Pathology Flashcards
Neurons most vulnerable to hypoxic-ischemic insults include
Purkinje cells of the cerebellum and
pyramidal cells of the hippocampus and neocortex (zones 3, 5, 6).
Red infarct
liver, lung, intestine, testes
LITL
Free radicals damage cells via
membrane lipid peroxidation, protein modification, DNA breakage.
Free radicals are produced via:
radiation exposure (eg, cancer therapy) metabolism of drugs (phase I) redox reactions nitric oxide (eg, inflammation) transition metals WBC (eg, neutrophils, macrophages) oxidative burst
MR! MR! WoN!
Free radicals can be eliminated by
Protein metal carriers (eg, transferrin, ceruloplasmin).
Antioxidants (eg, vitamins A, C, E)
Spontaneous decay
Enzymes (scavenging) (eg, catalase, superoxide dismutase, glutathione peroxidase)
PASE
Dystrophic calcification
fat necrosis
abscesses
infarcts
liquefactive necrosis
atherosclerotic plaques
thrombi
congenital CMV rubella schistosomiasis TB (lung and pericardium) and other granulomatous infections toxoplasmosis CREST syndrome
psammoma bodies
FAIL AT CREST momma!
Lipofuscin locations
heart, colon, liver, kidney, eye, and other organs.
KLECH
Localized Amyloidosis
A- Alzheimer disease (beta-amyloid protein)
D - Diabetes mellitus (Type 2) -Islet amyloid polypeptide (IAPP)
A - atrial amyloidosis - Isolated (ANP )
M - Medullary thyroid cancer - Calcitonin (A Cal)
S - Systemic Senile (age-related) amyloidosis [Normal (wild-type)transthyretin (TTR)]
ADAM’S amyloid
Histamine causes
Rubor (redness) and calor (warmth)
Tumor (swelling)
Dolor (pain)
“triple positive”
Bradykinin causes
Rubor (redness) and calor (warmth)
Dolor (pain)
NO cause
Rubor (redness) and calor (warmth)
Prostaglandins cause
Rubor (redness) and calor (warmth)
Dolor (pain) (PGE2)
Seratonin + Leukotrians cause
Tumor (swelling)
Fever explain process
Pyrogens (eg, LPS) induce macrophages to release IL-I and TNF -> inc COX activity in perivascular cells of the hypothalamus -> inc PGE2 -> inc temperature set point.
Acute phase reactants
UPREGULATED
Ferritin Fibrinogen SAA Hepcidin CRP
More Fn FiSH in the C! (sea).
Acute phase reactants
DOWNREGULATED
Albumin
Transferrin
Erythrocyte sedimentation rate increased by
Most anemias
Infections
information (eg, giant cell [temporal] arteritis,
polymyalgia rheumatica)
Cancer (eg, metastases, multiple myeloma)
Renal disease (end-stage or nephrotic syndrome)
Pregnancy
Inflammation and infection CRAP
Erythrocyte sedimentation rate decreased by
Sickle cell anemia (altered shape) Polycythemia (Inc RBCs "dilute" aggregation factors) HF Microcytosis hypoFibrinogenemia
Shape Size Amount and FF
Acute inflammation mediators
I - Inflammasome
M - mast cells
T - Toll-like receptors
A - arachidonic acid metabolites
N - neutrophils
ned
in the
B - basophils E - eosinophils A - antibodies (preexisting) C - complement H - Hageman factor (factor XII)
Acute inflammation outcome
S - Scarring
C -Chronic inflammation (antigen presentation by macrophages and other APCs - activation of CD4+ Th cells)
R - Resolution and healing (IL-10, TGF-beta)
A - Abscess (acute inflammation walled off by fibrosis)
P - Persistent acute inflammation (IL-8)
Leukocyte extravasation steps
Margination and rolling -> Tight binding (adhesion) -> Diapedesis (transmigration) -> Migration.
