarditis- inflammation of all 3 layers of heart :
A. endocarditis as small vegetation’s essentially on valves and preferentially on mitral valve impire
normal valve closure upon appearance of vegetation later resolve as scar valve stenosis …
B. myocarditis- histologic characteristic appearance of Aschoff body, most common cause of death
during acute phase
C. pericarditis-fibrinous exudate resolve alone
Subcutaneous Nodules
Erythema marginatum: reddish rash that begins on the trunk or arms as macules with clear center, next
spread outward typically spares the face.
Sydenham’s chorea: A characteristic series of involuntary rapid movements of the face and arms.
RHEUMATIC HEART DISEASE
Repeated Inflammation of the endocardium due to repited rheumatic fever attecks may result in
rheumatic heart disease (RHD).
RHD is the consequence of Fibrosis and scarring of the valves: valve leaflets become thick fibrotic and
deformed ,commissural fusion or shortening of cusps and thickening of chorda tendinae leads to
abnormalities that can result in valve stenosis or regurgitation
Manifestation
» Mitral valve –stenosis and/or insufficiency.
» Aortic valve – usually affected along with the mitral valve, by stenosis or insufficiency.
» Tricuspid valve – if affected, it occurs with the involvement of both mitral and aortic valves.
» Pulmonary valve – rarely involved.
Valvular stenosis and insufficiency. Mitral valve prolapse.
Stenosis – the failure of a valve to open completely, obstructing forward flow, usually caused by
VALVULAR STENOSIS & INSUFFICIENCY
chronic process e.g. calcification or valve scarring.
intrinsic disease of the valve cusps, or distortion of the supporting structures chords/papillary muscles.
valve.
heart disease, infective endocarditis and calcification (aortic valve).
stenosis:
» Usually age-associated calcification wear and tear damage to valve, appear around age of 60 risk
factors are same as for atherosclerosis
» Nodular Calcified masses on the outflow side of the cusps causing them to protrude into the
aortic sinuses, obstructing normal opening. Note no commissure fusion like in rheumatic fever.
» Post inflammatory scaring anther common reason for stenosis as in after rheumatic fever appear
usually together with commissural fusion and mitral valve involvement.
» In about 1% of all live birth see bicuspid aortic valve (2 leaflet instead of 3) most common
congenital valve diseas not rally problem only repercussion is for increased risk to develop aortic
calcification stenosis in general and earlier.
MITRAL VALVE PROLAPSE
“floppy” => the leaflets are being pushed back into the left atrium during systole.
» The affected leaflets are enlarged, thick and rubbery.
» Chordae tendinous are elongated, thin and may be ruptured.
» Histologically => impaired structural integrity, and increased deposition of mucoid material in
center of valve -spongiosa layer one who enclosed by fibrosa layer .
defect of c. t tissue (Marfan syndrome/ehelor danols syndrome).2ndry come upon other etiology as
ischemic dysfunction.
breathlessness and atypical chest pain.may be heard as murmur in middle of systole.
lead to left side congestive heart failure risk for ventricular arrhythmias and incres risk for infective
endocarditis on injured valve.
Infective and non-infective endocarditis. Complications related to prosthetic cardiac valves.
Inflammation of the endocardium, the inner layer of the heart.
ENDOCARDITIS
# Other structures that may be involved are the interventricular septum and the chordae tendinae.
colonies of microorganisms and inflammatory cells.
INFECTIVE ENDOCARDITIS
of the underlying tissue, and results in bulky vegetation’s abnormal masses composed of necrotic debris,
thrombus and organisms.
» Acute endocarditis – due to a destructive infection, caused by a highly virulent organism
(Staphylococcus aureus) that attacks a previously normal valve
» Subacute endocarditis – infections by organisms of low
virulence (streptococcus viridians part of
oral flora..) colonizing a previously abnormal heart, especially deformed valves
» Both acute and subacute forms are characterized by destructive vegetation’s (abnormal tissue
growth) in the heart valves, containing fibrin , inflammatory cells and microorganisms => aortic
and mitral valves are the most common sites of infection.
» These vegetations can penetrate into the underlying myocardium to produce an abscess cavity
(ring abscess).
» Fungal endocarditis tends to form larger vegetations than bacterial endocarditis.
» Systemic emboli may occur due to the fact that damage endocardium as damage endothelium
promote thrombose formation..
» Microscopically, subacute endocarditis contains granulation tissue at the bases of the vegetation
=> may indicate a chronic process.
» Over time, fibrosis, calcification may develop.
» Cardiac abnormalities predispose to infections => rheumatic heart disease (RHD), mitral valve
prolapsed, bicuspid aortic valve, and calcific valvular stenosis.
» Host factors also increase the risk of infective endocarditis.
» Endocarditis of previously damaged and abnormal valves is usually caused by Viridians
streptococci, while endocarditis of deformed and healthy valves is caused by Streptococcus
aureus.
» Fever, fatigue, and flu-like syndrome with more sever abrapt manifestation in acute one.
» May see Splenomegaly in the subacute form of infective endocarditis.
» In the acute form => rapidly developing fever, chills, weakness and fatigue.
» In 90% of patients with left side abnormalities, murmurs are present.
» Diagnosis is made on the basis of positive blood cultures and echocardiography findings.
» Complications include glomerulonephritis, septicemia, arrhythmias, and systemic embolization.
NON-INFECTIVE ENDOCARDITIS
thrombotic small masses composed of mainly fibrin and platelets unlike infective form thes are sterileno
microorganism and nondestructive lesions.
normal heart valves.
therefore, it NBTE is also referred to as MARANTIC ENDOCARDITIS.
» Vegetation’s are sterile, small (1-5mm dimeter) thrombotic mases occur around the line of
closure of the leaflets or cusps.
» They are composed of thrombus without accompanying inflammation of valve itself
underlying malignancy (adenocarcinomas).
agents to implant.
immune complex deposition on surface may lead to valve serious deformities fibrosis resemble to
recurrent rheumatic fever .
COMPLICATIONS RELATED TO PROSTHETIC VALVES
» Mechanical valves –
Double tilting disc made of pyrolytic carbon.Have excellent durability.
Require chronic anticoagulation treatment => increased risk of hemorrhage.
Cause hemolysis due to shear stress.
» Bioprosthetic valves –
Porcine or bovine tissues, or cryopreserved human valves.
Do not require anticoagulation.
Less durable => can fail due to matrix deterioration.
Undergo some degree of stiffening after implantation => may cause stenosis.
Calcification is also common.
valve infection .
In mechanical valves, infective endocarditis usually involves the suture line and
adjacent perivalvular tissue => may cause the valve to detach (bio valve itself may be infect along
surrounding tissue).
Myocarditis. Cardiomyopathies.
Inflammation of the myocardium with resulting injury by infective agent/ the inflammatory process is
MYOCARDITIS
the cause of the myocardial injury.
» Infections – viruses most common agents (Coxsackieviruses A and B , other enteroviruses and
less common CMV) in virus case usually its more the immune respond who responsible to damage,
bacteria Lyme diseas and borrhileia burgdorferi (Corynebacterium diphtheria, Neisseria
meningococcus), Chlamydial, Rickettsia, fungi (Candida), protozoa (Trypanosoma) => Chagas
disease.
» Non-infectious causes – systemic diseases of immune origin (SLE, polymyositis).
» Macro-The heart may appear normal or dilated. On more advanced stage the ventricular wall appear
lose (flabby), and surface may show patchy pallor (paleness) and/or hemorrhage pattern.
» Micro- see edema, interstitial inflammatory infiltrate with sings of injury to myocytes. There are 4
patterns of myocarditis:
1) Lymphocytic myocarditis – the most common form lymphocyte infiltrate edema and injured
myocytes in focal areas .
2) Hypersensitivity myocarditis – interstitial and characteristic perivascular infiltrates dense with
eosinophils. Also see lymphocytes and macrophages.
3) Giant-cell myocarditis – characterized by widespread inflammatory cellular infiltrates, containing
multinucleated giant cells (fused macrophages), a more aggressive edge of lymphocytic type with
diffused there is extensive necrosis inflammation covering larger areas then lymphocytic.
4) Chagas myocarditis – the myofibers are distended by trypanosomes58, accompanied by inflammatory
infiltrate of neutrophils, lymphocytes and macrophages.
other symptoms include fatigue, dyspnea, palpitations, pain and fever.
CARDIOMYOPATHIES
(hemochromatosis), muscular dystrophies, and genetic disorders of cardiac muscle cells.
And Secondary – the heart is involved as part of a general, multi-organ disorder.
» Dilated cardiomyopathy.
» Hypertrophic cardiomyopathy.
» Restrictive cardiomyopathy
DILATED CARDIOMYOPATHY
dysfunction, usually accompanied with hypertrophy.
diseas : many cases no major underlying reson discovered and it termed as idiopathic dilated
cardiomyopathies ,About 25%-35% of the cases have a familial basis, other cases result from toxic
exposure (alcoholism), myocarditis, and pregnancy associated changes;
» Alcohol and toxic exposure – metabolites of alcohol, especially acetaldehyde, have a direct toxic
effect on myocardium.
» Genetic influences – most common is autosomal dominant inheritance, but the other forms of
inheritance can also occur => most genetic abnormalities involve the myocytic cytoskeleton
Peripartum cardiomyopathy – occurs late in gestation or in the first few weeks-months after birth =>
caused by pregnancy-associated hypertension, volume overload, nutritional deficiency.
» Iron overload e.g. hematochromatosis
Secondary as myocardial presentation part of systemic disorder common second to other
cardiovascular disease: ischemia, hypertension, valvar disease, tachycardia induced
» Can occur at any age, mainly 20-50 years of age.Presents as slowly progressive congestive heart
failure. The main defect is ineffective contraction, eventually resulting in ejection fraction of less
than 25%.
» Secondary mitral regurgitations and abnormal cardiac rhythms are common
HYPERTROPHIC CARDIOMYOPATHY
preserved, but the heart does not relax, resulting in diastolic dysfunction. ventricular outflow obstruction
come in about 1/3 of cases.
hypertrophy as adaptive respond and disorders influencing ventricular stiffness. In most cases, there is
autosomal dominant missense point mutation in one of the several genes encoding the proteins of the
sarcomere => β-myosin heavy chain gene is most commonly affected, but also myosin-binding protein
C and troponin T.
» Massive myocardial hypertrophy without ventricular dilation. The ventricular cavity loses its round
shape and is compressed into a “banana-like” shape.
» Disproportionate thickening of the septum relative to the walls of the left ventricle => asymmetrical
septal hypertrophy.
» Impaired diastolic filling => provides reduced stroke volume despite the hypertrophied LV. Also the
severing the situation is patient with outflow obstruction Systolic ejection murmur.
» Beside reduced systemic blood supply secondly, the reduced cardiac output results in pulmonary
venous pressure, causing dyspnea.
» Clinical problems include atrial fibrillation, infective endocarditis of the mitral valve, chronic heart
failure, arrhythmias and sudden death.
RESTRICTIVE CARDIOMYOPATHY
during diastole while the contractile function of the left ventricle is usually unaffected.
radiation, amyloidosis, hemochromatosis, and sarcoidosis).
firm.
Micro interstitial fibrosis may seen or In case of specific cause to the cardiomyopathy, disease-specific
features can be seen (amyloid, iron overload etc.).
# There are 2 more forms of restrictive cardiomyopathy:
1) Endomyocardial fibrosis – disease of children and young adults in tropic countries, characterized
by dense fibrosis of the ventricular endocardium and sub endocardium, extending from the apex
to the AV valves.
2) Loffler endomyocarditis – causes endocardial fibrosis with mural thrombi, but it is not
geographically restricted.
3) Amyloidosis – deposition of extracellular proteins with the predilection for forming insoluble
beta-pleated sheets. Can be a part of systemic amyloidosis, or can be restricted to specific organ.
Congenital heart diseases.
Congenital heart diseases are abnormalities of the heart or great vessels that are
CONGENTIAL HEART DISEASE
present at birth, most of which arise during weeks 3-8 of gestation when major
cardiovascular structures develop…
» In most cases (~90%) the cause of the abnormality is unknown.
» Environmental factors – congenital rubella infection, teratogens exposure
etc..
Congenital rubella syndrome (CRS) can occur in a developing fetus of a
pregnant woman who has contracted rubella, usually in the first trimester
The classic triad for congenital rubella syndrome is:[4]
Sensorineural deafness (58% of patients)
Eye abnormalities—especially retinopathy, cataract,
and microphthalmia (43% of patients)
Congenital heart disease—especially pulmonary artery stenosis and patent
ductus arteriosus (50% of patients)
» Genetic factors – familial forms of congenital heart disease, and certain
chromosomal abnormalities (trisomy’s 13, 15, 18 & 21, and Turner
syndrome).
» Several congenital heart diseases are associated with mutation in
transcription factors => TBX560, NKX2.561
» Abnormal development of neural crest cells can cause defects in the
formation of the outflow tract => caused by deletions of a segment in the
long arm of chromosome 22.
1) Malformations causing a left-to-right shunt
2) Malformations causing a right-to-left shunt.
3) Malformations causing obstruction.
LEFT-TO-RIGHT SHUNTS
# Shunts permit the flow of blood from the left heart to the right heart.most
common CHD.
pulmonary blood flow, and expose the low pressure & low resistance
pulmonary circulation to increased pressure and volume, resulting in right
ventricular hypertrophy and eventually right-sided failure , but they are NOT
associated with cyanosis as an early feature.
- Atrial septal defects: abnormal fixed opening in atrial septum not closed by the
septum secundum, so a shunt exists across from left to right.
atrium in embryo life its open as valve closed on its left side by a flap of tissue
derived from the primary septum, which acts as a one way valve that allows
right-to-left blood flow keep embryo circulation. At the time of birth, pulmonary
vascular resistance drops and systemic arterial pressure rises, causing the pressure
in the left atrium to exceed those of the right atrium, resulting in the functional
closure of foramen ovale.
1) Ostium secundum ASD – the most common (90%), occurs when septum
secundum does not enlarge sufficiently to cover the ostium secundum. Significant
large lesion induce vol. overload so right atrial and ventricular dilation, right
ventricular hypertrophy, and dilation of the pulmonary artery.
2) Ostium premium ASD – less common (5%), occurs when the septum premium
and endocardial cushion fail to fuse; associated with other abnormalities in
structures derived from the endocardial cushion (AV valves malformations cleft
valves as antr leaflet mitral valve…).
3) Sinus venosus ASD – less common (5%), located near the entrance of SVC. often
accompanied by anomalous drainage of the pulmonary veins into the right atrium
or SVC.
openings do so but with time larger openings may end with pulmonary
hypertension with increased pulmonary arterial pressures that eventually led to
reversal and right-to-left shunt, resulting in marked right ventricular hypertrophy.
wall it develops present =Normally, the left atrial pressure keeps the foramen
closed, but if right atrial pressures rise with pulmonary hypertension (as with
pulmonary embolus), the foramen may open and even allow a thrombus to go
from right to left. This is a rare entity called “paradoxical embolus”……
- ventricular septal defects
# Incomplete closure of the ventricular septum. left-to-right shunts,
# The ventricular septum is formed by the fusion of an intraventricular muscular
ridge, and a thinner membranous portion that grows from the endocardial
cushion.
septum. Most VSDs close spontaneously in childhood.
» Size and location of defects are variable.
» In defects associated with significant left-to-right shunts, the right ventricle is
hypertrophied and often dilated.
» The diameter of the pulmonary artery is increased due to increased volume
ejected by the right ventricle.
severe left-to-right shunt, complicated by pulmonary hypertension and congestive
heart failure; progressive pulmonary hypertension results in reversal of the shunt
and cyanosis
- Patent ductus arteriosus
and a left-to-right shunt develops Ductal closure is delayed in infants with
hypoxia, resulting from respiratory distress or heart disease.
pulmonary artery to the aorta => bypass the unoxygenated lungs. After brith,
ductus arteriosus constrics and becomes ligamentum arteriosum.
the aorta just distal to the origin of the left subclavian artery.In PDAs, some of
the blood flowing out of the left ventricle is directed back to the lungs => volume
overload => dilation of proximal pulmonary arteries, left atrium and ventricle =>
pulmonary hypertension => right heart hypertrophy and dilation.
murmurs; large defects can lead to Eisenmenger syndrome with cyanosis and
congestive heart failure.
RIGHT-TO-LEFT SHUNTS
due to direct introduction of poorly oxygenated blood from the right side of the heart, into the
arterial circulation.
paradoxical embolism.
- Tetralogy of Fallot
The most common cause of cyanotic congenital heart disease. Results from abnormal
division into the pulmonary trunk and aortic root.
Pulmonic stenosis results in right ventricular hypertrophy and a right-to-left shunt across a
VSD, which also has an overriding aorta
Composed of 4 features:
1) VSD-near the membranous portion of the septum.
2) Obstruction to the right ventricular outflow tract- The proximal aorta is larger than normal
with diminished pulmonary trunk, pulmonary stenosis protects the lungs from overload and
pulmonary hypertension.
3) An aorta that overrides the VSD.
4) Right ventricular hypertrophy- The heart is large and “boot shaped” due to right ventricular
hypertrophy.
- Transposition of Great Vessels
aortopulmonary septa => aorta arises from the right
ventricle, and the pulmonary trunk originates from
the left ventricle. The atrium-to-ventricle connections
are normal.
systemic and pulmonary circulations, a condition
inadequate with postnatal life. A VSD, or ASD with
PDA, is needed for extra uterine survival. There is
right-to-left shunting.
cyanosis; the forecast of neonates with TGA depends
on the degree of shunting, the magnitude of tissue
hypoxia and the ability of the right ventricle to
maintain systemic pressure.
OBSTRUCTIVE LESION
# Congenital obstruction to blood flow that
occurs at the level of the heart valves, or
within a great vessel.
stenosis, and coarctation of the aorta.
Coarctation of the aorta
# The narrowing of the aorta. Males are affected twice as much as females but It
is common in girls who have Turner syndrome..
# There are 2 forms of aortic coarctation
Infantile –
» hypoplasia of the aortic arch narrowing of the aortic segment between
the left subclavian artery and ductus arteriosus just before it
Ductus arteriosus is usually patent and is the main source of blood
delivered to distal aorta.
The right side of the heart must supply the body (distal to the
narrowing), resulting in hypertrophy of the right ventricle.
Adult
- ridge-like in folding of the aorta, just opposite to ligamentum arteriosum sharp constriction of the aorta
- The constricted segment is made up of smooth muscle and elastic fibers that are continuous with the aortic media, lined by a thickened layer of intima
-Ductus arteriosus is closed
-Proximal to the contraction, the aortic arch and its branch vessels are dilated, and athersclrosed (in older patients).
-Hypertrophy of the left ventricle
Coarctation of the aorta may occur as a solitary defect, but in most cases (>50%) it is accompanied by a bicuspid aortic valve.
Chronic obstructive lung disease - chronic bronchitis and emphysema. Small airways disease
(SAD)
Pulmonary diseases can be classified as:
OBSTRUCTIVE VS. RESTRICTIVE
» Obstructive disease – characterized by limitation of airflow, Expiratory obstruction may result
from anatomic airway narrowing (asthma), or from loss of elastic recoil (emphysema) ,Includes 4
major diseases emphysema, chronic bronchitis, bronchiectasis, and asthma.
Spirometry changes: Decreased expiratory flow rate and decreased forced vital capacity
(FVC), with increased total lung capacity= tot. Amount of air in lung .
Most important FEV/FVC < 0.8 healthy (in COPD both decrease but FEV decrease a lot
from 4L/5L to 2L/4L=0.5)
» Restrictive disease – characterized by reduced expansion of lung parenchyma, accompanied by
decreased total lung capacity
FVC is reduced, and FEV is normal or proportionally reduced so FEV/FVC- near normal!
The restrictive defect occurs in:
severe obesity, diseases of pleura, and neuromuscular
CHRONIC OBSTRUCTIVE PULMONARY DISEASES (COPD)
bronchitis and emphysema both link to smoking and manifest together usually.
Unlike asthma also
an obstructive diseas in COPD the damage lead to IRREVERSIBLE airflow obstruction in asthma
there is REVERSIBLE airflow obstruction
EMPHYSEMA
from multiple small spaces a large air filled space is formed . With the loss of elastic tissue in the
surrounding alveolar septa, radial traction on the small airways is reduced. As a result, they tend to
collapse during expiration—an important cause of chronic airflow obstruction in severe emphysema
» Centriacinar emphysema Most commonly seen as a consequence of smoking in people with no
congenital deficiency of α1-antitrypsin The lesions are more common in the upper lobes
The proximal parts of the acini, formed by respiratory bronchioles, are affected (distal part spared) =>
both emphysematous and normal airspaces exist in the same acinus In severe cases, the distal acinus
also becomes involved
» Panacinar (panlobular) Associated with deficiency of α1-antitrypsin,
The acini are uniformly enlarged from the level of the terminal bronchiole to the alveoli
Tends to occur in lower lung areas
»Distal acinar (paraseptal) emphysema The proximal portion of the acinus is normal, but the distal part is
affected The emphysema is adjacent to the pleura, near areas of fibrosis, scarring or atelectasis * Cause is
unknown. Characterized by the presence of multiple enlarged airspaces (0.5mm-2cm) => may form cyst-like
structures referred to as bullae
»Irregular emphysema Clinically asymptomatic, and the most common form of emphysema.
The acinus is irregularly involved, this condition is almost always associated with scarring, such as in healed
inflammatory diseases.
Protease/antiprotease imbalance – always inhale some small particles (in-between 2-5 microns
less than 2 filter to lymph more than 5 cough out ) which stimulate inflammation
Exposure to toxic substances such as tobacco smoke and inhaled pollutants induce inflammation with
accumulation of neutrophils, macrophage & lymphocytes.
Neutrophils, the main source of cellular proteases, are found in peripheral capillaries (including those of the lungs), and gain access to the alveolar spaces. Release Elastase.
Exasseiv inflammation or lack of protease inhibitors result in emphysema:
- Exposure to toxic substances such as tobacco smoke and inhaled pollutants induce
inflammation with accumulation of neutrophils, macrophage & lymphocytes.
Smoking promotes accumulation of leukocytes, such as neutrophils and macrophages, in the alveoli,
and enhances the elastase activity of macrophages, which is NOT inhibited by α1-antitrypsin
- deficiency of α1-antitrypsin a major inhibitor of proteases (mainly elastase) encoded by
codominant genes The proteinase inhibitor allele (Pi) on chromosome 14- the most common
healthy allele is PiM , mutation as PiZ allele result in misfolding of it ; patients homozygous
to PiZ allele will present panacinar emphysema and may also manifest with liver cirrhosis
cause of accumulation of misfolded alpha 1 antitrypsin in the ER of hepatocytes ;
heterozygous patients are asymptomatic with lower levels of alpha 1 antitrypsin in blood ,
but upon smoking is a great risk for developing emphysema
- Oxidant-antioxidant imbalance – the lung contains antioxidants that keep oxidative damage
to a minimum => smoking increases the amount of free radicals, which deplete these
mechanisms; activated neutrophils also add oxygen species to the alveoli.
In general
- In emphysema there is loss of not only epithelial and endothelial cells but also mesenchymal cells, leading to
lack of extracellular matrix, the scaffolding upon which epithelial cells would have grown. Thus, emphysema
can be thought of as resulting from insufficient wound repair. By contrast, patients with fibrosing lung
diseases have excessive myofibroblastic or fibroblastic response to injury, leading to unchecked scarring.
enhanced volume, which often obscure the heart.Cantriacinar emphysema – lungs appear in deeper
pink, with less volume than in panacinar emphysema.
Micro -> Histologic examination reveals
destruction of alveolar walls without fibrosis, leading to enlarged air spaces.
lipes) weight loss, reduced FEV1, FEV1/FVC is reduced.
# Pink Puffer = Because of prominent dyspnea and adequate oxygenation of hemoglobin, these patients
sometimes are called “pink puffers.”
ASTHMA
respond following exposure to an allergen to which the person has been previously sensitized.
breathlessness, chest tightness, and cough. The hallmarks of the disease are:
Chronic bronchial
inflammation with eosinophils, Bronchial smooth muscle cell hypertrophy and hyperreactivity,
Increased mucus secretion.
1) Atopic (extrinsic) asthma Constitute ~70% of cases Patient has Genetic predisposition to type
I hypersensitivity (atopy) show family history of asthmatic or related hypersensitivity 1
reactions, clinically showed with Associated with other allergic diseases such as allergic rhinitis
and eczema. There is evidence for extrinsic allergen sensitization you can do skin test show
wheal and fler reaction immediate after exposure to this specific allergen.
2) Non-atopic (intrinsic) asthma- triggers are less clear there is negative skin test to common
inhalant allergens and normal serum concentrations of IgE. Caused by viral infections of the
respiratory tract /inhaled air pollutants. Characterized by increased bronchoconstriction response
due to increased airways reactivity Suspect that Viral inflammation of the respiratory mucosa
lowers the threshold of the sub epithelial vagal receptors to irritants.
3) Drug Induced Asthma- Several pharmacologic agents provoke asthma, aspirin being the most
striking example.Mechanism unknown. Maybe due to inhibition of COX pathway without
harming the lipoxygenase pathway shifting the balance toward leukotrines production that
causes bronchial spasm.
4) Occupational Asthma- Asthma attacks usually develop after repeated exposure to the inciting
antigen(s)
of asthma.Caused by IgE (type I hypersensitivity) and TH2-mediated70 immune responses to
environmental antigens (dust, pollens, animal hair, and food).
First exposure to allergen => TH2 cells activation => release of IL-4 & IL-5 => eosinophils recruitment
AND production of IgE (by plasma cells) => sensitization of mast cells (type I hypersensitivity)
reexposure to allergen => immediate reaction is triggered by sensitized mast cells => early reaction see
histamine realis increase primability of post capillary venoules and vasodilation of arteriole also realis
leukotrienes induce bronchoconstriction and vascular primability so initial see constriction and edema
late phase reaction initiated by recruited leukocytes that induce release of mediators from these cells,
and lead to epithelial damage e.g. eosinophils realis major basic protein damage epithel and maintain
bronchoconstriction Major basic protein induces mast cell and basophil degranulation, and is
implicated in peripheral nerve remodellin
# Macro
# Lungs are overdistended because of over inflation.
# Small area of atelectasis
# Bronchi and bronchioles are occluded by thick mucous plugs
# Shed epithelium = Curschmann spirals
eosinophil proteins)
# Air way Remodeling1)
Thickening of airway wall
2) Sub-basement membrane fibrosis
3) Increased vascularity in submucosa
4) An increase in size of the submucosal glands and goblet
Cell metaplasia of the airway epithelium
5) Hypertrophy and/or hyperplasia of the bronchial muscle
expiration.
The victim labors to get air into the lungs and then cannot get it out, so that there is
progressive hyperinflation of the lungs with air trapped distal to the bronchi, which are constricted and
filled with mucus and debris.
- Therapy, usually bronchodilators & corticosteroids.
CHRONIC BRONCHITIS
as a persistent productive cough for at least 3 consecutive months in at least 2
consecutive years.
» Simple chronic bronchitis – most common type, cough raises mucoid
sputum, but NO airway obstruction In the early stages of the disease.
» Chronic asthmatic bronchitis – hyper responsive airways with
bronchospasms => asthma episodes.
» Chronic obstructive bronchitis – heavy smokers that develop outflow
obstruction, usually with associated emphysema.
» Distinctive feature is hypersecretion of mucous.
Irritation (smoking, air pollutants) => hypertrophy & hyperplasia of
bronchial mucous glands, resulting in hyper secretion of mucous =>
increase in mucin-secreting goblet cells of smaller bronchi and
bronchioles
» Irritants also cause inflammation (cytotoxic T cells, macrophages and
neutrophils) *no Eosinophiles
» Whereas the defining feature of chronic bronchitis (mucus hypersecretion)
is primarily a reflection of large bronchial involvement, the morphologic
basis of airflow obstruction in chronic bronchitis is more peripheral and
results from (1) small airway disease, induced by goblet cell metaplasia
with mucous plugging of the bronchiolar lumen, inflammation, and
bronchiolar wall fibrosis, and (2) coexistent emphysema.
» Microbial infection often is present but has a 2ndry role, chiefly by
maintaining the inflammation and exacerbating symptoms.
» Macro = Mucosal lining is hyperemic and swollen by edema, covered by
mucinous or mucopurulent secretion.
» Micro = Enlargement of mucous secreting glands in the trachea and large
bronchi.
» Inflammatory infiltration of mononuclear cells
characterized by goblet cell metaplasia, fibrosis, inflammation, and mucous
plugging.
consequence of fibrosis (bronchiolitis obliterans). It is the submucosal fibrosis
that leads to luminal narrowing and airway obstruction. Changes of
emphysema often co-exist.
# Early stage = No obstruction, only productive cough, no ventilation
problems.
“Blue Bloaters”.
BRONCHIECTASIS
caused by loss of muscle and elastic tissue due to chronic necrotizing
infections. It can be congenital (children with cystic fibrosis, Kartagener
syndrome, immunodeficiency states) or acquired (post-infectious, systemic
autoimmune diseases, bronchial obstruction by foreign bodies or tumors),
most commonly located in the lower lobes, uni- or bilateral. Why obstructive?
Dilated airway impairs laminar air follow instead tubular flow and trapping of
air more force needed for expiration.
