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Neoplasia
N/A
128
Pathology
Graduate
08/08/2012

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Term
What is the definition of neoplasia?
Definition
"New growth" - an unregulated monoclonal proliferation of genetically altered ells
Term
What is the difference between a benign and a malignant neoplasm?
Definition
Benign = tumor remains localized, malignant = cancer that can invade and metastasize
Term
What are the malignant tumors that end with the suffix "oma"?
Definition
Lymphoma, melanoma, mesothelioma, seminoma
Term
What are important histopathological features of benign tumors?
Definition
Well differentiated, absent to mild pleomorphism (variation in size/shape of cells/nuclei), close to normal nuclear morphology, few or no mitoses, polarity, no tumor giant cells
Term
What are important histopathological features of malignant tumors?
Definition
Some loss of differentitation, pleomorphism (variation in size/shape of cells/nuclei), nuclear enlargement, hyperchromasia, large nucleoli, numerous atypical mitoses, loss of polarity, tumor giant cells present
Term
What is metaplasia?
Definition
The replacement of one type of cell with another type
Term
Metaplasia is nearly always found in association with what action?
Definition
Tissue damage and repair
Term
What is dysplasia?
Definition
"Disordered growth" - principally occurs in epithelium, characterized by cells with some anaplastic features and loss of polarity, may or may not progress to cancer
Term
What is carcinoma in situ?
Definition
Occurs when dysplastic changes involve the full thickness of the epithelium, considered "pre-invasive cancer" that will eventually progress to an invasive carcinoma
Term
What factors determine the rate of tumor growth?
Definition
Doubling time of the tumor cells, fraction of tumor cells in the proliferative pool (growth fraction), rate at which cells are shed or die
Term
How is tumor growth associated with a shortening of cell cycle time?
Definition
Not associated
Term
The rate at which tumors grow is primarily determined by what?
Definition
An excess of cell production over cell loss
Term
ChemoRx is usually prescribed to what type of tumors?
Definition
Tumors with high growth fractions
Term
What are some unique gross features of benign tumors?
Definition
Nearly always grow as well circumscribed masses that are localized, often have fibrous capsule, non invasive, freely movable and readily surgically excised
Term
What are some unique gross features of malignant tumors?
Definition
Invasive, poorly circumscribed and fixed to surrounding tissue, surgical resection difficult or impossible
Term
What are metastases?
Definition
Tumor implants discontinuous with the primary tumor, unequivocally marks tumor as malignant
Term
How does seeding of body cavities and surfaces occur in metastatic spread?
Definition
Occurs when a tumor penetrates into a body cavity, particularly characteristic of ovarian carcinomas
Term
How do lymphatics serve as a mechanism for metastatic spread of cancer?
Definition
Most common pathway for initial spread of carcinomas, follows natural routes of lymphatic drainage
Term
What is a "sentinel lymph node"?
Definition
The first node in a regional lymphatic chain that receives lymph flow from the primary tumor
Term
How does cancer spread through hematogenous means?
Definition
Most typical with sarcomas, occurs due to tumor penetrating into veins, liver and lungs are most frequent sites involved, can also spread intot he vertebral column
Term
What are the three categories of genetic predisposition to cancer?
Definition
Autosomal dominant inherited cancer syndromes, defective DNA-repair syndromes, familial cancer
Term
What are the characteristics of autosomal dominant inherited cancer syndromes?
Definition
Inheritance of single mutant gene greatly increases risk of cancer, usually a point mutation, tumors within this group are often associated with a specific marker phenotype
Term
What are some examples of common autosomal dominant inherited cancer syndromes?
Definition
Retinoblastoma, familial adenomatous polypsosis
Term
What are the characteristics of defective DNA-repair syndromes?
Definition
Group of cancer-predisposing conditions characterized by defects in DNA repair lead to DNA instability
Term
What are some examples of common defective DNA-repair syndromes?
Definition
Hereditary nonpolyposis colon cancer (most common), xeroderma pigmentosum
Term
What are the characteristics of familiar cancers?
Definition
Occurs at higher frequency in affected families, increases risk 2-3x, likely depends on multiple low-penetrance alleles, often early age onset
Term
How does chronic inflammation contribute to the development of cancer?
Definition
Proliferating cells accumulate genetic defects due to chronic inflammation causing compensatory proliferation of cells. Can also be caused by activated immune cells releasing mediators and reactive O2 species
Term
What are the four classes of genes that are the chief targets of genetic damage?
Definition
Proto-oncogenes, tumor suppressor genes, genes that regulate apoptosis, DNA repair genes
Term
What are the key alterations seen in malignant cells?
