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174 Cards in this Set

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What is cytokeratin?
Type of intermediate filament- epitheloid cells.
What is Vimentin?
Type of intermediate filament- mesenchymal cells (muscle, cartilage, fibroblasts, endothel).
What is Desmin?
Type of intermediate filament - smooth, sometimes striated muscles.
What and where are thin filaments?
Actin and Myosin, mainly in muscle cells/myofibroblasts.
What is Thymoma? How can you identify is histologically?
Epitheloid cells in thymus. Can dye for cytokeratin (marker for epitheloid).
Sign of infection with HPV in cell?
Aura in cytoplasm. A result of degradation in cytoplasm.
What do you mainly use histochemistry for?
non-neoplasm.
A-melanotic melanoma?
Melanoma in which you cannot identify melanin in H&E dyes- need to histochemically dye for melanin to prove melanoma.
What do you do in Immunohistochemistry?
Create MONOCLONAL antibodies.
What sections can you use immunohistochemistry on? Any processing?
Non-dyed sections. Requires optimal fixation (so no proteins are degraded). In order to expose the epitopes, must boil/MW/pressure/proteolytic enzymes the tissue
What does formaldehyde do to tissues?
Fixates aldehyde bonds, prevents degredation.
Rate of diffusion for formaldehyde?
5mm/day- so only the outer part of the tissue will be fixated (hence the need to quickly slice the tissue so all parts are fixated).
After fixation, what processing is often used?
Tissue processor that replaces water with paraffin, that solidifies in room temperature.
CD20 is a marker for?
Marker for B cells.
CD3 is a marker for?
Marker for T cells.
What does Immuno-fluorescence identify?
Recognizes proteins like Immuno-histochemistry.
Advantages of Immuno-fluorescence over Immuno-histochemistry?
Immuno-fluorescence works on frozen sections that have not been processed, hence very sensitive.
What is Immuno-fluorescence mainly used for?
Renal pathology.
What is FISH?
Fluorescence method for identifying specific DNA sequences.
What tissue do you use for FISH?
How is it done?
FISH works on unprocessed tissues, after they've been fixated etc.
You heat the tissue to cause DNA denaturation, add a probe with a fluorescent marker and there ya go.
When is there a need for PCR?
Small tissue sample and need for amplification, or inavailability of FISH.
What fixative can you use PCR on?
Tissues that have been fixated in formaldehyde.
What is Tamoxiphen? When is used?
Antibody for Estrogen receptor.
Used in treatment of breast cancer, when abundance of receptors can be identified in the tissue.
What is Herceptin?
Antibody for HER2.
What is Mabthera? When is it used?
Monoclonal antibody for CD20, used for lympho-proliferative neoplasms, B-cell type.
What is Gleevec (STI571)?
Tyrosine-kinase inhibitor.
What neoplasms respond to Gleevec?
CML, Gastrointestinal tumors.
What kind of substances is EM based on?
Substances that take up heavy metals will also take up the electrons shot at them.
In lungs: what do you see in EM in Adenocarcinoma? Mesothelioma?
Adenocarcinoma: short, few protrusion.
Mesothelioma: long, many protrusion.
What intrinsic mechanisms affect cell growth in tumors?
Production/loss rate ("Growth fraction").
What extrinsic mechanism affect cell growth in tumors?
Host factors- hormonal influences, blood supply (partially affected by tumor).
What is the cell cycle duration in malignant cells compared to normal cells?
Similar!
What percentage of the cells in a malignant neoplasm are dividing?
What happens to the rest of the cells?
10% in solid tumors, 25% in the most prosperous.
The rest: Some are in G0, some are differentiating, up to 80% die by apoptosis/necrosis.
How many divisions must a cell go through before it can be clinically identified (=1g)?
30.
(10^9 cells. Smallest clinically detectable mass)
How many divisions must a 1g mass go through before it's big enough to kill?
only 10!
(1Kg. 10^12 cells)
Are malignant tumors monoclonal or polyclonal?
Usually from a monoclonal source, but the tumor itself is polyclonal (gained many different mutation, each giving a unique advantage to its subclone).
What is TAF?
Who secretes it?
Tumor Angiogenesis Factor, secreted by cancer cells. Causes proliferation of Endothelial cells and creation of capillaries (up to 10 times that of normal proliferation).
How do you assess tumor growth rate (normal/abnormal)?
Compared to normal tissue growth rate.
Distance of blood supply from tumor cells?
Implications?
Up to 1cm is fine.
1cm-2cm: Cells go to G0.
Over 2cm from blood supply: necrosis.
Implications: chemo only affective for the cells closer to the blood supply.
Which cancers do not create metastases?
Basal cell carcinoma, Gliomas.
Where do Prostate and Breast cancer metastize?
Bones.
Where does lung cancer metastize?
Adrenal.
Where can lung carcinoma originate?
Pneumocytes, bronchial epithelium, metastases.
Where can lung sarcoma originate?
Fibroblasts, enthelium, muscle around bronchi, etc.
What can you see in primary brain cancer?
