Pathology E2 Flashcards
Neoplasia
New growth
Clonal proliferation of cells (benign or malignant)
Common progenitor (but not all cells ID)
Neoplasm
physical manifestation of neoplasia
solid mass OR dispersed
Benign characteristics
Well differentiated
Progressive, slow growth. May halt or regress
Mitotic figures –> rare, normal
Usu cohesive, expansile circumscribed masses
Absent metastasis
Exp. Benign nevus
Malignant characteristics
Lack of differentiation (anaplasia) Atypical structure Erratic growth - slow to rapid Mitotic figures --> numerous, abnormal Locally invasive Metastasis present
Exp. malignant melanoma
Benign vs malignant dx and tx
Definitive dx req. pathologic evaluation
Benign tumors –> often tx w/ surgery alone
Leiomyoma
Benign
- often cause sx
- may become lg
- well differentiated, demarcated
- slow growing
- freq multiple
- typically no metastasis
Leiomyosarcoma
Malignant
- often cause sx
- may become lg
- poor differentiation
- usu single
- commonly metastasize
Local vs distant recurrence
Local recurrence –> not ness malignant, could just be that didn’t remove all at initial tx
Distant recurrence –> metastasis
Epithelium neoplasm nomenclature
Malignant: carcinoma
Squamous papilloma
Benign proliferation of squamous epithelium
Colonic Adenoma
Benign lesions, most grow as exophytic polyps
Can progress to carcinoma
- detection by colonoscopy –> imp in prep adenocarcinoma
Colonic adenocarcinoma
Malignant, invasive tumor glands
Malignant glands have invaded the wall of the colon and the potential for metastasis is established
Most, not all “oma’s” are benign
Exceptions?
hepatoma, lymphoma, seminoma, melanoma, mesothelioma
In situ carcinoma
lack metastatic potential, but are treated as malignant because still phenotypic/genotypic char of invasive tumor cells. If no removal –> some will progress to invasive cancer
Ductal “carcinoma” in situ of the breast
Duct filled with neoplastic cells
- Often look poorly differentiated
- Sim to invasive ductal carcinoma, just cant break through basement membrane
Nomenclature: Mesenchymal neoplasms
Benign: -oma
Malignant: -sarcoma
Exp. osteoma vs osteosarcoma
Mixed epithelial / mesenchymal neoplasms
Benign exp?
Fibroadenoma, breast
Pleomorphic adenoma, salivary gland
Mixed epithelial / mesenchymal neoplasms
Malignant exp?
Carcinosarcoma, any location
Hematopoietic neoplasms
Lymphoma
- Hodgkin’s lymphoma
- Non-Hodgkin’s lymphoma
Pre-malignant lymphoid: “lymphoproliferative disorders”
Spectrum of lymphoid disorders
Non-neoplastic (hyperplasia)
Lymphoma (low grade)
Lymphoma (high grade)
Nomenclature: Hematopoietic neoplasms
Leukemia - malignant; arise in bone marrow, blood
- Acute (myeloid, lymphoid)
- Chronic (myeloid, lymphoid)
Pre-malignant entities: “myelodysplastic syndromes” and “myeloproliferative disorders”
Teratoma
- neoplasm composed of cell types derived from 2-3 germ layers
- arise via totipotent cells
- mature elements=benign, immature –> indeterminante course
- malignancies (teratocarcinoma) rare
Hamartoma
benign, proliferation of 1 or more tissue types indigenous to the site of origin, but disorganized.
- once thought congenital malformations, but many –> neoplastic (recurrent translocations)
Heterotopia / Choristoma
- ectopic rest of normal tissue.
