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Chapter 3: Principles of Neoplasia
Terms in this set (84)
What is neoplasia defined as
new tissue growth that is unregulated, irreversible, and monoclonal;
these features distinguish it from hyperplasia and repair
What does monoclonal mean
that the neoplastic cells are derived from a single mother cell.
How was clonality historically determined
by glucose-6-phosphate dehydrogenase (G6PD)
Describe the G6PD
1. Multiple forms exist (i.e. G6PDa, G6PDb, & G6PDc); only one isoform is
inherited from each parent.
2. In females, one isoform is randomly inactivated in each cell by lyonization
(G6PD is present on the X chromosome).
3. Normal ratio of active isoforms in cells of any tissue is 1:1 (e.g., 50% of cells have
G6PDa, and 50% of cells have G6PDb).
4. 1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from
5. Only one isoform is present in neoplasia, which is monoclonal.
6. Clonality can also be determined by androgen receptor isoforms, which are also present on the X chromosome.
How is the clonality of B lymphocytes determined
immunoglobulin (Ig) light chain
Describe the Ig light chain
1. Ig is comprised of heavy and light chains.
2. Each B cell expresses light chain that is either kappa or lambda.
3. Normal kappa to lambda light chain ratio is 3:1.
4. This ratio is maintained in hyperplasia, which is polyclonal.
5. Ratio increases to > 6:1 or is inverted (e.g., kappa to lambda ratio = 1:3) in
lymphoma, which is monoclonal,
Characteristics of a benign tumor
remain localized and do not metastasize.
Characteristics of a malignant tumor
(cancer) invade locally and have the potential to metastasize.
What is epithelium
line the cavities and surfaces of blood vessels and organs
What is mesenchyme
develop into the tissues of the lymphatic and circulatory systems, as well as connective tissues throughout the body, such as bone and cartilage.
What is lymphocyte
What is melanocyte
melanin-producing cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, meninges, bones, and heart
**Melanin is the pigment primarily responsible for skin color.
Nomenclature for benign epithelium tumor
Adenoma or Papilloma
Nomenclature for malignant epithelium tumor
Adenocarcinoma or Papillary carcinoma
Nomenclature for benign mesenchyme tumor
Nomenclature for malignant mesenchyme tumor
Nomenclature for benign lymphocyte tumor
(Does not exist)
Nomenclature for malignant lymphocyte tumor
Nomenclature for benign melanocyte tumor
Nomenclature for malignant melanocyte tumor
Leading cause of death in kids
(1) accidents, (2) cancer, and (3) congenital defects.
Leading cause of death in adults
(1) cardiovascular disease, (2) cancer, and (3) cerebrovascular disease.
Most common cancer incidence types in adults
1) breast/prostate, (2) lung, and (3) colorectal.
Most common cancer mortality types in adults
(1) lung, (2) breast/ prostate, and (3) colorectal
How does cancer begin
How many divisions occur before the earliest clinical symptoms arise
Each division (doubling time) results in increased mutations
1. Cancers that do not produce symptoms until late in disease will have undergone additional divisions and, hence, additional mutations.
2. Cancers that are detected late tend to have a poor prognosis.
What is the goal of cancer screening
catch dysplasia (precancerous change) before it becomes
carcinoma or carcinoma before clinical symptoms arise
What are the common cancer screening methods
1. Pap smear—detects cervical dysplasia (GIN) before it becomes carcinoma
2. Mammography—detects in situ breast cancer (e.g., DCIS) before it invades or
invasive carcinoma before it becomes clinically palpable
3. Prostate specific antigen (PSA) and digital rectal exam—detects prostate
carcinoma before it spreads
4. Hemoccult test (for occult blood in stool) and colonoscopy—detect colonic
adenoma before it becomes colonic carcinoma or carcinoma before it spreads
What initiates cancer formation
damage to DNA of stem cells, which overcomes DNA repair mechanisms, but is not lethal.
What are carcinogens
agents that damage DNA, increasing the risk for cancer.
