CH3 - Principles of Neoplasia Flashcards
Neoplasia is
new tissue growth that is unregulated, irreversible, and monoclonal
What features distinguish neoplasia from hyperplasia and repair?
unregulated, irreversible, and monoclonal
Monoclonal means
that the neoplastic cells are derived from a single mother cell
Clonality can be determined by?
glucose-6-phosphate dehydrogenase (G6PD) enzyme isoforms.
Multiple isoforms
G6PDA, G6PDb, and G6PDc exist; only one isoform is inherited from each parent.
lyonization
In females, one isoform is randomly inactivated in each cell by lyonization
G6PD is present on what chromosome
X
Normal ratio of active isoforms in cells of any tissue is
1:1 (e.g 50% of cells have G6PDa , and 50% ofcells have G6PDG)
In hyperplasia what happens to the ratio?
1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells).
In neoplasia what can be said about the isoform?
Only one isoform is present in neoplasia, which is monoclonal
Clonality can also be determined by
androgen receptor isoforms, which are also present on the X chromosome.
Clonality of B lymphocytes is determined by
immunoglobulin (Ig) light chain phenotype.
Ig is comprised of
heavy and light chains.
Each B cell expresses
light chain that is either kappa or lambda.
Normal kappa to lambda light chain ratio is
3:01
Kappa to lambda ratio in hyperplasia
This ratio is maintained in hyperplasia, which is polyclonal
kappa to lambda ratio in lymphoma?
Ratio increases to > 6:1 or is inverted (kappa to lambda ratio = 1:3) in lymphoma, which is monoclonal
Neoplastic tumors are
benign or malignant
Benign tumors
remain localized and do not metastasize
Malignant tumors
(cancer) invade locally and have the potential to metastasize.
Tumor nomenclature is based on
lineage of differentiation (type of tissue produced) and whether the tumor is benign or malignant
What benign growths result from the epithelium?
Adenoma, papilloma
What malignant growths result from the epithelium?
Adenocarcinoma and papillary carcinoma
What benign growths result from the mesenchyme?
Lipoma
What malignant growths result from the mesenchyme?
Liposarcoma
What benign growths result from the lymphocyte?
Does not exist
What malignant growths result from the lymphocyte?
Lymphoma/Leukemia
What benign growths result from the melanocyte?
Nevus (mole)
What malignant growths result from the melanocyte?
Melanoma
What is the 2nd leading cause of death in both adults and children?
cancer
What are the leading causes of death in adults?
(1) cardiovascular disease (2) cancer (3) cerebrovascular disease
What are the leading causes of death in children?
(1) accidents (2) cancer (3) congenital defects
What are the most common cancers by incidence in adults?
(1) breast/prostate (2) lung (3) colorectal.
What are the most common causes of cancer mortality in adults?
(1) lung (2) breast/prostate (3) colorectal
Cancer begins as a
single mutated cell.
Approximately how many divisions occur before the earliest clinical symptoms arise?
30
Cancers that do not produce symptoms until late in disease
will have undergone additional divisions and, hence, additional mutations.
Cancers that are detected late
tend to have a poor prognosis.
Goal of screening is
to catch dysplasia (precancerous change) before it becomes carcinoma or carcinoma before clinical symptoms arise.
Common screening methods include
- Pap smear 2. Mammography 3. PSA and DRE 4. Hemoccult test and colonoscopy
Pap smear
detects cervical dysplasia (CIN) before it becomes carcinoma
Mammography
detects in situ breast cancer (e.g DCIS) before it invades or invasive carcinoma before it becomes clinically palpable
PSA and DRE
Prostate specific antigen (PSA) and digital rectal exam detects prostate carcinoma before it spreads
Hemoccult test
for occult blood in stool
colonoscopy
detect colonic adenoma before it becomes colonic carcinoma or carcinoma before it spreads
Cancer formation is initiated by
damage to DNA of stem cells. The damage overcomes DNA repair mechanisms, but is not lethal.
Carcinogens are
agents that damage DNA, increasing the risk for cancer.
Important carcinogens include
chemicals, oncogenic viruses, and radical ions
DNA mutations eventually disrupt
key regulatory systems, allowing for tumor promotion (growth) and progression (spread)
Disrupted key regulatory systems include
proto-oncogenes, tumor suppressor genes, and regulators of apoptosis
Proto-oncogenes are essential to?
cell growth and differentiation;
mutations of proto-oncogenes form
oncogenes that lead to unregulated cellular growth.
Categories of oncogenes include
growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators
Growth factors induce
cellular growth (e.g PDGFB in astrocytoma),
Growth factor receptors
mediate signals from growth factors (e.g. ERBB2 HER2/neu in breast cancer).
What do signal tranducers do?
Relay receptor activation to the nucleus (eg. ras)
Ras is associated with
growth factor receptors in an inactive GDP-bound state.
Aflatoxins
Hepatocellular carcinoma Derived from Aspergillus, which can contaminate stored grains
Alkylating agents
leukemia/lymphoma side effect of chemotherapy
Alcohol
Squamous cell carcinoma of oropharynx and upper esophagus, pancreatic carcinoma, and hepatocellular carcinoma
Arsenic
Squamous cell carcinoma of skin, lung cancer, and angiosarcoma of liver. Arsenic is present in cigarette smoke.