- congenital anomaly; not neoplastic
GI most common
Incidence
of new CAs of specific site/type, arising in a specific time period
(typically expressed as the number of cancers per 100,000 population at risk)
Prevalence
New and pre-existing patients alive during specific time period
Cancer incidence
Estimated 15M new CAs worldwide, 9M deaths (25K deaths/day)
worldwide: lung, stomach, liver (men); breast, cervix, lung (women)
50% of cancer DXs (and deaths) in US: lung, breast, prostate and colorectum
Men vs women cancer incidence by site
Lung is #1 in both men and women
Men: prostate, lung, colon and rectum
Women: breast, lung, colon and rectum
Men vs women cancer deaths by site
Lung is #1 in both men and women
men: lung, prostate, colon and rectum
women: lung, breast, colon and rectum
Cancer survival
proportion of patients alive at some point after CA DX
overall survival –> alive
disease free survival –> alive without disease recurrence
Hereditary tumors
↓ age at DX
multiple tumors
bilateral tumors in paired organs
syndromes with Mendelian inheritance
TSGs
encode proteins critical for normal growth inhibitory pathways (misnomer)
- Knudson “two hit” hypothesis: both TSG alleles must be effected to lose function
Loss of heterozygosity
Many CA’s with hereditary component: 1 defective allele inherited, “predisposing” to CA; only 1 more “hit” needs to be acquired somatically
BCL-2
Regulate membrane permeability
↓↓ apoptosis in 85% of follicular lymphomas by t14:18 (juxtapose Ig heavy chain & BCL-2 genes)
Most hematopoietic & solid tumors overexpress at least 1 member of the BCL-2 family
Hereditary non-polyposis colon CA (HNPCC) or Lynch Syndrome
most common CA predisposition syndrome; autosomal dominant - mutations in MMR genes
Hallmarks of Cancer
- self-sufficiency in growth signal
- insensitivity to growth inhibitory signal
- altered metabolism (Warburg effect = switch to aerobic glycolysis)
- avoid apoptosis
- immortality (stem-cell like characteristics)
- ability to induce sustained angiogenesis (primary, mets)
- ability to invade, metastasize
- ability to evade immune system
Carcinogenesis initiation
acquire non-lethal, irreversible & transmissible genetic change in CA-related gene
Carcinogenesis promotion
reversible biologic processes that do not result in genetic damage, but favor devel of CA (estrogen in breast CA)
Tumor Growth Rate
determined primarily by % cells in growth phase (growth fraction)
Tumor Growth Fraction
% cells in growth phase
directly proportional to tumor’s susceptibility to chemoRX
Tumors with ↑TGR are ↑↑ responsive
Most common CA’s have doubling times of …
2-3 months
Breast molecular therapy genetic target. Predictive factor in responding to tx
mutated HER2
4 classes of regulatory genes (principal targets of CA)
- growth-inhibiting tumor suppressor genes (gatekeeper)
- growth-promoting proto-oncogenes (gatekeeper)
- apoptosis related genes (gatekeeper)
- DNA repair genes (caretaker)
RB associated tumor and action
retinoblastoma
osteosarcoma
action: cell cycle regulation
BRCA 1,2 associated tumor and action
TSG
breast
ovarian
prostate CA
action: DNA repair
p53 associated tumor and action
TSG
many common CAs
action: cell cycle, apoptosis
APC associated tumor and action
TSG colon CA (FAP)
action: inhibit signal transduction
TSGs
RB BRCA1,2 p53 APC NF1 NF2 WT1 p16 DPC DCC
role of RB in regulating the G1-S checkpoint
Hypo-phosphorylated: RB-E2F complex binds to DNA, recruits histone enzymes –> inhibits transcription
Growth factor gene products –> hyperphosphorylated RB: release of E2F, activation of S-phase genes
Cervical metaplasia (physiological)
Prepuberty –> glandular mucosa
Post puberty –> squamous mucosa
pre-cancerous lesions
Neoplastic
- dysplasia
- atypical hyperplasia
Dysplasia
applied to cervix, GI tract, GU tract, squamous lesions of the lung
architecture:
cellular and nuclear pleomorphism
nuclear hyperchromasia (dark)
increased mitotic activity with abnormal mitoses
intact basement membrane (Don’t have metastatic potential YET)
Atypical Hyperplasia
synonymous with “endometrial intraepithelial neoplasia”
applied to endometrium, breast and glandular lung lesions
3 ways to handle usual/atypical ductal hyperplasia/atypical lobular hyperplasia/lobular carcinoma in situ
- follow it, adhere to yearly mammograms. Possibly MRI
- tx prophylactically (tamoxifen, anti-estrogen therapy)
- In very high risk women (FHx or genetic defect), bilateral prophylactic mastectomy
Tumor grade
Degree of differentiation
exp.
