Neoplasia Flashcards by Sarah Gillen

Monoclonal refers to the idea that neoplastic cells are derived from a single mother cell. Clonality can be determined by ______ isoforms (or _______ receptor isoforms)

G6PD; androgen

[G6PD and androgen receptors are X-linked and remember that X inactivation is random; if all daughter cells express the same isoform of G6PD or androgen receptor, it is considered monoclonal]

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How is clonality of B cells determined?

By Ig light chain phenotype

[each B cell will have either kappa or lambda light chain (normally 3:1 ratio); normal response to infection is polyclonal cell division and ratio would remain 3:1. In something like lymphoma, ratio becomes something like 20:1]

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T/F: Neoplastic tumors are benign or malignant, but BOTH are considered monoclonal.

True

Difference is that benign tumors remain localized and do not metastasize. Malignant tumors (cancer) invade locally and have potential to metastasize

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Benign vs. malignant nomenclature for tumors of epithelium

Benign: Adenoma, papilloma

Malignant: adenocarcinoma, papillary carcinoma

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Benign vs. malignant nomenclature for tumors of mesenchyme

Benign: lipoma

Malignant: liposarcoma

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______ is the 2nd leading cause of death in both adults and children

Cancer

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Top 3 causes of death in adults

Cardiovascular disease
Cancer
Cerebrovascular disease

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Top 3 causes of death in children

Accidents
Cancer
Congenital defects

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Most common cancers in adults by incidence (3)

Breast/prostate
Lung
Colorectal

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Most common cancers in adults by mortality (3)

Lung
Breast/prostate
Colorectal

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Cancer begins as a single mutated cell. Approximately ______ divisions occur before earliest symptoms arise. Each division (doubling time) results in increased symptoms. Cancers that do not produce symptoms until late in disease will have undergone additional divisions and mutations, thus cancers that are detected late tend to have a _____ prognosis

30; poor

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Carcinogens damage cell DNA, including chemicals, oncogenic viruses, and radiation.

________ are chemicals derived from Aspergillus, which can contaminate stored grains. They are associated with the development of ______ ______

Aflatoxins; hepatocellular carcinoma

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Chemotherapy with ___________ is associated with the potential side effect of developing leukemia/lymphoma

Alkylating agents

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Alcohol is considered carcinogenic for what types of cancer?

Squamous cell carcinoma of the oropharynx and upper esophagus

Pancreatic carcinoma

Hepatocellular carcinoma

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______ is a chemical present in cigarette smoke that is associated with carcinogenesis for squamous cell carcinoma of the skin, lung cancer, and angiosarcoma of the liver

Arsenic

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Exposure to asbestos is more likely to lead to ________ than _______ (but can lead to either type of cancer)

Lung cancer; mesothelioma

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Cigarette smoke is the most common carcinogen worldwide, of which _____ _____ are particularly carcinogenic.

What types of cancer are most associated with cigarette smoke?

Polycyclyc hydrocarbons

Carcinoma of the oropharynx, esophagus, lung, kidney, and bladder

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________ are found in smoked foods and are responsible for high rates of stomach carcinoma in Japan

Nitrosamines

[Note: Nitrosamines are associated with intestinal-type of stomach cancer (vs. diffuse type)]

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________ is derived from cigarette smoke and is associated with carcinogenesis of urothelial carcinoma of the bladder

Naphthylamine

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Vinyl chloride is associated with carcinogenesis after occupational exposure; it is used to make polyvinyl chloride (PVC) for use in pipes. What type of cancer is associated with this occupational exposure?

Angiosarcoma of the liver

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Nickel, chromium, beryllium, or silica are common occupational exposures associated with carcinogenesis of ______

Lung carcinoma

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Oncogenic viruses include EBV, HHV-8, HBV and HCV, HTLV-1, and high-risk HPV.

What type(s) of cancer are associated with EBV?