- Tumors/foreign bodies/ plugs of mucous. With these conditions, the
bronchiectasis is localized to the obstructed lung segment. - CF (causing wide spread bronchiectasis) due to secretion of abnormally viscid
mucous which predisposes to infections of the bronchia tree. - Immunodeficiency states => due to repeated bacterial infections.
- Kartagener syndrome => an autosomal recessive disorder causing immotile cilia
(dynein protein) and impaired mucociliary clearance infections. (The syndrome
also affects the mobility of the spermatozoa causing sterility in men, situs
inversus and sinusitis)./ Young syndrome: infertility caused by azoospermia, but
without ultrastructural ciliary abnormalities - Necrotizing or suppurative pneumonia (esp. staph. Aureus & spp. Klebsiella).
May predispose patient to later bronchiectasis development e.g. post tuberculosis
bronchiectasis
persistent infection => direct demage to wall or Obstruction => impairs the
clearance of the airways => secondary infection
The tissue is also damaged in part by the host response of neutrophilic proteases,
inflammatory cytokines, nitric oxide This results in damage to the muscular and
elastic components of the bronchial wall.
Additionally, peribronchial alveolar
tissue may be damaged, resulting in diffuse peribronchial fibrosis.
The result is abnormal bronchial dilatation with bronchial wall destruction and
transmural inflammation. The most important functional finding of altered airway
anatomy is severely impaired clearance of secretions from the bronchial tree.
Impaired clearance of secretions causes colonization and infection with
pathogenic organisms, The result is further bronchial damage and a vicious cycle
of bronchial damage.
involving a lobe, segment of the lung. Far less commonly, it may be a diffuse
process involving both lungs; these cases most often occur in association with
systemic illnesses, such as cystic fibrosis (CF) bronchiectasis.
Macroscopically,
the lung has an irregular surface in the affected area. On cut surface, there are
multiple cavities / cystic formations (dilated bronchi), round or oval, of varying
sizes, with a thick, fibrous, gray-whitish wall and muco-purulent content,
associated with changes of the adjacent lung parenchyma (areas of condensation
or fibrosis). With progression, the lung parenchyma can be fully replaced by
dysfunctional bronchial dilatation.
MICRO:
» Chronic inflammation, ulceration of bronchial wall, ossification of bronchial
cartilage.
» Intense inflammatory exudate within the walls of the bronchi and bronchioles and
shedding of the lining epithelium cause extensive areas of ulceration.
» Usually the injury is so severe that the epithelium lining the bronchial tree cannot
regenerate and after healing abnormal dilation and scarring persists as Fibrosis of
the bronchial and bronchiolar walls and peribronchial fibrosis develop in more
chronic cases.
sputum, which may contain blood.Hypoxemia, hypercapnia.
Chronic complications => pulmonary hypertension or cor pulmonale (though
rare).
Bronchial asthma.
Intermittent and reversible airway obstruction result from bronchoconstriction triggered by hyperactive
ASTHMA
respond following exposure to an allergen to which the person has been previously sensitized.
breathlessness, chest tightness, and cough. The hallmarks of the disease are: Chronic bronchial
inflammation with eosinophils, Bronchial smooth muscle cell hypertrophy and hyperreactivity,
Increased mucus secretion.
1) Atopic (extrinsic) asthma Constitute ~70% of cases Patient has Genetic predisposition to type
I hypersensitivity (atopy) show family history of asthmatic or related hypersensitivity 1
reactions, clinically showed with Associated with other allergic diseases such as allergic rhinitis
and eczema. There is evidence for extrinsic allergen sensitization you can do skin test show
wheal and fler reaction immediate after exposure to this specific allergen.
2) Non-atopic (intrinsic) asthma- triggers are less clear there is negative skin test to common
inhalant allergens and normal serum concentrations of IgE.
Caused by viral infections of the
respiratory tract /inhaled air pollutants. Characterized by increased bronchoconstriction response
due to increased airways reactivity Suspect that Viral inflammation of the respiratory mucosa
lowers the threshold of the sub epithelial vagal receptors to irritants.
3) Drug Induced Asthma- Several pharmacologic agents provoke asthma, aspirin being the most
striking example.Mechanism unknown. Maybe due to inhibition of COX pathway without
harming the lipoxygenase pathway shifting the balance toward leukotrines production that
causes bronchial spasm.
4) Occupational Asthma- Asthma attacks usually develop after repeated exposure to the inciting
antigen(s).
of asthma.Caused by IgE (type I hypersensitivity) and TH2-mediated70 immune responses to
environmental antigens (dust, pollens, animal hair, and food).
First exposure to allergen => TH2 cells activation => release of IL-4 & IL-5 => eosinophils recruitment
AND production of IgE (by plasma cells) => sensitization of mast cells (type I hypersensitivity)
reexposure to allergen => immediate reaction is triggered by sensitized mast cells => early reaction see
histamine realis increase primability of post capillary venoules and vasodilation of arteriole also realis
leukotrienes induce bronchoconstriction and vascular primability so initial see constriction and edema
late phase reaction initiated by recruited leukocytes that induce release of mediators from these cells,
and lead to epithelial damage e.g. eosinophils realis major basic protein damage epithel and maintain
bronchoconstriction Major basic protein induces mast cell and basophil degranulation, and is
implicated in peripheral nerve remodellin
# Macro
# Lungs are overdistended because of over inflation.
# Small area of atelectasis
# Bronchi and bronchioles are occluded by thick mucous plugs
# Shed epithelium = Curschmann spirals
# Numerous eosinophils and Charcot- Leyden crystals (collections of crystalloids made up of
eosinophil proteins)
# Air way Remodeling1)
Thickening of airway wall
2) Sub-basement membrane fibrosis
3) Increased vascularity in submucosa
4) An increase in size of the submucosal glands and goblet
Cell metaplasia of the airway epithelium
5) Hypertrophy and/or hyperplasia of the bronchial muscle
expiration. The victim labors to get air into the lungs and then cannot get it out, so that there is
progressive hyperinflation of the lungs with air trapped distal to the bronchi, which are constricted and
filled with mucus and debris.
- Therapy, usually bronchodilators & corticosteroids.
Adult respiratory distress syndrome (ARDS). Atelectasis.
A clinical syndrome caused by diffuse alveolar capillaries and epithelium
ACUTE RESPIRATORY DISTRESS SYNDROME
damage, resulting in Rapid onset of severe, life threatening respiratory
insufficiency, cyanosis, severe arterial hypoxemia Deficient oxygenation of
the blood , usually with severe pulmonary edema .
(causing physical trauma).also : sepsis or shock e.g. Burns, diffuse pulmonary
infections (viral, mycoplasma, Pneumocystis, tuberculosis), mechanical
trauma, inhaled irritants chemical injury
» due to diffuse widespread damage to alveolar barrier73 Damage of the
capillary endothelium and alveolar epithelium lead to Increased capillary
permeability which result in accumulation of protein-rich fluid inside the
alveoli alveolar odema, loss of diffusion capacity, and widespread surfactant
abnormalities (due to damage to pneumovytes type II).
» thereby producing diffuse alveolar damage, with release of pro-inflammatory
cytokines, such as realis of IL-8, IL-1 and TNF by pulmonary macrophages
=> recruitment of neutrophils (IL-8), and activation of endothelium (IL-1,
TNF) => neutrophils release toxic mediators, such as reactive oxygen
species and proteases . Extensive free radical production overwhelms
endogenous anti-oxidants and causes oxidative cell damage. => Damage to
alveolar epithelium
» In the acute phase
The lungs are dark red, firm, airless and heavy
Capillary congestion, necrosis of alveolar epithelium, interstitial and
intra-alveolar edema
Neutrophils in capillaries (especially in sepsis)
Hyaline membranes line the distended alveolar ducts
» In the organized phase
Increased proliferation of type II pneumocytes => an attempt to
regenerate alveolar lining
Organization of fibrin exudates that result in intra-alveolar fibrosis
(“honey comb lung”)
Thickening of alveolar septa
especially if related to sepsis and development of multiorgan failure.
ATELECTASIS
# The term atelectasis is derived from the Greek words ateles and ektasis, which
mean incomplete expansion. The loss of lung volume caused by inadequate
expansion of airspaces or collapse of previously inflated lung.
# Results in shunting of inadequately oxygenated blood from pulmonary arteries
into the pulmonary veins, leading to ventilation-perfusion imbalance and
hypoxia.
» Resorption atelectasis – occurs when obstruction prevents air from
reaching the distal airways, most commonly by mucous or mucopurulent
plug => the level of obstruction determines the extent of the collapse (an
entire lung, a complete lobe or some segments); the air already present is
gradually absorbed and alveolar collapse follows.
» Compression atelectasis – associated with accumulations of fluids, blood
or air (pneumothorax) within the pleural cavity, which mechanically
collapse the adjacent lung.
» Contraction atelectasis – occurs when either local or generalized fibrotic
changes in the lung or pleura prevents the expansion and caus increase
elastic recoil during expiration.
Respiratory distress syndrome of the newborn. Sudden infant death syndrome.
A syndrome of premature infants caused by developmental insufficiency of
RESPIRATORY DISTRESS SYNDROME OF THE NEWBORN
surfactant production and structural immaturity of the lungs.
decreases with advancing gestational age.
section.
# The fundamental defect is the inability of the immature lung to synthesize
surfactant => in a healthy baby, surfactant is synthesized by type II
pneumocytes, and with first breath rapidly coats the surface of alveoli to
reduce surface tension.
requires greater effort to open alveoli => the infant rapidly tires, and
atelectasis develops.
leading to epithelial and endothelial
damage, and resulting in the
formation of hyaline membranes.
hormones => corticosteroids
stimulate the formation of surfactant
lipids, while high levels of insulin
suppress synthesis by counteracting
the effects of steroids.
» The lungs are of normal size, but
are heavy and relatively airless.
» Have a mottled purple color.
» The alveoli are poorly developed and collapsed.
» If the infant dies within a few hours => only necrotic cellular debris are
present in bronchioles.
» If the infant dies after a few days => Neonatal Respiratory Distress
Syndrome - NRDS (Hyaline membrane disease) is characterized by
collapsed alveoli alternating with hyperaerated alveoli, vascular
congestion and hyaline membranes (resulted from fibrin, cellular debris).
Hyaline membranes appear like an eosinophilic, amorphous material,
lining or filling the alveolar spaces and blocking the gases exchange.
Hyaline membrane is NEVER seen in stillborns or infants who die within
a few hours of birth.
weight of the infant; control of RDS focuses on prevention, either by delaying
labor until the fetal lung matures, or by inducing maturation of the lung.
oxygen for prolonged periods, however, is associated with two wellknown
complications: retrolental fibroplasia (also called retinopathy of
prematurity) in the eyes and bronchopulmonary dysplasia.
SUDDEN INFANT
DEATH SYNDROME
# Definition –
Sudden
unexpected
infant deaths in infants younger than 12 months of age that occur suddenly,
unexpectedly, and without obvious cause after a thorough investigation that
includes complete autopsy, examination of the death scene, and review of
clinical history.
# Pathogenesis – SIDS is a multifactorial condition of overlapping variables:
» A vulnerable infant – intrinsic developmental abnormalities in
cardiorespiratory control. Regions of the brain stem, particularly the
arcuate nucleus located in the ventral medullary surface, play a critical
role in the body’s arousal response to noxious stimuli such as hypercarbia,
hypoxia, and thermal stress encountered during sleep. In addition, these
areas regulate breathing, heart rate, and body temperature.
» A critical period in the development of homeostatic control
mechanisms– these factors may be attributed to the parents (young
mother, smoking during pregnancy, short intergestational intervals), or
to the infant (brain stem abnormalities, prematurity).
» An exogenous stressor – factors from the environment (prone sleep
position decres responsiveness to noxius stimultion, sleeping on soft
surface, hyperthermia).
# Morphology –
» Multiple petechiae present on the thymus, visceral and parietal pleura, and
epicardium.
» Lungs are congested Vascular engorgement (filled with blood), with or
without pulmonary edema.
» Hypoplasia of the arcuate nucleus.
Summary Sudden Infant death syndrome
SIDS is a disorder of unknown cause, defined as the sudden death of an infant younger than 1 year of age that remains unexplained after a thorough case investigation including performance of an autopsy. Most sids deaths occur between the ages of 2 anc 4 months.
The most likely basis for sids is a delayed development in arousal reflexes and cardiorespiratory control.
Numerous risk factors have been proposed, of which the prone sleeping position is best recognized, hence the success of the back to sleep program in reducing incidence of sids
Chronic restrictive lung diseases 1: idiopathic pulmonary fibrosis and interstitial pneumonias.
Smoking related interstitial lung diseases. Langerhans cell histiocytosis
A group of disorders characterized by involvement of the interstitium of the alveolar walls. Although
Topic not enough
CHRONIC RESTRICTIVE LUNG DISEASES (chronic interstitial)
may raise from chest wall abnormalities restrict breathing obesity ankylosing spongiusum –not a lung
disease but obstructive… (Pulmonary interstitium pulmonary interstitium is composed of the
basement membrane of the endothelial and epithelial cells, collagen fibers, elastic tissue, fibroblasts, a
few mast cells, and occasional mononuclear cells)
lungs since they are stiff more effort during breathing (dyspnea).
See reduced forced vital capacity (FVC-air blow out after full inhaltion~5L)and normal ratio of
FEV/FVC- as FEV is amount of air out in 1st min of forced expiration ~4,eventhow FVC is down to ~4
the FEV stays at ~3.5 hence ratio maintaind how come?
1st cuz no harm to airway problem in restrictive diseas is filling the lung not expiration as obstructive
so FVC down and FEV normal
2nd interstitial fibrosis increase recoil so expiration more easly
ratio, leading to hypoxia.
» Alveolitis – accumulation of inflammatory infiltrate within the alveolar walls and spaces.
» Persistent injurious agent leads to cellular interactions (lymphocytes, macrophages, neutrophils)
that result in parenchymal injury, causing proliferation of fibroblasts and interstitial fibrosis.
» Macrophages are the main promoters of interstitial fibrosis:
Activated macrophages => secretion of IL-8, and soluble mediators (proteases, oxidants) =>
recruitment and activation of neutrophils (IL-8) => epithelial injury and degradation of c.
tissue
! Macrophages also secrete FGF, TGF-β, and PDGF => attract fibroblasts and
stimulate their proliferation.
IDIOPATHIC PULMONARY FIBROSIS (fibrosing disease)
#A pulmonary disorder of unknown cause characterized by diffuse fibrosis of the lung interstitium, chronic
progressive disease may results in severe hypoxemia and death.
by some unidentified agent, TGF-β1 is released from injured type I pneumocytes and induces
transformation of fibroblasts into myofibroblasts leading to excessive and continuing deposition of
collagen and ECM.
» MACRO = Pleural surface has the appearance of cobblestone.Cut surface shows fibrosis. (white rubbery
area). Change affecting predominantly sub pleural regions peripheral region and lower lung zones the
pleural surface shows a cobblestone appearance due to the retraction of interlobular septa-associated par
septal scarring
MICRO = histomorphology of Usual interstitial pneumonia (UPI) ,refers to a morphologic entity defined
by a combination of
(1) Patchy interstitial fibrosis- with alternating areas of normal lung, very in intensity more pronounced
subpleural region
(2) scattered fibroblastic foci - foci comprises mainly dense eosinophilic collagen deposition In the
background fibroblasts and myofibroblasts are arranged in a linear fashion within matrix, over time
become more collagenous & less cellular.
(3) Architectural alteration due to chronic scarring or honeycomb change- dense fibrosis causes the
collapse of alveoli and formation of cystic spaces lines with hyperplastic type II pneumocytes, or
respiratory epithelium => HONEYCOMB FIBROSIS (Honeycomb change is defined by cystically
dilated airspaces frequently lined by columnar respiratory type epithelium in scarred fibrotic lung tissue)
and peripheral edema may develop in later stages.
Chronic restrictive lung diseases 2: Sarcoidosis. Pulmonary eosinophilia. Pneumoconioses.
A multisystem disease of unknown cause characterized by non-caseating granulomas in many tissues
SARCOIDOSIS (granulomatous disease)
and organs. Hilar nodes and lung involvement (leading to restrictive disease) are the most common
locations.
salivary gland involvement and SS like manifest…
one of the few pulmonary diseases with higher prevalence in NON-SMOKERS.
the development of a cell-mediated response to an unidentified antigen. The process is driven by CD4+
helper T cells. These abnormalities include:
» Intra-alveolar and interstitial accumulation of TH1 cells.
» Increase in TH1 derived cytokines => IL-2 resulting in T cell expansion, and IFN-γ resulting in
macrophages activation.
» Increase in the level of cytokines IL-8, TNF, macrophage inflammatory protein 1α =>
responsible for recruitment of additional T cells and monocytes => contribute to the formation of
granulomas.
» Polyclonal hypergammaglobulinemia.
» The role of genetic factors is suggested by familial and racial clustering of cases and association
with certain human leukocyte antigen (HLA) genotypes.
» NON-CASEATING granulomas => a compact collection of epithelioid cells and giant cells no
necrosis in granuloma center surrounded by an outer zone of T helper cells. granulomas are
found mainly in interstitium of lung
Peripheral to the granuloma => a thin layer of fibroblasts, which over time proliferates and
deposits collagen that replaces the entire granuloma with scar tissue. The granulomas eventually
are replaced by diffuse interstitial fibrosis, resulting in a so-called honeycomb lung.
» The granulomas may also contain:
1) Schauman bodies – laminated concretions composed of calcium and proteins.
2) Asteroid bodies – stellate inclusions enclosed within giant cells
» Enlargement of hilar and paratracheal lymph nodes. unlike in tuberculosis, lymph nodes in
sarcoidosis are “nonmatted” (no adherent) and do not ulcerate.
» Skin lesions => erythema nodosum75.
» Combined uveoparotid (uvea of eye + parotid) involvement is designated Mikulicz syndrome.
» Involvement of the eye and lacrimal glands may occur, as well as spleen involvement
(appearance of granulomas in the spleen & splenomegaly), and bone involvement (microscopic
granulomatous lesions).
» Granulomas in the liver are seen with no hepatomegaly or liver dysfunction.
PNEUMOCONIOSIS (fibrosing restrictive disease)
particles as mineral dusts, organic or inorganic particles.
» The reaction depends on the size and reactivity of the particles.For
example: smaller particles can reach distal airways and precipitate there.
Coal dust must be deposited in large amounts in order to cause lung
disease; silica and asbestos are more reactive, resulting in fibrotic
reactions in lower amounts.
» Fibrosis is mediated by alveolar macrophages the particles are
phagocytosed by alveolar macrophages (Key element in the initiation of
the injury & fibrosis) and trigger the release of mediators of inflammation
and fibroblast proliferation (TGF beta).
asbestos => nearly always due to exposure in the work place-pneumonioses is
an chronic restrictive diseas need prolonged exposure to develop.
COAL WORKER’S PNEUMOCONIOSIS
Coal partical upon smoking /coal mind worker….
- Almost everyone has more mild exposure to coal dust in air pollution expressed as
anthracosis and kinocyte = Inhaled carbon pigment is engulfed by alveolar or
interstitial macrophages, which then accumulate in the connective tissue along the
lymphatics, including the pleural lymphatics, or in lymph nodes. - Simple coal worker’s pneumoconiosis (CWP) accumulations of macrophages
occur with little to no pulmonary dysfunction. CWP shows as many centers of
anthracosis and fibrosis scattered along lung dominantly in upper regions, may
Progress into centrilobular emphysema impair normal functioning of lung.
Characterized by coal macules and the larger coal nodule.
- Coal macules = Consist of dust laden macrophage.
- Dust Nodule = Macules + small amount of Collagen fibers.
- Complicated CWP or progressive massive fibrosis (PMF)= in which fibrosis is
extensive and lung function is compromised, requires many years and more massive
exposure to develop, Extensive parts of lung tissue Appear as black scars .
Once smoking-related risk has been taken into account, there is no increased
frequency of lung carcinoma in coal miners, a feature that distinguishes CWP from
both silica and asbestos exposures.
SILICOSIS
Inhalation of silica, mostly in occupational settings as sandblasters and silica
miners ->
After inhalation the particles interact with epithelial cells and macrophages
-> Ingested silica particles cause activation and release of mediators by pulmonary
macrophages(more silica impairs the phagolysosome formation and put individual
susceptible to TB)
Morphology:
- Silicotic nodules -> (early stage). Tiny, discrete palt-to-blackened nodules in the
upper zone of the lung. - Micro -> concentrically arranged hyalinized collagen fibers surrounding an
amorphous center. - As the disease progresses, the individual nodules may coalesce into hard,
collagenous scars, with eventual progression to PMF. - Honeycomb pattern may develop
ASBESTOSIS AND ASBESTOS-RELATED DISEASES
macrophages. See chronic exposure in plumbers construction workers and
shipyard workers
1) Diffused interstitial pulmonary fibrosis as UIP with asbestos bodies a long
golden brown fibers with associated iron originated in macrophages tried
to eat it..
2) Localized fibrous Pleural plaques: well circumscribed plaques of dense
collagen, do not contain asbestos bodies but rare if no asbestos history;
may induce pleural effusions, or diffuse fibrosis in the pleura (rare).
3) Pleural effusions.- as Visceral pleura becomes fibrotic, may bind lung to
chest wall
4) Lung carcinoma and mesotheliomas- Asbestos also is oncogenic
5) Bronchogenic or Laryngeal carcinoma.
# Pathogenesis – Similar to other pneumoconiosis Initial injury is at bifurcations of
small airways and ducts; macrophages ingest fibers, release chemotactic factors
and fibrogenic mediators, causing interstitial fibrosis .Begins around respiratory
bronchioles and alveolar ducts extends distally - in lower lobes and subpleurally
(in contrast to coal workers’ and silicosis) progresses to middle and upper lobes,
eventually may causes honeycomb
» Diffuse pulmonary interstitial fibrosis.
» Asbestos bodies => golden-brown, beaded rods with translucent center,
consist of asbestos fibers coated with iron-containing proteinaceous
material; arise when macrophages attempt to phagocytose asbestos.
» Begins in the lower lobes and subpleurally, unlike CWP and silicosis.
» Contraction of fibrous tissue creates enlarged spaces enclosed within thick
fibrous walls => HONEYCOMB LUNG.
» Pleural plaques of collagen appear on the parietal pleura, and are the most
common manifestation => they DO NOT contain asbestos bodies.
diseases
BERYLLIOSIS
» Berylliosis, or chronic beryllium disease (CBD), is a hypersensitivity
granulomatous diseas caused by exposure to beryllium and its
compounds. Such risk for air/space industry workers or beryllium miners
or manufacturing of fluorescent light bulbs (which used to contain
beryllium compounds in their internal phosphor coating).
» With single or prolonged exposure by inhalation, the lungs become
hypersensitive to beryllium causing the development of Non-caseating
granulomas. The key to the pathogenesis of chronic beryllium disease
(CBD) is a delayed-type hypersensitivity reaction in which beryllium
most likely functions as a hapten antigen, stimulating local proliferation
and accumulation in the lung of beryllium-specific T cells.
» Beryllosis is characterized by non caseating granulomas mainly in lung
and hilar nodes but also in other organs It is distinguished from
sarcoidosis by history of exposure and syntisition to brilium .
» Link to incrased risk for lung cancer
» Ultimately, this process leads to restrictive lung disease.
» Patients experience cough and shortness of breath. Other symptoms
include chest pain, joint aches, weight loss and fever.
» Rarely, one can get granulomas in other organs including the liver.
» The onset of symptoms can range from weeks up to tens of years from the
initial exposure. In some individuals a single exposure can cause
berylliosis.
Pulmonary embolism. Pulmonary infarction. Bronchiectasis.
In the vast majority of cases the emboli is an thromboembolism that originate from the deep veins of
PULMONARY THROMBOEMBOLISM
lower limb (above the knee level) rear option is for paradoxical embolism from systemic circulation.
» Prolonged bed rest.
» Orthopedic surgery of the knee and hip./injury to endothelium
» Primary disorders of hypercoagulability.
# Most events are clinically silent~80% -The lung has a dual blood supply (pulmonary arteries AND the
bronchial arteries), so if normal bronchial circulation and adequate perfusion are maintained, the decrease
in blood flow will not result in necrosis.
Second, mostly it’s an small emboli who is self-resolving (organization/fibrinolysis) and don’t have
major impact on blood supply
infarction. For clinical symptom patents is one who already suffer from cardiopulmonary diseas and
occlusion of large to medium size vessel is involved:
» Large Emboli = in main pulmonary artery, it’s major branches or in it’s bifurcation (= Saddle embolus)
= Occlusion of a major vessel leads to increase in pulmonary artery pressure, diminished cardiac output,
right-sided heart failure (cor pulmonale), and even sudden death upon acute increase in pulmo.
Pressure sudden collapse of circulation.
» Small Emboli + compromised cardiovascular status (no dual supply), as may occur with congestive left
side heart failure, infarction results.
» Perfusion of lung areas that have become atelectasis:
- Ischemia = surfactant production decreases = alveolar collapse. Blood flow redirected to areas with more
oxygen perfusion.
More Decreased cardiac output results in widening of the difference in the arterialvenous
oxygen saturation.
» What is embolization? Intravascular solid, liquid or gaseous material that is carried by the blood stream
away from sait of origin Causes obstruction of an b.v. clinically present with effected organ.
HEMORRHAGIC PULMONARY INFARCTION
» Hemorrhagic infarct of the lung- is an area of ischemic necrosis produced by b.v. obstruction on a
background of passive congestion of lung from dual blood supply.
» Infarction, when b.v. occlusion leading to ischemia to tissue ending in necrosis = in lung area wedge
shape, with their base toward the pleura & Blocked vessel usually found in the apex.
- The hallmark of fresh infarcts is coagulative necrosis of the lung parenchyma and hemorrhage
- Lysis of RBC = infarct pales = Hemosiderin produced becoming red-brown.
- Scarring -> fibrous replacement = grey-white.
Histologically In infarct area, alveolar walls, vascular walls and bronchioles are necrotic.
They appear eosinophilic (pink), homogenous, lacking the nuclei, but keep their shapes “- coagulative necrosis.
Alveolar lumens from infarcted area are filled by red blood cells -hemorrhagic infarct (red).”
hemoptysis, anemia and diffuse pulmonary infiltration.
GOODPASTURE SYNDROME
interstitial pneumonitis => both are caused by antibodies against part of collagen IV.
» Diffuse alveolar hemorrhage.
Micro: focal necrosis of alveolar walls associated with intra-alveolar hemorrhage, fibrous
thickening of septa, and hypertrophy of septal lining cells.
» IgG antibodies => present linear pattern of deposition in immunofluorescence.
IDIOPATHIC PULMONARY HEMOSIDEROSIS
Goodpasture syndrome, but NO renal involvement or circulating anti-GBM antibodies.
remissions.
PULMONARY ANGIITIS AND GRANULOMATOSIS (Wegner granulomatosis)
necrotizing/granulomatous vasculitis (affecting small to medium blood vessels), and focal necrotizing
glomerulonephritis.
ulcerative lesions of the nose, palate and pharynx.
Bacterial pneumonias. Lung abscess.
Pneumonia can be very broadly defined as any infection in the lung. Development of such as infection
(Check topic in diff note again)
is due to impairment of normal defense mechanisms or lowered host resistance
clearance (mucociliary action) and alveolar clearance (alveolar macrophages) Impairment is due to
primary or acquired immunosuppression, suppression of cough reflex (drugs, virus, coma, anesthesia),
injury to mucociliary apparatus (smoking, virus, Kartegeners syndrome), injury to macrophages
(tobacco, alcohol, anoxia), pulmonary congestion /
edema or accumulation of secretions (cystic fibrosis)
Note: viral pneumonia predisposes to bacterial pneumonia
1) Bronchopneumonia – (affects bronchioles and adjacent alveoli) patchy distribution of inflammation
around bronchioles often raise multifocal and bilateral- more than one lobe => results from initial
infection of bronchioles that extended into the alveoli.
2) Lobar pneumonia – the inflammation involve full segment are homogenously filled with exudates that
can be visualized as segmental or lobar consolidation
Consolidation: exudative solidification of lung=>
main causative agent is Streptococcus pneumoniae
Classic involve entire lobe with 4 gross phases of lobar pneumonia nowadays less seen thanks to
AB treatment options Lobar pneumonia:
Initially congestion edema heavy red lung with bacteria and few neutrophils;
Then red hepatization (grossly resembles liver harder consistency) with massive congestion,
neutrophils, fibrin in alveolar space;
Then gray hepatization with fibrinopurulent exudate in alveoli RBC got lysed;
Then resolution with resorption of exudate exudate enzyme digested debris cleaned by MQ
/cough out/reorganize by fibroblasts
3) Atypical interstitial pattern
BRONCHOPNEUMONIA
Staphylococcus aureus, Klebsiella, E. coli and Pseudomonas.
» Bronchopneumonia affects one or more lobes, being frequently bilateral and basal. Macroscopically,
one can identify multiple foci of condensation (1 - 3 cm diameter), white-yellowish, imprecisely
circumscribed, centered by bronchiole, separated by normal lung parenchyma Pleural involvement is
less common than in lobar pneumonia. . in severe cases usually seen In children, it has a tendency to
confluence, resulting in large condensation area (pseudo lobar pneumonia)
» Microscopy: foci of inflammatory condensation centered by a bronchiole with acute bronchiolitis
(suppurative exudate rich in neutrophils in the lumen, foci of ulceration of the epithelium and parietal
inflammation).
