Principles of Neoplasia Flashcards
Epithelium (Benign)
Adenoma and Papilloma
Epithelium (Malignant/Cancer)
Adenocarcinoma and Papillary carcinoma
Mesenchyme (Benign)
Lipoma
Mesenchyme (Malignant/Cancer)
Liposarcoma
Lymphocyte (Benign)
Does not exist
Lymphocyte (Malignant/Cancer)
Lymphoma/Leukemia
Melanocyte (Benign)
Nevus (mole)
Melanocyte (Malignant/Cancer)
Melanoma
Alfatoxins
- hepatocellular carcinoma
- derived from Aspergillus, which can contaminate stored rice and grains
Alkylating agents
- leukemia/lymphoma
- side effect of chemotherapy
- many chemotherapy agents are myelosuppresive
Alcohol
- squamous cell carcinoma of oropharynx and upper esophagus
- hepatocellular carcinoma
Asbestos
- lung carcinoma
- mesothelioma
- exposure to asbestos is more likely to lead to lung cancer than mesothelioma
Arsenic
- squamous cell carcinoma of skin
- lung cancer
- angiosarcoma of liver
- present in cigarette smoke
Cigarette smoke
- carcinoma of oropharynx, esophagus, lung, kidney, bladder, and pancreas
- most common carcinogen worldwide
- polycyclic hydrocarbons are particularly carcinogenic
Nitrosamines
- stomach cancer
- found in smoked foods
- responsible for high rate of stomach carcinoma in Japan
Naphthylamine
- urothelial carcinoma of bladder
- derived from cigarette smoke
Vinyl chloride
- angiosarcoma of liver
- occupational exposure
- used to make polyvinyl chloride (PVC) for use in pipes
Nickel, chromium, baryllium, or silica
- lung carcinoma
- occupational exposure
EBV
- oncogenic virus
- nasopharyngeal carcinoma
- Burkitt lymphoma
- CNS lymphoma in AIDS
HHV-8
- oncogenic virus
- Kaposi sarcoma
HBV and HCV
- oncogenic virus
- hepatocellular carcinoma
HTLV-1
- oncogenic virus
- adult T-cell leukemia/lymphoma
High-risk HPV (e.g. subtypes 16, 18, 31, 33)
- oncogenic virus
- squamous cell carcinoma of vulva, vagina, anus, and cervix
- adenocarcinoma of cervix
Ionizing Radiation (nuclear reactor accidents and radiotherapy)
- AML
- CML
- papillary carcinoma of the thyroid
- generates hydroxyl free radicals
Nonionizing Radiation
- basal cell carcinoma
- squamous cell carcinoma
- melanoma of skin
- UVB sunlight is most common source
- results in formation of pyrimidine dimers in DNA, which are normally excised by restriction endonucleases
PDGFB
- platelet-derived growth factor
- mechanism: overexpression, autocrine loop
- associated tumor: astrocytoma
ERBB2 (HER2/neu)
- epidermal growth factor receptor
- mechanism: amplification
- associated tumor: subset of breast carcinomas
RET
- neural growth factor receptor
- mechanism: point mutation
- associated tumor: MEN2A, MEN2B and sporadic medullary carcinoma of thyroid
KIT
- stem cell growth factor receptor
- mechanism: point mutation
- associated tumor: gastrointestinal stromal tumor (GIST)
RAS gene family
- GTP-binding protein
- mechanism: point mutation
- associated tumor: carcinomas, melanoma, and lymphoma
ABL
- tyrosine kinase
- mechanism: t(9;22) with BCR
- associated tumor: CML and some types of ALL
c-MYC
- transcription factor
- mechanism: t(8;14) involving IgH
- associated tumor: Burkitt lymphoma
N-MYC
- transcription factor
- mechanism: amplification
- associated tumor: neuroblastoma
L-MYC
- transcription factor
- mechanism: amplification
- lung carcinoma (small cell)
CCND1 (cyclin D1)
- cyclin
- mechanism: t(11;14) involving IgH
- mantle cell lymphoma
CDK4
- cyclin-dependent kinase
- mechanism: amplification
- associated tumor: melanoma
p53
- regulates progression from G1 to S phase
- DNA damage –> p53 slows the cell cycle and upregulates DNA repair enzymes
- if DNA repair not possible –> induce apoptosis
- p53 induces apoptosis by upregulating BAX, which disrupts Bcl2… this then causes cytochrome c to leak from mitochondria and thus activate apoptosis
- both copies of the p53 gene must be knocked out for tumor formation
- loss is seen in >50% of cancers
- germline mutation results in Li-Fraumeni syndrome (2nd hit somatic), characterized by the propensity to develop multiple types of carcinomas and sarcomas
Rb
- regulates progression from G1 to S phase
- “holds” the E2F transcription factor, which is necessary for transition to the S phase
- E2F is released when Rb is phosphorylated by the cyclinD/cyclin-dependent kinase 4 (CDK4) complex
- Rb mutation results in constitutively free E2F, allowing progression through the cell cycle and uncontrolled growth of cells
- both copies of Rb gene must be knocked out for tumor formation
- sporadic mutation (both hits are somatic) is characterized by unilateral retinoblastoma
- germline mutation results in familial retinoblastoma (2nd hit is somatic), characterized by bilateral retinoblastoma and osteosarcoma
Bcl2
- prevent apoptosis in normal cells
- promote apoptosis in mutated cells whose DNA cannot be repaired
- normally stabilizes the mitochondrial membrane, blocking release of cytochrome c
- disruption of Bcl2 allows cytochrome c to leave the mitochondria and activate apoptosis
Bcl2 and Follicular Lymphoma
- Bcl2 is overexpressed in follicular lymphoma