Since it originates from Glia cells, you can see a gradual transformation and not an obvious mass with normal tissue beyond it.
Which carcinoma tends to spread in the WALLS of blood vessels?
Renal cell carcinoma (also hepatocellular carcinoma).
Using what do epithelial tumors metastize?
Lymph
Using what to mesenchymal tumors metastize?
Blood
What tissues are tumor-resistant?
Cartilage (low blood supply), striated muscle, tendons, elastic tissue (like wall of aorta).
What is a papiloma?
Benign epithelial neoplasm- raising of the epithelium alone (no mucous), fingers-shaped.
What is an adenoma?
Benign epithelial neoplasm- proliferation of glands, tightly arranged to create a mass, OR benign epithelial neoplasm that forms glandular patterns.
Where do you get primary adenomas?
Organs with a glandular epithelial component, such as breast, pancreas, thyroid, prostate, ovary.
What is a polyp?
Benign epithelial neoplasm- raising of the epithelium AND UNDERLYING MUCOUS.
*only benign*
What is an adenomatous polyp?
What is a papillary polyp?
Adenomatous polyp: raising of the mucous and epithelium, with many glands inside.
Papillary polyp: Raising of the mucous and epithelium, fingers-shaped.
What is APC?
Tumor suppressor, causes degredation of beta-catenin by ubiquitinization.
What is beta-catenin?
Protein that serves as a transcription factor, induces proliferation and intercellular adhesiveness (helps cadherin E).
What is APC inhibit?
beta-catenin, thus inhibiting the Wnt Pathway (that stabilizes beta-catenin and enables it to ener the nucleas).
In which cancers do you see damage to APC?
100% of FAC.
80% of other colic carcinoma.

Requires additional damages, usually to Kras or p53.
Which benign tumors are encapsulated?
Lipomas, fibromas (leiomyomas don't).
Which dye do you use for fat?
Sudan red.
Where do you see more matrix- Fibroma or Fibrosarcoma?
Fibroma.
What do you see in Capillary Hemangioma?
Cluster of tight capillaries- the younger the person, the tighter the capillaries.
What do you see in Cavernous Hemangioma?
Black affliction (these can also be metastases of melanoma. Can differentiate by radioactively marking erythrocytes).
What is a Choristoma?
Mature, organized tissue, in a location it's not usually at.
What is a Hamartoma?
Mature, disorganized tissue, in a location it's usually at (blood vessels in lungs).
NOT a neoplasm!
What is the difference between a Chrostima and a Hamartoma?
Chrostoma is an organized tissue at a foreign location.
Hamartoma is a disorganized tissue at a local location.
What is grading?
How well-differentiated the tissue is (1 is well, 3 is poorly).
Subjective, thus problematic.
What is staging?
TMN- size, metastases, nodes.
Usually you first assess TN.
What is carcinoma simplex?
50%-50% parenchyme-stroma.
What is carcinoma scirrhous?
Significantly more stroma, often secretes a lot of collagen.
Common in gallbladder, lung, pancreas.
What is carcinoma medullary?
Rich epitheloid component, less stroma- soft tumor.
Diffuse, thus hard to identify, or assess real size/borders (often assessed as smaller than they are).
The two types of carcinoma?
Usually, squamous cell carcinoma or adenocarcinoma.
What is Linitis Plastica?
Signet-ring cell carcinoma. The stomach does not expand (=typical of lymphoma as well).
What does signet-ring cell carcinoma secrete?
Mucin.
Functionally well-differentiated, morphologically poorly-differentiated.
What are Keratin pearls indicative of?
Squamous cell carcinoma, well-differentiated.
What do you see in adenocarcinoma?
Tight glands, covered in more than one layer of epithelium.
What tumors are typically spindle-cell sarcoma?
Fibrosarcoma, Leiomyosarcoma, Neurofibrosarcoma.
(should dye for cytokeratin to rule out carcinoma).
What is pleomorphic sarcoma?
Different types of cells- spindle, giant. All hyperchromatic.
Every mesenchymal tumor can look like this.
[you have pleomorphism in carcinoma etc as well]
What is round-cell sarcoma? Who is typically that?
Small abundunt cells, not a lot of cytoplasm, called "blue tumors".
Typical of Ewing, Neuroblastoma, certain carcinoma or lymphomas (Wilms tumor in kidney).
Who often can go de-differentiation?
Lipomas.
What is a cystadenoma?
Benign epithelial neoplasm that forms large cystic masses. Can be in a pattern of Papillary Cystoadenoma.
What are Teratomas?
Neoplasms representative of more than one germ layer, usually all three- principally encountered in the gonads.
Are Seminomas/Hepatomas benign?
No, despite suffix.
[hepatoma: HCC]
What is Anaplasia?
Lack of differentiation. Usually does not represent "reverse differentiation" of mature normal cells, but arise from stem cells.
Markers of anaplasia?