The alveolar lumens surrounding the bronchia are filled with neutrophils (“leukocytic
alveolitis”).
Capillaries in the alveolar walls show congestion. Inflammatory foci are separated by
normal, aerated parenchyma.
» Tissue destruction and necrosis => abscess formation.
» Accumulation of suppurative material in the pleural cavity => empyema.
» Organization of the intra-alveolar exudates that may convert areas of the lung into solid fibrous
tissue.
» Bacterial distribution (dissemination) can lead to meningitis, arthritis or infective endocarditis
Causes of lobar
Viral pneumonias. Pathology of COVID infection.
“Primary atypical pneumonia” is called primary because it develops independently of other diseases
Check diff note again
COMMUNITY-ACQUIRED ATYPICAL PNEUMONIAS
.”Atypical pneumonia” is atypical in that it is presentation with only moderate amounts of sputum,
absence of physical findings of consolidation, moderate elevation in WBC count, and lack of alveolar
exudates.
resistance Normal defense mechanisms are nasal clearance (sneezing, blowing, swallowing),
tracheobronchial clearance (mucociliary action) and alveolar clearance (alveolar macrophages)
Impairment is due to primary or acquired immunosuppression, suppression of cough reflex (drugs, virus,
coma, anesthesia), injury to mucociliary apparatus (smoking, virus, Kartegeners syndrome), injury to
macrophages (tobacco, alcohol, anoxia), pulmonary congestion / edema or accumulation of secretions
(cystic fibrosis)
Note: viral pneumonia predisposes to bacterial pneumonia
» Macroscopically – the affected areas are red-blue and congested.
» Histologically – inflammatory reaction is confined within the walls of the alveoli =interstitial
(inflammation affects the interstitial tissue, mainly the alveolar walls), with widened and edematous
septa; contain mononuclear infiltration of lymphocytes and histiocytes.
finding (interstitial inflammation just look a little clearer lung demarcations) mild to no fever
Lung carcinoma: histology and pathogenesis.
Lung cancer is 1st in cancer mortality in the us and 2nd in incidence in us 95% of lung cancer are
BRONCHIAL CARCINOMA
carcinomas and remaining 5% include: sarcomas, lymphomas and benign tumors as hamartoma’s.
cell carcinoma and small cell carcinoma
lung carcinoma (NSCLC) => SCLC metastasizes by the time of diagnosis surgery will not be helpful
but it is better treated by chemotherapy, while NSCLC are better treated by surgery
Now therapies are available that target specific mutated gene products present in the various
subtypes of NSCLC, mainly in adenocarcinomas. Thus, NSCLC must be sub- classified into histologic
and molecular subtypes.
» Carcinomas of the lungs arise due to the transformation of normal bronchial epithelium or
pneumocytes the alveolar epithelium into neoplastic cells. Exposure to carcinogens Dominantly
Cigarette smoking’s 85% of cancers are related (polycyclic aromatic hydrocarbons and arsenic –
squamous cell type especially associate) other environmental insults e.g. asbestos exposure (lung
cancer and to lesser extent mesothelioma) or radon (raise from uranium decay in soil as gas) are
the mainly responsible for the genetic changes that give rise to lung cancers.
» In smoking exposure mutation accumulation has an predictable order Inactivation of known
tumor suppressor genes ( short arm chromosome 3) occurs at an early stage and even found
at”healthy” smokers respiratory epithel , while p53 mutations occur at a later stage.
» There is a linear correlation between the intensity and duration of exposure to cigarette smoke
and the appearance of epithelial changes that begin with cell hyperplasia and squamous
metaplasia and progress to squamous dysplasia and carcinoma in situ, before culminating in
invasive cancer.
» Among the major histologic subtypes of lung cancer, squamous and small-cell carcinomas show
the strongest association with tobacco exposure. (remember S for Smoking)
» Carcinomas begin as firm, gray-white, small mucosal lesions.
» They may form intra luminal masses, invade the bronchial mucosa, or form large masses that are
pushed into adjacent lung parenchyma => some large masses might undergo cavitation due to
central necrosis, or develop focal areas of hemorrhage.
» Eventually, these tumors may invade the pleural cavity and chest wall.
» Carcinomas of the lung are silent lesions that extensively spread before any symptoms appear.
» Can produce cough, sputum, weight loss, dyspnea, bronchiectasis or pneumonia.
» NSCLCs have better prognosis than SCLC => if detected before metastasis occurs, cure is
possible by lobectomy or pneumonectomy.
» SCLCs are very sensitive to chemotherapy.
» Paraneoplastic syndromes include:
1) Hypercalcemia due to secretion of PTH related peptide.
2) Cushing syndrome from increased production of ACTH.
3) Syndrome of inappropriate secretion of ADH (SIADH).
4) Neuromuscular syndromes.
5) Clubbing of the finge
6) Thrombophlebitis, non-bacterial endocarditis, and DIC.
Squamous cell carcinoma Hypercalcemia most often is encountered
Adenocarcinoma = hematologic syndromes
Small cell carcinoma = The remaining syndromes
SMALL CELL CARCINOMA
treated by chemotherapy (with or without radiation).
# Consists of poorly differentiated, relatively SMALL cells
# It is thought to originate from neuroendocrine cells (APUD cells) in the bronchus called Feyrter cells.
Hence, they express a variety of neuroendocrine markers, and may lead to ectopic production of
hormones like ADH and ACTH that may result in paraneoplastic syndromes and Cushing’s syndrome.
involvement of hilar lymph nodes at an early stage.
Necrosis is present and may be extensive.
mutations and p53 mutations.
All the following Considered as non-small cell lung carcinoma (NSCLC); responds poorly to
chemotherapy, thus it is treated by surgery.
SQUAMOUS CELL CARCINOMA
epithelium => carcinoma in situ => well defined tumor mass obstructs the lumen of the bronchus =>
production of distal atelectasis and infection.
PEARLS and/or INTERCELLULAR BRIDGES, to poorly differentiated neoplasms.
# Most common tumor in NON SMOKERS and FEMALE. Tumer cells form glands that produce mucin,
usually forming smaller mass then other lung cancers growing slowly but metastise earlier then other
tumors
these are not the precursor lesions for this tumor.The precursor of peripheral adenocarcinomas is
thought to be atypical adenomatous hyperplasia (AAH)
Can progress to:
1.Adenocarcinoma in situ = Bronchioalveolar carcinoma name in past ,the initial progression from
hyperplasia less then 3 cm dimt.,grow alomg preexisting structures monolyer cuboidal tumor cells
not invading stroma and maintain alveolar architecture-named also lepidic growth.
2.Minimal invasive adenocarcinoma although less then 3cm got invasive component
3.Invasive adenocarcinoma = more the 5 mm depth.
papillary… acinar pattern –gland formation/papillary pattern-fibromuscular cores lined by glandular
tumor cells replacing normal alveolar lining(micropapillary no fibromuscular core but similar
papillary pattern )/mucinous-grow along alveolar septa not invasive in situ /solid type-see mucin
inside tumor cells may need special stain for recognizing, forming solid masses of cells.
The immuno histochemical profile can help differentiate between other various types of NSCLC. About 70% of
the Adenocarcinomas are positive for the thyroid transcription factor-1 (TTF-1).
BRONCHIOLOALVEOLAR CARCINOMA
parts of the lung, as a single nodule.
and preservation of alveolar architecture.
alveolar septa.
desmoplasia-no growth of fibros tissue
LARGE CELL CARCINOMA
treated by surgery.
# Composed of undifferentiated epithelial tumors that lack the cytologic features of small cell carcinoma,
show no glandular differentiation or mucin, and no keratin pearls or intercellular bridges.
CARCINOIDS TUMORS- BRONCHIAL
CARCINOIDS
neoplastic cells contain neurosecretory
granules in their cytoplasm, and may
secrete hormonally active peptides although
not usually manifest with paraneoplastic syndrome.
Tumor cells origin from the diffused
neuroendocrine system of the lung (korchinski cell) solid tumor with rich capillary network with Fine
delicate fibrovascularsepta inbt nests of cells Such as tumors morphology also seen in pancreas and
adrenal glands …
resectable and curable
Typical carcinoids (low grade) = These tumors are composed of nests of uniform cells that have
regular round nuclei with “salt and pepper” chromatin & central nucleoli. Less than 5mitotic figures
for HPF, no necrosis.
Atypical Carcinoids (Intermediate grade)= > 5 mitotic figures for HPF (40x objective) with/without
necrosis display a higher mitotic rate (but less than small or large cell carcinomas) and focal necrosis.
1) Expanding growth-Obstructing polypoid, spherical, intraluminal mass.
2) Invasing-Mucosal plaque that penetrates the bronchial wall to spread in the peribronchial tissue.
Cough, recurrent infections related to the intramural growth.
Rare- carcinoid syndrome characterized by attacks of diarrhea flushing and vomiting
Diseases of the pleura. Pleural effusion. Empyema. Mesothelioma.
Pleural effusion – the presence of fluid in the pleural space that can be either
BENIGN PLEURAL LESIONS
# Pathologic involvement of the pleura is almost always secondary complication of
some underlying pulmonary disease.
# Important primary disorders:
» primary intrapleural bacterial infections
» Primary neoplasm of the pleura known as malignant mesothelioma.
PLEURAL EFFUSION AND PLEURITIS
transudate (=hydrothorax) or exudate (Proteins & inflammatory cells) which
suggest pleuritis.
# There are 4 causes of pleural exudate formation:
» Microbial invasion through either direct extension of a pulmonary
infection, or blood borne seeding (empyema).
» Cancer (lung carcinoma, metastasis, mesothelioma).
» Pulmonary infarction.
» Viral pleuritis.
# These effusions are large frequently bloody => hemorrhagic pleuritis.
inciting cause is controlled.
organization, yielding adhesions or fibrous pleural thickening, and sometimes
minimal to massive calcifications.
PNEUMOTHORAX
# Refers to air or other gas in the pleural sac.
# Primary/simple/spontaneous = Without any pulmonary disease.
the consequence of rupture of any pulmonary lesion situated close to the pleural
surface that allows inspired air to gain access to the pleural cavity.
(Emphysema, lung abscess, tuberculosis, carcinoma)
- Pneumothorax may create a tension pneumothorax that shifts the
mediastinum => compromise of pulmonary circulation => may be fatal. - If the leak seals but the lung is not re-expanded within a few weeks
because of large amount of scarring so the lung cannot fully expand =>
serous fluid is collected in the pleural cavity => hydro pneumothorax - With prolonged collapse = the lung & the pleural cavity becomes
vulnerable to infections = formation Empyema (pyopneumothorax).
HEMOTHORAX
# The collection of whole blood in the pleural cavity.
# It is a complication of ruptured intra thoracic aortic aneurysm => almost always
fatal!!
# Must be differentiated from bloody pleural effusion where the are no blood clots.
Its cause is usually traumatic, from a blunt or penetrating injury to the thorax,
resulting in a rupture of the serous membranes.
This rupture allows blood to spill into the pleural space.
CHYLOTHORAX
# Pleural collection of lymphatic fluid that contains microglobules of lipids.
# The presence of chylothorax implies an obstruction of the major lymph ducts,
usually by intra thoracic cancer.
MALIGNANT MESOTHELIOMA
parietal).
! Less commonly occurs in the peritoneum and pericardium.
# ~50% of cases related to exposure to asbestos in the air.
» Preceded by extensive pleural fibrosis The tumors begin in a localized
area and spread widely over time. The affected lung is enveloped by a
yellow-white, firm, gelatinous layer of tumor .
» There are 3 patterns of mesothelioma:
1) Epithelial – cuboidal cells line tubular and microcystic spaces with
small papillary buds projecting into them = most common.
2) Sarcomatous – spindle shaped cells grow in non-distinctive sheets.
3) Biphasic – both patterns appear.
# Clinical Presents with recurrent pleural effusions, dyspnea, and chest pain.
Inflammations and tumors of the nasal cavity, pharynx and larynx.
the “common cold”, characterized by nasal congestion accompanied by watery discharge, sneezing, sore
ACUTE INFECTIONS
throat and slight increase in temperature.common pathogens that elicit the common cold are
rhinoviruses.Most infections are self-limited.
a cold, and is the most common form of pharyngitis.
peritonsillar abscesses.
influenza.Pain and airway obstruction are common findings.
the agents that produce the common cold and usually involve the pharynx and nasal passages as well as
the larynx.
The less common forms of laryngitis are tuberculous laryngitis, due to active tuberculosis, and
diphtheritic laryngitis.
Corynebacterium diphtheriae implants on the mucosa of the upper airways, where it elaborates a
powerful exotoxin that causes necrosis of the mucosal epithelium, accompanied by a dense
fibrinopurulent exudate, to create the pseudomembrane of diphtheria.
The major hazards of this infection are obstruction of major airways and absorption of bacterial exotoxins (producing myocarditis,
peripheral neuropathy, or other tissue injury)
NASOPHARYNGEAL CARCINOMA
nasopharyngeal epithelium and then infecting nearby tonsillar B lymphocytes
# There are 3 histological variants:
1) Keratinizing squamous cell carcinoma.
2) Non keratinizing squamous cell carcinoma.
3) Undifferentiated carcinoma = most linked to EBV. most common, and is characterized by large
epithelial cells with indistinct borders (“syncytial” growth) and eosinophilic nucleoli.
distant areas
LARYNGEAL TUMORS
# Non malignant lesions:
1.Vocal cord nodules (“polyps”)
» Are smooth and hemispheric protrusions located on the true vocal cords.
» The nodules are composed of fibrous tissue and covered by stratified squamous mucosa.
» These lesions occur mainly in heavy smokers or singers. = chronic irritation or abuse.
2.Laryngeal papilloma or squamous papilloma of the larynx
» A benign neoplasm, usually on the true vocal cords.
» Forms a soft, raspberry-like lump.
» Consists of multiple finger-like projections supported by central fibrovascular cores and covered
by stratified squamous epithelium.
» Caused by HPV6 and HPV11.
» Do not become malignant, and often spontaneously regress at puberty.
» Single lesion in adults, multiple lesions in children.
» Most commonly occurs after the age of 40, and is more common in men,
» Occurrence is greatly influenced by environmental factors, such as smoking, alcohol and asbestos
exposure.
» Most laryngeal carcinomas (95%) are typical squamous cell carcinomas.
» The tumor develops directly on the vocal cords in most cases, but may arise above the cords
(supraglottic) or below it (subglottic).
» The tumors begin as in situ lesions that later appear as gray, wrinkled plaques on the mucosal surface
= cause ulceration & fungation.
» The glottis tumors are usually keratinizing, well differentiated squamous cell carcinomas.
» Clinically manifest itself as hoarseness
» Glottis tumors are less likely to metastasize due to low lymphatic supply, while supraglottic tumors
metastasize to cervical lymph nodes.
Inflammatory lesions and tumors of the oral cavity and salivary glands.
Aphthous ulcer-painful ulcer in oral mucosa has grayish (granulation tissue base )
INFLAMMATORY LESIONS OF THE ORAL CAVITY
and its rimes surrounded by erythema .self-resolving in few days but tend to
reoccur exact etiology is unknown but may appear in link with inflammatory
bowl disease or Bechet syndrome.
(Recurrent aphthous ulcers, genital ulcers, and
uveitis due to immune complex vasculitis involving small vessels)
no scar seen along lips nostrils and oral mucosa.
Caused by HSV1 most commonly also HSV2 may cause it, upon infection it sets
in trigeminal ganglion following stress illness/mental/cold water it may reactivate
sending viruses down axon reaching epithel cell and develop characteristic lesion
as it cause lysis of these cells on the effected part of face innervate by this
ganglia primary infection non symptomatic usually if do it in children with ulcers
and fever enlarged lymph node or pharyngitis in older age.
2ndry infection characteristic appearance self-resolve few days
population e.g. after AB treatment or upon immune suppression characterly
arise as early manifestation of AIDS.
See pseudomembrane appearance of gray to white layer composed of
fibrinosupporative exudate and fungi easily scraped off.
PROLIFERATIVE & NEOPLASTIC LESIONFIBROUS
PROLIFERATIVE LESIONS
Submucosal nodular fibrous tissue masses9smooth pink nodule macro0 Occur most often
on the buccal mucosa.
gingiva of children, young adults. Richly vascular and typically are ulcerated, which gives
them a red to purple color.
PRECANCEROUS LESIONS
Lesions that suggest dysplastic process and in risk to undergo malignant transformation,
erythoplakia greater risk then leukoplakia…
clinically or pathologically as any other disease.”
caused by hyperkeratosis of mucosal epithelium with (squamous) thickening=
Hyperkeratosis overlying a thickened, acanthosis nonwipeable.
it may represent dysplastic epithelial changes then it considered as precancerous lesion
Strongly associated with use of tobacco.
Up to 25% of cases transform to squamous cell
carcinoma. Therefore, persistent or recurring white plaque must be biopsied for
histopathology analysis,whether dysplastic or malignant!
Erythroplakia – red, granular, circumscribed areas with marked epithelial dysplasia. The
most severe dysplastic changes are associated with erythroplakia, and more than 50% of
these cases undergo malignant transformation.
SQUAMOUS CELL CARCINOMA ()
# 95% of oral cavity cancers are squamous cell carcinomas the reminder is mainly
adenocarcinoma of salivary glands also lymphomas may arise…
abuse chronic irritations chronic inflammation(HPV16 and HPV18, ) immune suppression
» The predominant sites for oral cancer are ventral surface of the tongue, floor of the mouth,
lower lip…
» Early lesions are white to gray circumscribed thickening of the mucosa.
» Squamous cell carcinoma develops from dysplastic precursor lesions. Histologic patterns
range from well-differentiated keratinizing neoplasms to anaplastic, sometimes sarcomatoid
tumors (= both carcinoma & sarcoma properties1= rare)
chewing, but many are asymptomatic (thus the lesion is ignored).
Local infiltration follow by
metastasis to cervical nodes and from there to mediastinal nodes lung and liver.
SALIVARY GLAND DISEASES
*Major SG = parotid, sub-mandivular, Sub-lingual
Minor SG = Distributed throughout the mucosa.
XEROSTOMIA
major feature of the autoimmune disorder Sjögren syndrome, in which it usually is
accompanied by dry eyes.
as well as difficulty in swallowing and speaking.
SIALADENITIS
(predominant – parotid), bacterial => S. aureus, autoimmune => Sjogren syndrome).
infiltrate. In adults it can cause pancreatitis or orchitis (inflammation of the testis).
gland duct => saliva leaks into the surrounding tissue.
tissue that is filled with mucin and inflammatory cells.
formation (sialolithiasis), or may arise after retrograde entry of oral cavity
bacteria (S. aureus, S. viridians).
SALIVARY GLAND NEOPLASM-
# Relatively uncommon and represent less than 2% of all human tumors. ~80% of
tumors occur within the parotid glands usually at 60-70 years of age.
roughly, to the size of the gland. (Parotid => submandibular => sublingual)
malignant tumor of salivary glands is mucoepidermoid carcinoma (mainly in the
parotid gland).
swelling at the angle of the jaw.
Consist of a mixture of ductal (epithelial) and myoepithelial cells, so they exhibit
both epithelial and mesenchymal differentiation Mixed tumor.
Morphology – Rounded, well-demarcated masses rarely exceeding 6 cm in the
greatest dimension. The capsule is not fully developed, and expansile growth
produces protrusions into the surrounding tissues as Main cause for recurrence.
The most striking histologic feature is their characteristic heterogeneity
epithelial cells or myoepithelial cells dispersed within a mesenchyme- like
background of loose myxoid tissue containing islands of chondroid and, rarely,
foci of bone.
of the salivary glands, composed of variable mixtures of squamous cells and
mucus-secreting cells.
Morphology = solid tumor well circumscribed uncapsuled gray tumor often
contain inner small Cysts with mucin in it in micro see clusters of mucous,
squamous and intermediate and cells may line cyst or just as cluster.
Anatomical disorders and inflammations of the esophagus. Esophageal varices.
Mechanical Obstruction- caused by developmental abnormalities/fibrotic stricture/tumor…
ANATOMICAL DISORDERS OF THE ESOPHAGUS
» Atresia = a thin, noncanalized cord which replaces a segment of the esophagus. Atresia occurs
most commonly at or near the tracheal bifurcation and usually is associated with a fistula
connecting the esophagus and the bronchus/trachea.
» Esophageal stenosis = generally caused by Fibrous thickening of the submucosa (coming
thogether with Atrophy of the muscularis propria and Secondary epithelial damage). Hence,
Stenosis most often is due to inflammation and scarring, which may be caused by chronic gastroesophageal
reflux, irradiation, or caustic injury.
spasm of m. propria = functional obstruction, result in impaired forward movement of food to stomach.
» Achalasia- Incomplete relaxation of the lower esophageal sphincter in response to swallowing =>
obstruction of esophagus => dilation of proximal esophagus
Achalasia is characterized by the triad of:
1) Esophageal Aperistalsis.
2) Incomplete relaxation of the lower esophageal sphincter.
3) Increased tone of the lower esophageal sphincter.
Primary achalasia –idiopathic failure of distal esophageal inhibitory neurons damage to myenteric
ganglions.
Secondary achalasia is caused by pathological processes that impair esophageal function
Clinicaly-dysphagia Stasis of food may produce inflammation and ulceration, risk to develop squamus cell
carcinoma ~5% of patiants
esophagus
a segment of the stomach to protrude above the diaphragm. There are 2 patterns:
1) Sliding hernia – constitute 95% of cases; the protrusion of the stomach creates a bellshaped
dilation.
2) Paraesophageal hernia – a separate portion of the stomach enters the thorax through the
widened foramen.
INFLAMMATION OF THE ESOPHAGUS
# Esophagitis – injury to esophageal mucosa with subsequent inflammation.
junction as Mallory-Weiss tears.
Pathogenesis-Occur upon severe vomiting in which see inadequate relaxation of the musculature of the
lower sphincter so reflux result as injurus agent may see in alchol toxication ,Complications –
hematemesis .
*Boerhaave syndrome, char- acterized by transmural esophageal tears and mediastini- tis, occurs
rarely and is a catastrophic event.
against mechanic injury from food mainly the lower esophageal sphincter but also submucosal mucus
glands protect against acid of stomach come in contact with epithel.
The clinical condition is termed gastro- esophageal reflux disease (GERD). Contributing factors are
impaired anti-reflux mechanisms, sliding hiatal hernia, and increased gastric volume, obesity,
pregnancy, alcohol, and Tabbaco users.
Clinical features –Symptoms are heartburn with cheast pain and sour-tasting Complications, of reflux
esophagitis include esophageal ulceration, stricture development, and Barrett esophagus.
particularly odynophagia (pain with swallowing), the esophagus may be damaged by a variety of
irritants including alcohol, acids or alkalis, excessively hot fluids, and heavy smoking.
cytomegalovirus (CMV), or fungal organism’s :
» Candidiasis= is characterized by adherent, gray- white pseudomembranes composed of
densely matted fungal hyphae and inflammatory cells covering the esophageal mucosa.
» Herpes- viruses typically cause punched-out ulcers.
» CMV (Cytomegalovirus) causes shallower ulcerations.
numbers of eosinophils, particularly superficially and at sites far from the gastro- esophageal
junction.
Linked to food allergy majority of patients are atopic may present additional atopic allergic
rhianitis/dermatitis/asthma…
VARICES
cause portal hypertension, important complication is the cause of esophageal bleeding.
common reason worldwide is hepatic schistosomiasis.
stomach.
into the esophageal wall => varices produce NO symptoms until they are collapsed.
Barrett esophagus. Esophageal carcinoma.
A common complication of long-standing gastroesophageal reflux. (GERD)
BARRETT ESOPHAGUS
,Esophagus is normally lined by no keratinizing squamous epithelium (suited lo
Handle friction of a food bolus).
Chronic Acid reflux from the stomach causes
metaplasia to nonciliated columnar epithelium with goblet cells (better able to
handle the stress of acid).
Metaplasia occurs via reprogramming of stem cells, which then produce the new
cell Type.
Metaplasia is reversible, in theory, with removal of the driving stressor.
Hence treatment of gastroesophageal reflux may reverse Barrett
Esophagus.
of developing esophageal ADENOCARCINOMA.
gastroesophageal junction and upward, in correlation with micro appearance of
the metaplastic change of with esophageal squamous epithelium replaced by
metaplastic columnar epithelium.
ESOPHAGEAL CARCINOMA
» Adenocarcinoma –common in western countries influencing lower 1/3 of
esophagus linked to Barret metaplasia –dysplasia-carcinoma sequence
» Squamous cell carcinoma – most common variant worldwide, malignant
proliferation of the squamous cells with increased risk with irritation to
epithel lining as alcohol and Tabaco use.
SQUAMOUS CELL CARCINOMA
esophageal diseas e.g. achalasia/sever injury by chemicals digestion etc./
Chronic esophagitis (epithelial squamous dysplasia => carcinoma in situ =>
invasive cancer).
countries like Iran central china South America and South Africa.
p53 gene.
» Macro: tend to appear at upper segments then the adenocarcinoma
frequently seen in the middle third of the esophagus. Early lesions appear
as small, gray-white plaque like thickening of the mucosa.
Next The lesions grow to tumor masses, taking one of the following forms:
1) Polypoid exophytic masses that protrude into the lumen.
2) Ulcerating tumors.
3) Diffuse infiltrative neoplasms that cause thickening and rigidity
of the wall, and narrowing of the lumen.
» Micro: Squamous cell carcinomas are moderately to well differentiate.
Other variants are less common. Squamous cell carcinoma composed of
nests of malignant cells that partially recapitulate the stratified
organization of squamous epithelium.
or hoarseness upon invasion to recurrent laryngeal nerve Symptomatic
tumors are generally very large at diagnosis and have already invaded the
esophageal wall. These tumors may extend into adjacent structures:
respiratory tree, aorta, mediastinum & pericardium, cause damage.
ADENOCARCINOMA
metaplasia in the esophageal mucosa The development charcterly accrue by
Progression of Barrett esophagus to adenocarcinoma
mutations, especially p53 gene; additional changes involve HER2/c-ERB-B2,
cyclin D1, RB, p16 genes histologically seen as dysplasia with increased
severity upon progression.
other risk factors include obesity and chronic gastric reflux.
» Usually in the distal 1/3 of the esophagus, may invade the gastric cardia .
» Usually moderate or well differentiated mucin producing (intestinal type
mucosa) , Appear adjacent Barrett mucosa with high grade dysplasia (may be
displaced by adenocarcinoma)
by dysphagia to all food as its gradually obstructs the lumen; weight loss, fatigue
and weakness appear, followed by pain related to swallowing.
Metastasis generally occurs early even in superficial tumors, due to extensive
lymphatic network in esophagus that allows horizontal and longitudinal spread
Adenocarcinoma occurs in lower esophagus and lymph node metastases involve
gastric and celiac lymph nodes Recurrences are common
Pyloric stenosis. Acute gastritis. Chronic gastritis.
A congenital disorder occurs secondary to hypertrophy and hyperplasia of the muscular layers of the
PYLORIC STENOSIS
pylorus, causing a functional gastric outlet obstruction.
# More common in boys.
» Non-bilious vominting => the gastric content did not reach the duodenum to meet bile acids.
» Visible peristalsis (movment of stomach against obstruction) on abdominal surface.
» Corrected by surgical incision of the hypertrophied muscle.
CHRONIC GASTRITIS
may lead to epithelial intestinal metaplasia to intestinal lining see goblet cells . (not in book => check)
Helicobacter pylori 2nd one much less common is the AI type.
- .H. pylori chronic infection
»H. pylori organisms’ Small curved gram negative bacillus that colonizes the mucus layer of the stomach not
invading cells they Are responsible to vast majority of chronic gastritis cases , characterly effecting the
antrum .
» Pathogenesis – fecal oral transmission upon situated in mucus lining above gastric epithel it got Urease
enzyme- create ammonia from urea and secret it to protects the bacteria from the acidic environment but
also increase stimulation for acid production hence, H. pylori infection most often manifests as a
predominantly antral gastritis with high acid production, despite hypogastrinemia.
» 3complications:
1) H.pylori realis different toxins and protease who exerts damage on the gastric epithelium In addition to
the increased acid secretion that occurs in H. pylori gastritis together the infection result in peptic ulcer
disease of the stomach or duodenum.
2) Lymphoid aggregates with germinal centers and abundant subepithelial plasma cells within the
superficial lamina propria. Representing an induced form of mucosa-associated lymphoid tissue (MALT)
that has the potential to trans- form into lymphoma
3) Intestinal metaplasia – columnar gastric epithelium with goblet cells the indicators of intestinal
metaplasia increased risk for gastric adenocarcinoma.
»Morphology – H. pylori are found within the superficial mucus overlying the epithelium, Neutrophils within
the lamina propria and epithelium, Lymphoid aggregates with germinal centers and abundant subepithelial
plasma cells within the superficial lamina propria, Intestinal metaplasia.
Over time, chronic antral H. pylori gastritis may progress to pangastritis, resulting in multifo- cal atrophic
gastritis, reduced acid secretion, intestinal metaplasia, and increased risk of gastric adenocarcinoma in a
subset of patients (mechanism is yet clear).
» Clinical features – Nausea and vomiting. Urea breath (due to ammonia production by urease) Hematemesis
is uncommon.
