Robbins Chapter 7 Flashcards
What are 4 improper uses of “-oma”? (LMMS)
lymphoma, mesothelioma, melanoma, seminoma
- “-oma” means benign but these are MALIGNANT
What is anaplasia?
complete lack of differentiation (malignant neoplasms composed of poorly differentiated cells)
- IRREVERSIBLE; hallmark of malignancy
What do teratomas originate from?
totipotent germ cells
What are characteristics of a malignant nucleus? (4)
large nucleus (1:1 nucleus:cytoplasm ratio)
variable/irregular nuclear shape
coarsely clumpled chromatin
hyperchromatic (dark staining)
Difference between:
- Well Differentiated
- Moderately Differentiated
- Poorly Differentiated
- Undifferentiated
- looks like parent tissue
- original tissue not dominant pattern, some atypia
- small # of parent features, cellular anaplasia
- tissue of origin CANNOT be discerned, anaplasia
What is Carcinoma In Situ?
pre-invasive neoplasms involving full epithelial thickness but DO NOT penetrate basement membrane
- becomes invasive once it has penetrated BM
Tumor Capsules (Local Invasion) and the one exception
- rim of compressed fibrous tissue seen around benign tumors that separate them from host tissue (malignant have pseudo-capsules)
- created by fibroblasts due to hypoxia from growing tumor pressing on healthy tissue (makes tumor easy to find and feel)
Hemangiomas do NOT have a capsule and are not discrete
What is the only ABSOLUTE criterion for Malignancy?
Metastasis (strongly reduced possibility of cure)
- invasiveness is 2nd best characteristic
What are common pathways of spread for:
- Ovarian Carcinomas
- Breast Cancer
- Carcinomas of the lung
- Direct Seeding into potential space (“heavy glaze”)
- Lymphatic Spread (axillary LNs)
- Lymphatic Spread (perihilar tracheobronchial and mediastinal LNs)
What are the two most common ways carcinomas and sarcomas spread?
Lymphatic Spread –> mainly carcinoma, some sarcoma
Hematogenous Spread –> mainly sarcomas, some carcinomas
What is a Sentinel Node and why is important?
first node in a regional lymphatic basin that receives lymph from from the PRIMARY tumor
- biopsy to detect absence/presence of metastatic lesions
What cancers embolize through the paravertebral plexus?
vertebral carcinomas of prostate and thyroid
What are two cancers that mainly invade veins?
renal cell carcinoma –> to heart
hepatocellular carcinomas
Where do these cancers normally spread to:
- Breast Cancer
- Bronchogenic Carcinomas
- Neuroblastomas
- bone
- adrenals and brain
- liver and bones
What are the 3 most common cancers of Men and Women in developed nations?
Men: prostate, lung, colorectal
Women: breast, lung, colorectal
What are the 3 most common cancers of Men and Women in developing nations?
Men: lung, stomach, liver
Women: breast, cervix, lung
What age range in Men and Women is cancer seen to be the main cause of death in?
Men: 60-79 yo
Women: 40-79 yo
What causes:
- Squamous Metaplasia of the bladder
- Colonic Metaplasia of the stomach
- schistosomiasis infection
2. pernicious anemia and chronic atrophic gastritis
What cancer does exposure to Beryllium, Radon, and Chromium make workers more prone to?
Lung Cancer
B: missles, space fuels, nuclear reactors
R: uranium decay (quarries and mines)
C: metal alloys, pigments, preservatives
What are the two main steps of Chemical Carcinogenesis?
- Initiation - cell exposure to carcinogenic agent
- permanent, nonlethal DNA damage
- highly reactive electrophile (DNA bind/lesions)
- Promotion - induce tumors in initiated cells
- chemical agents that stimulate cell proliferation
- exposes carcinogenic potential of initiator
- *only works on initiated cells**
Direct vs Indirect Initiating Chemicals
Direct: does NOT require metabolic activation
- ex: chemotherapeutic agents (low risk)
In-Direct: requires metabolic activation
- products called “ULTIMATE CARCINOGENS”
- activated by CYP450 normally
Benzo[a]pyrene (Indirect Initiating Chemical) and Aromatic Amines/Azo Dyes
active component in soot (tobacco combustion forms)
- CYP1A1 (highly inducible form) metabolizes
- smoked meats (from animal fat)
Aromatic Amines/Azo Dyes from rubber industries
What is Aflatoxin B1 and what cancer does it cause?
