7 - Neoplasia Flashcards
Which appears to be the dominant risk factor category for neoplastic development, genetics or environmental factors?
Environmental
Do mixed tumors (pleomorphic adenomas) have cells from multiple germ layers?
No, they often have epithelial and myoepithelial cells (both from the same layer and clonal start)
What is a choristoma?
A nonneoplastic nodule of well-developed tissue in the wrong place (a heterotopic rest of cells)
What is a morphologic hallmark of malignancy?
Anaplasia
What are some signs of a lack of differentiation in malignant cells (anaplasia)?
Pleomorphism, abnormal nuclear morphology, mitoses, loss of polarity, central areas of ischemic necrosis, loss of function
What are the two most major characteristic behaviors of a malignancy?
Metastasis; local invasiveness
Do tumors have their own contained functional lymphatics?
No, the ones around the periphery of the tumor are sufficient
Is it accurate to say that carcinomas spread via lymphatics and sarcomas spread via hematogenous routes?
Yes, but it is misleading as the lymphatics and vascular systems are very interconnected.
What are two major spots of dissemination in hematogenous spread?
The liver and lungs
What tumors are very likely to spread to the vertebral column?
Proximal tumors (e.g. the thyroid and prostate) metastasize through the paravertebral plexus
What tumor has a high affinity for venous invasion and invades the branches of the renal vein and then the renal vein itself?
Renal cell carcinoma (it can even reach all the way up the inferior vena cava to the heart)
To where do breast cancers preferentially spread?
Bone
To where do bronchogenic carcinomas preferentially spread?
The adrenals and the brain
To where do neuroblastomas preferentially spread?
The liver and bones
What are the most common cancers in men?
Prostate, lung, and colon/rectum
What are the most common cancers in women?
Breast, lung, and colon/rectum
What four cancers account for more than 50% of cancer diagnoses and deaths in the U.S.?
Lung, female breast, prostate, an colon/rectum
What are the most common cancers in the world?
Lung, stomach, and liver in men; breast, cervix, and lung in women
What percentage of cancers worldwide are thought to be directly or indirectly caused by infectious agents?
15%
What is the single most important environmental factor contributing to premature death in the U.S.?
Smoking
What percentage of lung cancer deaths can be attributed to smoking?
90%
What are some acquired conditions that can predispose to cancer (3)?
Chronic inflammation, precursor leisons, immunodeficiency states
What are the four classes of normal regulatory genes that are the principal targets of cancer-causing mutations?
Proto-oncogenes, tumor suppressor genes, apoptosis-regulating genes, and genes involved in DNA repair
What are the mutations called that contribute to the development of a malignant phenotype?
Driver mutations
What are the three steps of tumor development?
Initiation, promotion, and progression
What is the Warburg effect?
Tumors switch to aerobic glycolysis from oxidative phosphorylation. Aerobic glycolysis provides rapidly dividing tumor cells with metabolic intermediates that are needed for the synthesis of cellular components, whereas mitochondrial oxidative phosphorylation does not
What is a particularly important proto-oncogene?
The signal transducer RAS (as well as MYC, P13K, BRAF, ERBB1 and 2)
What are the three RAS mutations in humans?
HRAS, KRAS, NRAS
What is the Philadelphia chromosome?
CML change; BCR-ABL kinase mashup between chromosomes 9 and 22
What two genes promote G1/S progression? What two genes inhibit it?
D cyclin genes, CDK4; RB, TP53
How is RAS usually activated?
Point mutations
Do both tumor suppressor alleles or both proto-oncogenes need to be knocked out?
Tumor suppressors (only one proto-oncogene mutation is needed)
What are some principal tumor suppressor genes?
RB, TP53, APC, NF1, NF2, VHL, MEN1
What is the most frequently mutated gene in human cancers?
TP53 (found in more than 50% of all cancers)
What is the gene that regulates the WNT pathway in colonic epithelium?
APC
What is the TGF-beta pathway?
A potent inhibitor of cellular proliferation
Which is the most commonly mutated apoptotic pathway in cancer, the intrinsic or extrinsic?
The intrinsic
What family of anti-apoptotic genes is often overexpressed in certain cancers?
BCL2
What are some possible mechanisms by which cancer cells have seemingly immortal potential?
(1) Evasion of senescence; (2) evasion of mitotic crisis; (3) the capacity for self-renewal
What diameter is a solid tumor limited to if it lacks the ability for angiogenesis?
1 to 2 mm
What is the principal proangiogenic factor?
VEGF
What are the steps of the metastatic cascade?