- Autoimmune gastritis
» Seen in ~10% of cases as t cell mediated type 4 HS attack on parietal cells –more concentrate in body
and fundus, a consequence of AI recognition of parietal cells Antibodies to parietal cells and intrinsic
factor that can be detected in serum and gastric secretions helpful for diagnosis
» In contrast with that caused by H. pylori, autoimmune gastritis typically spares the antrum and induces
hypergastrinemia :
Autoimmune gastritis is associated with loss of parietal cells and, which secrete acid and intrinsic factor=
Defective gastric acid secretion (achlorhydria).
Deficient acid production stimulates gastrin release hypergastrinemia, resulting in and hyperplasia of
antral gastrin-producing G cells- Antral endocrine cell hyperplasia
Parietal cell also secret intrinsic factor for vitamin B12 absorption, upon their destruction no intrinsic
factor leading to B12 deficiency and megaloblastic anemia (pernicious anemia).
» Morphology:
- Diffuse atrophy (mucosa of body and fundus are thinned).
- Inflammatory infiltrate more commonly is composed of lymphocytes, macrophages, and plasma cells.
- The inflammatory reaction most often is deep and centered on the gastric glands. (Unlike in H.pylori).
- Parietal and chief cell loss can be extensive, increased risk for intestinal metaplasia who lea to
increase risk for adenocarcinoma to dvelop.
ACUTE GASTRITIS
severe cases there may be mucosal erosion, ulceration, hemorrhage, hematemesis % melena.
acid damage to the mucosa.
»Heavy use of non-steroidal anti-inflammatory drugs (inhibit prostaglandins formation that increases acid
production).
»Excessive alcohol consumption.
»Ingestion of harsh chemicals(strong acid/base)
»Treatment with cancer chemotherapeutic drugs (reduces the ability of regeneration).
»Increased ICP => increased vagal stimulation => increased acid production by parietal cells
»Shock/sever burns => severe decrease in blood flow to organs.
» Ranges from localized to diffuse.
» Mild gastritis = The surface epithelium is intact, although scattered neutrophils may be present above
BM .
» More severe form = presence of erosion & hemorrhage = acute erosive hemorrhagic gastritis.
chronic ulcer see under it upon healing granulation tissue and fibrosis not in acute!
Caused from similar to above…:
- NSAID stop prostaglandin production so less bicarbonate secretion and reduced blood perfusion.
- curling ulcers upon hypoxia e.g. shock/burns come as multiple ulcers in stomach and proximal duodenum
- chushing ulcers upon IICP.
Clinically come with hematemesis –coffie ground vomit nausea treat underlying caus and give proton
pumps inhibitor.
Peptic ulcers (acute and chronic).
Ulcer is a Focal lack of mucosa, peptic ulcer most common sites of ulcers are the
GASTRIC ULCERATION
stomach and duodenum.
ACUTE PEPTIC ULCERATION
# As result of Acute peptic injury/complication of therapy with NSAIDs as well as
severe physiologic stress-shock.
» Stress ulcers =affecting patients with shock, sepsis, or severe trauma
come as multiple ulceration lesions.
» Curling ulcers =come as ulcers in stomach and proximal duodenum
seen in sever burn victims
» Cushing ulcers = arising in the stomach, duodenum, or esophagus of
persons with IICP see increase vagal stimulation so more Ach to G
cells more gastrin more HCL.
NSAID administration - prevents prostaglandin synthesis = This eliminates
the protective effects of prostaglandins, which include enhanced bicarbonate
secretion and increased vascular perfusion.
Also come as Acute gastritis can progress to acute gastric ulceration hence
same reasons e.g. Excessive alcohol consumption/Ingestion of harsh
chemicals(strong acid/base)/Treatment with cancer chemotherapeutic drugs
(reduces the ability of regeneration).
shallow erosions caused by superficial epithelial damage to deeper lesions that
penetrate the mucosa.
Rounded and small less than 1 cm in diameter acute stress ulcers are sharply
demarcated, with essentially normal adjacent mucosa, the ulcer base
frequently is stained brown to black by acid- digested extravasated red cells.
No scarring no granulation or fibrosis under ulcer yes necrotic debris and
neutrophils in depth of it…
coffee-ground hematemesis. Complications: bleeding (may be massive; 1-4%
of patients require transfusion), perforation, obstruction and loss of function
scarring
PEPTIC ULCER DISEASE – CHRONIC ULCER
NSAID use.
cause chronic gastritis are also responsible for PUD PUD generally develops
on a background of chronic gastritis.
Gastric hyperacidity is fundamental to the pathogenesis of PUD hence causes
Associated most often with Helicobacter pylori-induced hyperclorhidric chronic
gastritis and chronic NSAID use.
Also caused by high chlorhydro-peptic gastric
secretion, as a result of either parietal cell hyperplasia, excessive secretory
response (i.e., psychological stress) or impaired inhibition of stimulatory mechanism such as gastrin release as in chronic renal failure or
hyperparathyroidism bouth induce Hypercalcemia stimulates gastrin production
=> acid secretion.
(Zollinger-Ellison syndrome, characterized by multiple peptic ulcerations in the
stomach, duodenum, and even jejunum rear syndrome, is caused by uncontrolled
release of gastrin by a tumor and the resulting massive acid production).
small curvature in segment of antrum, more common in the proximal duodenum
than in the stomach. Histo see base with necrotic debries under it granulation
tissue rich in b.v. under it see fibrosis.
ulcer/get worse after meal upon gastric ulcer.
-Upper gastrointestinal bleeding - represents the most frequent complication of
a chronic peptic ulcer, which occurs in the active phase of the ulcer, caused by
the erosion of an arterial wall.
-Perforation - represents a surgical emergency in which the loss of substance
extends beyond the gastric serosa, resulting in the communication between the
stomach and the peritoneal space.
-Penetration - in the evolution of ulcers, inflammation of serosa leads to
adhesions with adjacent organs (liver, pancreas, greater omentum) so that,
when the loss of substance exceeds serosa, the ulcer base is represented by the
parenchyma of that organ, with no communication with the peritoneal cavity.
-Gastric stenosis - appears in chronic ulcers with extensive, abundant fibrosis.
-Malignant transformation - represents a very rare complication (less than 1 %
of the cases). In the malignant area, the ulcer’s borders are irregular,
anfractuous.
This complication is controversial, as some believe that the ulcer
represents in fact an ulcerated form of gastric carcinoma
Neoplasias of the stomach. Gastric carcinoma.
Polyp – any nodule or mass that originates from the mucosa, and projects above its level.
GASTRIC ADENOCARCINOMA
o The most common (~90% ( of gastric primary malignant tumors, Gastric adenocarcinoma is a
malignant epithelial tumor, originating from glandular epithelium of the gastric mucosa. According
to Lauren classification, gastric adenocarcinoma may be: intestinal type, diffuse type and mixed type.
o Pathogenesiso
Mutation – Diffuse type the loss of CDH1 gene who encodes E-cadherin (E-cadherin, a cell
adhesion molecule that participates in normal cell differentiation and tissue architecture), seems to be
a key step in the development of diffuse gastric cancer.
Hereditary (Familial) Gastric Cancer see
mutation of gene in one third.
CDH1 is a tumor suppressor gene, since mutation of the second CDH1 allele, perhaps as the result of environmental influences such as H. pylori infection or diet, is
required for full penetrance found also in sporadic type.
Molecular Biology The development of gastric cancer is thought to occur through a multi-step
process, in which the earliest lesion is atrophic gastritis, followed by the development of dysplasia,
adenoma, and then adenocarcinoma.
Progression from the preceding lesion to the next developmental
stage is accompanied by molecular genetic events. Mutation to p53, a tumor suppressor gene, is
found in 64% of gastric cancers.
o Environmental Risk Factors- Environmental factors appear to be related to the intestinal type of
gastric cancer and not to diffuse one.
Diets high in fresh fruit, leafy vegetables, ascorbic acid, and beta-carotene are associated with reduced risk.
Also increase consumption of nitrosamines in smoked
food hence may be the increase prevalence in japan and Eastern Europe the relationship between
alcohol consumption and gastric cancer is inconclusive.
o Adenocarcinoma of the stomach arises in the setting of atrophic gastritis, a condition in which
chronic inflammatory processes destroy stomach glands. related to the intestinal type of gastric
cancer and not to diffuse one. In the most severe cases, histology of the gastric mucosa reveals
features that characterize a pre-cancerous lesion known as intestinal metaplasia. Atrophic gastritis
may arise in response to:
1) chronic infection with Helicobacter pylori, 2) autoimmune chronic
gastritis Gastric carcinoma may develop in as many as 9% of patients with atrophic gastritis.
o Gastric Polyps Gastric polyps may evolve into gastric cancer. Hyperplastic polyps are the most
common and comprise about 80% of all gastric polyps. Their malignant potential significantly
increases when their size is greater than 0.5 cm in diameter. Adenomatous polyps have a significant
risk of cancer as well, and require endoscopic follow-up after removal.
o EBV- 10% of gastric adenocarcinomas are associated with Epstein-Barr virus (EBV) infection.
(unknown mechanism)
- Morphologically, EBV-positive tumors tend to occur in the proximal stomach and most commonly have
a diffuse morphology with a marked lymphocytic infiltrate.
o Morphology – Lauren classification = separates gastric cancers into intestinal and diffuse types:
1) Intestinal: (Mass, glandular)
Macro = elevated mass heaped up borders and central ulceration usually involve the lesser
curvature of the antrum.
Micro = Tumor cells describe irregular tubular structures, with stratification, multiple
lumens surrounded by a reduced stroma (“back to back” aspect). On presentation The
tumor invades the gastric wall, infiltrating the muscularis mucosae, the submucosa and
may even invade the muscularis propria. Often it associates intestinal metaplasia in
adjacent mucosa.
Depending on glandular architecture, cellular pleomorphism and
mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate
and poorly differentiate-alredy diffused type.
2) Diffuse:
Macro = Linitis plastica. The gastric wall is markedly thickened upon desmoplasia, and
rugal folds are partially lost.
Micro = diffuse-Tumor cells are discohesive no gland structure - mucinous (colloid)
adenocarcinoma, poorly differentiated (Lauren classification).
Tumor cells secrete mucus= “signet-ring cell”( mucus remains inside the tumor cell, it
pushes the nucleus against the cell membrane) also mucus may be delivered in the
interstitium producing large pools of mucus/colloid (optically “empty” spaces)
Infiltrative along layers of gastric wall induce reactivity of surrounding stroma
desmoplasia buildup of fibrous c.t.
o Clinical feature –
Both types of carcinomas are generally asymptomatic, and can be discovered by repeated endoscopic
examinations; advanced carcinoma involves abdominal discomfort or weight loss early satiety
anemia.
The most significant prognostic factor is depth of tumor invasion at the time of diagnosis. There are
three classifications of gastric tumors. The Boorman classification is based on the macroscopic
appearance of the tumor; the Lauren classification divides tumors into intestinal and diffuse types;
and the TNM classification reflects the
depth of tumor infiltration (T) at early stages, the lesion is confined to the mucosa and submucosa,
while in advanced stages the neoplasm has extended into the muscularis propria and serosa or final
T4 for invasion to other adjacent organs.
Node involvement (N) , and the presence of distant metastases (M).All gastric carcinomas may
eventually penetrate the wall and spread to regional and distal lymph nodes => Virchow node
(earliest lymph node metastasis that involves the supraclavicular lymph nodes) commonly
metastasize to liver also character for diffused type is the Krukenberg tumor (metastasis to ovary
which effect both ovaries see signant ring cell and desmoplasia components of tumor but in ovaries
Other stomach tumors
- Extranodal lymphoma about 5% of gastric malignancies -although may appear everywhere it
very common arise in GI especially at stomach ,most common as marginal zone b cell
lymphoma also its most frequent sait for EBV derived B cell lymphoma to proliferate .arise undr
stage of chronic inflamtion promoting the lymphatic proliferation… - Carcinoid tomor- malignant proliferation of neuroendocrine cells most common arise in GI
mainly small intestine but also in stomach e.g. from G cells, 2nd common place is the bronchial
three.
GASTRIC POLYPS
# Gastric polyps are uncommon.
neoplasia.
hyperplastic mucosal epithelium and inflamed edematous stroma; they are NOT true neoplasms
» Occur sporadically and in persons with familial adenomatous polyposis (FAP) but do not
have neoplastic potential.
» Their incidence has increased markedly as a result of the use of proton pump inhibitors
reduced acidity increased gastrin secretion glandular hyperplasia.
» These well-circumscribed polyps occur in the gastric body and fundus, often are multiple,
and are composed of cystically dilated, irregular glands lined by flattened parietal and chief
cells.
# Gastric adenoma (10%)-
» Adenomas almost always occur on a background of chronic gastritis with atrophy and
intestinal metaplasia.
» The risk for development of adenocarcinoma in gastric adenomas is related to the size of the
lesion.
» Commonly located in the antrum.
» Gastrointestinal adenomas exhibit epithelial dysplasia
Inflammatory bowel disease. Crohn disease. Ulcerative colitis.
Inflammatory bowel disease (IBD) is a chronic inflammatory condition resulting from
INFLAMMATORY BOWEL DISEASES
inappropriate mucosal immune activation.
- Ulcerative colitisinflammation is limited to the mucosa and submucosa and usually
extends to the distal colon and rectum. - Crohn disease transmural inflammation and usually found in the ileum and
proximal colon but has the potential to affect any part of the gastrointestinal tract
from mouth to anus.
common in western countries- North America Europe Ashkenazi Jews. .
colitis and Crohn disease.
» Genetic: There is a clear genetic predisposition for Crohn disease. First-degree
relatives have a 13-18% increase in incidence, and there are concordance rates of 50%
in monozygotic twins. Classic Mendelian inheritance is not seen, implying a
polygenic basis of the disease .
NOD2 is a susceptibility gene in Crohn disease. NOD2 encodes a protein that binds to
intracellular bacterial peptidoglycans and subsequently activates NF-κB Nuclear
factor kappa B (NF-κB) is an ubiquitous rapid response transcription factor in cells
involved in immune and inflammatory reactions, and exerts its effect by expressing
cytokines, chemokines, cell adhesion molecules…
» Mucosal immune response: Mechanism still uncertain, some combination that activate
mucosal immunity and suppress immunoregulation contribute to the development of
both disease.
Polarization of T cells to the T-helper cell type 1 (TH1) type is a well-recognized
feature of CD. Type 1 T helper (Th1) cells produce interferon-gamma, interleukin
(IL)-2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are
responsible for cell-mediated immunity and phagocyte-dependent protective
responses.
Emerging data indicate that TH17 cells also contribute to disease pathogenesis,
whereas IL-23(an R involve in development and maintenance of Treg) receptor
polymorphisms may confer protection from CD and UC.
Only in ulcerative colitis = TH-2 is involved & polymorphism of IL-10 gene.
» Epithelial Defect: Defects in intestinal epithelial tight junction barrier function are
present in patients with Crohn disease such as defect result in more primableepithel so
inflammation stimulating material e.g. bacteria can come in. Paneth cell granulesgot
antimicrobial materials may alter microbe composition link to develop IBD.
» Microbiota: The precise contribute to IBD pathogenesis remains to be defined.
Possible mechanism: Transepithelial flux of luminal bacterial components activates
innate and adaptive immune responses –in genetic susceptible individual, TNF other
inflammatory cytokines stimulating the increase priamability of epithel more influx
more cytokine- circle end as IBD.
» Environmental factors - especially cigarette smoking and diet, are also clearly
involved in CD Tobacco smoking doubles the risk of both initial and recurrent Crohn
disease (CD), unlike the apparent protective effect of tobacco seen in ulcerative colitis
CROHN DISEASE
# transmural inflammation and usually found in the ileum and cecum (proximal colon)
but has the potential to affect any part of the gastrointestinal tract from mouth to
anus.may be accompanied by extra-intestinal complications of immune origin =>
uveitis (inflammation of uvea), sacroilitis, migratory polyarthritis, erythema nodosum,
bile duct inflammatory disorders, and obstructive uropathy.
» MACRO = the mucosal surface shows patchy lesional distribution with sharply
delineated areas of disease surrounded by normal mucosa.
» Transmural involvement of the bowel by an inflammatory process with thickening of
mucosal wall The intestinal wall is rubbery and thick as a result of edema,
inflammation, fibrosis, and hypertrophy of muscularis mucosae => causing the lumen
to become narrow, Cobblestone appearance upon granular appearance of surface
mucosa .
» “Creeping fat” => formation of granulation tissue within the fissure involves the
stricture of the fissure, which will pull up the fat of the mesentery.
» Ulceration => focal in early stages (aphthous ulcers), elongated linear ulcers (due to
fusion of ulcers) as disease progresses
» MICRO = Microscopically, Crohn disease is characterized by transmural
inflammation, inflammatory cells extend from mucosa through submucosa and
muscularis and appear as infiltrates on the serosal surface anther characteristic future
is the presence of non-caseating granulomas
Clusters of neutrophils within a crypt are referred to as a crypt abscess and often are
associated with crypt destruction destruction of normal epithelial mucosa.
Epithelial metaplasia = Pseudo pyloric metaplasia /Paneth cell metaplasia also may
occur in the left colon, where Paneth cells normally are absent.
(days-weeks), malabsorption with nutritional deficiency.
» Risk for Fistula formation to other segments of the bowel, urinary bladder, vagina
or perianal skin.
» Abdominal abscesses or peritonitis.
» Intestinal stricture or obstruction.
» Perforations and peritoneal abscesses are common.
» Increased risk for colonic adenocarcinoma.
ULCERATIVE COLITIS
limited to the mucosa and submucosa.Begins in the rectum and extends proximally
(=in retrograde manner), and may involve the entire colon. (=Pancolitis)
mucosal ulcers rarely extend beyond the submucosa. Unlike in Crohn disease, mural
thickening is absent, the serosal surface is normal, and strictures do not occur.
» Isolated islands of regenerating mucosa bulge upward => pseudopolyps.
» Inflammatory infiltrates, crypt abscesses, crypt distortion, and epithelial
metaplasia = similar to Crohn.
» Ulcer- extending to submucosa.
» No granulomas.
days/weeks/months, and then subsides only to recur after an asymptomatic
interval.
» Toxic megacolon = caused by inflammation and damage to the
muscularis propria = cause neuromuscular damage.
» High risk of carcinoma development!! Depends on the extent of colonic
involvement, and the duration of the disease.
The morphology, staging and clinical features of colorectal carcinoma.
The vast majority of colorectal cancers are adenocarcinomas, tumors that arise from
the mucosa cells of the colon.
While most adenocarcinomas are well or moderately
differentiated, approximately 15% are poorly or undifferentiated tumors.
These tumors are associated with a poorer prognosis. Mucinous or colloid carcinomas, with
moderate to prodigious mucin production, are also associated with less favorable fiveyear survival rates.
THE MORPHOLOGY OF COLORECTAL CARCINOMA
# Morphologic patterns:
# Macro -> may occur anywhere along colon Both forms grow into the bowel wall
over time and may be palpable as firm masses.
» Proximal colon – tumors tend to grow as polypoid, exophytic mass that
extend along one wall of the cecum and ascending colon. but rarely cause
obstruction.
» Distal colon – carcinomas tend to encircle the lumen producing a
constrictive ring => narrowing of the lumen.
Micro -> composed of Tall columnar epithel with elongated, hyperchromatic
nuclei, increased size of nucleus.
Depending on glandular architecture, cellular
pleomorphism and mucosecretion of the predominant pattern, adenocarcinoma
may present 3 degrees of differentiation: well, moderate and poorly differentiate.
Well differentiated- The neoplastic glands are long and frond-like, similar to
those seen in a villous adenoma.
To more crowded gland appearance loss of
goblet cells and normal gland architecture….other character histo finding
include Necrotic debris in the gland lumen. And upon invasion of tumor cells
they induce Strong stromal desmoplastic response responsible for their
characteristic firm consistency even
May be composed of signet ring cells
that are similar to those in gastric cancer
The vast majority of colon carcinomas are adenocarcinomas, many of
which produce mucin. Cancers of the anus are most commonly squamous cell
carcinomas
CLINICAL FEATURES OF COLON CANCER
May Remain asymptomatic for years as symptoms develop gradually and slowly,
enhance the importance of screening from age 50/even younger at case of family
past:
» Cecal and right colonic cancers – appearance of fatigue, weakness and
iron deficiency anemia. In general Iron deficiency anemia in older men is
very suspicious for GI cancer until proven otherwise.
» Left-sided lesions – changes in bowel habits, left lower quadrant
discomfort, bleeding.
STAGING OF COLON CANCER
The two most important prognostic factors are depth of invasion and the presence
or absence of lymph node metastases.
For example tumors with muscularis
propria involvement is carrying much poor prognosis already compered to lesser depth of invasion also the occurrence of lymph node involvement much reduce
prognosis..
Colorectal tumors may spread by direct extension into adjacent structures, and by
metastasis through the lymph and blood vessels.
Sites of metastasis (in order of preference) => liver, regional lymph nodes, lungs,
bones. Note that The rectum does not drain by way of the portal circulation ->
usually doesn’t metastasize to the liver.
Staging of colorectal cancer refers to how far a cancer has spread on a scale from
0 to IV, with 0 meaning a cancer that has not begun to invade the colon wall and
IV describing cancer that has spread beyond the original site to other parts of the
body.
There is a close correlation between advancing stage and cancer mortality.
Tumor size does not appear to be important in terms of outcome.
The aggressiveness of colorectal cancer is based upon its ability to grow and invade
the colonic wall, lymphatic systeM
TNM Staging System -The TNM System, developed by the American Joint
Committee on Cancer (AJCC) is the most widely used, and is considered the
most precise and descriptive.
T stands for tumor and the depth to which it has
penetrated the colon wall, N stands for lymph node involvement, and M refers to
metastases, or whether the cancer has spread to other body parts Colorectal cancer most commonly spreads to the liver or the lungs
Detection and diagnosis is based on several test:
» Digital rectal examination.
» Fecal testing for presence of blood.
» Barium enema – barium sulfate fills the colon to give an X-ray picture.
» Sigmoidoscopy and colonoscopy.
» Biopsy for final confirmation.
» Radiographic studies (CT) to assess metastatic spread.
Acute and chronic liver failure. Cholestasis. Hepatic encephalopathy
The Liver –
The liver has the enormous task of maintaining the body’s metabolic homeostasis.
A healthy liver does the following:
1.It regulates the composition of blood, including the amounts of sugar (glucose), protein, and fat that
enters the bloodstream.
2.It removes bilirubin, ammonia, and other toxins from the blood.
3.It processes most of the nutrients absorbed by the intestines during digestion and converts those
nutrients into forms that can be used by the body.
The liver also stores some nutrients, such as vitamin
A, iron, and other minerals.
- It produces cholesterol and certain important proteins, such as albumin.
- It produces clotting factors, chemicals needed to help blood clot.
- It breaks down (metabolizes) alcohol and many drugs.
CLINICAL SYNDROMES
# The major clinical syndromes of liver disease are hepatic failure, cirrhosis, portal
hypertension, and cholestasis.
ACUTE AND CHRONIC HEPATIC FAILURE
Most severe outcome of liver disease that may develops as the end point of
progressive damage to the liver parenchyma or Less often, hepatic failure is the
result of sudden and massive destruction of hepatic tissue.
Note that Failure is almost certain when about 80%-90% of hepatic functioning tissue is lost
In many cases balance “tipped” toward dysfunction when increased stress exarted
on already injured liver such as systemic infections, electrolyte disturbances, surgery, heart failure and GI bleeding.
There are 3 categories of patterns of injury resulting in liver failure:
1) Acute liver failure with massive hepatic necrosis-
Characterized by massive hepatic necrosis, uncommon life threatening situation lead to
necessitates liver transplanted.
Most often Caused by drugs or viral hepatitis, in this type see Hepatic insufficiency that progresses into hepatic encephalopathy within 2-3 weeks.*subacute when ~3 month chain of events.
2) Chronic liver disease Most common route to hepatic failure represented
as end point of process inflicting chronic liver damage often manifest a cirrhosis.
The processes that initiate chronic damage to the liver can be
classified as:
1. Primarily hepatocytic (or parenchymal)
2. Biliary
3. Vascular
3) Hepatic dysfunction without overt necrosis -The hepatocytes are viable,
but cannot perform normal metabolic function Occurs in acute fatty liver
of pregnancy, toxicity, and Reye syndrome
Clinical features –
# In chronic liver failure
Jaundice a yellow discoloration of skin and sclerae (icterus), occurs
when systemic retention of bilirubin produces serum levels above 2.0 mg/dL.
Hypoalbuminemia => impaired synthesis of albumin; predisposes for peripheral edema.
Hyperammonemia => defective urea cycle function (takes place only in the liver)
Hyperestrogenemia => impaired estrogen metabolism; hypogonadism
and gynecomastia (in males)
Palmar erythema (a reflection of local vasodilatation)
Spider angiomas of the skin (v a central, pulsating, dilated arteriole from which small vessels radiate)
In acute liver failure May present as jaundice or encephalopathy, but
without the clinical signs of chronic liver failure (gynecomstia, spider angiomas etc.)
Complications –
# Accumulation of toxic metabolites Multiple organ systems failure
(respiratory/renal failure, pneumonia, sepsis, ).
# Coagulopathies due to impaired synthesis of blood coagulation factors
Massive GI bleeding.
CHOLESTASIS
# Bile congestion in liver result from condition in which bile cannot flow from
the liver to duodenum, decrease in bile flow may be due to impaired
secretion by hepatocytes or to obstruction of bile flow through intra-or
extrahepatic bile ducts.
Can be classified as:
# Obstruction – due to mechanical blockage in the duct system, such as
gallstone or malignancy or malformation.
# Metabolic/ intrahepatic cholestasis – due to disease of the
intrahepatic biliary tree or hepatocellular secretory failure cannot be
treated surgically.
# Morphology –may appear intracellular as bile brown pigment in
cytoplasem, also ext. cell in canaliculi system congested distant
canaliculi/filling space of disse etc.…
Symptoms include:
» Progressive fatigue
» Malabsorption of fat – no bile
» Jaundice- not always The presence of elevated serum concentration of
conjugated bilirubin is a principal sign of cholestasis. It results in
jaundice, which can be detected by scleral icterus at a concentration as
low as 2 mg/dL, and by dark urine. Pale stool (in obstructive
cholestasis)
» Elevated serum alkaline phosphatase
» Itchiness (pruritus)- unknown reason
» Skin xanthomas (accumulation of cholesterol)
HEPATIC ENCEPHALOPATHY
# Hepatic encephalopathy is a clinical syndrome of impaired brain function
occurring in patients with advanced liver failure=> manifests by the broad
spectrum of neuropsychiatric disturbances such as: behavioral abnormality,
confusion, deep coma and death
Associated with neurologic signs such as rigidity, hyperreflexia, EEG changes,
and seizures (rare).
Main characteristic is asterixis (flapping tremor) => non-rhythmic, rapid
extension-flexion movements of the head and extremities.
hyperammonemia is the main factor responsible for the brain abnormalities in
HE Two factors seem to be important in the genesis of this disorder:
» Severe loss of hepatocellular function - Nitrogenous compounds are
metabolized in liver urea cycle, resulting in the generation of urea which
is subsequently excreted through the urine
» Shunting of blood from portal to systemic circulation around the
chronically disease liver.
Exact patho mechanism is unclear but estimation: Ammonia bypasses the liver
and accumulates in the systemic circulation; it then crosses the blood-brain barrier
and is metabolized by astrocytes to synthesize glutamine Glutamine increases the
osmotic pressure within the astrocyte and is thought to cause mitochondrial
dysfunction the process of glutamine (Gln) synthesis from glutamate (Glu) and
ammonia, glutamate and as result GABA depletion
Ammonia influences also other mechanisms leading to development of hepatic
encephalopathy such as: impaired blood-brain barrier, changes in
neurotransmission, proinflammatory cytokines, and impaired cerebral blood flow
Acute setting -> elevation in blood ammonia -> impairs neuronal function
and promotes generalized brain edema.
Chronic settings -> Deranged neurotransmitter production -> neuronal dysfunction.
Hepatic bile formation serves two major functions:
Primary pathway for the
elimination of bilirubin, excess cholesterol and xenobiotics. Secreted bile salts
and phospholipid molecules promote emulsification of dietary fat in the lumen of
the gut.
In prhepatic see unconjugated bilirubin elevated in serum in hepatic see both and
in post hepatic see conjugated bilirubin elevated in serum.
Acute viral hepatitis. Pathomorphology, complications.
Hepatitis = A descriptor for specific histopathologic patterns of hepatocyte injury
associated with inflammation and, when chronic, with scarring.
Hence, Acute & chronic hepatitis = Distinguished in part by duration and in part by the pattern of
cell injury.
Causes: Hepatitis viruses A-E, Autoimmune, Drug- toxin- induced hepatitides
-> All share the same patterns of injury
MORPHOLOGY
» Mononuclear infiltrates predominate in all phases of most hepatitis
diseases because they all invoke T cell–mediated immunity.
» Distinction between acute and chronic hepatitis is based on the pattern of
cell injury and severity of inflammation.
» Acute hepatitis = less inflammation and more hepatocyte death than chronic hepatitis
Macro:
On gross inspection, liver involved by mild acute hepatitis appears normal or
slightly enlarged red liver; greenish if there is cholestasis.
At the other end of the spectrum, in massive hepatic necrosis the liver may shrink to 500to 700 g
and become transformed into a limp, red organ covered by a wrinkled, baggy capsule.