agent produced by Aspergillus that grows on improperly stored grains and nuts
- hepatocellular carcinoma in Africa and Far East
- Arginine –> Serine on Codon 249 (p53 protein mutation; infrequent in liver tumors from areas where this contamination does NOT occur)
UVB and Radiation Carcinogenesis
greatest risk of UV damage to the skin
- produces Pyrimidine dimers that are repaired by Nucleotide Excision Repair
Xeroderma Pigmentosum: defect in NER pathway
What is Human T-Cell Leukemia Virus Type-1 (HTLV-1)?
oncogenic RNA virus –> adult T-cell leukemia/lymphoma (ATLL)
- many tumors express FOXP3 (deaths from opportunistic infections)
How does HTLV-1 cause tumors to develop?
does NOT contain an oncogene; is a RETROVIRUS
- viral replication of TAX = viral transcription of viral RNA from 5’ long terminal repeat
- PI3K/AKT –> cell survival
- inc. Cyclin D2, dec. CDK inhibitors
- NF-kB –> cell survival
What is HPV and what is associated with Low-Risk Types and High-Risk Types?
oncogenic DNA virus that interrupts E1/E2 reading frame = lose E2 viral repressor and overexpress E6/7
Low Risk (6/11) = genital warts (nonintegrated genome) High Risk (16/18) = squamous cell carcinomas
What are the oncogenic properties of HPV oncoproteins E6 and E7?
E6 - degradation of p53, stimulate TERT (inc. telomerase)
- p53 Arg72 polymorphism = CERVICAL CANCER
E7 - binds Rb and displaces E2F TF (G1-S phase) and inactivates p21 and p27
What is EBV (oncogenic DNA virus) associated with and how does it infect?
associated with: African Burkitt Lymphoma, nasopharyngeal cancer, and B Cell lymphomas
- infects B cells by CD21 (latent, can propagate indefinitely in vitro = immortalized)
- develops self-limited infectious mononucleosis in immunocompotent individuals
How do LMP-1, EBNA-2, and vIL-10 help with EBV B Cell proliferation?
LMP-1: oncogene (CD40 always on)
- inc. NF-kB/JAK STAT and inc. Bcl2
EBNA-2: Notch receptor always on
- inc. cyclin D and SRC proto-oncogenes
vlIL-10 - no T cell activation by monocytes
EBV and its association with Burkitt Lymphoma and Nasopharyngeal Carcinoma
Burkitt Lymphoma
- no EBV protein expression (acts as B-cell mitogen)
- t(8;14) seen in sporadic and endemic forms
Nasopharyngeal Carcinoma
- infect epithelial cells via CD21
- 100% of carcinomas contain EBV (express LMP-1)
Hepatitis B and Hepatitis C viruses (HBx protein)
associated w/hepatocellular carcinoma
no viral oncogenes (effects are multifactorial)
cause chronic inflammation –> regeneration and genomic damage over time
produce HBx = activates TF and signal transduction pathways –> cancer development
H. pylori and development of Gastric Adenocarcinoma and Gastric Lymphoma
GA: CagA gene penetrates gastric epi cells –> stimulate growth factors
GL: B cell lymphoma lookin’ like Peyers Patches
- reactive T Cells stim B Cell proliferation (MALToma)
- monoclonal B cell proliferation
can eliminate H. pylori but B cells could acquire mutation that keeps them on WITHOUT T cell stimulus
Cushings Syndrome and Hypercalcemia of Malignancy (Paraneoplastic Syndromes)
CS: most common endocrinopathy
- small cell carcinoma of lung
- lots of corticotropin and POMC (lung cancer)
- puititary problems only have inc. corticotropin
HM: most common paraneoplastic syndrome
- breast, lung, kidney, ovary carcinomas
- extraosseus neoplasms (osteolysis/PTHRP)
- symptomatic hypercalcemia = CANCER
What is the most common lung neoplasm associated with Hypercalcemia?
squamous cell carcinoma
What two cancers would cause migratory thrombophlebitis (Trousseau Syndrome)?
pancreas and lung carcinomas
What two cancers is DIC associated with?
acute premyelocytic leukemia and prostatic adenocarcinoma
What are cancer Gradings and Stagings based on?