Margination and rolling defective in
leukocyte adhesion deficiency type 2 (dec. Sialyl Lewis X)
Tight binding (adhesion) defective in
leukocyte adhesion
deficiency type I (dec. CDl8
integrin subunit)
Margination and rolling molecules: location and target - Sialyl LewisX
on: LEUKOCYTE
binds:
E-selectin (upregulated by TNF and IL-I)
P-selectin (released from Weibel Palade bodies)
on: VASCULATURE/STROMA
Margination and rolling molecules: location and target - L-selectin
on: LEUKOCYTE
binds: GlyCAM-1, CD34 on VASCULATURE/STROMA
Tight binding (adhesion) molecules: location and target -ICAM-1 (CD54)
on:VASCULATURE/STROMA
binds: CDll/18 integrins
(LFA-1, Mac-I) on LEUKOCYTE
Tight binding (adhesion) molecules: location and target - VCAM-1 (CDI06)
on: VASCULATURE/STROMA
binds: VLA-4 integrin on LEUKOCYTE
Diapedesis (transmigration) WBC molecules: location and target - PECAM-1 (CD31)
on: VASCULATURE/STROMA
binds: PECAM-1 (CD31) on LEUKOCYTE
Migration - molecules: location and target - chemotactic signals
on: VASCULATURE/STROMA
Chemotactic factors: C5a, IL-8, LTB4, kallikrein, platelet-activating
factor
CD# of GlyCAM-1
CD34
CD# of PECAM-1
CD31
CD# of VCAM-1
CDI06
CD# of ICAM-1
CD54
CD# of LFA-1, Mac-I
CDll/18 integrins
Chronic inflammation OUTCOMES
Scarring, amyloidosis, and neoplastic transformation
SAN
Chronic inflammation STIMULI
Persistent infections (eg, TB, T pallidum, certain fungi, and viruses) - type IV hypersensitivity, autoimmune diseases, prolonged exposure to toxic agents (eg, silica) and foreign material.
Things that are not supposed to be there.
Wound healing MEDIATORS - FGF mediates
Stimulates angiogenesis
Wound healing MEDIATORS - TGF beta mediates
Angiogenesis, fibrosis
Wound healing MEDIATORS - VEGF mediates
Stimulates angiogenesis
Wound healing MEDIATORS - PDGF mediates
- Induces vascular remodeling
- smooth muscle cell migration
- Stimulates fibroblast growth (for collagen synthesis)
Wound healing MEDIATORS - Metalloproteinases mediates
Tissue remodeling
Wound healing MEDIATORS - EGF mediates
Stimulates cell growth via tyrosine kinases (eg, EGFR/ErbBl)
PDGF Secreted by
activated platelets and macrophages
PHASE OF WOUND HEALING - Proliferative (day 3-weeks after wound)
EFFECTOR CELLS.
Fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages.
Granulomatous inflammation infections ETIOLOGIES
• Bacterial: Mycobacteria (tuberculosis, leprosy), Bartonella henselae (cat scratch disease; stellate necrotizing granulomas), Listeria monocytogenes (granulomatosis infantiseptica), Treponema pallidum (3° syphilis) • Fungal: endemic mycoses (eg, histoplasmosis) • Parasitic: schistosomiasis
BLT w/ MAYO and Mushroom for SHIZEL!
Granulomatous inflammation NON-infections ETIOLOGIES in general:
Immune-mediated
Vasculitis
Foreign material
Chronic granulomatous disease
Granulomatous inflammation NON-infections ETIOLOGIES - Immune-mediated:
sarcoidosis, Crohn disease, 1° biliary cholangitis, subacute (de Quervain /granulomatous) thyroiditis
Sick Chicks Big Tits
Granulomatous inflammation NON-infections ETIOLOGIES (Vasculitis):
Granulomatosis with polyangiitis (Wegener)
Eosinophilic granulomatosis with polyangiitis (Churg Strauss)
Giant cell (temporal) arteritis
Takayasu arteritis
Granulomatous inflammation NON-infections ETIOLOGIES (Foreign material):
berylliosis
talcosis
hypersensitivity pneumonitis
Types of collagen in Hypertrophic and Keloid
Hypertrophic: 3
Keloid: 1 & 3
Hallmarks of cancer - in general, the 3 subtypes:
Growth, Don’t die, Tissue changes.
