Neoplasia Flashcards
Historically, how was clonality of a neoplasm established?
- by identifying G6PD isoform expression
- there are multiple isoforms but only one is inherited from each parent
- it is an X-linked gene, so in females, one is randomly inactivated in each cell, resulting in a normal ratio of 1:1 between the two inherited forms
- this 1:1 ratio is maintained in hyperplasia but only one isoform is present in a neoplasm
What is the normal kappa to lambda light chain ratio? What ratio is indicative of a monoclonal B cell proliferation?
- normally k:l is 3:1
- a ratio greater than 6:1 suggests monoclonality
What is a carcinoma?
a tumor of epithelial origin
What are the three leading causes of death among adults and children?
- adults: CV disease then cancer and then chronic respiratory disease
- children: accidents then cancer and then congenital defects
Approximately ___ divisions occur before the earliest clinical symptoms of a tumor arise.
30 divisions
Why do cancers that are detected late tend to have a poor prognosis?
because cancers that do not produce symptoms until late in the disease will have undergone additional divisions and hence have additional mutations
In which organs, is late detection of cancer most likely?
those with a large reserve capacity (i.e. the lung)
What are oncogenes?
proto-oncogenes, which now in their mutated state, promote unregulated cellular growth
What kinds of gene products do proto-oncogenes typically encode?
- growth factors and their receptors
- signal transducers
- nuclear regulators
- cell cycle regulators
What sort of Ras mutation leads to malignancy?
- Ras is associated with growth factor receptors in an inactive, GDP-bound state
- receptor binding causes GDP to be replaced by GTP, activating Ras
- Ras sends growth signals to the nucleus
- Ras then inactivates itself by cleaving GTP to GDP, a process that is augmented by GTPase activating protein
- however, if Ras becomes mutated, this inhibits the activity of the GTPase activating protein, prolonging the activated state of Ras
What are the two classic tumor suppressor genes?
- Retinoblastoma
- p53
What is the physiologic role of p53? How does it end up promoting oncogenesis?
- in response to DNA damage, it slows the cell cycle (at the G1/S transition) by activating p21, a kinase that inactivates various cyclin/CDK complexes, and upregulates DNA repair enzymes
- if the DNA cannot be repaired, it up regulates BAX, which disrupts Bcl2, inducing apoptosis
- if both copies are knocked out, then DNA damage is ignored, not repaired, and cell cycle progression continues
What is Li-Fraumeni syndrome? What causes it? How does it manifest?
- a gremlin mutation in p53 (first hit)
- this makes oncogenesis far more likely because then it only takes one somatic knockout of p53 (second hit)
- characterized by a propensity to develop multiple types of carcinomas and sarcomas
What is the physiologic role of Rb? How does it contribute to oncogenesis?
- it holds the E2F transcription factor, which is necessary for transition to the S phase
- when Rb is phosphorylated by the cyclinD1/CDK4 complex, E2F is released and the cell progresses through the cell cycle
- if both genes are knocked out, E2F is constitutively free and cell cycle progression is unregulated
Generally speaking, how many copies of an oncogene need to be affected for cancer to occur? What about tumor suppressor genes?
- oncogenes: just one mutated gene copy will suffice
- tumor suppressor genes: both copies usually need to be affected
What is familial retinoblastoma?
- a germline mutation in Rb (first hit) means only one somatic mutation (second hit) is required for oncogenesis
- characterized by bilateral retinoblastoma and osteosarcoma
Sporadic Rb mutations manifest as what sort of neoplasm?
unilateral retinoblastoma
What is telomerase? What is it’s role in oncogenesis?
- telomeres shorten with serial cell divisions, eventually resulting in cellular senescence
- tumor cells often up regulate telomerase, which preserves telomeres and allows for continued cell growth
Tumor cells often produce what angiogenic factors?
FGF and VEGF
Describe the process whereby neoplastic cells invade and spread.
- epithelial tumors are normally attached to one another by cellular adhesion molecules
- so they begin by down regulating these molecules, like E-cadherin, leading to dissociation
- the cells then attach to laminin and destroy the basement membrane using collagenase
- the cell attach to fibronectin in the ECM and spread locally
- eventually if they are able to enter the vasculature or lymphatics, they can metastasize
Describe three routes of metastasis and which tumors typically utilize each.