Grading: differentiation, architecture, mitosis
Staging: size of primary lesion, spread to LNs, blood-borne metastasis presence
- MOST IMPORTANT CLINICALLY
T (primary tumor), N (LN involvement), M (metastasis)
Where should a cancer biopsy be taken from?
between the outside edge and the necrotic center
periphery may not represent the tumor well
What cancers are indicated by antibodies for:
- cytokeratins
- desmin
- anti-CD20
- PSA
- Thyroglobulin
- ALK
- epithelial carcinomas
- muscle cancer
- B cell tumors
- prostate carcinomas
- thyroid carcinomas
- lung cancers and lymphoma expressing ALK fusion proteins
abs can also check for estrogen/progesterone receptors and HER2 receptors
When would you want to use:
- Quick Freeze
- Fine Needle aspiration
- Cytological Smears
- determine nature of mass lesion
- gather surrounding fluids from easily palpable lesions
- less invasive than needle biopsy
- usually from LNs
- pap smears (IN SITU STAGE)
- ID tumors of abdominal, pleural, joint, CS fluids
- tumors from easily shed locals
What does Flow Cytometry and Circulating Tumor methods provide to cancer diagnosos?
FC: look at multiple antigens of blood-borne cancers at the same time (rapid and quantitative)
CT: find rare cancers cells in blood using 3D flow cells coated in antibodies
How are PCR, FISH, DNA Microarrays useful in cancer diagnosis?
PCR - ID monoclonal (neoplastic) or polyclonal (reactive) T and B cell proliferations
FISH - ID characteristic translocations
DNA Microarray - genome-wide amps/deletions
What cancers do these tumor biomarkers help identify:
- PSA
- CEA (Carcinoembryonic Antigen)
- AFP (alpha fetoprotein)
- HCG
- CA-125
- prostatic carcinomas
- colon, pancreas, lung, stomach, breast carcinomas
- hepatocellular carcinomas
- testicular tumors
- ovarian tumors
none are useful for DEFINITIVE diagnosis of cancer
Driver Mutations and Loss of Function Mutations
DM: mutations that contribute to the malignant phenotype
- accumulation rate = speed of dz progression
LoF Mutations in genomic integrity genes are common early step on road to malignancy
What does a mutation in ERBB1 and an amplification in ERBB2 lead to?
ERBB1 –> EGFR = Adenocarcinoma of the Lung
- EGRF RTK always on
ERBB2 –> HER2 = breast carcinoma
- amplification of HER2 receptor, RTK always on
What does a translocation and a point mutation in ALK Receptor Proto-oncogenes lead to?
ALK translocation = adenocarcinoma of lung
ALK point mutation = neuroblastoma
What 2 growth factors do Glioblastomas and Sarcomas express?
G: PDGF and PDGF RTK
S: TGFa and EGFR
What are the most common abnormalities in proto-oncogenes in human tumors?
Point Mutations in RAS
What cancers develop from a translocation and point mutation of the proto-oncogene ABL (Nonreceptor Tyrosine Kinase)?
Translocation = chronic myelogenous leukemia (CML)
Point Mutation = acute lymphoblastic leukemia (AML)
What cancers develop from a translocation and amplification of MYC proto-oncogenes?
Translocation –> Burkitt Lymphoma
Amplification –> Neuroblastoma
specifically NMYC amplification
What cancer are BRAF mutations seen in 100% of the time?
hairy cell leukemia
Rb gene mutation and the two cancers somatic mutations cause
two hits required at RB on C13q14
AD inherited or undergo 2 random somatic mutations when NOT inherited
Somatic Mutation = retinoblastoma and osteosarcoma
What is the function of:
- p21
- p27
- p16
- p14
- induced by p53
- responds to TGF-b
- INK4 –> bind cyclin D-CDK4 (inhibitory to Rb)
- inc. p53 lvls by inhibiting MDM2
MDM2 effect on p53
p53 normally cause apoptosis via BAX but is negatively inhibited by MDM2
MDM2 degrades p53 (hyperactivity of MDM2 could lead to cancer proliferation)
p53 virtually undetectable in normal cells
How does HPV confer a high risk of cervical carcinoma?
if it expresses the E7 protein
TP53 mutations and Li-Fraumeni Syndrome
“Guardian of the Genome” –> LoF in 50% of cancers (C17p13.1)
- most likely NOT inherited (inheriting one defective allele = Li-Fraumeni Syndrome = 25x greater chance of cancer by 50)
- loss of p53 causes driver mutation accumulation
APC mutations and Familial Adenomatous Polyposis
“Gatekeeper of Colonic Neoplasm” –> locus on C5q21
helps with degradation of Beta-Catenin (WNT system)
APC loss = inc. Beta-Catenin (uncontested growth)
Familial Adenomatous Polyposis (start w/1 defective allele of APC) = malignant polyps –> colon cancer
What is the WNT System?