Micro:
Lobular disarray-loss of normal architecture
Hepatocyte injury-swelling (ballooning degeneration), in HCV: mild fatty
change of hepatocytes Hepatocyte necrosis isolated cells or clusters or apoptosis (shrinkage)
Inflammatory Influx- of mainly mononuclear cells into sinusoids inflammatory spillover into adjacent parenchyma When located in the
parenchyma away from portal tracts, these features are called lobular hepatitis, Kupffer cells undergo hyperplasia and Hypertrophy.
ACUTE VIRAL HEPATITIS
Infection of the liver caused by a small group of viruses’ initial infection and
following inflammation are the acute viral hepatitis in some cases it later may
progress to chronic infection yelling chronic viral hepatitis.
Acute hepatitis – less than 6 months of progression; initial features are
nonspecific flu-like symptoms with malaise (“feeling bad”), muscle and joint
pain, fever, nausea and vomiting => followed by jaundice and abdominal
discomfort.
Note that in viral hepatitis the Immune mediated mechanisms induce hepatocyte
damage in response to viral antigens.
Types of viruses:
1) Hepatitis A virus (HAV) and HEV:
both causing only acute form not progress to chronic infection hence
appearance of IgM noting acute infection while appearance of IgG signal
for resolution(note HAV got vaccine so IgG may link to immunized
individual).
Both Transmission by contaminated water and food Present in stool, got short incubation periods.
HEV infection associated with fuliment hepatitis (liver failure with massive liver necrosis)
2) Hepatitis B virus (HBV)
Causing acute hepatitis and in some caseas~20% may progress into chronic
case.
HBV-induced chronic liver disease is a precursor for development of hepatocellular carcinoma HBV-X is required for viral infectivity and may
have a role in the development of hepatocellular carcinoma by regulating p53 degradation and expression.
Prolonged incubation (4-26 weeks)
Transmission by blood and body fluids + vertical transmission from mother to
child It is NOT present in stool
Vaccine available= HBsAg
Serology:
o Hepatitis B core antigen (HBcAg) = retained in hepatocyte
o Hepatitis Be antigen (HBeAg) = Secreted to blood -> essential for infection
o Hepatitis B surface antigen (HBsAg) => produced & secreted to the blood in high amounts immunogenic.
1.acute infection – see HBsAg as initial serologic marker that rises denoting infection by virus, next in phase IgM against HBcAg
raise (in window period only one to appear in serum) in resolution
see IgG against both HBcAg and HBsAg providing protection
against future infections.
- Chronic infection- appearance of HBsAg longer than 6 months
as the mark of enter chronic state more in such patient no IgG
against HBsAg.
HBeAg or viral DNA as indicators that patient is
infective? there is IgG against HBcAg
- Patient who got vaccine or resolved the disease will have IgG against HBsAg (vaccine itself composed of viral surface AG)
3) Hepatitis C virus (HCV)
Transmission by blood and intravenous drug use
More likely to progress into chronic liver disease and eventual
cirrhosis
Incubation time 2-26 weeks
Acute hep. C is asymptomatic in 75% of cases
Persistent infection is the hallmark of HCV infection, occurring in
80% to 85% of patients with sub- clinical or asymptomatic acute
infection
Hepatitis C confers a significantly increased risk for hepatocellular carcinoma.
4) Hepatitis D virus (HDV)
Replication is dependent on HBV infection => replicates only when encapsulated by HBsAg.
Coinfection = infection by both HBV & HDV usually recover completely.
Superinfection = First HBV then HDV = acceleration of
hepatitis + more severe
Chronic hepatitis.
IgM anti-HDV antibody is the most reliable indicator of recent
HDV exposure
Clinical features & outcomes of viral hepatitis-
- Asymptomatic acute infection: serologic evidence only
- Acute hepatitis: anicteric or icteric
- Fulminant hepatitis: submassive to massive hepatic necrosis with acute liver failure.
- Chronic hepatitis: with or without progression to cirrhosis.
- Chronic carrier state: asymptomatic without apparent disease.
- HCV= development to chronic state is much more common then in HBV.
HCV= chronic.
PATHOMORPHOLOGY
Acute viral hepatitis can be caused by any of the hepatitis viruses.
# It is divided into 4 stages:
» Incubation period.
» Symptomatic pre-icteric phase – marked by nonspecific symptoms =>
fatigue, nausea, and loss of appetite.
» Symptomatic icteric phase – with jaundice and scleric icterus (=jaundice)
=> characterized by conjugated hyperbilirubinemia (causing dark colored
urine). Hepatocellular damage may occur (unconjugated
hyperbilirubinemia)
» Convalescence.
Alcoholic liver disease. Drug- and toxin-induced liver disease: different morphological forms of
injury.
Liver is the major detoxifying organ => subjected to injury by drugs and toxins. Metabolism of ethanol:
oxidation of ethanol to acetaldehyde by three different routes, and the generation of acetic acid.
Note that oxidation by alcohol dehydrogenase (ADH) takes place in the cytosol; the cytochrome P-450 system and its CYP2E1 isoform are located in the ER and catalase is located in peroxisomes.
Oxidation of acetaldehyde by
aldehyde dehydrogenase (ALDH) occurs in mitochondria.
The most common form of chronic liver diseas in the western world, manifest in 3 different forms
(collectively referred to as alcoholic liver disease)
» Hepatic steatosis (intra cellular fat accumulation)
Due to intake of ethanol (>60g/day) => Causes:
- Metabolism of ethanol by ADH produces NADH => signals the body it has enough
energy (although it doesn’t) stop glycosis + production of lipids
=> accumulation of these lipids in hepatocytes => steatosis!
Alcohol is oxidized by alcohol dehydrogenase which cause decrease in NAD+, and
increase NADH. NAD+ required for fatty acid oxidation in the liver, and by that
deficiency, fat accumulate in the liver of alcoholics
- Impaired assembly & secretion of lipoproteins.
- Increase peripheral catabolism of fat
Liver is enlarged (4-6kg), soft, yellow, and greasy micro see Fatty liver disease. steatosis
is most prominent around the central vein and extends outward to the portal tracts with
increasing severity.
The intracytoplasmic fat is seen as clear vacuoles smaller are microvasicles larger are macrovesicles may push nucleus aside..
Continued alcohol intake => fibrosis develops around the central veins and extends to
adjacent sinusoids (center to periphery)
Fatty change is a reversible state UNTIL fibrosis appears => by stopping alcohol
consumption
Clinical features – hepatomegaly with mild elevation of serum bilirubin and alkaline
phosphatase
Alcoholic hepatitis
» Usually associated with acute episode of excessive drinking it may stem from one or more of
the following toxic by products of ethanol and its metabolites: Acetaldehyde-disrupts
cytoskeleton and lipid membranes induce lipid peroxidation.
Alcohol-direct injury to cytoskeleton Mito and membrane fluidity
ROS-from ER metabolism & cytokine mediated inflammation (major cytokine TNF)-
stimulation for realis view ROS and alcohol stim.
Microbe of gut for endotoxin realis so
Kupffer cell realis cytokine
Ballooning = Swelling and necrosis => scattered cells undergo swelling due to
accumulation of fat, water and proteins, and then necrosis
Mallory dank bodies => scattered hepatocytes accumulate damaged intermediate
filaments, visible as eosinophilic cytoplasmic homogenous masses
Neutrophil infiltration => accumulate around degenerating hepatocytes; lymphocytes
and macrophages also enter the portal tracts and spill into the parenchyma
Steatohepatitis with Fibrosis => Generation of acetaldehyde and free radicals is
maximal in the centrilobular region this region is most susceptible to toxic injury
Pericellular fibrosis and sinusoidal fibrosis develop in this area of the lobule. Upon
repeated insult fibrosis become more prominent cirrhosis.
Clinical features – malaise, anorexia, presents with painful hepatomegaly and elevated
liver enzymes (AST > ALT) and fever; laboratory findings include hyperbilirubinemia,
elevated alkaline phosphate and neutrophilic leukocytosis
» Alcoholic cirrhosis
- Final and irreversible end stage organ form of alcoholic liver disease, ends as brown,
shrunken, non-fatty organ (<1kg) - For unknown reasons, cirrhosis develops in only a small fraction of chronic alcoholics.
- Concurrent viral hepatitis, particularly hepatitis C, is a major accelerator of liver disease
in alcoholics. The prevalence of hepatitis C among alcoholic is about 30% on other hand, - With complete abstinence, some regression of scar can be seen in all cases, and the
Micronodular liver transforms, with regeneration, into a macronodular - Cirrhotic organ;
- Characteristic diffuse nodularity of the surface is induced by the underlying fibrous
scarring. Small nodules with unorganized architecture are entrapped by fibrous tissue;
fatty accumulation is no longer
Seen in this “burned-out” stage. - Clinical features – Commonly, the first signs of cirrhosis relate to complications of
Portal hypertension (e.g., an abdomen grossly distended with ascites, wasted
extremities, and Caput medusa) alternatively, a patient may first present with lifethreatening variceal hemorrhage or hepatic encephalopathy. In other cases, cirrhosis
may be clinically silent, discovered only at autopsy or when stress such as infection or
trauma tips the balance toward hepatic insufficiency
Laboratory findings reflect
The developing hepatic disease, with elevated serum aminotransferase,
Hyperbilirubinemia, variable elevation of alkaline phosphatase, hypoproteinemia (globulins, albumin, and
clotting factors), and anemia. In chronic alcoholics, alcohol may become a major caloric source in the diet, displacing
Other nutrients and leading to malnutrition and vitamin deficiencies (e.g., thiamine, vitamin B12).
Among those with end-stage alcoholic liver disease, the immediate causes of death are:
- Hepatic failure
- Massive gastrointestinal hemorrhage
- Intercurrent infection (to which affected persons are predisposed)
- Hepatorenal syndrome
- Hepatocellular carcinoma in 3% to 6% of cases
NAFLD is condition in which fatty liver disease develops in persons who do not drink alcohol.
The liver Can show any of the three types of changes described earlier (steatosis, steatohepatitis, and cirrhosis).
NAFLD is associated with insulin resistance and Obesity.
DRUG- AND TOXIN-INDUCED LIVER DISEASE
# Liver is the major organ of detoxification; thus it is subjected to potential injury:
» Direct toxic damage to hepatocytes. (conversion of xenobiotic active toxin)
» Immune-mediated hepatocytes destruction. (acting as hapten)
Drug-induced liver disease is a common condition that may manifest as a mild reaction or, much more
seriously, as acute liver failure or chronic liver disease. The most important agent that produces toxic liver injury is alcohol.
Drug reactions may be classified as:
» Predictable – occur in anyone who accumulates a sufficient dose of the drug. E.g. Acetaminophen
toxicity = leading to acute failure & transplantation. The toxic agent is not acetaminophen itself,
but rather toxic metabolite produced by the cytochrome P-450 system in acinus zone 3 hepatocytes.
» Unpredictable – depends on the metabolic rate of the host and development of immune response to
the antigenic stimulus. (Individual variation) e.g. Chlorpromazine (an agent that causes cholestasis in
individuals who metabolize it slowly),
halothane (which can cause a fatal immune-mediated hepatitis in some persons exposed to this anesthetic on several occasions)
Morphology –
» Massive necrosis => the entire liver may be involved, or only random areas are affected; necrotic areas have red, may be depressed appearance. Upon Massive loss of hepatic substance => liver may shrink to 500-700g.
» Complete destruction of hepatocytes in continuous lobules leaves only reticulin framework and
preserved Drug/Toxin-Mediated Injury Mimicking Hepatitis
Clinically and histologically, drug-induced hepatitis cannot be distinguished from chronic viral hepatitis
or autoimmune hepatitis => serologic markers are critical for making a diagnosis.
» Acetaminophen toxicity = leading to acute failure & transplantation.
» Isoniazid = chronic hepatitis.
» Other drugs= induce autoimmune hepatitis.
Drug/Toxin-Mediated Injury with Steatosis
Fulminant liver failure and encephalopathy in children with viral illness who take aspirin
Presents with hypoglycemia, elevated liver enzymes, and nausea with vomiting; may Progress to coma and death Morphology: hepatocellular microvesicular steatosis. Cerebral edema
mitochondrial alternation in EM.
Metathroxate and corticosteroids induce steatosis
Amiodarone induce steattic hepatitis like alcohol
Acute pancreatitis. Chronic pancreatitis.
Pancreatitis- inflammation of pancreas range in severity from mild self-resolving to sever destructive event.
Acute pancreatitis
= function can return to normal if the underlying cause of inflammation is removed
Chronic pancreatitis is defined by irreversible destruction of exocrine pancreatic parenchyma.
ACUTE PANCREATITIS
Reversible relatively uncommon inflammatory
disorder that varies in severity,
Etiology: Most of cases are attributable to either
biliary tract disease or alcoholism.
Genetic mutation = mutation in gene PRSS1 = no
neg. feedback mechanism on trypsinogen =
hyperactivation of trypsin + other enzymes that
require trypsin cleavage for their activation.
20% idiopathic
Morphology
o The basic alterations in acute pancreatitis are:
(1) Microvascular leakage causing edema
(2) Necrosis of fat by lipases
(3) Acute inflammatory reaction
(4) Proteolytic destruction of pancreatic
parenchyma
(5) Destruction of blood vessels leading to interstitial hemorrhage.
o Mild form = Edema + Fat necrosis
Fat necrosis results from enzymatic destruction of fat cells; the released fatty acids
combine with calcium to form insoluble salts that precipitate in situ.
o Severe form (ex. acute necrotizing pancreatitis) necrosis of pancreatic parenchyma +
vascular damage (cause hemorrhage).
Macro = red-black hemorrhagic areas interspersed with foci of yellow-white, chalky
fat necrosis.
o Most severe form= hemorrhagic pancreatitis = extensive parenchymal necrosis is
accompanied by diffuse hemorrhage within the substance of the gland.
Pathogenesis
o Autodigestion of the pancreatic substance by inappropriately activated pancreatic enzymes.
Activation of trypsin is a critical triggering event in acute pancreatitis as it can activate itself
as well as other proenzymes (lots of pancreatic enzymes need cleavage for activation)
autodigestion.
Trypsin activates the kinin system activation of the clotting and complement systems.
3 pathways can cause enzyme activation:
- Pancreatic duct obstruction (gallstone, tumor) blockage of ductal flow=> increase
intraductal pressure => accumulation of enzyme rich interstitial fluid (containing active
lipase) => fat necrosis => inflammation => interstitial edema => edema compromises local
blood flow => ischemic injury to acinar cells.
- Primary acinar cell injury => ischemia, viral infections (e.g., mumps), drugs, and direct
trauma to the pancreas. - Defective transport of proenzymes within acinar cells in animal shown that metabolic
derangements contribute to abnormal transport of enzymes together with lysosomal
hydrolases result in activation.
Role of alcohol in acute pancreatitis:
1. Increases pancreatic exocrine secretion Increases contraction of sphincter of oddi.
- Direct toxic effect on acinar cells oxidative stress and membrane damage.
- Chronic ingestion results in secretion of protein rich fluid that causes obstruction of small
pancreatic ducts.
Clinical feature:
o Abdominal pain is the major manifestation of acute pancreatitis.
o Full-blown acute pancreatitis constitutes a medical emergency.
o The manifestations of severe acute pancreatitis are attributable to systemic release of
digestive enzymes and explosive activation of the inflammatory response: Leukocytosis,
DIC, ARDS (acute res. Distress syndrome) & diffuse fat necrosis.
o Can lead to shock
Pancreatic pseudocyst Liquefied areas of necrotic pancreatic tissue become walled off by fibrous
tissue to form a cystic space, lacking an epithelial lining
CHRONIC PANCREATITIS
Long-standing inflammation, fibrosis, and destruction of the exocrine pancreas. In late stages, the
endocrine parenchyma also is lost.
The chief distinction between acute and chronic pancreatitis is the irreversible impairment in
pancreatic function in the chronic state.
Etiology:
o The most common cause of chronic pancreatitis is long-term alcohol abuse.
o Less common:
Pancreatic duct obstruction (tumor/stone…)
Hereditary pancreatitis (PRRS1)
Associated with CFTR mutation => decreases bicarbonate secretion = > increase
viscosity of secretion => plugging.
Morphology:
o Parenchymal fibrosis, reduced number and size of acini, and variable dilation of the
pancreatic ducts. The ductal epithelium may be atrophied / hyperplastic .Islets of Langerhans
fused surrounded by sclerotic aggregates.
o Macro= the gland is hard, sometimes with extremely dilated ducts and visible calcified
concretions.
o Autoimmune pancreatitis (AIP)- distinct form of chronic pancreatitis:
Lymphoplasmacytic sclerosing pancreatitis-striking lymphocytes and plasma cells
infiltrate plus fibrosis
Idiopathic duct centric pancreatitis-mixed neutrophils and lymphcytic infiltrate
obliterating the duct epithel.
Pathogenesis:
Not well defined. Proposed hypotheses:
o Ductal obstruction: Alcohol => inc. protein conc. of secretion => plugs.
o Toxins: direct toxic effect injury to acinar cells and following inflammation /fibrosis.
o Oxidative stress: Alcohol generates ROS => membrane damage and chemokines expression
recruit inflammatory cells. (more oxidative stress assume to cause lysosomal and
proenzymes granules fusion subsequent enzyme activation and aggrevation of cell damage)
Clinical feature:
o Severe pancreatic exocrine insufficiency and chronic malabsorption may develop, as can
diabetes mellitus.
o Severe chronic pain may dominate the clinical picture
Acute pancreatitis. Chronic pancreatitis.
Testicular neoplasias.
- Heterogeneous group of neoplasms may be divided into 2 major groups
a. Germ cell tumor - ~95% of cases all malignant, usually occur between 15-40years
of age
b. Sex cord- stromal tumor (Sertoli or Leydig cells) - uncommon usually benign.
- Cause of testicular neoplasm remains unknown. Risk Factor:
a. Cryptorchidism (3-5 fold increase)
b. Testicular dysgenesis (testicular feminization and Klinefelter syndrome)
c. Caucasians > African Americans
d. Family history
e. An isochromosome of the short arm of chromosome 12 is found in all germ cell
tumors.
f. Most testicular tumors in post pubertal males arise from the in-site lesion
intratubular germ cell neoplasm- Lesion can be found in grossly normal
testicular tissue adjacent to germ cell tumors in all cases
- Clinical presentation
Firm, painless testicular mass
Semonimas - Account for 50% of testicular neoplasm remain confined to the testis for a
long time Spread mainly to paraarotic nodes- distant spread is rare.
Non seminomatous – tumor Tend to spread earlier by both lymph and blood vessels
Treatment: Radical orchiectomy and Chemotherapy
- Germ cell tumors- although described separately As many as 60% of germ cell tumors
are mixed and contain more than one component, tumors arising from pluripotent
neoplastic germ cells.
a. Seminoma- most common testicular cancer, good prognosis late metastasis react
to treatment
i. Gross: Soft, well-demarcated, gray-white tumor cut surface is
homogenous no hemorrhage or necrosis
ii. Micro Large polygonal, uniform cells with distinct border Clear,
glycogen-rich cytoplasm Round nuclei and visible nucleoli (resembles
ovarian dysgerminoma)
Arranged in small lobules, which are separated by fibrous septae in it may
see Lymphocytic infiltrate
Variant; spermatocytic seminoma
a. affect older men lack lymphocytic infiltrate and
syncytiotrophoblasts
b. Not associated with intralobular germ cell neoplasm Do not
metastasize
iii. In 10% of cases, syncytiotrophoblast are present that are the source of
minimally elevated serum hCG concentration
b. Embryonal carcinoma more rear 2-3% poor prognosis early metastasis poor
reaction to treatment
- Common appear at Age 20-30,malignant tumor comprised of
immature, primitive cells. - Gross: mass with hemorrhage and necrosis
Micro: large primitive appearing cells with basophilic cytoplasm
Indistinct cell borders and large hyperchromatic nuclei with
prominent nucleoli. Pleomorphic cells in cords, sheets or gland like
arrangement. - Tumor markers: Negative (pure embryonal carcinoma) but in many
cases tumor is mixed with choriocarcinoma or yolk sac tumor cells,
so their markers may appear.
c. Choriocarcinoma
- Highly malignant with early hematogenous metastases most common
in the liver and the lung. - Common appear at age of 20-30 in tumor see trophoblastic linageplacenta forming cells.
- Gross: often small, non-palpable lesions with hemorrhage on cut
surface, in compare to large metastatic centers it creates in different
locations
Micro: proliferation of syncytiotrophoblasts large eosinophilic
multinucleated cells pleomorphic nucleus intermingle with small
cuboidal cytotrophoblasts.
- Tumor marker- hCG
d. Yolk sac tumor (endodermal sinus tumor)
- Most common germ cell tumor in children younger than 3. Good
prognosis in children In adults, it is often mixed with embryonic
carcinoma. - Marco: large and may be well demarcated
- Micro: Low cuboidal to columnar epithelial cells forming microcyst,
lacelike (reticular) patterns. schiller-Duval a developing glomerulus
resembling structure character for tumor - Tumor marker- alpha fetoprotein AFP
e. Teratoma
- Neoplastic germ cells differentiate along somatic cell line Majority
are malignant in male in female bening… - Gross: often cystic masses that may contain cartilage
- Micro:tumor composed of mature fetal tissue derived from two or
three embryonic layers(ectodermal, endodermal and mesodermal) in a
haphazard arrangement. E.g. cartilage plus neuron plus glandular
/squamous epithel. - They may occur at any age in young age more common and bening
old age rear and malignant. Rarely, nongerm cell tumor may arise in
Teratoma (teratoma with malignant transformation) - Tumor marker: 90% of patients have elevated hGC and AFP
- Scrotal squamous cell carcinoma is associated with exposure to soot (chimney sweeps)
SEXCORD-STROMALTUMORS
A. Tumors that origin from stromal tissues of the testicle usually benign
- Leydig cell tumor: are derived from normal Leydig cells that produce testosterone and are
located in the interstitium of the testis. usually produces androgen, causing precocious puberty in
Children or gynecomastia in adults Characteristic Reinke crystals (eosinophilic rod-shaped
cytoplasmic structures that are the most definitive light microscopic marker of Leydig cell
differentiation) may be seen on histology.
- Sertoli cell tumor: tumor derived from Sertoli cells, located within seminiferous tubules, which
help support spermatogenesis. Sertoli cell tumors are typically composed of solid tubules
containing Sertoli cells and is usually clinically silent.
IV. LYMPHOMA
A. Most common cause of a testicular mass in males > 60 years old; often bilateral
R. Usually of diffuse large B-cell type
Epithelial tumors of the ovary.
Tumors of the ovary are amazingly varied. This diversity is attributable to the presence of
three cell types hence 3 tumor groups plus metastasis, the multipotent surface (coelomic)
epithelium, the totipotent germ cells, and the sex cord–stromal cells
SURFACE EPITHELIAL TUMORS
Most common type of ovarian tumor (70% of cases) in woman above 40 age Surface
Epithelial Tumors Serous Tumors and Mucinous Tumors, less common Endometrioid
Tumors and Brenner Tumor.
Derived from coelomic epithelium that lines the ovary; coelomic epithelium
embryologically produces the epithelial lining of the fallopian tube (serous cells),
endometrium, and endocervix (mucinous cells).
Two most common subtypes of surface epithelial tumors are serous -full of watery fluid
and mucinous- full of mucus-like fluid both are usually cystic.
Benign lesions usually are cystic (cystadenoma) and may have an accompanying
stromal component (cystadenofibroma) – benign more common in pre-menopause
woman ~40.
Malignant tumors may also be cystic (cystadenocarcinoma) or solid (carcinoma) –
malignant more common to post menopause woman~70.
Borderline tumors have features in between benign and malignant tumors.
risk factors
1) nulliparity- higher incidence in unmarried women
2) family history
3) and germline mutations in certain tumor suppressor genes- 10-15% familial associated
with BRCA1,2
Prolonged use of oral contraceptives somewhat reduces the risk
Most common malignant ovarian tumor, Prognosis is generally poor for surface epithelial
carcinoma (worst prognosis of female genital tract cancers).
Epithelial carcinomas tend to spread locally, especially to the peritoneum. CA-125 is a
useful serum marker to monitor treatment response and screen for recurrence.
1) SEROUS TUMORS
The most common of the ovarian epithelial tumors most are benign but this category
account for highest frequency malignant tumor of ovary
two types of serous carcinomas:
- low-grade (KRAS, BRAF, or ERBB2 mutations)
- high-grade (96% of tumors have mutations in TP53)
morphology: MACRO=
- Most serous tumors are large, spherical to ovoid, cystic structures up to 30 to 40
cm in diameter, may have number of compartments.
- In the benign form, the wall is smooth cystadenocarcinoma shows nodular
irregularities as it infiltrates its surrounding Serosal penetration and solid areas of
growth are suggestive of malignancy.
- The cystic spaces usually are filled with a clear serous fluid.
MICRO=
- benign tumors contain a single layer of tall columnar epithelial cells that line the
cystor cysts. The cells may be ciliated.
- In carcinoma Papillary formations are complex and multilayered, nests or
undifferentiated sheets of malignant cells invade the axial fibrous tissue.
Metastasis along lymph node periartic and local. Psammoma bodies
(concentrically laminated calcified concretions)
- Tumors of low malignant potential-which exhibit less cytologic atypia and,
typically, little or no stromal invasion.
2) MUCINOUS TUMOR
Similar to serous tumors essential difference the neoplastic epithelium consists of
mucin-secreting cells 80% are benign
Morphology:
MACRO produce cystic masses with mucinous nature of the cystic contents. They are
more likely to be larger and multicystic the serous type.
Micro= the cysts are lined by mucin-producing epithelial cells
Compared with serous tumors, mucinous tumors are much less likely to be bilateral.
This feature is sometimes useful in differentiating mucinous tumors of the ovary from
Krukenberg tumor is a metastatic mucinous tumor that involves both ovaries; most
Commonly due to metastatic gastric carcinoma (diffuse type)
Implantation of mucinous tumor cells in the peritoneum with production of massive
amounts of mucin is called pseudomyxoma peritonei in most cases, this disorder is
caused by metastasis from the gastrointestinal tract, primarily the appendix to ovary
3) Endometrioid tumor
Endometrioid rumors are composed of endometrial-like glands and are usually malignant.
i. May arise from endometriosis
ii. 15% of endometrioid carcinomas of the ovary are associated with an
Independent endometrial carcinoma (endometrioid type). Have mutations in the PTEN
tumor suppressor gene (similar to endometroid endometrial tumor)
They are bilateral in about 30% of cases they are distinguished by the formation of
similar tubular glands to those of the endometrium within the lining of the cystic space.
4) Brenner Tumor
Brenner tumors are composed of bladder-like epithelium and are usually benign.
may arise from the surface epithelium or from urogenital epithelium trapped within the
germinal ridge
macro=solid, usually unilateral ovarian tumor smoothly encapsulated and gray-white on
cut section
Micro=abundant stroma containing nests of transitional-type epithelium resembling that
of the urinary tract
GERM CELL TUMORS
2nd most common type of ovarian tumor (15% of cases) usually occur in young women of
reproductive age.
4 major groups: Tumor subtypes mimic tissues normally produced by germ cells.
- Fetal tissue—cystic Teratoma and embryonal carcinoma
1) Benign (mature) cystic Teratoma (90% of germ tumor)
tumor composed of mature tissues derived from all three germ cell layers: ectoderm,
endoderm and mesoderm Most common germ cell tumor in females;
bilateral in 10% of cases with Cystic cavity On cut section, they often are filled with
sebaceous secretion and hair (ball) foci of bone and cartilage, nests of bronchial or
gastrointestinal epithelium, and other tissues also are present
Struma ovarii is a Teratoma composed primarily of thyroid tissue.
incidentally are discovered in young women as ovarian masses or are found on
abdominal radiographs or scans because they contain foci of calcification (tooth-like
structures)
Benign, but presence of immature tissue (usually neural) or somatic malignancy (Usually
squamous cell carcinoma of skin) indicates malignant potential.
Malignant(immature) teratomas (10%) are found early in life (18y) predominantly
solid on cut section, and punctuated by areas of necrosis Uncommonly cystic foci are
present that contain sebaceous secretion similar to those of mature teratomas
On microscopic examination presence of immature elements or minimally
differentiated
- Oocytes—dysgerminoma
Tumor composed of cells with clear cytoplasm and central nuclei (resemble oocytes);
Testicular counterpart is called seminoma (both result of gonadal dysgenesis)
Solid large to small gray masses Sheets or cords of large clear cells separated by scant
fibrous strands Stroma may contain lymphocytes and occasional granulomas
All malignant but Good prognosis; responds to radiotherapy
- Yolk sac—endodermal sinus tumor
Malignant tumor that mimics the yolk sac; most common germ cell tumor in Children
Serum AFP is often elevated.
Schiller-Duval bodies (glomerulus-like structures) are classically seen on Histology
- Placental tissue—choriocarcinoma
Malignant tumor composed of trophoblasts and syncytlotrophoblasts; mimics placental
tissue, but villi are absent (unlike mole)
Small, hemorrhagic tumor with early hematogenous spread create larger metastatic
masses than primary focus.
