Chapter 7 Flashcards
2 basic tissue components of benign and malignant neoplasms; which component typically gives rise to the neoplastic cells?
Parenchyma = generally gives rise to neoplatic cell component — this is what classification of tumors is based on
Reactive stroma = supportive tissue skeleton on which the parenchymal component resides - responsible for growth and spread
How is a mixed tumor of the salivary gland different from an adenoma of the colon?
Mixed tumor of salivary gland = pleiomorphic adenoma (benign) — contains more than one neoplastic cell type, usually derived from one germ layer
Adenoma of the colon = benign epithelial neoplasm derived from glands, may form adenomatous polyp
How is a cystic teratoma of the ovary fundamentally different from a mixed tumor of the salivary gland?
Primary difference is that teratomas may come from all 3 germ layers, while mixed tumors usually come all from same germ layer, even if different cell types are involved
Hallmark of malignancy characterized by lack of differentiation
Anaplasia
4 grades of differentiation
Well differentiated — closely resembles parent tissue
Moderately differentiated — features of the original tissue type identifiable but not in normal pattern, with additional atypia
Poorly differentiated — small minority of cell constituents allow ID of parent tissue; associated with cellular anaplasia
Undifferentiated — cannot discern parent tissue of origin; always associated with anaplasia
Histopathologic criteria used when classifying something as “anaplastic”
Pleomorphism
Abnormal nuclear morphology
High mitotic rate
Loss of polarity
Additional blood vessel formation with central areas of necrosis
Metaplasia vs. dysplasia
Metaplasia = replacement of one type of cell with another; found in association with tissue damage, repair, and regeneration
Dysplasia = disordered growth; encountered principally in epithelia, characterized by loss in uniformity of individual cells as well as loss in their architectural orientation
Define carcinoma in situ
Dysplastic changes are marked and involve full thickness of epithelium, but lesion does not penetrate the basement membrane
Carcinoma in situ is best characterized as ________
Pre-neoplastic (argument could be made for “benign” as well)
Most common histopathologic features used to assess rate of growth in a neoplasm
Slow growing cancers typically have capsule (rim of compressed fibrous tissue)
Malignant/rapidly growing tumors are typically poorly demarcated and lack well-defined cleavage plane; some have pseudoencapsulation (rows of cells penetrating margin and infiltrating adjacent structures)
Pathologic features that individually (and almost always in aggregate) distinguish malignant from benign tumors
Atypical structure with some lack of differentiation (anaplasia)
Erratic rate of growth; mitotic figures may be numerous and abnormal
Locally invasive, infiltrating surrounding tissue
Metastasis
2 examples of malignancies that rarely metastasize
Gliomas
Basal cell carcinomas
3 major pathways by which metastasis may occur
Direct seeding of body cavities or surfaces
Lymphatic spread
Hematogenous spread
Describe metastasis by direct seeding of body cavities/surfaces
May occur whenever a malignant neoplasm penetrates into a natural “open field” lacking physical barriers
Most often involves peritoneal cavity (can also be pleural, pericardial, subarachnoid, joint spaces, etc.)
Describe pattern of lymphatic spread in the metastasis of breast vs. lung cancers
Breast —> axillary nodes or internal mammary arteries
Lung —> perihilar tracheobronchial and mediastinal nodes
Carcinomas typically metastasize via lymphatic spread, however there are some exceptions. What are 4 carcinomas that tend to metastasize via hematogenous spread?
Renal cell carcinoma - via renal v. to IVC
Hepatocellular carcinoma - via hepatic v.
Follicular carcinoma of thyroid
Choriocarcinoma
First node in a regional lymphatic basin that receives lymph flow from the primary tumor
Sentinal node
The most common tumor of men in the US and most of developed world is prostate cancer, but in certain countries or regions (most located in developing world), cancers of the liver, stomach, esophagus, bladder, lung, oropharynx, and immune system rise to the top of the list.
Similarly, the incidence of breast cancer is generally much higher in women in developed countries than in most parts of the developing world.
What are some probable reasons for the difference in incidence in prostate and breast cancers?