- carcinomas tend to spread by lymphatics
- hematogenous spread is characteristic of sarcomas and some carcinomas (RCC, HCC, follicular carcinoma of the thyroid, choriocarcinoma)
- ovarian carcinoma utilizes seeding of body cavities
What is omental caking?
a feature of ovarian carcinoma, a cancer which tends to metastasize by seeding the peritoneum, and as the tumor grows, it tends to fill the peritoneum forming this feature
Which is a more important prognostic factor, grading or staging?
staging
What is grading of a cancer?
microscopic assessment of differentiation taking into account architectural and nuclear features
What is TNM staging? Which aspect of it is most important for prognosis?
- T: tumor size and depth of invasion
- N: spread to regional lymph nodes
- M: metastasis (most important for prognosis)
Define anaplasia.
a complete lack of differentiation of cells in a malignant neoplasm
What is the “seed and soil” theory of metastasis?
- a tumor embolus acts as the seed
- the location of metastasis depends on the characteristics of the target tissue (aka soil)
What is a hamartoma?
a benign malformation of disorganized overgrowth of tissues in their native location
What is a choristoma? Give an example.
- a term used to describe a benign malformation consisting of normal tissue in a foreign location
- gastric tissue located in the distal ileum in Meckel diverticulum
What terms are used to describe a benign or malignant tumor of the following cell types:
- smooth muscle
- striated muscle
- connective tissue
- melanocyte
- smooth muscle: leiomyoma and leiomyosarcoma
- striated muscle: rhabdomyoma and rhabdomyosarcoma
- connective tissue: fibroma and fibrosarcoma
- melanocyte: nevus/mole and melanoma
What are the three most common cancers? Which three cancers contribute the most mortality?
- incidence: prostate/breast > lung > colorectal
- mortality: lung > prostate/breast > colorectal
What is the current trend among the two genders with regards to lung cancer incidence?
- decreasing incidence for men
- no change for women
What are psammoma bodies? Where are they found?
- laminated, concentric spherules with dystrophic calcification
- seen in papillary carcinoma of thyroid, serous papillary cystadenocarcinoma of ovary, meningioma, and malignant mesothelioma (PSaMMoma body)
For what tumors is alkaline phosphatase a relevant serum marker?
- mets to bone or liver
- Paget disease of bon
- seminoma
How is a-fetoprotein used as a tumor serum marker?
- HCC
- hepatoblastoma
- yolk sac tumor
- mixed germ cell tumor
In addition to it’s role as a tumor serum marker, what congenital defects are a-fetoprotein levels used to detect?
- high levels associated with neural tube and abdominal wall defects
- low levels associated with Down syndrome
For what tumors is B-hCG a relevant serum marker?
hydatidiform moles and choriocarcinomas
For what tumors is CA15-3/CA 27-29 a relevant serum marker?
breast cancer
For what tumors is CA 19-9 a relevant serum marker?
Pancreatic adenocarcinoma
For what tumors is CA 125 a relevant serum marker?
Ovarian cancer
For what tumors is calcitonin a relevant serum marker?
medullary thyroid carcinoma
For what tumors is CEA a relevant serum marker?
very nonspecific but very sensitive for colorectal and pancreatic cancers
In addition to cancer, what conditions can elevate PSA?
- prostatitis
- BPH
What is P-glycoprotein? Which tumor type classically expresses it?
- aka MDR1, it is used by cancer cells to pump toxins out of cells
- classically expressed by adrenal cell carcinoma
What is cachexia? How does it present? What mediates it?
- a state of weight loss, muscle atrophy, and fatigue that occur in states of chronic disease
- mediated by TNF, IFNy, IL-1, and IL-6
Metastasis to the brain is most likely from which primary tumor sites?
lung > breast > prostate > melanoma > GI
Metastasis to the liver is most likely from which primary tumor sites?
colon»_space; stomach > pancreas
Metastasis to the bone is most likely from which primary tumor sites? Which of these form lytic and which form plastic lesions?
- prostate, breast > lung, thyroid, kidney
- prostate and breast tend to be blastic
- lung, kidney, and thyroid tend to be lytic
What is naphthylamine?
a derivative of cigarette smoke associated with urothelial carcinoma of the bladder
Alcohol is a risk factor for which cancers?
- squamous cell carcinoma of the oropharynx and upper esophagus
- hepatocellular carcinoma
- chronic pancreatitis and pancreatic cancer
What role do nickel, chromium, beryllium, and silica play as carcinogens?
they are all possible occupational exposures associated with lung cancer
How is ionizing radiation a carcinogen? With which cancers is it associated?
- it generates hydroxyl free radicals from water in tissue
- it is associated with AML, CML, and papillary carcinoma of the thyroid
How is non-ionizing radiation a carcinogen? With which cancers is it associated?
- results in the formation of pyrimidine dimers in DNA
- associated with skin cancer (basal cell, squamous cell, and melanoma)
What are aflatoxins and where are they found? With which cancer are they associated?