High beta-hCG is characteristic (produced by syncytiotrophoblasts)
poor respond to chemotherapy(unlike gestational related type)
SEX CORD STROMAL TUMORS
sex cord tumors are ones of stroma come from theca granulosa cells or from fibrocytes
really
Granulosa-theca cell tumor
Neoplastic proliferation of granulosa and theca cells Often produces estrogen; presents
with signs of estrogen excess
i. Prior to puberty—precocious puberty
ii. Reproductive age—menorrhagia or metrorrhagia
iii. Postmenopausal (most common setting granulosa-theca cell tumors) Endometrial
hyperplasia with postmenopausal uterine bleeding
Malignant, but minimal risk for metastasis
- Sertoli- leydig cell tumor
Composed of Sertoli cells that form tubules and Leydig cells (between tubules)
with characteristic Reinke crystals
May produce androgen; associated with hirsutism and virilization
- Fibroma
Benign tumor of fibroblast, solid gray tumor.
Associated with pleural effusions and ascites (Meigs syndrome); resolves with removal of
tumor.
Pathology of the infertility. Gestational trophoblastic disease and neoplasias. Ectopic
pregnancy
NORMAL HISTOLOGY REVIEW:
1) Membranes: The amnion lines the amniotic sac containing the fetus. The
amnion consists of a single layer of cuboidal epithelium, its basement membrane,
and a collagen layer.
The fibrous chorion lies deep to the amnion, chorion are fetal
in origin. Deep to it is the decidual layer (maternal in origin). This layer contains
decasualized maternal cells, vessels, fibrin, and often some degree of hemorrhage.
2) Umbilical cord: The outer surface of the umbilical cord is covered by amniotic
epithelium. Normally, 3 vessels (2 arteries and 1 vein) are embedded in (Wharton’s
jelly).
3) Placental disk: The chorionic plate (fetal surface) consists of a single layer of
cuboidal amniotic epithelium overlying a paucicellular collagenous matrix
(chorion) containing numerous large vessels of fetal origin.
Below this are the villi (large stem villi to small terminal villi) separated by clear or blood containing
spaces (the intervillous space) where the maternal blood circulates around the fetal
villi.
The villi consist of an outer layer of syncytiotrophoblasts deep to the
syncytial trophoblast cells is a single, discontinuous layer of cytotrophoblasts cells
(larger, cuboidal cells).
The cellular matrix consists of macrophages and fibroblasts with numerous vessels the resulting smaller and more highly branched terminal
villi increase the effective surface area in contact with the intervillous space thereby increasing gas and nutrient exchange without a significant increase in
placental mass.
The basal plate (maternal surface) consists of intermediate trophoblast cells, decasualized maternal cells and maternal vessels Normally, these
vessels are invaded by extravillous trophoblast cells, remodeled with elimination of
surrounding smooth muscle layers and enlarging the lumens leading into the
sinusoidal intervillous spaces.
PLACENTAL INFLAMMATIONS AND INFECTIONS
Infections may reach the placenta by either of two paths:
1) ascension through the birth canal
- more common in most instances, they are bacterial and are associated
with premature rupture of the fetal membranes.
- Major causative organism: Mycoplasma, Candida, and the numerous
bacteria of the vaginal flora.
- Micro = the chorioamnion shows neutrophilic infiltration associated with
edema and congestion (acute chorioamnionitis). - the infection may involve the umbilical cord and placental villi, resulting
in acute vasculitis of the cord (funisitis).
2) Hematogenous (transplacental) spread
- Micro = on histologic examination, placental villi are the most frequently
affected structures (villitis). - Causative agents: Syphilis, tuberculosis, listeriosis, toxoplasmosis, and
various viruses (rubella, cytomegalovirus, herpes simplex virus) all can
cause placental villitis. - Transplacental infections can affect the fetus and give rise to the socalled TORCH (toxoplasmosis, other infections, rubella,cytomegalovirus
infection, herpes) complex .
ECTOPIC PREGNANCY
Ectopic pregnancy is defined as implantation of a fertilized ovum in any site
other than the uterus.
In more than 90% of these cases, implantation occurs in the fallopian tube
(oviducts-tubal pregnancy);
other sites include the ovaries and the abdominal cavity Gestation within the
abdominal cavity occurs when the fertilized egg drops out of the fimbriated
end of the oviduct and implants on the peritoneum.
Any factor that retards passage of the ovum through the oviducts predisposes
to ectopic pregnancy slowed passage is attributable to chronic
inflammation and scarring, tumors and endometriosis etc.
MORPHOLOGY
- In all sites, early development of ectopic pregnancies proceeds normally,
with formation of placental tissue, the amniotic sac, and decidual changes.
- With tubal pregnancies, the invading placenta eventually burrows
through the wall of the oviduct, causing intratubal hematoma (hematosalpinx) The tube is usually distended by freshly clotted blood
containing bits of gray placental tissue and fetal parts. - intraperitoneal hemorrhage major risk see sudden intense abdominal
pain and blood loss. - Surgical emergency;
- The histologic diagnosis depends on visualization of placental villi or, rarely, of the embryo.
GESTATIONAL TROPHOBLASTIC DISEASE
Following conception instead of develop embryo develop trophoblastic tumor
have been divided on histopathologic grounds into three overlapping
morphologic categories: hydatidiform mole, invasive mole, and
choriocarcinoma. These demonstrate a range of aggressiveness from benign
hydatidiform moles to highly malignant choriocarcinomas.
All elaborate human chorionic gonadotropin (hCG), which can be detected in
the blood and urine at levels considerably higher than those found normally at
that stage of pregnancy.
1) Hydatidiform Mole: Complete and Partial
The typical hydatidiform mole is edematous swollen chorionic villi, appearing grossly as grapelike structures. The swollen villi are covered by varying
amounts of normal to highly atypical chorionic epithelium (proliferating
trophoblasts).
There are two distinctive subtypes of hydatidiform moles: complete and partial.
Invasive Mole
Invasive moles are complete moles that are more invasive locally but do not
have the aggressive metastatic potential of a choriocarcinoma.
An invasive mole retains hydropic villi, which penetrate the uterine wall
deeply, possibly causing rupture and sometimes life-threatening hemorrhage.
MICRO= the epithelium of the villi shows atypical changes, with
proliferation of both trophoblastic and syncytial components.
Hydropic villi may embolize to distant organs, such as lungs or brain Bout
invasive and hydatidform:
- Uterus expands as if a normal pregnancy is present, but the uterus is much larger
And hCG much higher than expected for date of gestation. - Classically presents in the second trimester as passage of grape-like masses
through the vaginal canal with prenatal care, moles are diagnosed by routine
ultrasound in the early first trimester. Fetal heart sounds are absent, and a
‘snowstorm’ appearance seen on ultrasound. - Treatment is curettage. Subsequent (3-hCG monitoring is important to ensure
adequate mole removal and to screen for the development of choriocarcinoma.
In invasive case sometime scraping not enough and see prolonged hCG elevation in
some cases chemotherapy needed
3) Gestational Choriocarcinoma
Choriocarcinoma, a very aggressive malignant tumor, arises either from
gestational chorionic epithelium or within the gonads as a germ cell tumor.
Approximately 50% of choriocarcinomas arise from complete hydatidform
moles; other arise after abortion/normal pregnancy and germ cell path…
MORPHOLOGY Choriocarcinomas usually appear as hemorrhagic, necrotic
uterine massesprimary lesion “self-destruct,” and only the metastases tell the
story. Very early invade myometrium and send metastasis.
In contrast with hydatidform moles and invasive moles, chorionic villi are not
formed; instead, the tumor is composed of anaplastic cuboidal cytotrophoblasts and syncytiotrophoblasts
In most cases, choriocarcinoma manifests with a bloody, brownish discharge In
general, the β-hCG titers are much higher than those associated with a mole.
widespread vascular spread usually has occurred to the lungs (50%), vagina
(30% to 40%), brain, liver, or kidneys.
these tumors are remarkably sensitive to chemotherapy Nearly 100% of
affected patients are cured. By contrast, response of ones that arise in the
gonads (ovary or testis) is relatively poor.
PREECLAMPSIAPregnancy-induced hypertension, proteinuria, and edema, usually arising in the
third trimester; seen in approximately 5% of pregnancies
Hypertension may be Due to abnormality of the maternal-fetal vascular interface in
the placenta; resolves with delivery
Eclampsia - is preeclampsia with seizures. HELLP is preeclampsia with thrombotic
microangiopathy involving the liver; characterized by Hemolysis, Elevated Liver
enzymes, and Low Platelets Both eclampsia and HELLP usually warrant immediate
delivery.
Non-neoplastic changes of the breast and benign breast tumors.
The designation fibrocystic is applied to a miscellany of changes in the female breast that consist
predominantly of cyst formation and fibrosis. (not neoplastic)
Overall, fibrocystic changes are the most common breast abnormality seen in premenopausal
women. The changes tend to arise during reproductive age and are most likely a consequence of the cyclic breast changes that occur normally in the menstrual cycle.
NON PROLIFERATIVE CHANGES
NON-PROLIFERATIVE FIBROCYSTIC CHANGE
Characterized by an increase in fibrous stroma associated with dilation of ducts and
formation of variably sized cysts primarily affects the terminal duct lobular unit, not the
large duct.
Macro: changes usually are multifocal and often bilateral. The cysts range from less than
1 cm and up to 5 cm in diameter. Unopened, they are brown to blue (blue dome cysts)
and are filled with watery, turbid fluid. The secretions within the cysts may calcify,
producing microcalcifications on mammograms.
Micro=epithelial lining that in larger cysts may be flattened or even totally atrophic
Apocrine metaplasia = a variant of non-proliferative fibrocystic change the lining cells
are large and polygonal with abundant granular, eosinophilic cytoplasm (apical secretory
granules) and small, round, deeply chromatic nuclei, do not increase risk for neoplastic
change!
The stroma surrounding all types of cysts usually consists of compressed fibrous tissue
that has lost the delicate, myxomatous appearance of normal breast stroma.
EPITHELIAL HYPERPLASIA
a variant of proliferative fibrocystic change in which fined more than the 2 normal
lining epithelial layers of the duct. Normal ducts and lobules of the breast are lined by
two layers of cells—a layer of luminal cells overlying a second layer of myoepithelial
cells.
MICRO= The ducts or lobules may be filled with orderly cuboidal cells within which
small gland patterns (called fenestrations)
The proliferating epithelium projects as multiple small papillary excrescences into the
ductal lumen ductal papillomatosis).
atypical ductal/lobular hyperplasia is used to describe hyperplasia’s that exhibit
changes that start to resemble ones of carcinoma in situ(see description next pic)
Both atypical ductal and lobular hyperplasia are associated with an increased risk of
invasive carcinoma.
SCLEROSING ADENOSIS
hyperplastic process involving an increased number of glandular components (number of
glands in one TDLU) =adenosis plus stromal proliferation that create hard palpable
mass=sclerosis
Less common but worth mentioning cause Its clinical and morphologic features may
mimic those of carcinoma.
MACRO= the lesion has a hard, rubbery consistency, similar to that of breast cancer.
MICRO= shows a characteristic: enlarged TDLU Preservation of luminal lining of
epithelium and myopithel layer (Help to distinguish from invasive ductal carcinoma)
with surrounding Dens Stromal fibrosis, which may compress and distort the
proliferating glands.
BENIGN BREAST TUMORS
E.
FIBROADENOMA
The most common benign neoplasm of the female breast. no increased risk of carcinoma
It is a biphasic slow growing tumor composed of fibroblastic stroma and epithelium-lined
glands = only the stromal cells are clonal and truly neoplastic.
They seen as solitary mobile masses firm consistency number of cm size mass.
Estrogen sensitive grows during pregnancy and may be painful during the menstrual
cycle also they peak in appearance in 3rd decade of life and after menopause, they may
regress and calcify.
A cut section shows a uniform grayish white color, punctuated by softer yellow-pink
specks representing the glandular areas.
MICRO: The epithelial proliferation appears as duct-like spaces of various shapes and
sizes surrounded by a loose fibroblastic stroma. Depending on the proportion and the
relationship between these two components, there are two main histological features:
intracanalicular and pericanalicular. Often, both types are found in the same tumor.
Intracanalicular fibroadenoma: stromal proliferation predominates and compresses the
ducts, which are irregular, reduced to slits.
Pericanalicular fibroadenoma: fibrous stroma
proliferates around the ductal spaces, so that they remain round or oval, on cross section.
The basement membrane is intact.
PHYLLODES TUMOR
Fibroadenoma-like tumor However, the stromal element of these tumors is more cellular
and abundant, often forming epithelium lined leaflike projections (phyllodes is Greek for
“leaflike”).
Less common than fibroadenomas arise de novo, not from preexisting fibroadenomas.
changes suggesting malignancy include increased stromal cellularity, anaplasia, high
mitotic activity, rapid increase in size, and infiltrative margins but most phyllodes
tumors remain localized and are cured by excision
INTRADUCTAL PAPILLOMA
Intraductal papilloma is a benign neoplastic papillary growth. Most often seen in
premenopausal women.
These lesions typically are solitary and found within the principal lactiferous ducts or
sinuses.
The clinical presentation may include
* Serous or bloody nipple discharge
* The presence of a small subareolar tumor a few millimeters in diameter
* Nipple retraction
MICRO= they are composed of multiple papillae, each having a connective tissue core
covered by epithelial cells that are double-layered, with an outer luminal layer overlying
a myoepithelial layer. The presence of a double-layered epithelium helps to distinguish
intraductal papilloma from intraductal papillary carcinoma.
Precancerous diseases of the breast. Breast carcinomas.
2nd to lung cancer in cancer related death among women The lifetime risk of developing breast cancer is
1 in 8 for women and 20-30% mortality rate in the United States.
risk factors for breast cancer:
1) Age. Risk increases after age of 30 , especially after menopause
2) Geographic Variations. The risk is significantly higher in North America and northern Europe than in
Asia and Africa. These differences seem to be environmental rather than genetic in origin.
3) Family history
4) Age at menopause greater than 55
5) 1st Pregnancy after age of 35/nulliparous
6) Benning breast diseas as proliferative atypical hyperplasia
7) Other Risk Factors.
- Prolonged exposure to exogenous estrogens postmenopausally, as occurs with hormone replacement
therapy/Oral contraceptives- no effect. - Ionizing radiation its age-period of time depended before age of 30 during breast development and
its dose depended also (therapy radiation increase risk but mammography not-smaller dose). - Less establish relation to: Obesity-alcohol consumption and a diet high in fat
pathogenesis:
three sets of influences seem to be important:
1) Genetic changes
Is overexpression of the HER2/NEU proto-oncogene, which undergoes amplification in ~ 30% of
invasive breast cancers. This gene is a member of the epidermal growth factor receptor family,
and its overexpression is associated with a poor prognosis. Also Amplification of RAS and MYC
genes also has been reported in some human breast cancers.
Gene expression profiling has demonstrated the presence of four molecular subtypes with
distinct natural histories and clinical behavior. these generally align with the presence or absence
of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor
receptor 2 (HER2):
(1) Luminal A (estrogen receptor–positive, HER2/NEU-negative);most common good
prognosis associated with age
(2) Luminal B (estrogen receptor–positive, HER2/NEU overexpressing); less good
prognosis
(3) HER2/ NEU positive (HER2/NEU over expressing, estrogen receptor– negative); less
common more aggressive appear at younger ages
(4) basal-like (estrogen receptor–negative and HER2/NEU-negative).also called triple
negative appear more in African American woman carry poor prognosis and appear at
younger age pre-menopausal.
~10% of cases are hereditary breast cancer specific related to one mutation, manifest as
premenopausal appearance see also in first degree relative and bilateral tumor/other related
tumor e.g. ovarian
Roughly one third of women with hereditary breast cancer have mutations in BRCA1 or
BRCA2 ).both BRCA1 an BRCA2 are believed to function in a common DNA repair pathway
BRCA1 and BRCA2 are classic tumor suppressor genes, in that cancer arises only when both
alleles are inactivated or defective—the first caused by a germline inherited mutation and the
second by a subsequent somatic mutation.
Less common genetic diseases associated with breast cancer are the Li-Fraumeni syndrome,
Cowden syndrome (caused by germline mutations in PTEN—mentioned earlier under
endometrial carcinoma) and the ataxia-telangiectasia gene carriers.
2) Hormonal Influences.
Estrogen excess = hormonal imbalance Estrogens stimulate the production of growth factors (such
as TGF-α, PDGF, and FGF) may promote tumor development through paracrine and autocrine
mechanisms.
3) Environmental Variables. See above geography treatments alcohol obesity etc.…
Morphology:
The most common location of tumors within the breast is in the upper outer quadrant (50%), followed
by the central portion (20%).
Breast cancers are classified according to whether they have or have not penetrated the limiting
basement membrane:
A. Noninvasive
1. Ductal carcinoma in situ (DCIS)
2. Lobular carcinoma in situ (LCIS)
B. Invasive (infiltrating)
1. Invasive ductal carcinoma (“not otherwise specified”), the most common subtype of invasive
carcinoma
2. Invasive lobular carcinoma
3. Medullary carcinoma
4. Colloid carcinoma (mucinous carcinoma)
5. Tubular carcinoma
6. Other types
Noninvasive (in situ) Carcinoma
include: DCIS and LCIS. both types usually arise from ductal epithelium of the terminal duct lobular
unit.
DCIS tends to fill and expand ductal lumen with proliferating ductal cells and necrosis, By contrast,
LCIS usually expands but does not alter the acini of lobules
PAGET DISEASE OF THE NIPPLE
is caused by the extension of DCIS up the lactiferous ducts and into the contiguous skin of the nipple, producing
a unilateral crusting exudate over the nipple and areolar skin.
In almost all cases, an underlying carcinoma is present, and approximately 50% of the time this
carcinoma is invasive.
Prognosis is based on the underlying carcinoma and is not affected by the presence of Paget disease.
Invasive (Infiltrating) Carcinoma
1) Invasive ductal carcinoma
- A majority (70% to 80%) of cancers fall into this group. type of cancer usually is associated with DCIS
and, rarely, LCIS.
- Most ductal carcinomas produce a desmoplastic response = which replaces normal breast fat (resulting
in a mammographic density) and forms a palpable mass - The microscopic appearance is quite heterogeneous, ranging from tumors with well-developed tubule
formation and low-grade nuclei to tumors consisting of sheets of anaplastic cells The tumor margins
typically are irregular - About two thirds express estrogen or progesterone receptors, and about one third overexpress
HER2/NEU.
2) Invasive lobular carcinoma
- Origen from lobule neoplastic cells morphologically identical to the cells of LCIS (monomorphic, mucin
vacuoles). Two thirds of the cases are associated with adjacent LCIS. - The cells invade individually into stroma and are often aligned in “single-file/indian file” strands or
chains. Associated with mutations in E cadherin - Most exhibit desmoplastic reaction so create palpable mass.
- Lobular carcinomas have a unique pattern of metastases among breast cancers; they more frequently
spread to cerebrospinal fluid, serosal surfaces, gastrointestinal tract, ovary, uterus, and bone marrow. - Almost all of these carcinomas express hormone receptors, whereas HER2/NEU overexpression is rare.
3) Inflammatory carcinoma
4) Medullary carcinoma
- is a rare subtype of carcinoma, create cohesive sheets of high pleomorphic cells with well
circumscribed, “pushing” borders, associated with prominent lymphocyte and plasma cells infiltration
- Medullary carcinomas occur with increased frequency in women with BRCA1 mutations And its triplenegative tumor.
5) Colloid (mucinous) carcinoma
- also is a rare subtype.The tumor cells produce abundant extracellular mucin into the surrounding stroma
Like medullary carcinomas, they often present as well-circumscribed masses and can be mistaken for
fibroadenomas.On gross evaluation, the tumors usually are soft and gelatinous.
- Most express hormone receptors
6) Tubular carcinomas
Common Features of Invasive Cancers
- Invasive cancers tend to become adherent and fixed to the pectoral muscles or deep fascia of the chest
wall and the overlying skin, with consequent retraction or dimpling of the skin or nipple.first indication
of malignancy. - Involvement of the lymphatic pathways may result in localized lymphedemaIn such cases, the skin
becomes thickened around exaggerated hair follicles, giving an appearance known as peau d’orange
(“orange peel”).
Clinical course:
At the time of clinical detection, the carcinoma typically is 2 to 3 cm in size, and involvement of the
regional lymph nodes (most often axillary) is already present in about 50% of patients.
Breast cancer spread occurs through lymphatic and hematogenous channels. Favored locations are the
lungs, skeleton, liver, adrenals, and (less commonly) brain, but no site is exempt.
Prognosis
tumor-node-metastasis (TNM) staging classification:
1) Tumor invasion and size. In situ carcinomas carry an excellent prognosis (5-year survival rate greater
than 90%), as do invasive carcinomas less than 2 cm in size (5-year survival rate of 87%).
2) Extent of lymph node involvement. With no axillary node involvement, the 5-year survival rate is close
to 80%.
Survival is inversely related to the number of involved lymph nodes and is less than 50% with 16 or
more involved nodes.
Sentinel node biopsy is currently the mainstay for staging the axila = This procedure identifies the
primary lymph node(s) that drain the breast parenchyma using dye or a radioactive tracer (or sometimes
both). Once identified, sentinel nodes are removed and examined microscopically.
3) Distant metastases. Patients who develop hematogenous spread are rarely curable
4) Histologic grade. The most common grading system for breast cancer evaluates tubule formation,
nuclear grade, and mitotic rate.
5) The histologic type of carcinoma. All specialized types of breast carcinoma (tubular, medullary, and
mucinous) are associated with a somewhat better prognosis than carcinomas of no special type (ductal
carcinomas). A major exception is inflammatory carcinoma, which has a poor prognosis.
6) The presence or absence of estrogen or progesterone receptors. The presence of hormone receptors
confers a slightly better prognosis.
Overexpression of HER2/NEU. Overexpression is associated with a
poorer prognosis. However, the clinical importance of evaluating HER2/NEU lies in predicting response
to trastuzumab (Herceptin), a monoclonal antibody that binds and inhibits the function of HER2/NEU.
Hyperpituitarism. Pituitary adenomas
- Pituitary gland
a. Small, bean shaped structures located at the base of the brain, on the sella turcica.
b. Connected to the hypothalamus by a stalk composed of axons and a rich venous plexuse.
c. Central role in regulation of other endocrine glands
d.Composed of two functionally and morphologically distinct components:
1.The anterior pituitary, or adenohypophysis, is composed of epithelial cells derived embryologically from the
developing oral cavity. In routine histologic sections, see array of cells containing basophilic cytoplasm,
eosinophilic cytoplasm, or poorly staining (chromophobic) cytoplasm the staining properties of these cells are
related to the presence of various trophic polypeptide hormones within their cytoplasm .
The pink acidophils secrete growth hormone (GH) and prolactin (PRL)
The dark purple basophils secrete corticotrophin (ACTH), thyroid stimulating hormone (TSH), and
gonadotrophins follicle stimulating hormone-luteinizing hormone (FSH and LH)
The pale staining chromophobes have few cytoplasmic granules, but may have secretory activity.
The release of trophic hormones is in turn under the control of factors produced in the hypothalamus; while most hypothalamic factors are stimulatory and
promote pituitary hormone release, others (e.g., somatostatin and dopamine) are inhibitory in their effects Rarely, signs and symptoms of pituitary disease may be caused
by excess or lack of the hypothalamic factors, rather than by a primary pituitary abnormality.
2.The neurohypophysis shown here resembles neural tissue, with glial cells, nerve fibers, nerve endings, and
intra-axonal neurosecretory granules. The hormones vasopressin (antidiuretic hormone, or ADH) and oxytocin
made in the hypothalamus (supraoptic and paraventricular nuclei) are transported into the intra-axonal
neurosecretory granules where they are released.
Diseases of the pituitary, accordingly, can be divided into those that primarily affect the anterior lobe and those that primarily affect the posterior lobe.
Hyperpituitarism and pituitary adenoma
Hyperpituitarism arises from excessive secretion of trophic hormones. It most often results from an anterior
pituitary adenoma but also may be caused by other pituitary and extrapituitary lesions .Causes of
hyperpituitarism:
a. Adenoma arising in anterior lobe (most common)
b. Hyperplasia and carcinoma of anterior lobe
c. Secretion of hormones by extrapituitary tumors
d. Hypothalamic disorders
Pituitary adenomas
Benign tumor of anterior lobe Found in adult 30-50 years old.
pituitary adenomas are usually composed of a single type of cell type and produce a single predominant
hormone.
Some adenomas secrete two hormones Most common combination- GH and prolactin
Plurihormonal adenomas- rare
May be functional (hormone producing and clinical sings), nonfunctional ( clinical silent) or hormone
negative
i. Nonfunctional and hormone negative (null cell) Likely to come to clinical attenation at a later stage
May cause hypopituitarism due to compression of the normal pituitary tissue
ii. Functional tumors represent with features based on the type of hormone produced.
Most adenomas occur as isolated lesion Microadenomas- less than 1 cm Macroadenoma- exceeds 1 cm in
diameter.
Most cases are sperodic but ~3% of adenomas are associated with multiple endocrine neoplasia.
Pathogenesis
One of most common mutations is Constitutive activation of a stimulatory G protein. A mutation in the alpha-subunit that interferes with its intrinsic GTPase activity Results in persistent generation of cAMP and
unchecked cellular proliferation Alpha subunit is encoded by GNAS1 gene
Pituitary adenomas that arise in the context of familial MEN-1 syndrome harbor mutation from MEN-1 gene
(interfer with check point regulation on p27) appear at younger age
Other abnormality is P53 mutation aggressive tumor.
Morphology
Usually well circumscribed, soft small lesion. Small tumors are confined by sella turcica, while larger lesions
typically extend into supracellar region, where they compress optic chiasm and adjacent structures.
Invasive adenomas- In 30% of cases, adenomas are grossly nonencapsulated and infiltrate adjacent bone,
dura and (uncommonly) bone.
Microscopically- mark by cellular monomorphism and absence of reticulin network.
Composed of relatively uniform, polygonal cells arrayed in sheets, cords or papillae Very little mitotic
activity Cytoplasm may be acidophilic, basophilic or chromophobic depending on type of secretory product.
Supportive CT-reticulin, is relatively absent accounting for soft consistency
Different adenomas subtypes
1. Prolactinoma
Most common type of pituitary adenoma Hyperprolactinemia due to Lactotroph cells secrete prolactin.
Hyperprolacinemia may be caused by other conditions than adenoma pregnancy, high dose estrogen
therapy/dopamine inhibiting drugs, renal failure, hypothalamic lesions or Stalk effect- any mass in the
suprasellar compartment that may disturb the normal inhibitory influence of hypothalamus on prolactin
secretion.
Clinical features
- Galactorrhea, amenorrhea and infertility
- Decreased libido and impotence
- Manifestation of hyperprolactinemia is more obvious in postmenopausal women.
- Growth hormone producing adenoma
GH producing , somatotroph cells, neoplasms are the second most common type of functional pituitary
adenoma Clinical manifestation may be subtle, so spmatotroph cell adenoma may be quite big by the time they
come to clinical attention
Microscopically Densely or sparsely granulated cells and GH within cytoplsm
Lab Elevated GH Elevated somatomedin C (IGF-1)
Giantism Occurs in children and adolescents prior to fusion of the growth plates Tall structure and long extremities
Acromegaly Occurs in adults after the growth plates have fused Prominent jaw Flat, broad forehead Enlarged
hands and feet The internal organs are typically enlarged
GH excess is also associated with a number of other disturbances Abnormal glucose and diabetes mellitus
Generalized muscle weakness Hypertension Arthritis Osteoporosis Congestive heart failure
- Corticotroph cell adenomas
Usually small at the time of diagnosis Usually stained positive with PAS as a result of the accumulation of
glycosylated ACTH proteins ACTH is synthesized as part of a larger prohormone that includes melanocyte
stimulating hormone, there may be hyperpigmentation.
May be clinically silent or may cause hypercortisolism (Cushing syndrome) because of stimulatory effect on
adrenal cortex.
Cushing disease- when hypercorticolism is caused by excessive production by pituitary gland
Nelson syndrome- aggressive corticotroph adeomona may develop after surgical removal of adrenal glands for treatment of cushing syndrome. Due to loss of the inhibitory effect of adrenal chorticoids on a preexisting corticotroph microadenoma
- Other anterior pituitary neoplasm
Gonadotroph (LH and FST-producing hormones) adenoma
Difficult to recognize
a. Secrete hormones inefficiently and variably
b. Secretory product do not cuase a recognizable clinical syndrome
Most frequent in middle age when tumor becomes large enough to cause neurological symptoms
Impaired vision Headaches Diplopia
FSH is usually the predominant secreted hormone.
Thyrotroph (TSH-produsing hormone) adenoma Rare cause of hyperthyroidism
Pituitary carcinoma Rare Local extension beyond the sella turcica Always distant metastases
Benign and malignant tumors of the thyroid gland.
- Thyroid Adenoma
a. Benign neoplasms derived from follicular epithelium appearing as solitary nodule.(multy
nodular pattern is for multinodular goiter)
b. Pathogenesis
In toxic adenomas one who produce TH see mutations in compartments of TSH receptor
signaling pathway Gain of thyroid autonomy (independ of TSH see TH secretion) such as
mutations in Gene encoding TSH receptor and less common in Alpha subunit of G protein as
signal trasducer part in signaling pathway of TSH receptor
In some of non-functional follicular adenoma exhibit mutations of RAS of PIK3CA which
shared with subsets of follicular carcinomas hence some of it may arise from adenoma…
c. Morphology
i. Solitary nodule compress non-neoplastic thyroid. Has well defined capsule
.(multinodular goiter no capsule multiple nodules no compression of parenchyma)
ii. Micro cells are arranged in uniform follicles that contain colloid-well differentiated.