Environmental influences likely underlie most differences in incidence:
Infectious agents like HPV Smoking Alcohol consumption Diet Obesity Reproductive history Environmental carcinogens
Occupational cancer associated with arsenic exposure (by-product of metal smelting, exposure to medications/herbicides/fungicides)
Squamous cell carcinoma of skin
Lung carcinoma
Occupational cancer associated with asbestos exposure (found in construction of older buildings, friction materials, roofing tiles, floor papers, etc)
Lung, esophageal, gastric, and colon carcinoma; mesothelioma
[note that lung carcinoma more commonly occurs than mesothelioma]
Occupational cancer caused by benzene exposure (component of light oil; used in dry cleaning, printing, paint, rubber, detergents)
Acute myeloid leukemia
Occupational cancer due to beryllium exposure (missile fuel, space vehicles, nuclear reactors)
Lung carcinoma
Occupational cancer due to cadmium exposure (yellow pigments and phosphors; found in solders, batteries, metal platings, coatings)
Prostate carcinoma
Occupational cancer due to chromium exposure (metal alloys, paints, pigments, preservatives)
Lung carcinoma
Occupational cancer due to exposure to nickel compounds (nickel plating, ceramics, batteries, byproduct of stainless steel welding)
Lung and oropharyngeal carcinoma
Occupational cancer due to exposure to radon + its decay products
Lung carcinoma
Occupational cancer due to vinyl chloride exposure
Hepatic angiosarcoma
What type(s) of cancer are associated with the following chronic inflammatory state:
Asbestosis, silicosis
Mesothelioma
Lung cancer
What type(s) of cancer are associated with the following chronic inflammatory state:
IBD
Colorectal carcinoma
What type(s) of cancer are associated with the following chronic inflammatory state:
Lichen sclerosis
Vulvar squamous cell carcinoma
What type(s) of cancer are associated with chronic inflammatory states due to Sjogren syndrome or Hashimoto thyroiditis?
MALT lymphoma
What type(s) of cancer are associated with the following chronic inflammatory state:
Opithorchis, cholangitis (due to liver flukes)
Cholangiocarcinoma, colon carcinoma
What type(s) of cancer are associated with the following chronic inflammatory state:
H. Pylori induced gastritis/ulcers
Gastric adenocarcinoma, MALT lymphoma
What type(s) of cancer are associated with the following chronic inflammatory state:
Hepatitis
Hepatocellular carcinoma
What type(s) of cancer are associated with the following chronic inflammatory state:
Osteomyelitis
Carcinoma in draining sinuses
What type(s) of cancer are associated with the following chronic inflammatory state:
Chronic cystitis d/t schistosomiasis
Bladder carcinoma
_______ = thickening of squamous epithelium that may occur in oral cavity, penis, or vulva, and give rise to squamous carcinoma
Leukoplakia
Benign neoplasm that, if left untreated, progresses to cancer in 50% of cases
Colonic villous adenoma
3 examples of benign neoplasms at extremely low risk for malignant transformation
Lipomas
Uterine leiomyomas
Pleomorphic adenomas
Inherited cancers are usually due to what type of mutation?
Germline mutation in tumor suppressor gene
Developmental attributes known as cancer hallmarks
Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Altered cell metabolism Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Ability to invade and metastasize Ability to evade host immune response
PDGFB (platelet-derived growth factor) is a proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
Overexpression —> Astrocytoma
ERBB2 [HER2/neu] is a proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
Overexpression/amplification —> subset of breast carcinomas (important for therapeutic implications)
RET is a neural growth factor receptor and known proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
Point mutation —> MEN2A, MEN2B, and sporadic medullary thyroid cancer
KIT is a stem cell growth factor receptor and known proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
Point mutation —> GI stromal tumor
The RAS gene family codes for GTP binding proteins that are known proto-oncogenes that undergo what type of mutation and is associated with what type of cancer?
Point mutation —> carcinomas, melanomas, lymphomas (many types)
ABL is a tyrosine kinase and known proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
t(9;22) with BCR —> CML, some types of ALL (adult types)
c-MYC is a transcription factor and known proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
t(8;14) involving Ig heavy chain locus (leading to massive production of MYC —> Burkitt lymphoma
N-myc is a transcription factor and known proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
Amplification —> neuroblastoma
L-myc is a transcription factor and known proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
Amplification —> small cell lung cancer
CCNDI (cyclin D1) is a known proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
t(11;14) involving Ig heavy chain —> mantle cell lymphoma
CDK4 is a known proto-oncogene that undergoes what type of mutation and is associated with what type of cancer?
Amplification —> melanoma
Gatekeeper of colonic neoplasia
APC (adenomatous polyposis coli protein)
When APC is mutated or absent, destruction of ______cannot occur - so it translocates to the nucleus and coactivates genes that promote entry into the cell cycle, and cells behave as if they are under constant stimulation by the ____ pathway
Beta-catenin; WNT
Familial and sporadic cancers associated with APC
Familial: familial colonic polyps and carcinomas
Sporadic: carcinomas of stomach, colon, pancreas, melanoma
____ is a regulatory gene that functions as an inhibitor of RAS/MAPK signaling; what types of cancers are associated with it?