What cancer is associated with Aflatoxins
**Derived from Aspergillus, which can contaminate stored grains
What cancer is associated with Alkylating agents
**Side effect of chemotherapy
What cancer is associated with Alcohol
Squamous cell carcinoma of oropharynx and upper esophagus, pancreatic carcinoma, and hepatocellular carcinoma
What cancer is associated with Arsenic
Squamous cell carcinoma of skin, lung cancer, and angiosarcoma of liver
**Arsenic is present in cigarette smoke.
What cancer is associated with Asbestos
Lung carcinoma and mesothelioma
**Exposure to asbestos is more likely to lead to lung cancer than mesothelioma.
What cancer is associated with Cigarette smoke
Carcinoma of oropharynx, esophagus, lung, kidney, and bladder
**Most common carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogenic.
What cancer is associated with Nitrosamines
**Found in smoked foods; responsible tor high rate of stomach carcinoma in iapan
What cancer is associated with Naplithy lamine
Urothelial carcinoma of bladder
**Derived from cigarette smoke
What cancer is associated with Vinyl chloride
Angiosarcoma of liver
**Occupational exposure; used to make polyvinyl chlurkle (PVC) for use in pipes
What cancer is associated with Nickel, chromium, beryllium, or silica
What cancer is associated with EBV
Nasopharyngeal carcinoma, Burkitt lymphoma, and CNS lymphoma in AIDS
What cancer is associated with HHV-8
What cancer is associated with HBV and HCV
What cancer is associated with HTLV-1
Adult T-cell leukemia/lymphoma
What cancer is associated with High-risk HPV (e.g., subtypes 16, 18,31,33)
Squamous cell carcinoma of vulva, vagina, anus, and cervix; adenocarcinoma of cervix
What cancer is associated with Ionizing (nuclear reactor accidents and radiotherapy)
AML, CML, and papillary carcinoma of the thyroid
**Generates hydroxyl free radicals
What cancer is associated with Non Ionizing (UVB sunlight is most common source)
Basal cell carcinoma, squamous cell carcinoma, and melanoma of skin
**Results in formation of pyrimidine dimers in DNA, which are normally excised by restriction endonuclease
DNA mutations do what
eventually disrupt key regulatory systems, allowing for tumor promotion (growth) and progression (spread).
**Disrupted systems include proto-oncogenes, tumor suppressor genes, and regulators of apoptosis.
What are proto-oncogenes
essential for cell growth and differentiation; mutations of
proto-oncogenes form oncogenes that lead to unregulated cellular growth.
What are the categories of oncogenes
growth factors (induce cellular growth), growth factor receptors (mediate signals from growth factors), signal
transducers (relay receptor activation to nucleus), nuclear regulators, and cell cycle regulators (mediate progression through cell cycle)
Associated tumor with PDGFB
Associated tumor with ERBB2 [HER2/neu]
Subset of breast carcinomas
Associated tumor with RET
MEN 2A, MF:N 211 and sporadic medullary carcinoma of thyroid
Associated tumor with KIT
Gastrointestinal stromal tumor
Associated tumor with RAS
Carcinomas, melanoma, and lymphoma
Associated tumor with ABL
CML & some types of ALL
Associated tumor with c-MYC
Associated tumor with n-MYC
Associated tumor with l-MYC
Lung carcinoma (small cell)
Associated tumor with CCND1 (cyclin D1)
Mantle cell lymphoma
Associated tumor with CDK4
What are tumor supressor genes
Regulate cell growth and, hence, decrease ("suppress") the risk of tumor formation; p53 and Rb (retinoblastoma) are classic examples.