Hallmarks of cancer - Growth
It generally consists of…
Growth signal self-sufficiency
Anti-growth signal insensitivity
Hallmarks of cancer - Don’t die
It generally consists of…
Evasion of apoptosis
Limitless replicative potential
Hallmarks of cancer - Tissue changes
It generally consists of…
Sustained angiogenesis
Tissue invasion
Metastasis
Warburg effect
Growth signal self-sufficiency:
Mutations in genes encoding:
• Proto-oncogenes - t growth factors - autocrine loop (eg, inc. PDGF in brain tumors)
• Growth factor receptors - constitutive signaling (eg, HER2/neu in breast cancer)
• Signaling molecules (eg, RAS}
• Transcription factors (eg, MYC)
• Cell cycle regulators (eg, cyclins, CDKs)
Anti-growth signal insensitivity:
- Mutations in tumor suppressor genes (eg, Rb}
* Loss of E-cadherin function - loss of contact inhibition (eg, NF2 mutations}
Evasion of apoptosis:
Mutations in genes that regulate apoptosis (eg, TP53, BCL2 - follicular B cell lymphoma).
Limitless replicative potential:
Reactivation of telomerase - maintenance and lengthening of telomeres - prevention of
chromosome shortening and cell aging.
Sustained angiogenesis
Inc. pro-angiogenic factors (eg, VEGF} or dec. inhibitory factors. Factors may be produced by tumor or stromal cells.
Vessels can sprout from existing capillaries (neoangiogenesis}
Endothelial cells are recruited from bone marrow (vasculogenesis).
Vessels may be leaky and/or dilated.
Tissue invasion
Loss of E-cadherin function - loosening of intercellular junctions - metalloproteinases degrade
basement membrane and ECM - cells attach to ECM proteins (eg, laminin, fibronectin} - cells
migrate through degraded ECM (“ locomotion”} - vascular dissemination.
Metastasis
Tumor cells or emboli spread via lymphatics or blood - adhesion to endothelium - extravasation and homing. The site of metastasis can be predicted by the site of the primary tumor, as the target organ is often the first-encountered capillary bed (“seed and soil” theory). Some cancers show organ tropism (eg, lung cancers commonly metastasize to adrenals).
Warburg effect
The shift of glucose metabolism away from mitochondrial oxidative phosphorylation toward glycolysis.
Immune evasion in cancer
- Dec. MHC class I expression by tumor cells - cytotoxic T cells are unable to recognize tumor cells.
- Tumor cells secrete immunosuppressive factors (eg, TGF-beta) and recruit regulatory T cells to down-regulate immune response.
- Tumor cells up-regulate immune checkpoint molecules, which inhibit the immune response.
Antibodies targeting PD-1
Nivolumab
Pembrolizumab
Antibodies targeting PD-L1/2
Atezolizumab
Durvalumab
Avelumab
Antibody targeting CTLA-4
Ipilimumab
CTLA-4 on T cells outcompetes CD28 for
B7 on APCs
CD# of B7
80/86
These tumors metastasize to the brain
Lung> breast > melanoma, colon, kidney.
These tumors metastasize to the Liver
Colon»_space; Stomach > Pancreas (Cancer Sertintly Penetrates).