NF1
Familial: neurofibromatosis type 1 - neurofibromas and peripheral nerve sheath tumors
Sporadic: neuroblastoma, juvenile myeloid leukemia
_____ is a regulatory gene that functions in cytoskeletal stability and Hippo pathway signaling; what type of cancers is it associated with?
NF2 (merlin)
Familial: neurofibromatosis type 2 (acoustic schwannoma, meningioma)
Sporadic: schwannoma, meningioma
____ is a regulatory gene that functions as an inhibitor of hedgehog signaling; what type of cancers is it associated with?
PTCH (patched)
Familial: gorlin syndrome (basal cell carcinoma, medulloblastoma, benign tumors)
Sporadic: basal cell carcinomas, medulloblastoma
_____ is a regulatory gene that functions as an inhibitor of PI3/AKT signaling; what cancers are associated with it?
PTEN
Familial: Cowden syndrome - benign skin, GI, and CNS growths; breast, endometrial, and thyroid carcinoma
Sporadic: diverse cancers - particularly carcinomas and lymphoid tumors
_____ is a regulatory gene that functions as a component of TGF-beta signaling pathway, repressor of MYC and CDK4 expression, and inducer of CDK inhibitor expression; what types of cancer is it associated with?
SMAD2, SMAD4
Familial: juvenile polyposis
Sporadic: frequently mutated in colonic and pancreatic carcinoma
____ protein functions as an inhibitor of hypoxia-induced transcription factors (e.g., HIF1-alpha)
VHL
Germline loss of function mutations in VHL protein cause VHL syndrome, and AD disorder associated with high risk of what cancers? What paraneoplastic syndrome?
Renal cell carcinoma
Pheochromocytoma
Cerebellar hemangioblastoma
Retinal angioma
Paraneoplastic syndrome = polycythemia (high RBC count) - due to the cerebellar hemangioblastoma
_____ is an activator of AMPK family of kinases and functions in supression of cell growth when cell nutrient and energy levels are low; what cancers is it associated with?
STK11 (liver kinase B1 or STK11)
Familial: Peutz-Jeghers syndrome (GI polyps, GI cancers, pancreatic carcinoma)
Sporadic: diverse carcinomas
Cancers associated with SDHB and SDHD which function in TCA cycle/oxphos
Paraganglioma, familial pheochromocytoma
CDH1 (e-cadherin) functions in cell adhesion and inhibitor of motility; what cancers are associated with its dysfunction?
Gastric carcinoma, lobular breast carcinoma
p53 may be inactivated by viral oncoproteins, such as ____ associated with HPV
Rb may also be inactivated by viral oncoproteins, such as ____ associated with HPV
E6
E7
Therapeutic implications of a cancer associated with mutated TP53
Less likely to be killed by irradiation and conventional chemotherapy, because they mediate their effects by inducing DNA damage and subsequent apoptosis
Rare syndrome in which patients inherit one defective copy of TP53 and have very high incidence of diverse cancers
Li-Fraumeni syndrome
ALK is a growth factor receptor that may undergo translocation, fusion gene formation, or point mutation to contribute to what cancers?
Adenocarcinoma of lung, certain lymphomas, neuroblastoma
BRAF is a proto-oncogene associated with RAS signal transduction that may undergo point mutations or translocations to contribute to what cancers?
Hairy cell leukemias, melanomas, benign nevi, colon carcinoma, and dendritic cell tumors
Bcl2 is a regulator of apoptosis. What type of mutation does it undergo and what cancers is it associated with?
t(14;18) —> increased Bcl2 production —> apoptosis will not occur — this is normally not an issue EXCEPT in follicle, so it contributes to follicular lymphoma
Warburg effect
Upregulation of glucose and glutamine uptake, which provide carbon sources of synthesis of nucleotides, proteins, and lipids
In cancers, oncogenic mutations involving growth factor signaling pathways and other key factors such as MYC deregulate these metabolic pathways
Cancer cells acquire lesions that inactivate senescence signals and reactivate ______, which act together to convey limitless replicative potential
Telomerase
Regulators of angiogenesis
p53 induces synthesis of angiogenesis inhibitor thrombospondin-1
RAS, MYC, and MAPK signaling all upregulate VEGF expresion
Mechanisms by which tumors may avoid immune system detection
Selective outgrowth of antigen-negative variants
Loss or reduced expression of histocompatibility Ags
Immunosuppression mediated by expression of certain factors (e.g., TGF-beta, PD-1 ligand, galectins) by the tumor cells
How do those with HNPCC syndrome end up with increased risk of colon cancer?