- t(14,18) moves Bcl2 (chromosome 18) to the Ig heavy chain locus (chrom. 14), resulting in increased Bcl2
- mitochondrial membrane is further stabilized, prohibiting apoptosis
- B cells that would normally undergo apoptosis during somatic hyper-mutation in the lymph node germinal center accumulate, leading to lymphoma
Telomerase and Tumor Development
- telomerase is necessary for cell immortality
- normally, telomeres shorten with serial cell divisions, eventually resulting in cellular senescence
- cancers often have upregulated telomerase, which preserves telomeres
Angiogenesis and Tumor Development
- necessary for tumor survival and growth
- FGF and VEGF (angiogenic factors) are commonly produced by tumor cells
Avoiding Immune Surveillance
- necessary for tumor survival
- mutations often result in production of abnormal proteins, which are expressed on MHC class I
- CD8+ T cells detect and destroy such mutated cells
- tumor cells can evade immune surveillance by downregulating expression of MHC class I
- immunodeficiency (both primary and secondary) increases the risk for cancer
Tumor Invasion and Spread
- epithelial tumor cells are normally attached to one another by cellular adhesion molecules (e.g. E-cadherin)
- downregulation of E-cadherin leads to dissociation of attached cells
- cells attach to laminin and destroy basement membrane (collagen type IV) via collagenase
- cells attach to fibronectin in the extracellular matrix and spread locally
- entrance into vascular or lymphatic spaces allows for metastasis (distant spread)
Routes of Metastasis (lymphatic spread)
- lymphatic spread is characteristic of carcinomas
- initial spread is to regional draining lymph nodes
Routes of Metastasis (hematogenous spread)
- hematogenous spread is characteristic of sarcomas and some carcinomas
- renal cell carcinoma (often invades renal vein)
- hepatocellular carcinoma (often invades hepatic vein)
- follicular carcinoma of the thyroid
- choriocarcinoma
Seeding
-seeding of body cavities is characteristic of ovarian carcinoma, which often involves the peritoneum
Clinical Features (Benign and Malignant Tumors)
- benign tumors tend to be slow growing, well circumscribed, distinct, and mobile
- malignant tumors are usually rapid growing, poorly circumscribed, infiltrative, and fixed to surrounding tissues and local structures
- biopsy or excision is generally required before a tumor can be classified as benign or malignant with certainty
- some benign tumors can grow in a malignant-like fashion, and some malignant tumors can grow in a benign-like fashion
Histological Features (benign tumors)
- usually well differentiated
- organized growth
- uniform nuclei
- low nuclear to cytoplasmic ratio
- minimal mitotic activity
- lack of invasion (of basement membrane or local tissue)
- no metastatic potential
Histological Features (metastatic tumors)
- classically poorly differentiated (anaplastic)
- disorganized growth (loss of polarity)
- nuclear pleomorphism and hyperchomasia
- high nuclear to cytoplasmic ratio
- high mitotic activity with atypical mitosis
- invasion (through basement membrane or into local tissue)
- metastatic potential is the hallmark of malignancy - benign tumors never metastasize
- immunohistochemistry is used to characterize tumors that are difficult to classify on histology
Serum Tumor Markers
- proteins released by tumor into serum (e.g. PSA)
- useful for screening, monitoring response to treatment, and monitoring recurrence
- elevated levels require tissue biopsy for diagnosis of carcinoma (e.g. biopsy of prostate with elevated PSA)
Grading of Cancer
- microscopic assessment of differentiation (i.e. how much a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features
- well differentiated (low grade) resembles normal parent tissue
- poorly differentiated (high grade) does not resemble parent tissue
- important for determining prognosis; well-differentiated cancers have better prognosis than poorly-differentiated cancers
Staging of Cancer
- assessment of size and spread of a cancer
- key prognostic factor; more important than grade
- determined after final surgical resection of the tumor
- utilizes TNM staging system
- T: tumor (size and/or depth of invasion)
- N: spread to regional lymph nodes; second most important prognostic factor
- M: metastasis; single most important prognostic factor
Immunohistochemical Stain (keratin)
-epithelium
Immunohistochemical Stain (vimentin)
-mesenchyme
Immunohistochemical Stain (GFAP)
-neuroglia
Immunohistochemical Stain (desmin)
-muscle
Immunohistochemical Stain (neurofilament)
-neurons
Immunohistochemical Stain (PSA)
-prostatic epithelium
Immunohistochemical Stain (ER)
-breast epithelium
Immunohistochemical Stain (thyroglobulin)
-thyroid follicular cells
Immunohistochemical Stain (chromogranin)
-neuroendocrine cells (e.g. small cell carcinoma of lung and carcinoid tumors)
Immunohistochemical Stain (S-100)
-melanoma, Schwannoma and Langerhans cell histiocytes