- squamous cell CA (intercellular bridges, keratinization)
- adeno CA (gland formation)
Cytologic features
-mitotic rate, abnormal mitosis, nucleus abnormalities
HIGHER GRADE –> MORE AGGRESSIVE
Well differentiated (G1) squamous cell CA
intercellular bridges
stratified, flattened cells
cytologically bland
↓ mitoses
Moderately differentiated (G2) squamous cell CA
more cellular, less organized
↓ flattened cells
↓ stratification
↑ mitoses
Poorly differentiated (G3) squamous cell CA
↓ morphologic evidence of
squamous differentiation
pleomorphic cytology
↑ mitotic activity
Undifferentiated (G4) squamous cell CA
- no evidence of squamous differentiation
- need IHC to prove squamous differentiation (cytokeratin 5/6, p40, p63)
Staging of tumors
Extent of tumor based on patho and clinical findings
TNM Classification
T: Site and extent of primary tumor
N: Involvement of regional lymph nodes
M: Distant metastasis
AJCC Classification
0 to IV - (tumor size, nodal spread, and distant metastasis)
Breast CA staging
0 – carcinoma in situ, 100% survival rate I - no nodal/distant metastases II - no distant metastases III - distant metastases IV - distant metasteses present
Immunohistochemistry (IHC)
Using Abs to test for specific proteins
- categorize undifferentiated malignant tumors
- assess for invasion, metastases
- determine site of origin of occult primary tumors
- classify leukemias and lymphomas
assess prognostic and predictive factors
Immunohistochemistry process
Primary antibody detects a specific cellular epitope in tumor
Detection step localizes the site of primary antibody binding (secondary Ab (has dye) binds primary antibody)
Prognostic factors
prognosis of tumor INDEPENDENT of tx
- Presence / absence of metastases
- Tumor grade
- Tumor size
- Tumor proliferative activity
Predictive factors
likelihood of response to a specific tx
- ER in breast CA (TAMOXIFEN)
- HER2/neu in breast CA (TRASTUZUMAB and PERTUZUMAB)
- EGFR mutation in lung ACA (ERLOTINIB and GEFITINIB)
Flow Cytometry
immunophenotyping hematologic malignancies
spun through laser
tase with Abs
look at tons of Abs at same time
Cytogenetics
req culture of living tumor cells
FISH
using DNA probe to look for gene
- Can assess status of a single gene
- Primarily prognostic/predictive uses
- Applied to routine histologic sections
Oncotype Dx
Multi-gene assessment
- Reverse transcriptase PCR assay – RNA based
Calculates “recurrence score” = risk assessment for distant recurrence in patients with breast CA
circulating tumor cells (CTCs)
Tumor cells often in blood circulation before metastasis
NF1
TSG
inhibits signal transduction
- neurofibromas
Proto-oncogenes
mediate cell prolif/diffrent in normal cells
- non-lethal mutation –> oncogenes that promote cell growth
- NO 2 hit requirement
abl ras HER2 EGFR MEN 1,2 c-myc l-myc n-myc bel-2
Rb mechanism of cancer
hypO-P Rb binds E2F (trace for S genes)
hypEr-P Rb does NOT bind E2F –> proceeds to S phase
mutation in Rb ^ no checkpoint, all goes to S
p53 mechanism of cancer
activation of normal p53 –> arrest of cell cycle in G1 and DNA repair
mut –> genetically damaged cells proliferate –> malignant tumors
E7/E6 mechanism of cancer
E7 bind to Rb –> inactivation
E6 binds to p53 –> inactivation
Common distant mets for liver
colon, stomach, pancreas, breast, lungs
Common distant mets for brain
lung, breast, melanoma, kidney, GI tract
Common distant mets for bone
breast/prostate, lung, kidney, thyroid, testis
Common distant mets for peritoneum
ovation, primary peritoneal CA, lonular Ca of breast, appendices CA, melanoma
CK