If Neoplastic cells have bright eosinophilic granular cytoplasm and small nucleus
they called oxyphils/hurthle cells(and adenoma classified as hurthle cell adenoma)
May exhibit focal nuclear pleomorphism, atypia, and prominent nucleoli- endocrine
atypia.
Not infiltrate capsule its completely intact unlike in follicular carcinoma.
d. Clinical features
i. Usually painless nodules, large masses may produce local symptoms like difficulty in
swallowing.
ii. Vast majority are not functional but some may produce thyroid hormone and cause
hyperthyroidism (toxic adenoma)
iii. After injection of radioactive iodine, most adenomas take up iodine less avidly than
normal parenchyma. Therefore on radionuclide staining appears as cold nodules
relative to normal gland Toxic adenoma, however appears at warm nodules in the scan
- Carcinomas of the thyroid
All carcinomas on gross look as solitary nodule may be encapsuled or diffuse infiltrative marigin….
And all usually cold nodules.
Papillary carcinoma
- Epidemiology
a. Most common form of thyroid cancer(~85%) although thyroid cancer as itself is rear ~1% of
cancer cases..
b. Tumor may occur at any age
- Pathogenesis
a. Environmental- radiation exposure
b. Genetics- Activation of MAP kinase pathway featured in most of papillary subtypes, may done
by one of the two major mechanism - Rearrangements of RET or NTRK I (neuroytophic thyrosine kinse I) – encode for
tyrosine kinase receptor(fusion gene by usually non expressed in follicular epithel
RET(encode tyr kinas part of receptor) and PTC gene constantly expressed gene
(papillary thyroid carcinoma gene) so formed RET/PTC product gene and gain of
function to pathway) - Point mutation in gene of RAF protein , an intermediate signaling component in
the MAP kinase pathway - Gross May show as encapsulate or diffuse invasive form uni or multifocal Lesions may contain area of
fibrosis and calcification and often are cystic
Micro
a. Diagnostic essential feature is the appearance of Clear “orphan annie eye” nuclei
b. The tumor typically exhibits a papillary pattern with dense fibrovascular cores (true papilla) and
along rims see neoplastic cells pileup on each other.
c. Occasional psammoma bodies- concentrically calcified structure present in papillae
- Clinical features
a. Non-functional tumors
b. Indolent lesion with 10-year survival rate at 95% Over a dozen variant of papillary thyroid
carcinoma Most common- follicular variant Encapsulated Lower incidence of lymph node
metastases(if do so to cervical nodes)
c. Prognosis depends on age, extrathyroidal extension and present of distant metastases.
Follicular carcinoma
- Accounts for 15% of malignant thyroid tumors Female>male; age 40-60
- Pathogenesis
a. Environment- ionizing radiation and deficiency of dietary iodine more Frequent in areas with
dietary iodine deficiency
b. Genetics
i. Mutation in the PI-3K/AKT signaling pathway resulting in constant activation of
oncogenic pathway.
- Gain of function point mutation or Amplification of PI3K
- Loss of function mutation of PTEN (a tumor suppressor and a negative regulator
of the pathway)
ii. PAX8/PPARG fusion genes may impire the complete cell diffrantiation.
1. PAX8- homeobox gene that is important in thyroid development
- Peroxisome proliferator-activated receptor gene- gene which codes for a nuclear
hormone receptor - Morphologya. Microscopically-uniform cell appearance forming small follicles including colloid –not arranged
areas with back to back follicle irregular shape areas only tumor cells no CT or c cells etc..
Encapsulated but invade the capsule! And may see hurthle cells
b. Grossly may be widely invasive of minimally invasive minimally invasive carcinoma is sharply
demarcated and may be indistinguishable from follicular adenoma on gross examination
- Clinical features
a. Manifests as solitary cold thyroid nodules. In rare cases may be hyperfictional
b. Unlike carcinoma usually lymphatic spread it show Hematogenouse dissemination to lung, bone
and liver( which other carcinomas show it ? hepatocellular renal cell carcinoma and
choriocarcinomas )
Medullary carcinoma
- Neuroendocrine neoplasm arise from C cell (parfollicular cells) and secretes calcitonin. In some cases,
tumor cells elaborate other polypeptide hormones such as somatostatin, serotonin and VIP. - Majority are sporadic and minority are familial associated with MEN 2A or 2B syndromes or notassociated with MEN syndrome.
a. Sporadic and familial not associated with MEN- occur in adult. 50-60 yo
b. Familial associated with MEN- seen in younger patients including children.
- Pathogenesis
a. Genetics:
i. Familial medullary thyroid cancer occur in multiple endocrine neoplasia type 2 and are
associated with germline RET proto- oncogene mutation that leads to constitutive
activation of receptor
ii. RET mutations are also seen in sporadic cases.
b. Environment- ionizing radiation
- Morphology
a. May arise as a solitary nodule or as multiple lesions on both thyroid lobes.
b. Micro:
i. Nests of polygonal neoplastic cells in amyloid stroma derived from altered calcitonin
molecules.
ii. Calcitonin is demonstrated within the cytoplasm of tumor cells and in stroma
iii. EM reveleas variable number of intracytoplasmic membrane bound, electron-dense
granules
iv. Familial medullary carcinoma
- Multicentricity- large lesion contain areas of necrosis and hemorrhage and may
extend through the capsule of the gland - Multicentric C cell hyperplasia in the surrounding thyroid parenchyma
a. It is believed to be precursor lesions from which medullary carcinoma
arise.
- Clinical features
a. Manifests as a mass in the neck
i. Associated with compression effects such as dysphagia and hoarseness
b. In some cases manifests as secretion of peptide hormones
i. Diarrhea caused by VIP
c. Early detection of familial cases can be done by
i. Patient’s relatives for elevated calcitonin level
ii. RET mutations
Anaplastic carcinoma
- Presentation Females>males; age >60 years Firm, enlargeing, bulky mass Tendency for early
widespread metastasis and invasion of the trachea and esophagus
a. Risk factor- past history of well differentiated thyroid carcinoma
- Pathogenesis
a. De novo or more common as Dedifferentiation of well-differentiated papillary or follicular
carcinome
b. Genetics Molecular alteration seen in well differenatiated carcinoma (RAS or PIK3CA mutation)
Inactivation of TP53 is essentially restricted to anaplastic carcinoma
c. Environment- ionizing radiation
3. Micro: undifferentiated, anaplastic cells
a. large pleomorphic giant cells
b. spindle cells with sacromatous appearance
c. mixed spindle and giant cell lesions
4. Prognosis: very aggressive and rapidly fatal.
Tumors of the bone (osteoma, osteoid osteoma, osteoblastoma, osteosarcoma).
BENIGN
1) OSTEOMA
Osteomas are benign lesions most commonly encountered in the head and
neck, including the paranasal sinuses
They typically present in middle age as solitary, slowly growing, hard,
exophytic masses on a bone surface.
Multiple lesions are a feature of Gardner syndrome
MICRo = , osteomas recapitulate cortical type bone and are composed of a
mixture of woven and
lamellar bone.
Although they may cause local mechanical problems (e.g., obstruction of a
sinus cavity) and cosmetic deformities, they are not locally aggressive and
do not undergo malignant transformation.
2) OSTEOID OSTEOMA AND OSTEOBLASTOMA
Benign tumor of the osteoblast
Osteoid osteomas and osteoblastomas are benign neoplasms with very
similar histologic features.
appear during the teenage years and 20s, with a male predilection
They are distinguished from each other primarily by their size and clinical
presentation.
Osteoid osteomas arise most often beneath the periosteum or within the
cortex in the proximal femur and tibia or posterior spinal elements = mainly
long bones,and are by definition less than 2 cm in diameter, Localized pain,
most severe at night, is an almost universal complaint with osteoid osteomas,
and usually is relieved by aspirin.
osteoblastomas are larger and most often in the vertebral column. they also
cause pain, although it often is more difficult to localize and is not
responsive to aspirin.
. Malignant transformation is rare unless the lesion is treated with
irradiation.
Morphology:
MACRO = both lesions are round-to-oval masses of hemorrhagic, grittyappearing tan tissue.
A rim of sclerotic bone is present at the edge of both types of tumors = it is
much more conspicuous in osteoid osteomas.
MICRO = examination, both neoplasms are composed of interlacing
trabeculae of woven bone surrounded by osteoblasts
The intervening stroma is loose, vascular connective tissue containing
variable numbers of giant cells.
MALIGNANT
1) OSTEOSARCOMA
Osteosarcoma is a bone-producing malignant mesenchymal tumormalignant proliferation of osteoblast.
After myeloma and lymphoma, osteosarcoma is the most common
primary malignant tumor of bone, accounting for approximately 20%
of primary bone cancers;
Although any bone Can be involved, most tumors arise in the
metaphyseal region of the long bones of the extremities, with almost
60% occurring about the knee, 15% around the hip, 10% at the
shoulder, and 8% in the jaw.
Risk factores: paget disease, familial RB, radiation. Spontaneous
osteosarcoma occur in TP53 mutation.
Several subtypes of osteosarcoma are distinguished on the basis of the
site of involvement within the bone (e.g., medullary versus
cortical),degree of differentiation, number of involved sites, presence
of underlying disease, and histologic features;
the most common type of osteosarcoma is primary, solitary,
intramedullary, and poorly differentiated, producing a predominantly
bony matrix.
Morphology:
Macro = are gritty-appearing, gray-white tumors, often exhibiting
hemorrhage and cystic degeneration. Tumors frequently destroy the
surrounding ortices, producing soft tissue masses, Extensibly
infiltrating.
Micro = Tumor cells vary in size and shape and frequently have large
hyperchromatic nuclei; bizarre tumor giant cells are common, as are
mitotic figures.
The production of mineralized or unmineralized bone (osteoid) by
malignant cells is essential for diagnosis of osteosarcoma
When malignant cartilage is abundant, the tumor is called a
chondroblastic osteosarcoma.
Clinical :
- Osteosarcomas typically manifest as painful enlarging masses,
although a pathologic fracture can be the first sign.
- Radiographic imaging usually shows a large, destructive, mixed
lytic and blastic mass with indistinct infiltrating margins = The
tumor frequently breaks through the cortex and lifts the periosteum, resulting in reactive periosteal bone formation.
- A triangular shadow on the x-ray film between the cortex and
raised periosteum (Codman triangle) is characteristic of osteosarcomas. - Osteosarcomas typically spread hematogenously; ademonstrable
pulmonary metastases,
BENIGN
1) OSTEOCHONDROMA
Tumors of bone with overlying cartilage cap.
Solitary osteochondromas typically are first diagnosed in late
adolescence and early adulthood (
multiple osteochondromas become apparent during childhood, occurring
as multiple hereditary osteochondromas,autosomal dominant disorder.
Inactivation of both copies of the EXT1 or EXT2 genes through mutation
in chondrocytes is implicated in both sporadic and hereditary
osteochondromas
These tumor suppressor genes encode
glycosyltransferases essential for polymerization of heparin sulfate, an
important component of cartilage.
Osteochondromas develop only in bones of endochondral origin arising
at the metaphysis near the growth plate of long tubular bones, especially
about the knee
Occasionally they develop from bones of the pelvis, scapula, and ribs
and in these sites = long bones
Morphology:
- Range from 1-20 cm in size, and have a cartiligneous cup
- Hyaline cartilage
Clinical Features
- Osteochondromas are slow-growing masses that can be painful
- Solitary osteochondromas rarely progress to chondrosarcoma or
other sarcomas, but malignant transformation occurs more
frequently in those with multiple hereditary osteochondromas.
2) CHONDROMA
Chondromas are benign neoplasms of hyaline cartilage.
When they arise within the medulla, they are termed enchondromastypically are solitary and located in the metaphyseal region of tubular
bones, the favored sites being the short
tubular bones of the hands and feet.
Ollier disease is characterized by multiple chondromas preferentially
involving one side of the body, and Maffucci syndrome is characterized
by multiple chondromas associated with soft tissue spindle cell
hemangiomas.
when on the bone surface, they are called juxtacortical chondromas.
Pathogenesis:
- Enchondromas occurring in Ollier disease and Maffucci syndrome
frequently contain point mutations in either isocitrate
dehydrogenase I (IDH1) or IDH2 that create a new enzyme
activity. (The same IDH mutations occur as somatic mutations in
acute myeloid leukemias and gliomas), the mutations occurred
early during embryonic development, an example of genetic
mosaicism.
Morphology:
- Enchondromas are gray-blue, translucent nodules usually smaller
than 5 cm in greatest dimension.
- Micro = , they are well circumscribed and composed of hyaline
cartilage containing cytologically benign chondrocytes. - At the periphery, there is endochondral ossification, while the
center frequently calcifies and dies. I - in the hereditary multiple chondromatoses, the islands of cartilage
exhibit greater cellularity and atypia, making them more difficult
to distinguish from chondrosarcoma.
Clinical Features
- On x-ray imaging, the unmineralized nodules of cartilage produce
well-circumscribed oval lucencies surrounded by thin rims of radiodense bone (O-ring sign).
- Solitary chondromas rarely undergo malignant transformation, but
those associated with enchondromatoses are at increased risk for
such change. (Maffucci syndrome is associated with an increased
risk for development of other types of malignancies,
including ovarian carcinomas and brain gliomas.)
MALIGNANT
CHONDROSARCOMA
Chondrosarcoma is a malignant connective tissue tumor (sarcoma) whose
cells manufacture and secrete neoplastic cartilage matrix.
It is subclassified according to site (e.g., intramedullary versus juxtacortical)
and histologic variants
most patients are age 40 or older, with men >female.
MORPHOLOGY:
- Conventional chondrosarcoma, the most common variant,
arises within the medullary cavity of the bone to form an expansile
glistening mass that often erodes the cortex
It is composed of malignant hyaline and myxoid cartilage. - Myxoid chondrosarcomas are viscous and gelatinous in
consistency, and the matrix oozes from the cut surface.
The adjacent cortex is thickened or eroded, and the tumor grows
with broad pushing fronts into marrow spaces and the surrounding
soft tissue
- Tumor grade is determined by cellularity, degree of cytologic
atypia, and mitotic activity Low-grade tumors high grade - Approximately 10% of patients with conventional lowgrade
chondrosarcomas have a second high-grade poorly differentiated
component (dedifferentiated chondrosarcomas) - Other histologic variants include clear cell and mesenchymal
chondrosarcomas.
Clinical features:
- Chondrosarcomas commonly arise in the pelvis, shoulder, and ribs;
in contrast with enchondromas, chondrosarcomas rarely involve
the distal extremities. - They typically manifest as painful, progressively enlarging masses.
- the more radiolucent the tumor the greater the likelihood that it is
high grade. - Metastasize hematogenously to the lung and skeleton.
Brain parenchymal infections: Brain abscess. Viral encephalitides. Cerebral toxoplasmosis,
cysticercosis. Fungal encephalitis.
A parenchymal infection of the brain that is almost invariably associated with
VIRAL ENCEPHALITIS
meningeal inflammation –meningioencephalitis.
(i.e., involve the entire brain) or localized to a part of the brain.
#characteristic histologic features:
-perivascular and parenchymal mononuclear cell infiltrates
-microglial nodules
-neuronophagia
polio
immune mechanisms after systemic viral infections. Intrauterine viral infection may
cause congenital malformations, as occurs with rubella.
FUNGAL ENCEPHALITIS
Fungal infections usually produce parenchymal granulomas or abscesses, often
associated with meningitis.
The most common fungal infections have distinctive patterns:
Candida albicans usually produces multiple microabscesses, with or without
granuloma formation.
Mucormycosis is the term used to describe rhinocerebral infections caused by
several fungi belonging to the order Mucorales. It typically presents as an
infection of the nasal cavity or sinuses of a diabetic patient with ketoacidosis.
It may spread to the brain through vascular invasion or by direct extension
through the cribriform plate.
The proclivity of Mucor to invade the brain directly sets it apart from other fungi,
which tend to reach the brain by hematogenous dissemination from distant sites.
Aspergillus fumigatus tends to cause a distinctive pattern of widespread septic
hemorrhagic infarctions because of its marked predilection for blood vessel wall
invasion and subsequent thrombosis.
Cryptococcus neoformans can cause both meningitis and meningoencephalitis,
often in the setting of immunosuppression.
It can be fatal in as little as 2 weeks or may exhibit indolent behavior, evolving
over months or years. The CSF may have few cells but elevated protein, and the
mucoid encapsulated yeasts can
be visualized on India ink preparations. Extension into the brain follows vessels
in the Virchow-Robin spaces.
As organisms proliferate, these spaces expand, giving rise to a “soap bubble”–
like appearance.
In endemic areas, Histoplasma capsulatum, Coccidioides immitis, and
Blastomyces dermatitidis also can infect the CNS, especially in the setting of
immunosuppression
OTHER MENINGOENCEPHALITIDES
Cerebral Toxoplasmosis. Cerebral infection with the protozoan Toxoplasma
gondii can occur in immunosuppressed adults or in newborns who acquire the
organism transplacentally from a mother with an active infection.
In adults, the clinical symptoms are subacute, evolving during a 1- or 2-week
period, and may be both focal and diffuse. Due to inflammation and breakdown
of the blood-brain barrier at sites of infection, there’s edema around lesions (socalled
ring enhancing lesions).
In newborns who are infected in utero, the infection classically produces the triad
of chorioretinitis, hydrocephalus, and intracranial calcifications.
The CNS abnormalities are most severe when the infection occurs early in
gestation during critical stages of brain development.
Necrosis of periventricular lesions gives rise to secondary calcifications as well
as inflammation and gliosis, which can lead to obstruction of the aqueduct of
Sylvius and hydrocephalus.
Morphology
When the infection is acquired in immunosuppressed adults, the brain shows
abscesses, frequently multiple, most often involving the cerebral cortex (near the
gray-white junction)
and deep gray nuclei. Acute lesions consist of central foci of necrosis with
variable petechiae surrounded by acute and chronic inflammation, macrophage 33#
infiltration, and vascular proliferation. Both free tachyzoites and encysted
bradyzoites may be found at the periphery of the necrotic foci
Cysticercosis - is the consequence of an end-stage infection by the tapeworm
Tenia solium
If ingested larval organisms leave the lumen of the GI, where they would
otherwise develop into mature tapeworms, they encyst.
Common within the brain andsubarachnoid space. Cysticercosis typically
manifests as a mass lesion and can cause seizures. .
The organism is found within a cyst with a smooth lining. The body wall and
hooklets from mouth parts are most commonly recognized. If the encysted
organism has died, there can be an intense inflammatory infiltrate in the
surrounding brain, often including eosinophils, which may be associated with
marked gliosis.
Amebiasis - manifests with different clinical syndromes, depending on the
responsible pathogen.
Naegleria spp., associated with swimming in nonflowing warm fresh water,
cause a rapidly fatal necrotizing encephalitis.
Acanthamoeba causes a chronic granulomatous meningoencephalitis.
Brain parenchymal infections: Brain abscess. Viral encephalitides. Cerebral toxoplasmosis,
cysticercosis. Fungal encephalitis.
Cerebrovascular diseases, ischemic and hemorrhagic stroke (global cerebral ischemia, focal
cerebral ischemia, primary intraparenchymal hemorrhage).
clinical outcome: different upon different severity and duration of insult
CEREBROVASCULAR DISEASES
Brain disorders arise from pathologic processes involving blood vessels constitute a
major cause of death in the developed world. Most common the damage appear Due
to ischemia (85% of cases) but also can be the result of a hemorrhage (15% , out off
10% is intracerebral and 5%is subarachnoidal).
3 types of cerebrovascular pathologies :
(1) thrombotic occlusion of vessels
(2) embolic occlusion of vessels
(3) Vascular rupture.
“Stroke” is a clinical term for symptoms that arise from cerebrovascular problems,
particularly when symptoms begin acutely.
Thrombosis and embolism cause ischemic injury or infarction of specific regions of
the brain, depending on the vessel involved. A similar pattern of injury occurs
diffusely when there is complete loss of perfusion.
Hemorrhage accompanies rupture of vessels, leading to direct tissue damage as well
as secondary ischemic injury.
ISCHEMIC ENCEPHALOPATHY (global focal ischemia)
The brain tissue requires a constant delivery of glucose and oxygen from the blood.it
needs about 15% of cardiac output and responsible for 20% of body total oxygen
consumption Neurons are dependent on serum glucose as an essential energy source
and are
particularly susceptible to ischemia (undergo necrosis within 3 - 5 minutes).
Cerebral blood flow remains constant over a wide range of blood pressure and
intracranial pressure due to autoregulation of vascular resistance and it not influence
from regulatory mechanisms .
Ischemia is when no blood supply so bout sugar and o2 cant rich hypoxia when no o2
supply alone
o Functional hypoxia: cause by decrease partial pressure of O2 (e.g altitude),
impaired oxygen carrying capacity (e.g anemia) or inhibition of 02 by tissue
(e.g poisoning).
o Ischemia: either transient or permanent, due to tissue hypoperfusion (e.g
hypotension)
Such as injureis may be global or focal:
Global Cerebral Ischemia widespread ischemic/hypoxic injury to the brain . can occur
in the setting of sever systemic hypotension systolic pressures of less than 50mmHgsuch
as in cardiac arrest, shock, and severe hypotension
#main reasons:
-low perfusion (e.g due to atherosclerosis)
-acute decrease in blood flow (e.g cardiogenic shock)
-chronic hypoxia (e.g., anemia)
-repeated episodes of hypoglycemia.
In mild situations: transient confusional state, usually full recovery
In moderate situations: infracts in regions that are fed by the very end of the
circulation- watershed areas. Damage to highly vulnerable regions:
In severe situations: widespread neuronal death irrespective from regional
sensitivity , diffuse necrosis.
If such as patient survive he remain in persistent vegetative state . Other
patients meet the clinical criteria for “brain death,” including evidence of
diffuse cortical injury and brain stem damage, including absent reflexes and
respiratory drive.
#morphology:
Swollen brain , wide gyri and narrow sulci poor demarcated gray and white
zone.
The histopatho changes that accompany irreversible infury have 3 catagories:
1. 12-24 hours: early changes, acute neuronal change (red neurons).
- 24 hours-2 weeks: Subacute changes, include necrosis of tissue, influx of
macrophages, vascular proliferation, and reactive gliosis. - After 2 weeks: Repair,characterized by removal of all necrotic tissue, loss
of organized CNS structure, and gliosis . In the cerebral cortex the
neuronal loss and gliosis produce an uneven destruction of the neocortex.
VASCULAR DEMENTIA
B. 2nd most common cause of dementia as cerebrovascular diseas ie
hypertension atherosclerosis lead to modrate global ischemic demage to cortex
and hippocampus leading to dementia –treatment improve prognosis
Focal cerebral ischemia
Focal cerebral ischemia occurs when there is impierd blood flow in a
particular cerebral vessel so there is reduces blood flow to the particular brain
region, increasing the risk of cell death to that area And the development of
infarction.
cerebral arterial occlusion- mainly thromboembolism cardiac mural
thromboemboli.
branches or areas of stenosis.
#transiant ischemic attak when symptom last less then 24 hr if more its an
ischemic stroke=infarction
BRAIN INFRACTIONS
Cerebral infarction is focal brain necrosis due to complete and prolonged ischemia
that affects all tissue elements, neurons, glia, and vessels
# The majority of thrombotic occlusions causing cerebral infarctions are due to
atherosclerosis; the most common sites of primary thrombosis are the carotid
bifurcation, middle cerebral artery, and basilar artery.
# there are 2 types:
Non hemorrhagic- Thrombotic stroke is due to rupture of an atherosclerotic plaque.
Atherosclerosis usually develops at branch points (e.g., bifurcation of internal
Carotid and middle cerebral artery in the circle of Willis).Results in a pale infarct at
the periphery of the cortex Can be treated with thrombolytic therapy.
Hemorrhagic-result from reperfusion of ischemic tissue, . Hemorrhagic infarcts are
most common in embolism(common source of emboli is the left side of the heart e.g.,
atrial
Fibrillation). Blood leaks from collateral / occluding thrombus or embolus breaks up .
Most Usually involves the middle cerebral artery and
Results in a hemorrhagic
infarct at the periphery of the cortex.
Lacunar stroke occurs secondary to hyaline arteriolosderosis, a complication of
hypertension.
i. Most commonly involves lenliculostriale vessels, resulting in small cystic
areas of infarction
#morphology:
MACRO:
Macroscopically may not be detectable for 6‐12 hours
48‐72 hours Softening and disintegration of the infarcted region. May be oedema and
herniation.
Weeks to months: Cyst formation
MICRO:
Ischemic neuronal change –red neurons after about 12 hr initial microscopic finding
Initial influx of neutrophils from the blood stream enter the infarct through damaged
vessels about 48 hr. from unset .
Then in the following about 2 weeks macrophages
immigrate (They ingest the products of degradation of neurons and myelin and may
stay months to years in the lesion) also see at point core of infract disintegrate and
capillary in periphery proliferate
Astrocyte at edge of lesion enlarged divide and send network of glial cell processes
Results in formation of a fluid-filled cystic space surrounded by gliosis This is
completed in approximately 2 months the blood brain barrier is once again sealed
No scar formation!
INTRACRANIAL HEMORRHAGE
#Hemorrhage within the skull can occur in a variety of locations and be linked to
veraity of causes:
Epidural hematoma usually associated with trauma
Subdural hematoma
Subarachnoid hematoma- most commonly seen with aneurysms
Intracerebral (parenchymal) hemorrhage-link to hypertention about 15% of
death of chronic hypertention patient
Intraventricular hemorrhage, also known as hematocephalus internus.
Primary Brain Parenchymal Hemorrhage
#Spontaneous intraparenchymal hemorrhages occur most commonly in mid to late
adult life~60 years . Most are caused by rupture of a small intraparenchymal vessel.
occur in the basal ganglia, thalamus, pons, and cerebellum.
rim surrounding a cavity develops (neurons necrosis like in hemorrhagic infarction).
b.v. weakening the b.v. may lead to rupture (unlike hypertension related this one
manifested as lobar hemorrhage)
epidural hematoma
temporal bone with rupture of the middle meningeal artery; bleeding separates the
dura from the skull leading to formation of Lens-shaped lesion on CT
This sack is filling with blood in interval without any clinical sing may precede
eliciting neurologic signs even rapture put pressure on brain -Herniation is a lethal
complication.
subdural hematoma
#Subdural hemorrhage -Collection of blood underneath the dura;stems from
traumatically severed ‘‘bridging veins’’ that connect superficial cerebral veins and the
dural venous sinuses. This venous bleeding may stop on its own as soon as the
pressure outside the veins exceeds the pressure inside the vascular lumen. Increased
rate of occurrence in the elderly due to age-related cerebral atrophy,which stretches
the veins
Subarachnoid Hemorrhage and Saccular Aneurysms
berry aneurysm; other causes include AV malformations and an anticoagulated state
Present as a sudden headache with nuchal rigidity.LP show xanthochromia (yellowish
appearance of cerebrospinal fluid) - morphology: bleeding in the base of the brain.
a) Saccular aneurysms-(berry aneurysms) most common non traumatic cause, Berry
aneurysms are thin-walled saccular outpouching» that lack a media layer
, increasing the risk tor rupture.
Most frequently located in the anterior circle of Willis at branch points of the
anterior communicating artery
- Associated with Marfan syndrome and autosomal dominant polycystic kidney
disease
c) Charcot–Bouchard aneurysms (also known as miliary aneurysms or
microaneurysms) are aneurysms of the brain vasculature which occur in small blood
vessels (less than 300 micrometre diameter).
Charcot–Bouchard aneurysms are most
often located in the lenticulostriate vessels of the basal ganglia and are associated
with chronic hypertension.
[1] Charcot–Bouchard aneurysms are a common cause
of cerebral hemorrhage.
b) Traumatic
Meningeal neoplasms. Metastatic neoplasms of the brain.
Meningioma:
Predominantly Benign tumor of meningioepithelial cells of the arachnoid membrane.
Most common in adults more in female (the tumor express astrogen receptors!)
Multiple meningioma, especially in association with 8th nerve schwannomas or glial tumor
may indicate neruofibromatosis type 2. About half of meningiomas not associated with NF2
have acquired loss-of function mutations in the NF2 tumor suppressor gene on chromosome
22.
Imaging reveals a round mass attached to the dura. May present with seizures – due to
pressure on the cortex
Morphology: macro: masses that attach dura and compress the brain but DO NOT invade it.
micro: syncytial – whorled clusters of cells without cisible cell membranes, that sit in tight
groups.
The cells will show a unique pattern:
- maningiothelial cells in kind of onion skin whorled pattern. Some foci of dystrophic
calcification create psammoma bodies. - Fibroblastic component elongated cells and abundant collagen deposition btw them.
3.hence denoting features of no. 1 and 2 it’s an transitional tumor which shares features of
the syncytial and fibroblastic types
By Grading meningioma’s divide it into 3 categories: well differentiated benign slow
growing tumor as described in morphology, atypical WHO grade II/IV also bening and
recognized by the presence of certain histologic features increased cellularity higher mitotic
rate and tend to recurred, anaplastic WHO grade III/IV the highly aggressive malignant
variant.