Defective DNA mismatch repair system — so their genome shows microsatellite instability, characterized by changes in length of short repeats throughout the genome
Most known carcinogens are metabolized by what enzymes?
Cytochrome p450-dependent monooxygenases
Aflatoxins are carcinogens produced by aspergillus mold and confer risk to what type of cancer?
Hepatocellular carcinoma
Disorder associated with defects in nucleotide excision repair and thus increased risk of skin cancer in areas exposed to UVB light, due to inability to repair pyrimidine (typically thymidine) dimers
Xeroderma pigmentosa
Cushing syndrome is a paraneoplastic syndrome related to what type(s) of cancer?
Small cell carcinoma of lung
Pancreatic carcinoma
Neural tumors
SIADH is a paraneoplastic syndrome related to what type(s) of cancer?
Small-cell carcinoma of lung
Intracranial neoplasms
Hypercalcemia is a paraneoplastic syndrome related to what type(s) of cancer?
Squamous cell carcinoma of lung
Breast and renal carcinomas
ATLL
Hypoglycemia is a paraneoplastic syndrome related to what type(s) of cancer?
Ovarian sarcoma
Fibrosarcoma
Other mesenchymal sarcomas
Polycythemia is a paraneoplastic syndrome related to what type(s) of cancer?
Renal carcinoma
Cerebellar hemangioma
Hepatocellular carcinoma
Myasthenia is a paraneoplastic syndrome related to what type(s) of cancer?
Bronchogenic carcinoma
Thymic neoplasms
Disorders of the CNS and PNS are paraneoplastic syndromes related to what type(s) of cancer?
Breast carcinomas
Acanthosis nigricans is a paraneoplastic syndrome related to what type(s) of cancer?
Gastric carcinoma
Lung carcinoma
Uterine carcinoma
Dermatomyositis is a paraneoplastic syndrome related to what type(s) of cancer?
Bronchogenic carcinoma
Breast carcinoma
Hypertrophic osteoarthropathy and clubbing of the fingers are changes associated with a paraneoplastic syndrome that occurs with what type(s) of cancer?
Bronchogenic carcinoma
Thymic neoplasms
Venous thrombosis (trousseau phenomenon) is a paraneoplastic syndrome related to what type(s) of cancer?
Pancreatic carcinoma
Bronchogenic carcinoma
Other cancers
DIC is a paraneoplastic syndrome related to what type(s) of cancer?
Acute promyelocytic leukemia
Prostatic carcinoma
Nonbacterial thrombotic endocarditis is a paraneoplastic syndrome related to what type(s) of cancer?
Advanced cancers
Red cell aplasia is a paraneoplastic syndrome related to what type(s) of cancer?
Thymic neoplasms
Definition of grading vs. staging of tumors
Grading based on degree of differentiation (cytologic appearance)
Staging based on size of primary lesion, extent of spread, and presence/absence of metastasis
Utility of flow cytometry in cancer diagnosis
Mainly used to identify cellular antigens expressed by B and T cell lymphomas and leukemias as well as myeloid neoplasms
HCG as tumor marker
Trophoblastic tumors
Nonseminomatous testicular tumors
Calcitonin as tumor marker
Medullar carcinoma of thyroid
Catecholamines as tumor markers
Pheochromocytoma
ACTH or ACTH-like substances as tumor markers
Small-cell carcinoma of lung
Pancreatic carcinoma
Neural tumors
ADH or ANP hormones as tumor markers
Small cell carcinoma of lung
Intracranial neoplasms
PTHRP, TGF-alpha, TNF, or IL-1 as tumor markers
Squamous cell carcinoma of lung
Breast carcinoma
Renal carcinoma
ATLL
Insulin as tumor marker
Ovarian carcinoma
Fibrosarcoma
Other mesenchymal sarcomas
EPO as tumor marker
Renal carcinoma
Cerebellar hemangioma
Hepatocellular carcinoma
Alpha-fetoprotein as tumor marker
Hepatocellular carcinoma
Nonseminomatous germ cell tumors of testes
Carcinoembryonic antigen as tumor marker
Carcinomas of colon, pancreas, lung, stomach, and heart
Neuron-specific enolase as tumor marker
Small cell cancer of lung
Neuroblastoma
CA-125 as tumor marker
Ovarian cancer
CA-19-9 as tumor marker
Colon cancer
Pancreatic cancer
CA-15-3 as tumor marker
Breast cancer
What type of cancer is associated with a t(15;17) translocation and is associated with DIC - indicated by fibrin split products and purpuric lesions?
Acute myeloid leukemia