cytokeratin, common epithelial marker
carcinoma
(breast, prostate, lung, colon)
LCA
leukocyte common antigen
lymphoma
S-100
common neuroendocrine marker
melanoma
PSA
prostate CA marker
CEA
colorectal, pancreatic, gastric, breast CA marker
CA-125
ovarian CA marker
AFP
hepatocellular CA, NS-GCT serum marker
lymphatic spread is characteristic of
carcinomas
hematogenous spread is characteristic of
sarcomas
chromogranin
neuroendocrine IHC stain
germ cell tumor
ß-HCG, AFP, PLAP
vimentin
soft tissue/sarcoma
markers of bone formation
alkaline phosphatase
precollagen peptides P1NP
osteocalcin
markers of bone resorption
urinary calcium
N- and C-telopeptides (collagen crosslinkers)
lung squamous cell CA
a paraneoplastic syndrome
mediator: PTH
systemic effect: hypercalcemia
lung small cell CA
a paraneoplastic syndrome
mediator: ACTH
systemic effect: Cushing syndrome (hypercortisol)
osteoblasts
bone formation via secreting organic bone matrix proteins
regulate osteoclasts
osteoclasts
resorb bone, form respiration pits
differentiation mediated via RANK/RANKL –> binding activates osteoclasts (OPG binds RANK and stops osteoclast inhibition)
Regulation of osteoclast differentiation
via RANK/RANKL
RANKL on both osteocytes and osteoblasts.
OPG normally binds RANKL so RANKL doesn’t activate osteoclasts
Vitamin D deficiency
decreased Ca/phosphate absorption
poor bone mineralization
sx: leg bowing in kids
osteomalacia
adults, softened bones
rickets
via vitamin D deficiency in kids
osteoporosis
kyphosis, height loss, fragility fractures
dx: dual energy XR absorpitometry (DXA)
tx: bisphosphonates (antiresorptives, inhibit osteoclasts)
Paget’s
chronic, progressive skeletal disorder
focal abnormal inc in bone resorption via osteoclasts
compensation –> increased osteoblast activity
result: disorganized bone with woven/lamellar bone in certain sites
sclerotic lesions of bone marrow replaced by vascular fibrous tissue
risks: inc with age, genetic component
can get osteosarcoma
tx: antiresorptives
Achondroplasia
recipe disease
most comm form of hereditary dwarfism (1/30,000), AD, fully penetrant
Defect in FGFR3, point mutation
^ usually acts like brake to slow bone growth (during endochondral ossification) in resting cartilage
sx: small stature, gene VARUM, frontal bossing, foramen magnum stenosis (prevents CSF from getting out)
prenatal dx: 90% new mut
related to paternal age (mut from father)
affected individuals –> 50% chance affected child
no cure
osteogenesis imperfecta
ingredient disease
bone fragility due to defective type I COLLAGEN
most common defect is quantitative, AD pattern, likely premature stop codon
blue sclera –> sign of abnormal collagen
variation in severity (normal intelligence, broad forehead, etc)
ineffective tx: ca, phosphorous…
effective tx: bracing, bisphosphonates (inhibit osteoclast resporption, which is inc in OI) combine w growth hormone
Prenatal: fractures in utero are concerning for severe OI
Blout’s disease
“oven” disorder
result of abnormal compression of bone leading to growth retardation
histo changes in ZONE OF RESTING CARTILAGE
genu VARUm, internal rotation of tibia
Morquio’s disease
cleanup disorder
AR mucopolysaccaridosis
cant degrade GAG (keratin sulfate –> cornea and cartilage) –> thickening of tissues, dysfunctional cell/organ formation, accumulation of lysosomes and extracellular tissue
–> skeletal dysplasia
ODONTOID HYPOPLASIA genu VALGUM (medial epiphyseal plate issue)
synovial fluid analysis (inflammation)
wbc: 5,000 - 75,000
neutrophils: >50%
synovial fluid analysis (bacterial infection)