Role of p53
regulates progression of the cell cycle from G1 to S phase:
1) In response to DNA damage, p53 slows the cell cycle and upregulales DNA repair enzymes
2) If DNA repair is not possible, p53 induces apoptosis.
i. p53 upregulates BAX, which disrupts Bcl2.
ii. Cytochrome c leaks from the mitochondria activating apoptosis,
3) Both copies of the p53 gene must be knocked out for tumor formation (Knudson two-hit hypothesis).
i. Loss is seen in > 50% of cancers.
ii. Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic),
characterized by the propensity to develop multiple types of carcinomas and sarcomas
Role of Rb
also regulates progression from G1 to S phase:
1) Rb "holds" the E2F transcription factor, which is necessary for transition to the S
2) E2F is released when RB is phosphorylated by the cyclinD/cyclin-dependent
kinase 4 (CDK4) complex
3) Rb mutation results in const it utively free E2F, allowing progression through the
cell cycle and uncontrolled growth of cells.
4) Both copies of Rb gene must be knocked out for tumor formation (Knudson two-
i. Sporadic mutation (both hits are somatic) is characterized by unilateral
retinoblastoma (Fig. 3,1).
ii. Germline mutation results in familial retinoblastoma (2nd hit is somatic),
characterized by bilateral retinoblastoma and osteosarcoma.
Role of Bcl2
Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose
DNA cannot be repaired:
1. Bcl2 normally stabilizes the mitochondrial membrane, blocking release of
2. Disruption of Bcl2 allows cytochrome c to leave the mitochondria and activate
What cancer is Bcl2 over expressed
follicular lymphoma-> Mitochondrial membrane is further stabilized, prohibiting apoptosis-> B cells that would normally undergo apoptosis during somatic hypermutation in
the lymph node germinal center accumulate, leading to lymphoma.
What features are needed for tumor survival and growth
Telomerase (preserves telomeres, which shorten with serial cell divisions, eventually resulting in cellular senescence)
Angiogenesis (FGF and VEGF are expressed by tumor cells)
Avoiding immune surveillance (down regulate expression of MHC class 1)
How does accumulation of mutations eventually result in tumor invasion & spread
1. Epithelial tumor cells are normally attached to one another by cellular adhesion molecules (e.g., E-cadherin).
2. Downregulalion of E-cadherin leads to dissociation of attached ceils.
3. Cells attach to laminin and destroy basement membrane (collagen type IV) via
collagen a se.
4. Cells attach to fibronectin in the extracellular matrix and spread locally,
5. Entrance into vascular or lymphatic spaces allows for metastasis (distant spread).
Lymphatic spread is characteristic of what type of cancer
carcinomas (Initial spread is to regional draining lymph nodes)
Hematogenous spread is characteristic of what type of cancer
sarcomas and 4 carcinomas:
1. Renal cell carcinoma (often invades renal vein)
2. Hepatocellular carcinoma (often invades hepatic vein)
3. Follicular carcinoma of the thyroid
What type fo carcinoma is seeding of body cavities characteristic of
ovarian carcinoma, which often involves the peritoneum ("mental caking")
Benign vs Malignant tumor characteristics
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.
Histological features of Benign vs Malignant tumors
1. Organized growth
2. Uniform nuclei
3. Low nuclear to cytoplasmic ratio
4. Minimal mitotic activity
5. Lack of invasion (of basement membrane or local tissue)
6. No metastatic potential
Malignant= poorly differentiated:
1. Disorganized growth (loss of polarity)
2. Nuclear pleomorphism and hyperchromasia
3. High nuclear to cytoplasmic ratio
4. High mitotic activity with atypical mitosis
5. Invasion (through basement membrane or into local tissue)
Which tissue type has an Immunohistochemical stain positive for Keratin
Which tissue type has an Immunohistochemical stain positive for Vimentin
Which tissue type has an Immunohistochemical stain positive for Desmin
Which tissue type has an Immunohistochemical stain positive for GFAP
Which tissue type has an Immunohistochemical stain positive for Neurofilament
Which tissue type has an Immunohistochemical stain positive for PSA
Which tissue type has an Immunohistochemical stain positive for ER
Which tissue type has an Immunohistochemical stain positive for Thyroglobulin
Thyroid follicular cells
Which tissue type has an Immunohistochemical stain positive for Chromogranin
Neuroendocrine cells (e.g., small cell carcinoma of lung and carcinoid tumors)
Which tissue type has an Immunohistochemical stain positive for S-100
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