These tumors metastasize to the Bone
Prostate, Breast> Kidney, Thyroid, Lung
PB/KTL
Prostate - Blastic Breast - Mixed Kidney - Lytic Thyroid - Lytic Lung - Lytic + blastic
BCR-ABL
JAK2
GENE PRODUCT
Non-receptor tyros ine kinase
BRAF GENE PRODUCT
Serine/threonine kinase
BCL-2 GENE PRODUCT
Antiapoptotic molecule (inhibits apoptosis)
c-KIT GENE PRODUCT
CytoKlne receptor
KRAS GENE PRODUCT
GTPase
BRAF ASSOCIATED NEOPLASM
Ly - lymphoma (NON-Hodgkin )
M - Melanoma
P - papillary thyroid carcinoma
H - hairy cell leukemia
BCL-2 ASSOCIATED NEOPLASM
Follicular and diffuse large B Cell Lymphomas
c-KIT ASSOCIATED NEOPLASM
Gastroi ntestinal stromal tumor (GIST)
KRAS ASSOCIATED NEOPLASM
C - Colon cancer
L - lung cancer
i
P - pancreatic cancer
RET
ALK
HER2/neu (c-erbB2)
Receptor tyrosine kinase
RET
MEN 2A and 2B, papillary thyroid carcinoma
ALK
Lung Adenocarcinoma (Adenocarcinoma of the Lung Kinase)
HER2/neu (c-erbB2)
Breast and gastric carcinomas
BiG
PTEN GENE PRODUCT
Negative regulator of P13k/AKT pathway
PTEN ASSOCIATED CONDITION
Breast, prostate, and endometrial cancer
APC GENE PRODUCT
Negative regulator of beta-catenin/WNT pathway
CDKN2A GENE PRODUCT
p16, blocks G1 -> S phase
CDKN2A ASSOCIATED CONDITION
Melanoma, pancreatic cancer
BRCA1/BRCA2 GENE PRODUCT & ASSOCIATED CONDITION
DNA repair protein
Breast, ovarian, and pancreatic cancer
BOP
NF1 GENE PRODUCT & ASSOCIATED CONDITION
Neurofibromin (Ras GTPase activating protein)
Neurofibromatosis is type 1
VHL GENE PRODUCT
Inhibits hypoxia-inducible factor la
Cigarette smoke Carcinogen cause
R - Renal cell carcinoma: Kidney A - adenocarcinoma (Pancreas) T - Transitional cell carcinoma: Bladder S - Squamous cell carcinoma: CELL Cervix Esophagus Larynx Lung (+small cell)
Alkaline phosphatase IMPORTANT ASSOCIATIONS
Metastases to bone or liver, Paget disease of bone, seminoma (placental ALP).
Exclude hepatic origin by checking LFTs and GGT.
a -fetoprotein IMPORTANT ASSOCIATIONS
Hepatocellular carcinoma Endodermal sinus (yolk sac) tumor Mixed germ cell tumor Ataxia-telangiectasia Neural tube defects. (HE-MAN is the alpha male!)
Normally made by the fetus. Transiently elevated in pregnancy. High levels associated with neural tube and abdominal wall defects, low levels associated with Down syndrome.
Calcitonin IMPORTANT ASSOCIATIONS
Medullary thyroid carcinoma (alone and in MEN2A, MEN2B).
hCG IMPORTANT ASSOCIATIONS
hydatidiform moles
Choriocarcinomas (gestational trophoblastic disease),
Gonadal - testicular cancer
Mixed germ cell tumor.
hCG Matters
Radon EXPOSURE & IMPACT
A by-product of uranium decay, and accumulates in basements.
Lung cancer (2nd leading cause after cigarette smoke)
GFAP STAIN
NeuroGlia (eg, astrocytes, Schwann cells, oligodendrocytes) -> Astrocytoma, Glioblastoma
S-100 STAIN
Neural crest cells -> Melanoma, schwannoma, Langerhans cell histiocytosis
Vimentin STAIN
Mesenchymal tissue (eg, fibroblasts, endothelial cells, macrophages) -> Mesenchymal tumors (eg, sarcoma), but also many other tumors (eg, endometrial carcinoma, renal cell carcinoma, meningioma)
P-glycoprotein
Also known as multidrug resistance protein I (MDRI). Classically seen in adrenocortical carcinoma but also expressed by other cancer cells (eg, colon, liver). Used to pump out toxins, including chemotherapeutic agents (one mechanism of dec. responsiveness or resistance to chemotherapy over time).