METASTATIC TUMORS
Mostly carcinomas; The most common primary sites are lung, breast, skin (melanoma),
kidney, and gastrointestinal tract. Metastatic lesions, mostly carcinoma, account for quarter
to half of intracranial tumors Carcinomas are more commonly metastatic to the nervous
system than lymphoid malignancies.
Sarcomas infrequently metastasize to the brain.
Metastases form sharply demarcated masses, often at the gray-white junction, and elicit
edema. The boundary between tumor and brain parenchyma is sharp, with surrounding
reactive gliosis.
Beside local direct effect on brain may see evolvement of Paraneoplastic syndrome may involve the
peripheral and CNS, sometimes even preceding the clinical recognition of the malignant neoplasm.
Many but not all patients with PNS have antibodies against tumor antigens.
Manifestation of paraneoplastic syndrome:
Subacute cerebellar degeneration ataxia with destruction of purkinje cells, gliosis and mild
inflammation infiltrate.
Limbic encephalitis = causing sub-acute dementia and perivascular inflammatory cuffs, Microglial
nodules and some neuronal loss in the medial temporal lobe.
Subacute sensory neuropathy = altered pain sensation with loss of sensory neurons from dorsal
root ganglia.
Syndrome of rapid onset psychosis, catatonia, epilepsy and coma – associated with ovarian teratoma
and Ab against NMDA receptor
Multiple sclerosis and other demyelinating diseases. Leukodystrophies.
Within the CNS, axons are tightly ensheathed by myelin, an electrical insulator that allows
rapid propagation of neural impulses.
Myelin consists of multiple layers of specialized, plasma membranes that are assembled by
oligodendrocytes.
Although myelinated axons are present in all areas of the brain, they are the dominant
component in the white matter; therefore, most diseases of myelin are primarily white matter
disorders.
The myelin in peripheral nerves is similar to the myelin in the CNS but has several
important differences:
(1) made by Schwann cells; (2) each Schwann cell in a peripheral
nerve provides myelin for only one internode, while in the CNS, many internodes are
created by processes coming from a single oligodendrocyte;
and (3) the specialized proteins
and lipids are also different; Therefore, most diseases of CNS myelin do not involve the
peripheral nerves to any significant extent, and vice versa.
In general, diseases involving myelin are separated into two broad groups.
Demyelinating diseases -acquired conditions characterized by damage to previously
normal myelin. The most common diseases in this group result from immunemediated
injury, such as multiple sclerosis (MS); Other processes include viral
infection of oligodendrocytes, and injury caused by drugs and other toxic agents.
Dysmyelinating diseases, myelin is not formed properly or has abnormal turnover
kinetics. Associated with mutations that disrupt the function of proteins that are
required for the formation of normal myelin sheaths. The other general term for these
diseases is leukodystrophy
MULTIPLE SCLEROSIS
An autoimmune demyelinating disorder characterized by distinct episodes of neurologic
deficits, separated in time, attributable to white matter lesions that are separated in space.
It is the most common of the demyelinating disorders
The disease may become clinically apparent at any age, although onset in childhood or after
age 50 is relatively rare. Women are more than men.
In most patients, the illness shows relapsing and remitting episodes of neurologic
impairment.
Pathogenesis
Autoimmune diseases, caused by loss of tolerance to self proteins (myelin antigens).
A genetic risk factor is HLA-DR variants, the DR2 allele being the one that most
significantly increases the risk for developing MS.
Other genetic causes are polymorphisms in the genes encoding receptors for the
cytokines IL-2 and IL-7, which are known to control the activation and regulation of T
cell–mediated immune responses. Immune-mediated myelin destruction is thought to
have a central role in MS.
A central role for CD4+ T cells has been suggested, with an increase in TH17 and TH1
CD4+ cells thought to be a critical component of the injury to myelin.
There is also evidence for important contributions from CD8+ T cells and B cells.
Toxic effects of lymphocytes, macrophages, and their secreted molecules have been
implicated in initiating the process of axonal injury, sometimes even leading to neuronal
death.
Morphology
MS is primarily a white matter disease with affected areas showing multiple, wellcircumscribed,
depressed, gray, irregularly shaped lesions termed plaques.
These commonly arise near the ventricles. They also are frequent in the optic nerves and
chiasm, brain stem, ascending and descending fiber tracts, cerebellum, and spinal cord.
In an active plaque there is evidence of ongoing myelin breakdown with abundant
macrophages containing myelin debris.
Small active lesions often are centered on small veins.
Active plaques fall into four classes
Type I, which has macrophage infiltrates with sharp margins;
Type II, which is similar to type I but also shows complement deposition (suggesting an
antibody-mediated component);
Type III, with less welldefined borders and oligodendrocyte apoptosis;
Type IV, with nonapoptotic oligodendrocyte loss.
When plaques become quiescent (inactive plaques), the inflammation mostly disappears,
leaving behind little to no myelin. Instead, astrocytic proliferation and gliosis are
prominent.
Clinical features
The course of MS is variable, but commonly there are multiple relapses followed by
episodes of remission;
As a consequence, over time there is usually a gradual accumulation of neurologic
deficits.
Changes in cognitive function can be present, but are often much milder than the other
deficits.
The CSF shows a mildly elevated protein level with an increased proportion of
immunoglobulin; in one third of cases, there is moderate pleocytosis.
When the immunoglobulin is examined further, oligoclonal bands usually are identified.
These antibodies are directed against a variety of antigenic targets and can be used as
markers of disease activity.
OTHER ACQUIRED DEMYELINATING DISEASES
Immune-mediated demyelination can occur after a number of systemic infectious illnesses,
including relatively mild viral diseases.
It is believed that immune cells responding to pathogen-associated antigens are cross
reactive against myelin antigens, resulting in myelin damage.
There are two general patterns of postinfectious autoimmune reactions to myelin; they are
associated with acute-onset monophasic illnesses.
In acute disseminated encephalomyelitis, symptoms typically develop a week or two after an
antecedent infection and are nonlocalizing (headache, lethargy, and coma); Symptoms
progress rapidly, and the illness is fatal in as many as 20% of cases
Acute necrotizing hemorrhagic encephalomyelitis is a more devastating related disorder,
which typically affects young adults and children.
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease centered on the optic
nerves and spinal Cord; Antibodies to the water channel aquaporin-4 are both diagnostic and
pathogenic.
Central pontine myelinolysis is a nonimmune process characterized by loss of myelin
involving the center of the pons, most often after rapid correction of hyponatremia. May be
related to edema induced by sudden changes in osmotic pressure. It occurs in alcoholism and
severe electrolyte or osmolar imbalance.
Although the most characteristic lesion occurs in the pons, similar lesions can be found
elsewhere in the brain. Because of the involvement of fibers in the pons carrying signals to
motor neurons in the spinal cord, patients often present with rapidly evolving quadriplegia.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that occurs
after reactivation of JC virus in immunosuppressed patients.
LEUKODYSTROPHIES
Inherited dysmyelinating diseases in which the clinical symptoms derive from abnormal
myelin synthesis or turnover.
Some of these disorders involve lysosomal enzymes, while others involve peroxisomal
enzymes; a few are associated with mutations in myelin proteins.
Most are of autosomal recessive inheritance, although X-linked diseases also occur
Morphology
Most pathologic change are found in the white matter, which is diffusely abnormal in
color (gray
and translucent) and volume (decreased).
Early in their course, some diseases may show patchy involvement, while others have a
predilection for occipital lobe involvement; In the end, though, nearly all of the white
matter usually is affected.
With the loss of white matter, the brain becomes atrophic, the ventricles enlarge, and
secondary changes can be found in the gray matter.
Myelin loss leads to infiltration of macrophages, which often become stuffed with lipid.
Some of these diseases also show specific inclusions created by the accumulation of
particular lipids.
Clinical features
Affected children are normal at birth but begin to miss developmental milestones during
infancy and childhood.
Diffuse involvement of white matter leads to deterioration in motor skills, spasticity,
hypotonia, or ataxia.
In general, the earlier the age at onset, the more severe the deficiency and clinical course.
Peripheral neuropathies (primary axonal degeneration, segmental demyelination, GuillainBarré
syndrome, CIDP, diabetic peripheral neuropathy).
CLASSIFICATION OF MUSCLE DISEASES
A motor unit is made up of a motor neuron and the skeletal muscle fibers innervated by
that motor neuron’s axonal terminals hence muscle diseases may araise as :
Peripheral nerves consist of fascicles that contain myelinated and unmyelinated axons. .Myelin is a
spiral sheet of cell membrane wrapped around the axon. Unmyelinated axons are covered by
Schwann cell cytoplasm, but there is no spiraling.
Axonal neuropathies direct injury to the axon. The entire distal portion of an affected axon
degenerates atrophy of myofibers. The axon breaks down and secondary degrade of the
myelin (Wallerian degeneration).The morphological hallmark is decrease in the density of
the axons, which will lead to decrease in the strength of amplitude of nerve impulse. Causes
are may be diabetes or vascular disease…
Demyelinating neuropathies Schwann cell injury or myelin damage = slow nerve
conduction. Segmental demyelination –in individual myelin internodes* Remyelination may
occur (with shorter internodes & thin myelin) if repetitive process see “Onion bulb”
formations are concentric layers of Schwann cell processes and collagen around an axon
.later secondary axonal degeneration may also occur. May result from inflammatory diseases
like in topic or some tumors NFB schwannoma
Causes neuropathies include inflammatory neuropathies from SLE till 2 disease I talk about
these topic, metabolic disorder e.g. Diabetic (poly)neuropathy chronic axonal neuropathy with
some segmental demyelination, hereditary Charcot Mari tooth neuropathy, vascular such as
vasculitis One of the commonest and amyloid neuropathy, infectious-leprosy, neoplastic invasion
of peripheral nerves, toxin alcohol lead exogenous glucocorticoids etc. …
Patterns of peripheral neuropathies
Polyneuropathies usually affect peripheral nerves in a symmetric way Axonal loss is typically
diffuse and more pronounced in the distal segments of the longest nerves. Patients commonly
present with loss of sensation.
multiplex, in which the damage randomly affects portions of individual nerves, resulting in a right
radial nerve palsy and wrist drop together with loss of sensation in the left foot
A simple mononeuropathy involving only a single nerve most commonly is the result of traumatic
injury or entrapment (e.g., carpal tunnel syndrome).
DISORDERS ASSOCIATED WITH PERIPHERAL NERVE INJURY
Guillain-Barre syndrome
Acute autoimmune demyelinating peripheral neuropathy, It is a rapidly progressive disorder
affecting motor axons that results in ascending weakness that may lead to death from failure
of respiratory muscles over a period of only several days- One of the most common life
threatening diseases of the peripheral nervous system
It appears to be triggered by an infection or a vaccine that breaks down self-tolerance,
thereby leading to an autoimmune response.
Associated infectious agents include
Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, and human immunodeficiency
virus.
Antibodies and activated T-lymphocytes, reacting with antigens present on peripheral
nerves, elicit an inflammatory and macrophage reaction that destroys myelin and axons. The
strongest evidence of a humoral immune reaction in these neuropathies is that plasma
exchange results in significant clinical improvement.
Peripheral nerves show mononuclear
cell infiltrates rich in macrophages. , demyelination (myelin proteins are the source of
elevated CSF protein)..
Axonal damage, which accounts for the permanent deficits, is variable and may be severe. The pathology is most severe in nerve roots and proximal nerve
segments and less pronounced in more distal nerves. In the phase of recovery, the nerve
contains thin myelin sheaths, indicating myelin regeneration.
Treatments include plasmapheresis (to remove offending antibodies), intravenous
immunoglobulin infusions and supportive care, such as ventilator support.
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Typically manifests as a symmetric demyelinating disease. With similar immune pathomechanism
as GBS but unlike it CIDP follows a chronic, relapsing-remitting or progressive
course. occurs at increased frequency in patients with other immune disorders, such as systemic
lupus erythematosus and HIV infection.
The peripheral nerves show segments of demyelination and remyelination In long-standing
cases, chronically regenerating Schwann cells may concentrically wrap around axons in
multiple layers in an onion-skin pattern.
Both motor and sensory abnormalities are common, such as difficulty in walking, weakness,
numbness, and pain or tingling sensations. Some patients recover completely, but more often
recurrent bouts of symptomatic disease lead to permanent loss of nerve function.
Treatment includes plasmapheresis and administration of immunosuppressive agents.
Diseases of the skeletal muscles (dystrophinopathies, inflammatory myopathies). Diseases of
the neuromuscular junction (myasthenia gravis).
Muscle fiber types: 1. Slow twich, aerobic
= type I
2. fast twich, anaerobic = type II
Normal distribution of muscle fibers- checkboard pattern.
Muscle atrophy: abnormally small myofibers due to variety of disorders, for example
immobilization, exogenous glucocorticoids, Cushing syndrome.
Neurogenic atrophy:
Atrophy of muscle that results from damage to the nerve that stimulates the muscle. E.g: diabetic
neuropathy, spinal cord injuries and syndromes that cause nerve impingement.
Reminder: loss of a single neuron will affect all muscle fibers in a motor unit, then the adjacent
intact neurons send out sprouts to engage the NMJ which is injured. = now these fibers will have
the same innervating neuron. This process is called fiber type grouping.
Symptoms of neurogenic atrophy:
Stooped posture
Limited neck movement
Leg contractions
Heart failure (sometimes)
Disorders in the NMJ:
Produce functional abnormalities due to the disruption in the transmission of signals across the
NMJ- resulting in muscle weakness. Most common NMJ disorders:
- Myestenia gravis.
- Lambert – eaton syndrome
(Picture)
Therapy myestenia gravis:
- anti-choline esterase inhibitors.
- immunosuppression.
- Plasmapheresis
- Thymectomy (in patients with thymic lesion).
Lambert – Eaton syndrome:
Antibodies against presynaptic Ca2+ channels at the NMJ.
Arises as a paraneoplastic syndrome, most commonly due to small cell carcinoma.
Leads to impaired Ach release.
Proximal muscle weakness which improve with use.
Eyes are usually spared.
Muscular dystrophies:
Muscle dystrophy = inherited disporders of degeneration of muscle tissue with associated muscle
weakness and replacement of skeletal muscle by fibrofatty tissue.
Muscle dystrophy is due to primary inherited disease ( a muscle disease itself) in contrast to
muscle atrophy which is secondary due to loss of innervation, malnutrition etc.
- X linked MD (Duchenne and Becker MD)
Dystrophinopathies = Duchenne and Becker muscular dystrophy.
Dystrophinopathies are the most common form of muscular dystrophy.
Duchenne (DMD) and Becker (BMD) are the 2 most common examples, linked to
mutation in dystrophine gene. (DMD is more severe).
Both are X-linked MD associated with:
1. muscle wasting.
2. replacement of skeletal muscle by adipose tissue.
3. deletion of dystrophin (the mutation in the dystrophin gene is spontaneous!)
Dystrophin: plays a role of a “linker” protein btw the myofibrilar cytoskeleton to the
ECM.
Morphology: 1. Ongoing myofiber necrosis and regeneration.
2. replacement by fibrosis and fat.
3. micro level: in immunohistochemical method- complete absence of Membrane associated dystrophin.
Pathogenesis : loss of function mutation in the dystrophin gene located on the short arm of X chromosome.
Clinical features: progress to involve distal muscles (begins in pelvic => shoulders).
Calf pseudohypertrophy is characteristic finding, heart failure.
- Autosomal MD:
Several of the autosomal MD affect the proximal muscles (similar to X linked MD) and are
called limb girdle muscular dystrophy. It can be recessive or dominant. - Myotonic Dystrophy:
Myotonia = sustained involuntary contraction of a group of muscles.
Inherited as autosomal dominant, CTG trinucleotide repeat expansion on chromosome 19, which
will affect the synthesis of the intracellular protein kinase.
The disease will be present at late childhood with gait abnormalities, hands, wrist and facial muscles weakness.
Myopathy:
Myopathy = muscle disease. (such as the muscle dystrophy).
Primary myopathy should be distinguished from secondary neuropathic changes caused
by disorders that disrupt muscle innervation (even though both are associated with altered
muscle function but due to different reasons).
Myopathic condition are often associated with segmental necrosis and regeneration of
individual muscle fibers. Inflammatory infiltrate and intracellular inclusions may also be
present.
Congenital myopathies:
- ion channel myopathies: characterize by myotonia, relapsing episodes of hypotonic paralysis,
or both. Hyperkalemic periodic paralysis results from mutations in the gene for the skeletal
muscle sodium channel protein.
2.myopathies due to inborn errors of metabolism: disorders of glycogen synthesis and
degradation, lipid handling, carnitine transport.
- mitochondrial myopathies: mutations in mitochondrial or nuclear DNA that encodes
mitochondrial constituents. (will shoe maternal inheritance). These disorders will be present at
young adulthood with proximal muscle weakness and ocular musculature.
The most important pathological finding in skeletal muscle are irregular muscle fibers and
aggregates of abnormal mitochondria.
Acquires myopathies:
1.Toxic muscle injury: for example thyroxine myopathy: (intrinsic exposure). Either acute or
chronic proximal muscle weakness. The findings will include myofiber necrosis, regeneration
and interstitial lymphocytes. Examples for extrinsic exposure: ethanol, chloroquine.
- Inflammatory myopathies:
Dermatomyositis: Inflammatory disorders of the skin and skeletal muscle.
Unknown etiology, some cases are associated with carcinoma => paraneoplastic syndrome.
Clinical features: bilateral proximal weakness, distal involvement can develop, rush of
upper eyelids (helioptrope rash), malar rash, red papules on the elbows.
Micro: perivascular mononuclear cells infiltrate, myofiber damage, inflammation at the
perimysium => perifascicular atrophy (it helps to differentiate it from polymyositis which
shows endomysial inflammation)
Polymyositis: autoimmune disorder with increased expression of MHC I on myofibers.
Resemble dermatomyositis but skin is NOT involved.
Endomysial inflammation (CD8+) with necrotic muscle fibers.
- muscle infraction in the setting of diabetes.
Pancreatic neoplasms. Tumors of the endocrine pancreas (islet-cell tumors)
Pancreatic exocrine neoplasm can be cystic or solid. They can be benign or malignant.
- Cystic neoplasm-5% OF ALL PANCREATIC TUMORS
a. Serous cystadenomas
i. Composed of glycogen rich cuboidal cells surrounding small cysts
containing clear’ strew-colored fluid.
ii. More common in females and in the seventh decade of life. Almost
uniformly benign and curable by removed surgically.
iii. Associated with somatic mutation of the von hipple-lindau tumor
suppressor gene which its product binds to hypoxia induced factor alpha-1
and results in its degradation.
b. Mucinous cystic neoplasm
i. Vest majority raise in women In the body or tail of pancreas Present as
painless, slow growing mass.
ii. Cyst space is large and filled with steaky-viscose mucin walls are lined by
columnar mucinous epithelium with an associated densely cellular stroma
(similar to ovary).
iii. Benign ones categorized by degree of dysplasia (cellular and architectural
abnormalities) into “mucinous cystic neoplasm with low-grade dysplasia,”
“mucinous cystic neoplasm with moderate dysplasia,” and “mucinous
cystic neoplasm with high-grade dysplasia.” These are all curable when
completely removed surgically.
iv. About a third of mucinous cystic neoplasms have progress to malignant
invasive type these are designated as “mucinous cystic neoplasm with an
associated invasive carcinoma.”
c. Intraductal papillary mucinous neoplasm
i. Intraductal papillary mucinous neoplasms are tumors (neoplasms) that
grow within the pancreatic ducts (intraductal) characterized by the
production of thick fluid by the tumor cells (mucinous).
ii. Arise in the main pancreatic duct or its major branches as papillary tumor
distending the lumen histologically look as Cyst containing mucin lack
the cellular stroma seen in mucinous cystic neoplasm
iii. Again if benign categoriesed by severity of dysplasia and malignant said
to be associated with adenocarcinoma component.
iv. Unlike other cystic tumor they More frequent in males and more
Frequently involved the head of pancreas(not tail as former
- Pancreatic neoplasma. adenocarcinoma arising from pancreatic ducts:
i. very high mortality rate
ii. Most common seen in older age around 70
iii. Risk factor- smoking (double the risk), chronic pancreatitis and diabetes
mellitus
b. Pathogenesis
i. As all cancers it’s a genetic disease arising as a consequence of inherited
and acquired mutations in cancer associated genes. There is a progressive
accumulation of genetic changes in pancreatic epithelium as it proceeds
from non-neoplastic, to noninvasive lesion in small ducts and ductules to
invasive carcinoma.
ii. Three morphologic forms of non-invasive pancreatic neoplasia have been
defined all may progress to carcinoma (pancreatic intraepithelial neoplasia
(PanIN), mucinous cystic neoplasm (MCN) and intraductal papillary
mucinous neoplasm (IPMN)). pancreatic intraepithelial neoplasia is the
most potent of these to do this progress.
Its an small papillary lesion ~1/2
cm raise in small pancreatic ducts, found next to carcinoma lesion and
share similar genes mutations with it (all such lesions has dramatic
telomerase shortening…)
iii. Four genes are most commonly affected by somatic mutation of this
neoplasm : K-RAS- GTPase found in vast majority of pancreatic cancers
,P16 , SMAD4 and P-53 also frequent involved genes.
iv.
The progression from normal ducts to pancreatic intraepithelial neoplasia
is associated with both architectural and cytological changes. In PanIN-1
the nuclei are uniform and basally oriented the nuclei in PanIN-2 are
slightly larger, more basophilic and there is some loss of nuclear polarity
the nuclear pleomorphism in PanIN-3 can be significant.
c. Presentation -signs and symptoms tend to appear only late in the course
i. Abdominal pain epigastric plus weight loss.
1. Diabetics – mainly if tumor in the body/tail where islets are
prominant
ii. Obstructive jaundice – Most carcinoma of the head obstructs the distal
common bile duct as it courses through the head of the pancreas.
iii. Pancreatitis
iv. ~10% may present with migratory thrombophlebitis (The Trousseau sign)
medical sign rare variant of venous thromboembolism (VTE) that is characterized by recurrent, migratory thrombosis in superficial veins and
in uncommon sites, such as the chest wall and arms.
This syndrome is
particularly associated with pancreatic and lung cancer.
d. Morphology
i. Site: pancreatic head (60%), body (15%), tail (5%), diffuse involves the
entire organ (20%) as hard greyish white masses poorly definde
ii. Pancreatic cancer highly invasive metastasize to nearby organs Distant
metastases to lung and bone
iii. Micro Seen as poorly formed glands surround by dens fibrotic stromadesmoplasia
iv. Less common variant of pancreatic cancer Adensquamous carcinomas
(with squamous cells) or Undifferentiated carcinoma with osteoclast-like
giant cell ( with monocyte linage cells)
e. Screening- endoscopic US and CT Treatment: surgical excision (whipple
procedure) Prognosis: very poor 1 year survival rate Tumor markers: CEA and
CA19-9 (not specific and not sensitive)
Pancreatic neuroendocrine tumors1. Pancreatic neuroendocrine tumors (also known as islet cell tumors or islet cell carcinoma)
are a type of neuroendocrine tumor found in the pancreas.
Only 2 percent of pancreatic
tumors arise in the islet cells. The vast majority of tumors found in the pancreas are
adenocarcinoma.
- All PanNET, except insulinoma, are regarded as having malignant potential. if they are
malignant, the liver is the most common site of metastasis Proliferative rate is one of the
best correlates to outcome - Genomic sequencing of sporadic PanNet has identified recurrent alteration genes
a. MEN1-(multiple endocrine neoplasia type 1)
b. Loss of function mutation in tumor suppressor genes such as PTEN which is a
negative regulators of oncogenic TOR signaling pathway - Insulinoma (b-cell tumor)
a. Most common type of islet cell tumor
b. Tumor produces insulin - major symptom is Hypoglycemia (which occurs when
plasma glucose level falls below 50 mg/dL) , sweating, hunger, confusion, insulin
come Lab: elevated insulin and C-peptides
c. As no malignant potential Most insulinomas are cured by surgical resection
d. Morphology
i. Majority are identified while they are small (less than 2 cm diameter) and
localized to the pancreas Most are solitary lesions
ii. Hitologically- Benign tumor looks like giant islets do not present much
evidence of anaplasia and they may be deceptively encapsulated.
- Deposition of amyloid (of amylin) in the EX tissue is a
characteristic feature - Under EM, neoplastic b-cells, like their normal counterparts,
display distinctive round granules.
Gastrinoma (g-cell tumor)
iii. Tumor produces gastrin and classicaly present as Zollinger-Ellison
syndrome
- Elevated serum gastrin
- Gastric hyperacidity
- Intractable peptic ulcer which may also occur in unusual locations
such as the jejunum
iv. May also arise outside the pancreas duodenum
v. Gastrinomas can occur as isolated, sporadic neoplasms or as multiple,
MEN-1 associated neoplasms
vi. Morphology
- Over half of gastrin-producing tumors are locally invasive or have
already metastasized at the time of the diagnosis. - Gastin producing tumors are histologically bland and rarely exhibit
marked anaplaisa
Glucagonoma (alpha-cell tumor)
vii. Glucagonomas are typically large and occur almost entirely within the
pancreas.
Glucagonomas secrete excessive amounts of glucagon, causing glucose
intolerance, weight loss, and a pathognomonic rash known as necrolytic
migratory erythema. Hyperglycemia (diabetes), anemia and skin rash
Somatostatinoma
viii. Tumor produces somatostatin Somatostatin inhibits
- Insulin secretion = diabetes
- Gastric secretion = hypochlorhydria
- Cholecystokinin secretion = gallstone and steatorrhea
VIPoma
ix. Tumor produces vasoactive intestinal peoptide
x. WDHA syndrome: watery diarrhea, hypokalemia and acholohydria
With respect to the digestive system, VIP seems to induce smooth muscle relaxation (lower
esophageal sphincter, stomach, and gallbladder),
stimulate secretion of water into pancreatic
juice and bile stimulating pancreatic bicarbonate secretion, and cause inhibiting gastrinstimulated gastric acid secretion also dilating peripheral blood vessels
The genetic basis of colorectal carcinoma.
Most common malignancy of GI as colorectal cancer is 3rd most common site of cancer and also 3rd in
cancer related death Incidence increases with age, and reaches its peak at age 60-70.
Both genetic and environmental factors contribute to the development of colorectal cancers:
» In young individuals => pre-existing ulcerative colitis or one of the polyposis syndromes.
» Individuals with hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome).
» Dietary factors => low content of fibers with high content of carbohydrates, high fat content, and
decreased intake of protective nutrients such as vitamins (A, C & E).
» Genetic factors => COX-2 is over expressed in colorectal cancer patients; inhibition by aspirin
and non-steroidal anti-inflammatory drugs may exert a protective effect against colon cancer.
Colorectal carcinogenesis – there are 2 major pathways for the development of colorectal cancer both
describe accumulation of mutations but involve different genes and different defected mechanism
leading to such as accumulation:
- APC/β-catenin pathway (adenoma-carcinoma sequence)
- Characterized by chromosomal instability associated with stepwise accumulation of
mutations in a number of oncogenes and tumor suppressor genes
- Initially there is localized epithelial proliferation, followed by the formation of small
adenomas that progressively enlarge, become more dysplastic and eventually develop
into invasive cancer
-Sequence of events:
- Loss of APC tumor suppressor gene – both copies of the gene must be lost may be part of
FAP syndrome one is already inherited or just acquired mutation in 2 copies; APC
protein bind and promotes the degradation of β-catenin in cytosol => if absent APC
accumulation of β-catenin, it translocate to nucleus bind TcF leads to transcription of
growth promoting genes such as cyclin D1 and MYC that promote cell
proliferation(usually such as thing happened upon WANT exposure hence path named
WANT pathway), more!
It cause gene expression of different repressors for E cadherin
and suppress contact inhibition of growth.
If APC is neutralized it related as mutation permissive for polyp development
- Mutation of K-RAS – the gene encodes signal transduction GTPase in pathway of GF
TKR receptors as PI3K/AKT or MEPK pathways. it alternates between activated GTP
bound state and inactivated GDP bound state => when mutated, the molecule remains
active constant growth signal to cell and lead to formation of adenomatous polyp. - loss of tumor suppressors allows the emergence of carcinoma. loss of tumor suppressor
genes SMAD2 and SMAD4, encoding components of the TGFβ pathway TGF-β
signaling normally inhibits the cell cycle by binding to TGFbeta receptor and inducing
CDKI molec expression as SMAD are signal transducers in this pathway , loss of these
genes may allow unrestrained cell proliferation . Also, loss of p53 – a tumor suppressor
gene that inhibits neoplastic formation by inducing apoptosis if lost neoplastic cell now
can evade death.
- Mismatch repair pathway (microsatellite instability)
In patients with DNA mismatch repair deficiency (due to loss of mismatch repair genes) mutations
accumulate in microsatellite repeats a condition referred to as microsatellite instability.
These mutated microsatellite seq.may disrupt the coding sequence of TGF-b receptor (Leads to
uncontrolled cell growth.) or of the pro-apoptotic protein BAX (enhances the survival of genetic
abnormal clones).
Other common DNA mismatch repair defects are Mutation in the oncogene BRAF & hyper
methylation of CpG islands. By contrast, KRAS and TP53 typically are not mutated. Thus, the
combination of microsatellite instability, BRAF mutation, and methylation of specific targets, such
as MLH1, is the signature of this pathway of carcinogenesis.