Definition
Self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, sustained angiogenesis, ability to invade and metastasize, defective DNA repair
Term
What are proto-oncogenes?
Definition
Normal genes involved in cellular growth and proliferation, encodes proteins involved in replication
Term
What are oncogenes?
Definition
Mutated proto-oncogenes that have the ability to promote cell growth in the absence of normal growth-promoting signals
Term
How do growth factors act?
Definition
Most act via paracrine signaling
Term
How are cancer cells associated with growth factors?
Definition
Many cancer cells acquire the ability to synthesize a growth factor to which they are responsive in an autocrine loop, most often the gene is not mutated but rather overexpressed. Some tumors have continuous receptor activation (most common) caused by mutations or overexpression
Term
What is the RET proto-oncogene and how is it associated with cancer?
Definition
Encodes for a growth factor receptor (RET), point mutations cause medullary thyroid carcinoma, gene rearrangement causes papillary thyroid carcinoma
Term
How is the epidermal growth factor receptor family associated with cancer?
Definition
ERBB1 is overexpressed in up to 80% of squamous cell carcinomas of the lung, ERBB2 is amplified in 25% of breast cancers
Term
What are signal transducing proteins?
Definition
Receive signals from outside the cell and transmits them to the cell's nucleus, best example of a signal transducing oncoprotein is the RAS family
Term
What are the characteristics of the RAS family of signal transducing proteins?
Definition
3 RAS genes - HRAS, KRAS, and NRAS, 15-20% of all human tumors contain mutated RAS, plays an important role in signal cascades between growth factor receptors and the nucleus
Term
What is the most common oncogene involved in human tumors associated with transcription factors?
Definition
MYC (c-MYC)
Term
What are the characteristics of the MYC (c-MYC oncogene)?
Definition
Proto-oncogene encodes for a transcription factor which is rapidly induced when cells receive a growth signal, oncogene codes for a mutated transcription factor
Term
Progression of cells through the cell cycle is orchestrated by what?
Definition
Cyclins and cyclin-dependent kinases that phosphorylate key target proteins that drive the cell cycle
Term
How is cyclin D or CDK4 associated with cancer?
Definition
Overexpression is common in neoplastic transformation, seen in many cancers
Term
What are tumor suppressor genes?
Definition
Genes that encode for products that halt or slow cell proliferation, growth-inhibitory pathways may initiate apoptosis
Term
What are cyclin-dependent kinase inhibitors?
Definition
CDKIs inactivate CDKs and inhibit progression through the cell cycle, down regulated by mitogenic signaling pathways, inactivation mutations frequently seen in many human malignancies
Term
How is retinoblastoma a model for the "two-hit" hypothesis of oncogenesis?
Definition
Two mutations involving both alleles of RB are required to produce retinoblastoma, many cases are familial in which children inherit one defective RB allele in the germ line
Term
Why is the G1-S checkpoint a critical step in cell division?
Definition
Passing this checkpoint causes the cell to enter the S phase, meaning they are then committed to dividing
Term
What is the function of the RB protein?
Definition
Regulates G1-S checkpoint of the cell cycle, blocks entry into S phase by binding to E2F
Term
What is the most common target for genetic alteration in human tumors?
Definition
P53 gene, homozygous loss occurs in virtually ever type of cancer
Term
What is the function of the P53 gene?
Definition
Transcription factor that senses cellular stress, esp. DNA damage and helps regulate response and can induce apoptosis in response to DNA damage, blocking or inactivity contributes to tumor growth
Term
How does loss of P53 effect clinical treatment?
Definition
Malignant neoplasms lacking P53 are relatively resistant to chemotherapy and irradiation
Term
Germ-line mutations in the adenomatous polyposis coli (APC) gene is associated with what?
Definition
Familial adenomatous polyposis
Term
What is the function of the APC gene?
Definition
Down-regulates growth promoting signals, both copies must be lost for a tumor to arise
Term
The INK4a/ARF (CDKN2A) gene locus encodes what protein products?
Definition
p16/INK4a which blocks cyclin mediated phosphorylation of RB and P14/ARF which activates the P53 pathway by inhibiting MDM2
Term
What is the function of TGF-beta?
Definition
Potent inhibitor of proliferation, bindes to receptor for phosphorylation of R-Smads, mutation of TGF-beta is seen in all pancreatic cancers and most colon cancers
Term
What is the function of PTEn?
Definition
A membrane associated phosphatase, acts as a tumor suppressor by slowing the PI3K/AKT pathway which promotes cell growth and survival, germline mutations lead to Cowden syndrome, somatic mutations seen in vaious tumors
Term
How do tumors avoid apoptosis?