- derived from Aspergillus, they often contaminate stored rice and grains
- there is a very strong association with hepatocellular carcinoma worldwide
Alkylating agents are associated with which cancers?
leukemias and lymphomas
What is the carcinogenic risk of aromatic amines?
transitional cell carcinoma
What is the carcinogenic risk associated with arsenic?
- squamous cell carcinoma of teh skin
- lung cancer
- liver angiosarcoma
What is the carcinogenic risk of asbestos?
bronchogenic carcinoma > mesothelioma
What is the most common carcinogen worldwide?
cigarette smoke
What is the most carcinogenic component of cigarette smoke?
polycyclic hydrocarbons
Cigarette smoke is a carcinogen with risks for what cancers?
- transitional cell carcinoma of the bladder
- squamous cell carcinoma of the esophagus, larynx, and lung
- renal cell carcinoma
- small cell carcinoma of the lung
- pancreatic adenocarcinoma
What are nitrosamines? Where are they found? What do they cause? Where are they most prevalent?
- they are compounds found in smoked foods
- they pose a risk for stomach cancer
- they are responsible for the high rate of stomach carcinoma in japan
What is the second leading cause of lung cancer after cigarette smoke?
the carcinogen radon
What is the carcinogenic effect of vinyl chloride? Where is it found?
- is is an occupational exposure used in the making of PVC pipes
- it is well studied and highly tested with a link to angiosarcoma of the liver
Describe the effect of carbon tetrachloride as a carcinogen.
it causes centrilobular necrosis and fatty change of the liver
What is acanthosis nigricans and with which diseases is it commonly associated with?
- hyperpigmented, velvety plaques in the axilla and on the neck
- associated with gastric adenocarcinoma (but more so with obesity and insulin resistance)
What is a Leser-Trelat signs and for which cancers is it a commonly associated neoplastic syndrome?
- it is the sudden onset of multiple seborrheic keratoses
- it is most associated with GI adenocarcinomas
Describe hypercalcemia as a paraneoplastic syndrome include mechanism and associated cancers.
- PTHrP is the mechanism associated with squamous cell carcinomas of the lung, head, and neck as well as renal, bladder, breast, and ovarian carcinomas
- elevated calcitriol is the mechanism associated with lymphoma
Which cancer is most strongly associated with the paraneoplastic syndrome of Cushing syndrome?
small cell lung cancer via elevated ACTH
Which cancer is most strongly associated with the paraneoplastic syndrome of SIADH?
small cell lung cancer via elevated ADH
Which cancers are most strongly associated with the paraneoplastic syndrome of polycythemia? What is the mechanism?
- RCC, HCC, hemangiobalstoma, pheochromocytoma, and leiomyoma
- via elevated EPO
Which cancer is most strongly associated with the paraneoplastic syndrome of pure red cell aplasia and what is it?
an anemia with low reticulocyte count associated with thymoma
What is Good syndrome and with which cancer is it a strongly associated paraneoplastic syndrome?
- it is a hypogammaglobulinemia
- associated with thymoma
What is Trousseau syndrome and with which cancers is it a strongly associated paraneoplastic syndrome?
- it is a migratory superficial thrombophlebitis
- associated with adenocarcinomas, especially pancreatic
What is nonbacterial thrombotic (marantic) endocarditis and with which cancers is it a strongly associated paraneoplastic syndrome?
- it is the deposition of sterile platelet thrombi on heart valves
- associated with adenocarcinomas, especially pancreatic
What is anti-NMDA receptor encephalitis and with which cancer is it a strongly associated paraneoplastic syndrome?
- it is a syndrome of psychiatric disturbance, memory deficits, seizures, dyskinesias, autonomic instability, and language dysfunction
- associated with Ovarian teratoma
What is opsoclonus-myoclonus ataxia syndrome and with which cancers is it a strongly associated paraneoplastic syndrome?
- described as “dancing eyes, dancing feet,” it is a neuromuscular paraneoplastic syndrome
- associated with neuroblastoma in children or small cell lung cancer in adults
What is paraneoplastic cerebellar degeneration and with which cancers is it a strongly associated paraneoplastic syndrome?
- it is cerebellar degeneration due to antibodies against Hu, Yo, and Tr antigens in purkinje cells
- associated with small cell lung cancer, gynecologic and breast cancers, and Hodgkin lymphoma
What is paraneoplastic encephalomyelitis and with which cancers is it a strongly associated paraneoplastic syndrome?