WNT signals FRZ = prevents Beta-catenin from being degraded
Beta Catenin binds to TCF (DNA binding factor) = promotion of colonic epithelial growth (inc. MYC and Cyclin D1)
What TP53 mutants are treated the best and what two cancers are caused by them?
wild-type mutations treated easier
cancers: testicular teratocarcinoma and lymphoblastic leukemias
Von Hippel Lindau function and mutation (what 2 cancers are pts at risk for?)
component of ubiquitin ligase that normally degrades HIF and TFs that respond to hypoxia (Chromosome 3)
- Von Hippel-Lindau Syndrome (AD inherited) w/inc. risk of renal cell carcinoma and pheochromocytoma
- mutations associated with inc. lvls of angiogenic growth factors and metabolism alterations
E-cadherin function and mutation (what cancer are pts at risk for?)
normally anchors B-catenin to intracellular membrane and mediates cell-cell connections
Germline LoF (CDH1) = familial gastric carcinoma
SNAIL can downregulated E-cadherins
CDKN2a function and mutation
encodes p16 and p14 (inhibits MDM2)
germline mutations
p16 methylated in some cervical cancers
What cancers are associated with LoF in TGF-bR2 and inactivation of SMAD? (TGF-b pathway)?
LoF = colon, stomach, endometrium cancer
Inactivation = pancreatic cancer
SMAD normally upregulates CDKi/downregulates proliferative genes
PTEN function and mutation
found on C10q23 –> normally halts PI3K/AKT
Cowden Syndrome
- mutated –> skin appendages and tumors
- inc. epithelial cancers (breast, endomet., thyroid)
What are NF1 and NF2 associated with?
NF1 –> optic nerve gliomas
NF2 –> bilateral schwannomas of acoustic N.
- makes neurofibromin 2 (MERLIN)
Patched (PTCH) function and Gorlin Syndrome
tumor suppressor that negatively regulates hedgehog
mutation = unopposed Hedgehog signaling (inc. NMYC and D cyclins)
Gorline Syndrome = germline mutations
- inc. risk of basal cell carcinoma and medulloblastoma
Warburg Effect (PI3K, RTK, MYC)
inc. aerobic glycolysis and glutamine/glucose uptake
- provides intermediates for rapidly dividing cells that OxPhos cannot provide
PI3K –> upregulates GLUT, lipid/protein synth
RTK –> M2 isoform of pyruvate kinase
MYC –> support anabolic state and cell growth
What affects does PTEN and STK11 have on the Warburg Effect?
PTEN = oppose PI3K pathway
STK11 = antagonizes Warburg changes
What do the most common mutation of apoptosis in cancer involve?
caspase 9
What do most B-cell lymphomas over-express in order to evade programmed cell death?
Bcl-2 due to t(14;18) translocation
Cancer-Testis Antigens
MAGE-1 (Melanoma Antigen Gene)
- only expressed in testis; silent in adults
- tumor specific since sperm have no MHC1
What two Mucin (glycoproteins/glycolipids) are expressed by ovarian Carcinomas?
CA-125 and CA-19-9
What can kill mature B-cell lymphoma/leukemia and what CD is expressed by T cell lymphomas/Hodgkin lymphomas?
Anti-CD20 can kill B-cell lymphoma and leukemias
CD30 for T cell lymphomas and Hodgkins
Hereditary Nonpolyposis Colon Cancer Syndrome
AD inherited cecum and proximal colon cancer
- defect in mismatch repair
microsatellite instability (1-6 nucleotide repeats inc/dec in disease)
Why are COX2 inhibitors important?
decrease incidence of colonic adenomas and are approved for treatment of Familial Adenomatous Polyposis
What cancers are epigentic methylation mutations (MLL1 and MLL2) and chromatin remodeling mutation (SNF5) related to?
MLL1 –> infants with acute leukemia
MLL2 –> follicular lymphoma
SNF5 –> malignant rhaboid tumor
What miRNA are associated with B cell lymphomas and chronic lymphocytic leukemias?
BCL: miR-155 (indirectly upregulates MYC)
CLL: miR-15/16 (upregulation of Bcl-2)
What translocation is associated with:
- CML (Chronic Myelogenous Leukemia)
- AML (Acute Myeloid Leukemia)
- Burkitt Lymphoma
- Mantle Cell Lymphoma
- Follicular Lymphoma
- t(9;22)
- t(8;21) OR t(15;17) –> PML-RARA gene
- give All-trans RA to displace receptor repressors
- t(8;14)
- t(11;14)
- t(14;18)