Definition
Decreased Fas expression renders tumor cells less susceptible to apoptosis by cytoxic T cells, increased FLIP production inhibits cleavage of pro-caspase-8, overxpression of Bcl-2, P53 mutations inhibit Bax expression
Term
How is telomerase associated with cancer?
Definition
Majority of malignant cells express telomerase for limitless replicative potetnial
Term
What is angiogenesis?
Definition
Vascularization of tumors, allowing them to enlarge beyond 1-2mm in diameter
Term
How does angiogenesis occur in neoplasms?
Definition
3 methods: proteases by tumor cells or stromal cells release basic fibroblast growth factors, hypoxia increases HIF1-alpha which increases transcription of VEGF and bFGF genes, neoplastic cells commonly express VEGF and bFGF
Term
What are the two phases of the metastatic cascade?
Definition
Invasion of the ECM and vascular dissemination, homing of tumor cells, and colonization
Term
Extravasation of tumor emboli at distant sites involves what?
Definition
Adhesion to endothelium and basal membrane using adhesion molecules and proteases (expression of CD44 favors metastatic spread)
Term
What factors influence site of metastases?
Definition
Anatomic location of primary tumor, adhesion molecules present on the tumor cells, chemokine receptors expressed on the tumor cells
Term
Defects in which DNA repair systems are involved in the development of cancer?
Definition
Mismatch repair, nucleotide excision repair, and recombination repair
Term
What is hereditary nonpolposis colon cancer syndrome?
Definition
Defect in genes involved in DNA mismatch repair increasing the risk of colon cancer characterized by microsatallite instability
Term
What is xeroderma pigementosum?
Definition
A familial cancer syndrome with defective DNA repair, associated with multiple skin cancers, improper DNA excision repair of pyrimidine dimers caused by UV light
Term
How are BRCA1 and BRCA2 genes related to familial breast cancer?
Definition
Mutations account for 1/4 of familial breast cancers, gene products involve din homologous recombination of DNA repair that repairs double strand breaks
Term
What is the Warburg effect?
Definition
Even in the presence of ample oxygen, cancer cells shift their glucose metabolism away from oxidative phosphoryation to aerobic glycolysis
Term
Why does the Warburg effect increase glycolysis?
Definition
Halting oxidation of glucose at pyruvate conserves carbon to be used in anabolic pathways, principle limiting factor of cell division is the availability of carbon, not ATP
Term
What type of chromosomal rearrangements can activate proto-oncogenes?
Definition
Translocations and inversions
Term
How can translocation activate proto-oncogenes?
Definition
Overexpression by swapping its regulatory element or sequences from two different chromosomes recombining to form a hybrid gene that encodes a chimeric protein that promotes growth
Term
Leukemias and lymphomas tend to arise from what type of errors?
Definition
Chromosomal abnormalities
Term
What causes Burkitt lymphoma?
Definition
MYC gene is contiguous to regulator elements of the IgH gene, causing MYC over-expression
Term
What causes follicular lymphoma?
Definition
BCL2 gene becomes contiguous to regulatory elements of the IgH gene, leads to BCL2 overexpression
Term
What causes chronic myeloid leukemia?
Definition
ABL-BCR fusion gene encodes a constitutively active tyrosine kinase, causing cells to receive an unregulated growth signal
Term
Chromosomal deletion errors are most common in what type of cancers?
Definition
None-hematopoietic solid tumors, associated with loss of tumor suppressor genes
Term
What causes gene amplification?
Definition
Defects in DNA replication causing multiple copies of a gene and overexpression
Term
What are epigenetic changes?
Definition
Heritable, reversible changes in gene expression that occur without mutations, occurs either through DNA methylation or histone modifications
Term
What is EZH2?
Definition
Enzymatic component of a multiprotein complex known as polycomb repressive complex 2 which places repressive chromatin marks at the promoter of certain genes, repression leads to repression of some tumor suppressors
Term
EZH2 has been shown to be overexpressed in what kinds of cancers?
Definition
Breast and prostate carcinomas
Term
What are microRNAs?
Definition
Short single stranded RNAs about 22 nucleotides in length, binds to complementary sequences on target mRNAs which blocks translation for post-transcriptional gene silencing, can increase or decrease expression of oncogenes or tumor suppressor genes
Term
Decreased expression of certain miRNAs can occur in what cancers?
Definition
Leukemias and lymphomas (increased BCL2 expression) and lung cancers (increased RAS expression)
Term
Individual tumors accumulate an average of how many mutant genes?
Definition
About 90 mutant genes
Term
What are the 2 stages of chemical carcinogenesis?