Psammoma bodies are seen in:
S - Somatostatinoma y M - Malignant Mesothelioma P - Prolactinoma T - thyroid (Papillary carcinoma) O - Ovarian serous papillary cystadenocarcinoma M - Meningioma
Paraneoplastic syndromes of Small cell lung cancer
ACTH
ADH
Paraneoplastic Encephalomyelitis - Antibodies against Hu antigens in neurons.
Lambert-Eaton myasthenic syndrome - Antibodies against presynaptic (P/Q-type) Ca2+ channels at NMJ.
Paraneoplastic Cerebellar degeneration - Antibodies against antigens in Purkinje cells
Opsoclonus- myoclonus ataxia
A/C ALOE
Dermatomyositis MOST COMMONLY ASSOCIATED TUMOR(S)
Adenocarcinomas, especially ovarian
Acanthosis nigricans & Sign of Leser-Trelat MOST COMMONLY ASSOCIATED TUMOR(S)
Gastric adenocarcinoma and other visceral malignancies
Hypertrophic osteoarthropathy
MOST COMMONLY ASSOCIATED TUMOR(S)
Adenocarcinoma of the lung
Hypertrophic osteoarthropathy
DESCRIPTION/MECHANISM
Abnormal proliferation of skin and bone at distal extremities -> clubbing, arthralgia, joint effusions, periostosis of tubular bones.
Paraneoplastic syndromes of Thymoma
Pure red cell aplasia - Anemia with low reticulocytes
Good syndrome - Hypogammaglobulinemia
Myasthenia gravis - Antibodies against postsynaptic ACh receptors at NMJ.
Nonbacterial thrombotic (marantic) endocarditis DESCRIPTION/MECHANISM
Deposition of sterile platelet thrombi on heart valves
Nonbacterial thrombotic (marantic) endocarditis MOST COMMONLY ASSOCIATED TUMOR(S)
Adenocarcinomas, especially pancreatic
Polycythemia
DESCRIPTION/MECHANISM & MOST COMMONLY ASSOCIATED TUMOR(S)
Inc. Erythropoietin
Pheochromocytoma Renal cell carcinoma (kidney) HCC (Liver) Hemangioblastoma Leiomyoma (Uterine)
Pheo HULK
Inc. PTHrP
MOST COMMONLY ASSOCIATED TUMOR(S)
Squamous cell carcinomas of the lung, head, and neck .
Renal, bladder.
Breast, and ovarian carcinomas.
1,25-(OH)2 vitamin D3 (calcitriol)
MOST COMMONLY ASSOCIATED TUMOR(S)
Lymphoma
Anti-NMDA receptor encephalitis
MOST COMMONLY ASSOCIATED TUMOR
Ovarian teratoma
Anti-NMDA receptor encephalitis
DESCRIPTION/MECHANISM
L - language dysfunction A - autonomic instability M - memory deficits P - Psychiatric disturbance S - seizures
Dimmed - dyskinesias
Opsoclonus-myoclonus ataxia syndrome seen in:
Neuroblastoma (children), small cell lung cancer (adults)
Paraneoplastic cerebellar degeneration
DESCRIPTION/MECHANISM & MOST COMMONLY ASSOCIATED TUMOR(S)
Antibodies against antigens in Purkinje cells.
Small cell lung cancer (anti-Hu), gynecologic and breast cancers (anti-Yo), and Hodgkin lymphoma (anti-Tr)
YO! HuTr!
Apocrine metaplasia of the breast…
no increased risk for cancer
Metastatic calcification
In normal tissues - Predominantly in interstitial tissues of:
kidney
lung
gastric mucosa
these tissues lose acid quickly; inc pH favors Ca2+ deposition)Nephrocalcinosis of collecting ducts may lead to nephrogenic diabetes insipidus and renalfailure
Metastatic calcification 2° to…
2° to hypercalcemia (eg, 1° hyperparathyroidism, sarcoidosis, hypervitaminosis D) or high
calcium-PHOSPHATE product levels (eg, chronic kidney disease with 2° hyperparathyroidism, long-term dialysis, calciphylaxis, multiple myeloma)
Usually abnormal