bacterial infection:
> 50,000->100,000
70%
type A synovial cell
phagocytic, produce synovial fluid, exchange waste and solute between synovium and vessels in CT beneath
type B synovial cell
fb-like, secrete proteins
articular cartilage
hyaline cartilage
Type II collagen
chondrocytes
destroyed via IL-1/TNF signaling (trigger chondrocytes)
lacks blood supply, lymphatic drainage, innervation
osteoarthritis
noninflammory, wbc under 2000
loss of articular cartilage with possible osteophyte formation
chondrocytes –> dec type II collage/proteoglycan, inc catabolic metalloproteases
–> bone fibrillation and eburnation
- majority cases IDIOPATHIC
- pain often worst during activity and at night after days activities
- seen in large, weight bearing joints
- ganglion and synovial cysts
RA
chronic, systemic inflammatory disorder
I response and CD4 mediated non-suppurative synovitis
destruction of articular cartilage ankylosis of joints panes formation synovium with papillary proliferative growth rheumatoid nodules swan neck deformity ulnar deviation boutonniere deformity of thumb synovial cysts (usually baker's cyst)
avascular necrosis
osteonecrosis, ischemic necrosis
direct damage to bone vasculature - ischemia (fracture, corticosteroids..) creeping substitution to attempt to replace infarct - TRIANGULAR SHAPE OF BONE NECROSIS - YELLOW BONE - glucocorticoids and xs alcohol --> 80% of cases - alc osteonecrosis * men - SLE osteonecrosis * women
gout
articular deposition of monosodium rate crystals in joints, subcutis, kidney
top formation
long needles, yellow, - birefringence
pseudogout
intra-articular accumulation of any insoluble crystal (like Ca pyrophosphate)
rhomboid in shape, weakly birefringent
blue, + birefringence –> pseudo gout
ELDERLY
most common tumors in bones are
metastatic
originate via prostate, breast, thyroid, lung, kidneys
most common site of infection
long bone (rich vascular supply)
Diaphysis
which tumors commonly here
Ewing’s sarcoma, lymphoma, myeloma, fibrous dysplasia, enchondroma, osteoid osteoma
Metaphysis
non-ossifying fibroma, osteoid osteoma, osteosarcoma, chondrosarcoma, osteoblastoma, enchondroma, fibrous dysplasia, bone cysts, osteochondroma
Epiphysis
chondroblastoma, giant cell tumor
cartilage forming tumors
osteochondroma, enchonroma, chondrosarcoma
bone forming tumors
osteoma, osteoid osteoma, osteoblasto, osteosarcoma
cartilage and other tumors
Ewing sarcoma, giant cell tumor, tumors of adipose tissue
osteochondroma
most common benign tumor of bone young patients location: physes perpendicular lesion carilingous cap looks normal
endochondroma
benign
adults
small bones of hand
radiolucency, hypercellular, sclerotic ring
chondrosarcoma
malignant
most common cartilaginous tumor
middle aged population
large lesions, small irregular nuclei, abnormal mitoses
osteoid osteoma
relieve pain with NSAIDs
benign, younger adults
only in bones formed via endochondral ossification
presents with woven bone, central nidus (XR), sclerotic rim
osteosarcoma
conman triangle on xray most common primary malignancy of bone under 20 and elderly (elderly usu w/ syndrome like paget's) Rb mut --> higher risk CODMAN'S TRIANGLE
Ewing sarcoma
onion skin appearance on XR population = teens location: femur, long bones small round blue cells t(11;22)(q24;q12)
Giant cell tumor
soap bubble
adults over 20
location: all bones
osteoclast-type giant cells, pigmented villonodular synovitis involvement, soft tissue mass, hemorrhagic
chondrosarcoma
malignant cartilage-forming tumor
lipoma
subQ
benign
liposarcoma
LE, retroperitoneum