(1) Invasion of the extracellular matrix (ECM) and (2) vascular dissemination, homing of tumor cells, and colonization
What is the first step of cancer cell invasion?
Alterations in intercellular adhesion molecules (E-cadherins) (dissociation of cancer cells from one another)
What is the second step of cancer cell invasion?
Degradation of the basement membrane and interstitial connective tissue
What are the final steps of cancer cell invasion?
Changes in attachment of tumor cells to ECM proteins; locomotion is the final step of invasion, propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis
Do all cells in a tumor hold all the necessary steps of metastasis?
No, different cells acquire different mutations, but the most successful cells continue to proliferate (clonal evolution model)
What is the main class of tumor antigens?
Products of mutated genes (aberrantly expressed cellular proteins, oncogenic virus antigens, oncofetal antigens, altered cell surface glycoproteins)
What immune cells have antitumor effects?
Cytotoxic T cells, natural killer cells, macrophages
What makes tumors especially difficult for immune surveillance to detect and completely eliminate?
Immune surveillance detects and eliminates the antigen-positive cells, leaving only the antigen-negative cells that are undetectable to proliferate
Do some tumor cells secrete immunosuppressive factors?
Yes.
What expedites the acquisition of driving mutations?
The increased mutation rates in cancers
Describe hereditary nonpolyposis colon cancer syndrome (HNPCC). What is the underlying issue?
An autosomal dominant disorder characterized by familial carcinomas of the colon; defects in DNA mismatch repair genes
Describe xeroderma pigmentosum.
An inherited disorder of nucleotide excision repair; UV rays causes an increased risk of thymidine dimers
What are some rare cancer syndromes involving DNA repair and hypersensitivity to DNA-damaging agents?
Bloom syndrome (ionizing agents), ataxia-telangiectasia (ionizing agents), Fanconi anemia (chemotherapeutic drugs)
What are some systemic signs and symptoms that can result from chronic inflammation associated with cancer?
Anemia, fatigue, cachexia
What are some possible mechanisms by which chronic inflammation can lead to cancer development?
Release of angiogenic and growth factors (by leukocytes and activated stromal cells), degradation of adhesion molecules (by inflammatory proteases), enhanced resistance to cell death
What are some examples of chromosomal changes that cause dysregulation of cancer-associated genes?
Translocations (e.g. Burkitt lymphoma, MYC), deletions (e.g. Retinoblastoma, RB), gene amplification (e.g. neuroblastoma, NMYC), chymothrypsis (chromosome ‘shattering’ and haphazardly reassembled)
What are some of the epigenetic changes that can cause dysregulation of cancer-associated genes?
Methylation of tumor suppressor genes; histone changes
What are some of the miRNAs invloved in cancer epigenetics?
OncomiRNAs, tumor suppressive miRNAs
What symptoms characterize cancer cachexia?
Equal loss of fat and muscle, elevated BMR, evidence of systemic inflammation
What is a possible cause of cachexia?
Tumor necrosis factor-alpha secretion
What are some paraneoplastic syndromes of cancer?
Endocrinopathies (e.g. Cushings), hypercalcemia, acanthosis nigricans, DIC
What is the difference between grading and staging of tumors?
Grading: determined by cytologic appearance; based on the idea that behavior and differentiation are related, with poorly differentiated tumors having more aggressive behavior
Staging: determined by surgical exploration or imaging, is based on size, local and regional lymph node spread, and distant metastases; of greater clinical value than grading
What is flow cytometry?
Mainly used to identify cellular antigens expressed by “liquid” tumors
What tumor marker is associated with trophoblastic and nonseminomatous testicular tumors?
beta-HCG
What tumor marker is associated with medullary carcinoma of the thyroid?
Calcitonin
What tumor marker is associated with pheochromocytoma?
Catecholamine and metabolites
What tumor marker is associated with liver cell cancer and nonseminomatous testicular cancers?
alpha-fetoprotein
What cancers are associated with carcinoembryonic antigen (CEA)?
Carcinomas of the colon, pancreas, lung, stomach, and heart
What tumor marker is associated with prostatic acid phosphatase?
Prostate cancer
What tumor marker is associated with neuroblastoma and small-cell cancer of the lung?
Neuron-specific enolase
What tumor marker is associated with multiple myeloma?
Immunoglobulins
What tumor marker is associated with prostate cancer?
Prostate-specific antigen, prostate-specific membrane antigen, and prostatic acid phosphatase
What tumor marker is associated with ovarian cancer?
CA-125