Asbestos
Lung carcinoma and mesothelioma. Exposure to asbestos is more likely to lead to lung cancer than mesothelioma.
Cigarette smoke
Carcinoma of oropharynx, esophagus, lung, kidney, and bladder. Most common carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogenic.
Nitrosamines
Stomach carcinoma, Found in smoked foods, responsible for high rate of stomach carcinoma in japan
Naplithylamine
Urothelial carcinoma of bladder. Derived from cigarette smoke
Vinyl chloride
Angiosarcoma of liver, occupational exposure; used to make polyvinyl chlurkle (PVC) for use in pipes
Nickel, chromium, beryllium, or silica
Lung carcinoma Occupational exposure
Oncogenic viruses
EBV, HHV-8, HBV and HCV, HTLV-1, High-risk HPV
EBV
Nasopharyngeal carcinoma, Burkitt lymphoma and CNS lymphoma in AIDS
HHV-8
Kaposi sarcoma
HBV and HCV
Hepatocellular carcinoma
HTLV-1
Adult T-cell leukemia/lymphoma
High-risk HPV (e.g. subtypes 16, 18, 31, 33)
Squamous cell carcinoma of vulva, vagina, anus, and cervix; adenocarcinoma of cervix
Ionizing radiation
(nuclear reactor accidents and radiotherapy) AML, CML and papillary carcinoma of the thyroid. Generates hydroxyl free radicals.
Non Ionizing (UVB sunlight is most common source)
Basal cell carcinoma, squamous cell carcinoma, and melanoma of skin
Non Ionizing radiation results in?
formation of pyrimidine dimers in DNA, which are normally excised by restriction endonuclease
Ras Receptor binding causes
GDP to be replaced with GTP, activating ras.
What does activated ras do?
sends growth signals to the nucleus
How is Ras deactivated?
inactivates itself by cleaving GTP to GDP; this is augmented by GTPase activating protein
Mutated ras
inhibits the activity of GTPase activating protein. This prolongs the activated state of ras, resulting in increased growth signals.
Cell cycle regulators mediate what?
progression through the cell cycle (e.g. cyclin and cyclin-dependent kinase).
Cyclins and cyclin-dependent kinases (CDKs) do what?
form a complex which phosphorylates proteins that drive the cell through the cell cycle.
The cyclin D / CDK4 complex does what?
phosphorylates the retinoblastoma protein, which promotes progression through the G-S checkpoint
What do tumor supressor genes do?
Regulate cell growth decreasing (suppress) the risk of tumor formation;
What are some classic examples of tumor supressor genes?
p53 and Rb (retinoblastoma)
What does p53 regulate?
progression of the cell cycle from G to S phase
In response to DNA damage, what does p53 do?
slows the cell cycle and upregulales DNA repair enzymes.
PDGFB
Platelet-derived growth factor, overexpression, autocrine loop, astrocytoma
FRBB2 [HER2f neu]
Epidermal growth factor receptor, Amplification mechanism, Subset of breast carcinomas
RET
Neural growth factor receptor, Point mutation MEN 2A, MEN 2B and sporadic medullary carcinoma of thyroid
KIT
Stem cell growth factor receptor, Point mutation, Gastrointestinal stromal tumor
RAS gene family
GTP-binding protein, Point mutation, Carcinomas, melanoma, and lymphoma
ABL
Tyrosine kinase T(9;22) with BCR CML and some types of ALL
What are the nuclear regulators?
C-MYC, N-MYC, L-MYC
c-MYC
Transcription factor, t(8;I4) involving IgH, Burkitt lymphoma
N-MYC
Transcription factor, Amplification, Neuroblastoma
L-MYC
Transcription factor, Amplification, Lung carcinoma (small cell)
CCND1 (cyclin D1)
Cyclin t(11;14) involving IgH, Mantle cell lymphoma
If DNA repair is not possible, what does p53 do?
induces apoptosis.
How does p53 induce apoptosis?
upregulates BAX, which disrupts Bcl2 leading to cytochrome c leaks from the mitochondria activating apoptosis
Knudson two-hit hypothesis
both copies of the p53 gene must be knocked out for tumor formation, Both copies of Rb gene must be knocked out for tumor formation
Loss of p53 is seen in what percentage of cancers?
> 50% of cancers.
p53 Germline mutation results in
Li-Fraumeni syndrome (2nd hit is somatic),
Li-Fraumeni syndrome is characterized by?
the propensity to develop multiple types of carcinomas and sarcomas,
Rb
regulates progression from G0 to S phase.
How does Rb regulate the progression 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.
Sporadic mutation
(both hits are somatic) and it is characterized by unilateral retinoblastoma
Rb Germline mutation results in
familial retinoblastoma (2nd hit is somatic) and is characterized by bilateral retinoblastoma and osteosarcoma.
What is the function of regulators of apoptosis?
Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (e.g Bcl2)
Bcl2
normally stabilizes the mitochondrial membrane, blocking release of cytochrome c
Disruption of Bcl2 allows what to happen?