- caused by antibodies against Hu antigens in neurons
- associated with small cell lung cancer
What is Lambert-Eaton myasthenic syndrome and with which cancers is it a strongly associated paraneoplastic syndrome?
- it is caused by antibodies against presynaptic Q- and P-type calcium channels at the NMJ
- associated with small cell lung cancer
With which cancers is EBV associated?
- Burkitt lymphoma
- Hodgkin lymphoma
- nasopharyngeal carcinoma
- primary CNS lymphoma in immunocompromised patients
With which cancers are HBV and HCV associated?
- hepatocellular carcinoma
- lymphoma
With which cancers is HHV-8 associated?
Kaposi sarcoma
With which cancers is HPV associated?
cervical and penile/anal carcinoma as well as head and neck cancer
With which cancers is H. pylori associated?
gastric adenocarcinoma and MALToma
With which cancers is HTLV-1 associated?
adult T-cell leukemia/lymphoma
With which cancers is liver fluke (aka Clonorchis sinensis) associated?
cholangiocarcinoma
With which cancers is Schistosoma haematobium associated?
squamous cell bladder cancer
What is the gene product of ALK and with which neoplasm is a mutation of it strongly associated?
it encodes a receptor tyrosine kinase and is associated with lung adenocarcinoma
What is the gene product of BCR-ABL and with which neoplasms is a mutation of it strongly associated?
it encodes a tyrosine kinase and is associated with CML and ALL
What is the gene product of BCL-2 and with which neoplasms is a mutation of it strongly associated?
it encodes an antiapoptotic molecule and is associated with follicular and diffuse large B cell lymphomas
What is the gene product of BRAF and with which neoplasms is a mutation of it strongly associated?
it encodes a serine/threonine kinase and is associated with melanoma and non-Hodgkin lymphoma
What is the gene product of c-KIT and with which neoplasm is a mutation of it strongly associated?
it encodes a cytokine receptor and is associated with GIST
What is the gene product of c-MYC and with which neoplasm is a mutation of it strongly associated?
it encodes a transcription factor and is associated with Burkitt lymphoma
What is the gene product of HER2/neu and with which neoplasms is a mutation of it strongly associated?
it encodes a tyrosine kinase and is associated with breast and gastric carcinomas
What is the gene product of JAK2 and with which neoplasms is a mutation of it strongly associated?
it encodes a tyrosine kinase and is associated with chronic myeloproliferative disorders
What is the gene product of KRAS and with which neoplasms is a mutation of it strongly associated?
it encodes a GTPase and is associated with colon, lung, and pancreatic cancer
What is the gene product of L1-MYC and with which neoplasm is a mutation of it strongly associated?
it encodes a transcription factor and is associated with lung tumors
What is the gene product of n-MYC and with which neoplasm is a mutation of it strongly associated?
it encodes a transcription factor and is associated with neuroblastoma
What is the gene product of RET and with which neoplasms is a mutation of it associated?
it encodes a tyrosine kinase and is associated with MEN 2A and 2B (medullary thyroid cancer)
What is an APC gene mutation associated with?
FAP and colorectal cancer
What is the gene product of BRCA1/BRCA2 and with which neoplasms is a mutation of it associated?
- encodes a DNA repair protein
- associated with breast and ovarian cancer
What is the gene product of CDKN2A and with which neoplasms is a mutation of it associated?
- encodes p16, which blocks the G1 to S transition
- associated with melanoma and pancreatic cancer
What is a DCC gene mutation associated with?
a tumor suppressor gene associated with colon cancer
What is a DPC4/SMAD4 gene mutation associated with?
a tumor suppressor gene associated with pancreatic cancer
What is the gene product of MEN1 and with which condition is a mutation of it associated?
it encodes renin and is associated with MEN1
What is the gene product of NF1 and with which condition is a mutation of it associated?
it encodes a Ras GTPase activating protein called neurofibromas and is associated with neurofibromatosis type 1
What is the gene product of NF2 and with which condition is a mutation of it associated?
it encodes merlin (aka schwannomin) a tumor suppressor protein associated with neurofibromatosis type 2
What is a PTEN gene mutation associated with?
breast, prostate, and endometrial cancer
What is the gene product of TSC1 and with which condition is a mutation of it associated?
encodes the hamartin tumor suppressor protein and is associated with tuberous sclerosis
What is the gene product of TSC2 and with which condition is a mutation of it associated?
encodes the tuberin tumor suppressor protein and is associated with tuberous sclerosis
What is the gene product of VHL and with which condition and neoplasm is a mutation of it associated?
encodes a protein that inhibits hypoxia inducible factor 1a and is associated with VHL disease and renal cell carcinoma