Nasopharyngeal carcinoma

Burkitt lymphoma

CNS lymphoma in AIDS

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Oncogenic viruses include EBV, HHV-8, HBV and HCV, HTLV-1, and high-risk HPV.

What type(s) of cancer are associated with HHV-8?

Kaposi sarcoma

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Oncogenic viruses include EBV, HHV-8, HBV and HCV, HTLV-1, and high-risk HPV.

What type(s) of cancer are associated with HBV and HCV?

Hepatocellular carcinoma

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Oncogenic viruses include EBV, HHV-8, HBV and HCV, HTLV-1, and high-risk HPV. What type(s) of cancer are associated with HTLV-1?

Adult T-cell leukemia/lymphoma

Oncogenic viruses include EBV, HHV-8, HBV and HCV, HTLV-1, and high-risk HPV. What type(s) of cancer are associated with high-risk HPV (e.g., subtypes 16, 18, 31, 33)?

Squamous cell carcinoma of vulva, vagina, anus, and cervix Adenocarcinoma of the cervix

Types of cancer associated with ionizing radiation

AML CML Papillary carcinoma of the thyroid

Ionizing radiation is associated with nuclear reactor accidents and radiotherapy. It is associated with carcinogenesis via the generation of ________

Hydroxyl free radicals

The most common source of nonionizing radiation is _____________. Exposure results in formation of ______ ______ in DNA, which are normally excised by ______ ______

UVB sunlight; pyrimidine dimers; restriction endonuclease

Types of cancer associated with nonionizing radiation exposure

Basal cell carcinoma Squamous cell carcinoma Melanoma of the skin

DNA mutations eventually disrupt key regulatory systems which allows for tumor promotion (growth) and progression (spread). The 3 key regulatory systems that are disrupted are proto-oncogenes, tumor suppressor genes, and regulators of apoptosis. What are proto-oncogenes essential for, and how are they disrupted during carcinogenesis?

Proto-oncogenes are essential for cell growth and differentiation Mutations form oncogenes which lead to unregulated cell growth

4 categories of oncogenes

Growth factors Growth factor receptors Signal transducers Cell cycle regulators

One category of proto-oncogenes is growth factors. One of the primary examples of this is development of astrocytoma due to overexpression of ______________ which operates on astrocytes via autocrine-loop

Platelet-derived growth factor (PDGFB)

Another category of protooncogenes is growth factor receptors. One example of this is amplification of ____________ which is an epidermal growth factor receptor, leading to development of a subset of breast carcinomas

ERBB2 [HER2/neu] [chemotherapeutic implications because designer antibody treatment can treat breast cancer with this type of amplication]

Another category of protooncogenes is growth factor receptors. One example of this is a point mutation in ______ which is a neural growth factor receptor associated with MEN2A, MEN2B, and sporadic medullary carcinoma of the thyroid

RET

Another category of protooncogenes is growth factor receptors. One example of this is a point mutation in ______ which is a stem cell growth factor receptor associated with development of gastrointestinal stromal tumor

KIT

Another category of protooncogenes is the signal transducers. One example of this is a point mutation in the _____ gene family, which encode a GTP-binding protein associated with development of carcinomas, melanomas, and lymphoma

RAS [RAS-GTP association has ability to carry message to nucleus; RAS has ability to cut off phosphate so that not too much signal is sent. Common mutation is in GAP which prevents the removal of phosphate and excess signaling is sent to nucleus]

Another category of protooncogenes is the signal transducers. One example of this is a t(9;22) translocation of BCR with ______, which is a tyrosine kinase, leading to CML and some types of ALL

ABL [Remember t(9;22) is Philadelphia chromosome]

Another category of protooncogenes is the nuclear regulators. These include c-MYC, N-MYC, and L-MYC. How is c-MYC associated with carcinogenesis?

c-MYC is a transcription factor that may undergo translocation t(8;14) involving IgH —> Burkitt Lymphoma [MYC is on Chr 8]

Another category of protooncogenes is the nuclear regulators. These include c-MYC, N-MYC, and L-MYC. How is N-MYC associated with carcinogenesis?