Definition
Initiation (cell exposed and DNA damaged) and promotion (cell then stimulated to proliferation. Promoters are nontumorigenic by themselves)
Term
Most known carcinogens are metabolized by what?
Definition
Cytochrome P-450
Term
The risk of skin cancer caused by UV light depends on what?
Definition
Intensity of exposure, quantity of melanin in the skin, and type of UV light
Term
What are the type of UV light and which one is principally responsible for the causation of skin cancer?
Definition
UVA, UVB, and UVC, UVB is usually responsible for skin cancer. UVC could cause damage but is filtered out by the ozone layer
Term
What are the two types of ionizing radiation?
Definition
Electromagnetic (x-rays, gamma) and particulate (alpha and beta particles)
Term
What are the most frequeny malignancies induced by ionizing radiation?
Definition
In descending order of frequency: leukemia, thyroid carcinoma, and lung/breast/salivary gland carcinomas
Term
What is HTLV-1?
Definition
A retrovirus known to cause cancer, infects CD4+ T cells and causes T cell leukemia/lymphoma
Term
What gives HTLV-1 its transforming ability?
Definition
The tax gene which encodes for a protein which activates transcription of seberal host cell genes involved in proliferation and differentiation of T cells, inactivates p16/INK4a and enhances cyclin D, interfereing with DNA repair and upregulating anti-apoptotic genes
Term
What are the different types of human papillomavirus (HPV)?
Definition
Low-risk (type 6 & 11) causes genital warts while high risk (type 16 & 18) causes carcinoma of the cervix and vulva where HPV is integrated into the host genome
Term
What is the Epstein-Barr virus (EBV)?
Definition
A member of the herpes family that infects B cells and some epithelial cells, involved with Burkitt lymphoma, B-cell lymphomas in immunosuppressed patients, and nasopharyngeal carcinoma
Term
What are the two gene products of Epstein-Barr Virus (EBV) and what are their effects?
Definition
LMP-1 is a transmembrane protein that functions as an active CD40 receptor and EBNA2 which acts as a transcription factor and upregulates cyclin D and other protooncogenes
Term
How does EBV cause B-cell lymphomas in immunosuppressed patients and nasopharyngeal carcinoma.
Definition
Through the expression of LMP-1 abd EBNA2
Term
How is Burkitt lymphoma unique?
Definition
Only cancer caused by EBV that does not involve LMP-1 and EBNA2, instead acts as a B-cell mitogen, causing mutations and therefore lymphoma
Term
How does Hep B and C cause hepatocellular carcinomas?
Definition
Chronic hepatocellular injury leads to chronic inflammation and thus compensatory proliferation of hepatocytes which increases mutations and the risk for cancer. Responsible for 70-85% of hepatocellular carcinomas
Term
What is helicobacter pylori?
Definition
Gram-negative bacterium that causes chronic gastritis and peptic ulcers, the very first bacteria classified as a carcinogen
Term
How does helicobacter pylori cause gastric adenocarcinoma?
Definition
Epithelial injury induces chronic inflammation and compensatory mutations, causing mutations and cancer
Term
Which strains of helicobacter pylori increase the risk of adenocarcinoma?
Definition
Strains with the CagA gene which activates growth factor signal pathways in gastric epithelial cells
Term
How does helicobacter pylori cause Malt lymphoma?
Definition
Is a B-cell lymphoma that arises in the gastric mucosa, infects reactive T cells which stimulate a polyclonal B-cell proliferation, requires T cell stimultion, eradication of H. pylori with antibiotics can be curative
Term
What observation supports the idea of immune surveillance where tumor cells can be recognized by the immune system and eliminated?
Definition
Immunocompromised individuals have an increased risk of developing certain malignancies and the presences of tumor-specific T cells and anti-tumor antibodies in some patients
Term
What is the major immune defense mechanism against tumors?
Definition
CD8+ T cells
Term
What are some examples of normal cellular proteins that may be abnormally expressed in tumor cells and then act as tumor antigens?
Definition
Tyrosinase which is normally expressed at low levels in melanocytes and MAGE antigens which are normally expressed only in gametes in the testes
Term
How can oncogenic viruses produce tumor antigens?
Definition
Produces proteins that are recognized as foreign by the immune system, best examples are HPV and EBV
Term
How do oncofetal antigens produce tumor antigens?
Definition
These are proteins that are expressed at high levels in fetal tissue and some cancer cells but not in normal adults, carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) are used as tumor markers
Term
How do altered cell surface glycolipids and glycoproteins act as tumor antigens?