Cytochrome c to leave the mitochondria and activate apoptosis
Bcl2 in follicular lymphoma?
it is overexpressed in follicular lymphoma,
Why is Bcl2 overexpressed in follicular lymphoma?
t(14;18) moves Bcl2 (chromosome 18) to the Ig heavy chain locus (chromosome 14), resulting in increased Bcl2.
How is apoptosis inhibited in follicular lymphoma?
Mitochondrial membrane is further stabilized by overexpressed Bcl2, prohibiting apoptosis.
In follicular lymphoma, how does the inhibition of apoptosis lead to lymphoma?
B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate, leading to lymphoma.
What is necessary for cell immortality?
Telomerase
Normally telomeres do what?
shorten with serial cell divisions, eventually resulting in cellular senescence
What is the relationship between cancers and telomerase?
cancers often have up regulated telomerase, which preserves telomeres
Angiogenesis and tumors
(production of new blood vessels) is necessary for tumor survival and growth.
FGF and VEGF
(angiogenic factors) are commonly produced by tumor cells.
Tumor survival and the immune system?
Avoiding immune surveillance is necessary for tumor survival
Immune surveillance and tumor survival?
Mutations often result in production of abnormal proteins, which are expressed on MHC class 1, CD8+ T cells detect and destroy such mutated cells, Tumor cells can evade immune surveillance by downregulating expression of MHC class 1.
How do tumor cells evade immune surveillance?
by downregulating MHC class 1
Immunodeficiency and cancer
(both primary and secondary) increases risk for cancer
Accumulation of mutations eventually result in what?
tumor invasion and spread
Epithelial tumor cells are normally attached to one another by what?
cellular adhesion molecules (e.g., E-cadherin).
Downregulalion of E-cadherin leads to what?
dissociation of attached cells
How do the tumor cells spread locally?
Cells attach to laminin and destroy basement membrane (collagen type IV) via collagenase. Cells attach to fibronectin in the extracellular matrix and spread locally
Metastasis of tumor cells.
Entrance into vascular or lymphatic spaces allows for metastasis (distant spread)
What are the routes of metastasis?
Lymphatic, hematogenous, seeding of body cavities
Lymphatic spread is characteristic of what?
carcinomas
Where does the initial lymphatic spread occur?
In the regional draining lymph nodes
Hematogenous spread is characteristic of what?
sarcomas and some carcinomas
What are some examples of hematogenous spread?
renal cell carcinoma, hepatocellular carcinoma, follicular carcimoma of the thyroid, choriocarcinoma
Seeding of body cavities is characteristic of?
ovarian carcinoma, often involves the peritoneum ‘omental caking’
What is omental caking?
where the peritoneum is often involved in ovarian carcinoma
Describe 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.
What is generally required before a tumor can be classified as benign or malignant with certainty?
Biopsy or excision
Why is biopsy necessary?
Some benign tumors can grow in a malignant-like fashion, and some malignant tumors can grow in a benign-like fashion.
Benign tumors are usually
well differentiated
What are some characteristics of benign tumors?
- 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 tumors are classically
poorly differentiated (anaplastic)
Characteristics of malignant tumors include
- 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)
What is the hallmark of malignancy?
Metastatic potential - benign tumors never metastasize
What is the target cell type for the immunohistochemical stain of Keratin?
Epithelium
What is the target cell type for the immunohistochemical stain of Vimentin
Mesenchyme
What is the target cell type for the immunohistochemical stain of desmin
Muscle
What is the target cell type for the immunohistochemical stain of Neurofilament
Neurons
What is the target cell type for the immunohistochemical stain of PSA
Prostatic epil helium
What is the target cell type for the immunohistochemical stain of ER
Breast epithelium
What is the target cell type for the immunohistochemical stain of Thyroglobulin
thyroid follicular cells
What is the target cell type for the immunohistochemical stain of chromogranin?
neuroendocrine cells (small cell carcinoma of lung and carcinoid tumors)
What is the target cell type for the immunohistochemical stain of S-100?
Melanoma
What is used to characterize tumors that are difficult to classify on histology?
Immunohistochemistry
What are serum tumor markers?
Proteins released by tumor into serum (e.g PSA)
Serum tumor markers are useful for what?
screening, monitoring response to treatment, and monitoring recurrence
Elevated levels of serum tissue markers require what?
it requires tissue biopsy for diagnosis of carcinoma (e.g., biopsy of prostate with elevated PSA),
What is involved in the grading of cancer?
Microscopic assessment of differentiation (how much a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features
What is low grade?
Well differentiated?resembles normal parent tissue
What is high grade?
poorly differentiated?does not resemble parent tissue
Cancer grading is important for what?
determining prognosis; well-differentiated cancers have better prognosis than poorly-differentiated cancers.
What is staging of cancer?
its an assessment of size and spread of a cancer,
How does the staging of cancer compare to the grading of cancer?
Key prognostic factor; more important than grading
When is the staging of cancer determined?
after final surgical resection of the tumor
What is the 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
In the TNM staging system what is the most important prognostic factor?
Metastasis