N-MYC is a transcription factor that may undergo amplification to produce neuroblastoma

Another category of protooncogenes is the nuclear regulators. These include c-MYC, N-MYC, and L-MYC. How is c-MYC associated with carcinogenesis?

L-MYC is a transcription factor that may undergo amplification to produce small-cell lung carcinoma

Another category of protooncogenes is the cell cycle regulators. What is the most highly regulated step of the cell cycle?

G1 —> S phase

Cell cycle regulator associated with potential for t(11;14) translocation involving IgH —> Mantle cell lymphoma

CCND1 (Cyclin D1) [Cyclin D1 is required for progression from G1 to S phase]

Cell cycle regulator associated with potential for undergoing amplification to develop melanoma

CDK4

Tumor suppressor genes regulate cell growth — thus decreasing the risk of tumor formation. The 2 classic examples are ____ and ____

Rb and p53

What is the role of p53 in regulation of the cell cycle?

p53 regulates cell cycle progression from G1 to S phase In response to DNA damage, p53 slows the cell cycle and upregulates DNA repair enzymes. If repair is not possible, p53 induces apoptosis by recruiting BAX (BAX destroys Bcl2, the stabilizer of the mitochondrial membrane)

T/F: tumor formation only requires that one copy of p53 be knocked out

False — both copies of p53 must be knocked out for tumor formation [knudsons 2-hit hypothesis]

Loss of p53 is seen in >50% of cancers. A germline mutation in p53 results in _________________, which is characterized by increased risk for multiple types of carcinomas and sarcomas

Li-Fraumeni syndrome

What is the role of Rb in regulation of the cell cycle?

Rb regulates progression from G1 to S phase by “holding” E2F transcription factor (E2F is necessary for transition to S phase) E2F is released when Rb is phosphorylated by cyclinD/CDK4 complex, and progression to S phase in the cell cycle ensues

How does a mutation in Rb lead to cancer?

Rb mutation results in constitutively free E2F, allowing progression through cell cycle and uncontrolled growth of cells

Like p53, both copies of Rb must be knocked out for tumor formation. What is the difference in phenotype in sporadic vs. germline mutation of Rb?

Sporadic mutation — unilateral retinoblastoma Germline mutation (familial retinoblastoma) — bilateral retinoblastoma, osteosarcoma

Regulators of apoptosis prevent apoptosis in normal cells and promote apoptosis in mutated cells whose DNA cannot be repaired. What is the role of Bcl2 in regulating apoptosis?

Bcl2 normally stabilizes mitochondrial membrane, blocking the release of cytochrome c Disruption of Bcl2 allows cytochrome c to leave mitochondria and activate apoptosis

Bcl2 overexpression is associated with what type of cancer? What is the pathogenesis?

Follicular lymphoma t(14;18) moves Bcl2 (chr 18) to Ig heavy chain locus (chr 14) —> increased Bcl2 —> super-stabilized mitochondrial membrane [The follicles are where we want a lot of apoptosis to occur! If somatic hypermutation fails to produce B cells that react to antigen, we want those cells to undergo apoptosis]

How is telomerase activity usually altered in cancer and why is this significant?

Cancers have upregulated telomerase which preserves telomeres Telomerase is necessary for cell IMMORTALITY, allows cancer cells to continue dividing. Normally, telomeres shorten with serial cell divisions resulting in senescence in which a cell stops dividing

Angiogenesis is necessary for tumor growth and survival, thus _____ and _____ are commonly produced by tumor cells

FGF; VEGF

Avoiding immune surveillance is necessary for tumor survival. How do tumor cells do this?

By downregulating expression of MHC I — so abnormal proteins produced by the tumor won’t be expressed on the surface and cannot be recognized by circulating CD8 T cells that would otherwise have the ability to kill the tumor cell [thus immunodeficiency (primary and secondary) increase the risk for cancer]

Accumulations of mutations in tumor cells results in invasion and spread. What basic cellular changes need to occur for the processes of invasion and spread?