Definition
Most tumors express higher than normal levels, useful as tumor markers and targets for immunotherapy. Melanomas often express gangliosides GM2 and GD3 at high levels
Term
What are cell type-specific antigens?
Definition
Tumors express molecules that are normally present on the cells of origin (differentiation antigens) that are important for identifying tissue of origin as potential targets for immunotherapy. Ex. B-cell lymphomas and CD20
Term
How do CD8+ T cells act as anti-tumor effectors?
Definition
Recognizes peptides from tumor Ag's which are complexed with class I MHC molecules, activated CD8+ T cells initiate apoptosis in the tumor cell. Most important effector cells against tumors
Term
How do natural killer cells act as anti-tumor effector mechanisms
Definition
NK cells are lymphocytes capable of killing tumor cells without prior sensitization by recognizing surface molecules induced by stress such as DNA damage, recognizes class I MHC molecules (increased expression in many tumor cells), plays an important role in eliminating tumor cells wihout class I MHC molecules
Term
How do macrophages act as anti-tumor effector mechanisms?
Definition
Activated T-cells and NK cell secrete IF-gamma which activates macrophages which secrete mediators that kill tumor cells
Term
What antibodies act as anti-tumor mechanisms?
Definition
No evidence of anti-tumor antibodies produced in vivo are protective, though administration of monoclonal antibodies directed against tumor antigens can be effective therapeutically
Term
By what methods do tumor cells evade immune surveillance?
Definition
Selective outgrowth of antigen negative variants, loss or reduced expression of MHC molecules, lack of costimulation of T cells, immunosuppression, and apoptosis of cytoxic T-cells
Term
What costimulation is necessary to activate T cells?
Definition
Presentation of peptides bound to MHC molecules and presence of costimulatory molecules such as B7-1 or CD80 which many tumor cells fail to express
Term
What oncogenic agents secreted by tumors may suppress the immune system?
Definition
TGF-beta, activation of CTLA4 receptors and regulatory T cells
Term
How do tumors induce apoptosis of cytoxic T-cells?
Definition
Some neoplasms express FasL which causes apoptosis in activated T cells
Term
What is cancer cachexia?
Definition
A condition commonly seen in cancer patients characterized by progressive loss of body fat and lean body mass, weakness, anemia, and anorexia. 1/3 of deaths from cancer caused by cachexia
Term
How does cachexia differ from starvation?
Definition
Weight loss seen in cachexia results equally from loss of fat and lean muscle, basal metabolic weight is higher, is NOT caused by nutritional demands of the tumor or anorexia
Term
What causes cancer cachexia?
Definition
Mediators released by immune cells or tumor cells such as cytokines (esp TNF), proteolysis-inducing factor, and lipid metabolizing factor
Term
How is cancer cachexia treated?
Definition
Only effective Rx is removal of the tumor
Term
What are paraneoplastic syndromes?
Definition
Symptoms/signs in cancer-bearing individuals that cannot be explained by local invasion or distant spread of the tumor
Term
What causes paraneoplastic syndromes?
Definition
Tumor secreted substances and immune responses to the tumor, occurs in 10% of cancer patients, may represent earliest manifestation of an occult malignancy, may cause clinical problems/be lethal
Term
How are tumors graded?
Definition
Based on the histologic appearance of the tumor, depends on degree of anaplasia, architectural features, and mitotic index
Term
What is the TNM staging system?
Definition
T = primary tumor, N = lymph node involvement, M = metastases
Term
What is of greater clinical value, staging or grading?
Definition
Staging
Term
Can tumor market assays determine the diagnosis of malignancy?
Definition
No, lack the required sensitivity
Term
How are cancer diagnosed histologically?
Definition
Needle biopsy, excisional biopsy, or cytologic methods (fine needle aspiration or smears from body fluids)
Term
How does immunohistochemistry work in the diagnosis of cancer?
Definition
Tissue section is incubated with antibody directed against an antigen of interested, then with an a tagged antibody directed against the first antibody, then incubated with a substrate for the tagging enzyme, causing a brown precipitate to form wherever the antigen of interest is present
Term
How is flow cytometry used in the diagnosis of cancer?
Definition
Used to measure the DNA content of individual cells and the specific surface antigens on individual tumor cells, used to assist in the diagnosis and classification of lymphomas and leukemias
Term
What might molecular techniques be used for in the laboratory diagnosis of cancer?
Definition
Prognosis of N-MYC gene amplification and deletions of 1p in neuroblastomas, detection of minimal residual disease or recurrence such as in ABL-BCR transcripts by PCR patients treated for CML, and the diagnoses of hereditary predisposition of cancer such as germ-line BRCA1 or BRCA2 mutations
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