Downregulation of E-cadherin Cells attach to laminin and destroy basement membrane Cells attach to fibronectin in extracellular matrix and spread locally Entrance into vascular or lymphatic spaces allows for metastasis (entry to vessels causes spread to different sites, entry into lymphatics allows spread to LNs)

_______ spread is characteristic of carcinomas

Lymphatic [Initial spread is to regional draining LNs]

______ spread is characteristic of sarcomas

Hematogenous

Hematogenous spread is characteristic of sarcomas. HOWEVER, there are 4 carcinomas that tend to spread hematogenously and are thus the exception to this rule. What are the 4 carcinomas that spread hematogenously?

Renal cell carcinoma (via renal vein) Hepatocellular carcinoma (via hepatic vein) Follicular carcinoma of the thyroid Choriocarcinoma

Seeding of body cavities is characteristic of what type of cancer?

Ovarian carcinoma [‘Omental caking’]

General histologic features of benign tumors (well differentiated)

``` Organized growth Uniform nuclei Low nuclear to cytoplasmic ratio Minimal mitotic activity Lack of invasion No metastatic potential ```

General histologic features of malignant tumors (usually poorly differentiated)

``` Disorganized growth Nuclear polymorphism with hyperchromasia High nuclear to cytoplasmic ratio High mitotic activity Invasion ```

_______________ is used to characterize tumors that are difficult to classify on histology

Immunohistochemistry [labeled Ab placed on cells, if it binds, that helps identify certain cell markers]

Immunohistochemistry can be used to identify intermediate filaments, which are a subtype of filament that makes up the cytoskeleton. Intermediate filaments vary based on cell type, and can thus be used to identify the type of cell within a tumor. What intermediate filaments serve as markers of epithelium, mesenchyme, muscle, neuroglia, and neurons?

Epithelium = keratin Mesenchyme = vimentin Muscle = desmin Neuroglia = GFAP Neurons = neurofilament

Immunohistochemical marker of prostatic epithelium

PSA

Immunohistochemical marker of breast epithelium

Immunohistochemical marker of thyroid follicular cells

Thyroglobulin

Immunohistochemical marker of neuroendocrine cells (e.g., small cell carcinoma of the lung and carcinoid tumors)

Chromogranin

Immunohistochemical marker of melanoma

S-100

Keratin is an intermediate filament characteristic of _________

Epithelium

Vimentin is an intermediate filament characteristic of _________

Mesenchyme

Desmin is an intermediate filament characteristic of _________

Muscle

GFAP is an intermediate filament characteristic of _________

Neuroglia

Neurofilament is an intermediate filament characteristic of _________

Neurons

Serum tumor markers are ______ released by the tumor. These are useful for screening, monitoring response to treatment, and monitoring recurrence. Elevated levels require _____ _____ for diagnosis of carcinoma

Proteins; tissue biopsy

Grading of cancer is microscopic assessment of differentiation, taking into account architectural and nuclear features. What is the difference between the terminology “well differentiated” vs. “poorly differentiated”?

Well-differentiated = resembles parent tissue Poorly differentiated = does not resemble parent tissue [note: grading is important for determining prognosis. Well-differentiated tumors have a better prognosis while poorly differentiated tend to have worse prognosis]

Grading of cancer is microscopic assessment of differentiation, taking into account architectural and nuclear features. In other words, grading asks the question of whether the neoplastic cells resemble surrounding tissue. On the other hand, staging of cancer is based on what?

Size and spread

Which is more important in determining prognosis — grade or stage?

Stage! Staging is the key prognostic factor; determined after final resection of tumor

How is stage of cancer determined?

TNM system: T = Tumor size or depth of invasion N = Spread to regional LNs (second most important prognostic factor) M = Metastasis (single most important prognostic factor)