(5)
PALMO
1. Pleomorphism- both cell and nuclei vary in size and shape between cells.
2. Abnormal nuclear morphology- abundance of DNA, hyperchromatic, disproportionally large (1:1 instead of 1:4).
3. Mitoses, odd spindles.
4. Loss of polarity.
5. Others- Tumor giant cells, vascular stroma is scant, central ischemic necrosis.
What is the difference between a tumor giant cell and an inflammtory giant cell?
Inflammatory giant cells are dervied from macrophages.
Inflammatory giant cells contain many small, normal appearing nuclei (compared to hyperchromatic, large and sometimes single in tumor).
Where is dysplasia mainly encountered?
Epithelia.
Signs of dysplasia?
1. Loss in uniformity of individual cells.
2. Loss in their architectural orientation.
3. Pleomorphism.
4. Hyperchromatic nuclei.
5. Mitotic figures more abundant, although almost always conform to normal patterns.
Why are keratin pearls markers of well differentiated tumors?
Because it means the cell is differentiated enough to function.
Which cancers spread by seeding of body cavities?
Ovarian carcinomas.
Usually involves peritoneal cavity.
What are the two manners by which cancer causes enlargement of lymph nodes?
1. Spread and growth of cancer cells in the lymph node.
2. Reactive hyperplasia, even without cancer cells in the node (reacting to tumor cell debris/antigens),
Which organs are most frequently involved secondarily in hematogenous dissemination?
Liver (portal) and lungs (caval blood).
What mode of inheritance is common in defective DNA repair syndromes?
AR.
What is HNPCC?
Hereditary Non-Polypoid Colon Cancer, AD condition caused by inactivation of a DNA mismatch repair gene- most common cancer predisposition syndrome.
What features characterize familial cancers?
1. Early age at onset.
2. Tumors arising in 2+ close relatives of the index case.
3. Sometimes, multiple/bilateral tumors.
How does chronic inflammation promote cancer?
1. Production of cytokines, which stimulate the growth of transformed cells.
2. Increase the pool of tissue stem cells, which become subject to the effect of mutagens.
3. Directly promote genomic instability through the production of ROS.
What are the primary targets of genetic damage?
1. Growth-promoting protooncogenes (dominant).
2. Growth inhibiting tumor suppressor genes (recessive).
3. Genes that regulate apoptosis (dominant/recessive).
4. Genes involved in DNA repair (recessive).
What is Haplo-insufficiency?
Loss of function of a *recessive* gene cause by the damage to a *single* allele.
How do CDK drive the cell cycle?
By phosphorylating target proteins (duh, they're kinases!).
What does cyclin D like?
CDK4.
First complex created!
What does the cyclin D-CDK4 complex do?
Phosphorylates RB, causing it to dissociate from the E2F transcription factor.
Mutations in the complex can mimic mutation in RB.
When is RB re-activated?
During the M phase, by cellular phosphatases.
What does cyclin E like?
CDK2.
Enables further progression through the S phase.
What does cyclin A like?
CDK2, again!
enables progression through G2/M checkpoint.
What does cyclin B like?
CDK1.
Enables progression through prophase.
(exit from mitosis requires inactivation)
Name two groups of CDK inhibitors.
Cip/Kip
INK4/ARF
Where do cells damaged by ionizing radiation arrest?
G2/M checkpoint.
(involves p53 and others)
What is the difference between oncoproteins and protooncogens?
Oncoproteins are devoid of regulatory elements, their production is constitutive.
What causes Hirschsprung disease?
Complete loss of RET function.
What gene is involved in breast cancer?
ERBB2, also called HER2
(not 1. think 2 breasts?)
Who usually has KRAS mutations?
Carcinomas.
Who usually has HRAS mutation?
Bladder.
Who usually has NRAS mutation?
Hematopoietic tumors.
What does RAS do?
1. Transduce growth-factor signals.
2. Involved in regulation of the cell cycle, by modulating cyclin levels (still using MAP Kinase).
What is ABL?
NON-receptor tyrosine-kinase.
What happens when (normal) MYC is activated without survival signals?
Apoptosis!
What is the locus of the RB gene?
13q14
What does E6 do? E7?
E6: promote degradation of p53.
E7: bind to RB.
What happens in Li-Fraumeni syndrome?
Persons inherit one mutant allele of p53.
In which domain of the p53 protein do most mutations occur?
DNA binding domain!
What does MDM2 do?
Inhibits p53 by promoting its degradation using ubiquitinization.
(if cell has managed to repair its DNA, p53 activates its own inhibitor).
What does p53 do?
Stimulates transcription of several genes that mediate cell-cycle arrest (by p21, during late G1) and apoptosis (by BAX).
How is p53 activated?
Phosphorylation, after damage to DNA or other stressors.
What is the difference between RB and p53?
RB polices the *normal* cell cycle, p53 only shows up when there are problems.
What do p63 and p73 do?
Partially make up for p53.
What does TGF-beta do, in reagrds to tumors?
Induces inhibition of cellular proliferation- tumor suppressor, often inactivated in HNPCC.
ALSO, immunosuppressant, thus also *helps* tumors.
What do mutant NF1/2 do?
NeuroFibromatosis -> NeuroFibrosarcoma.
What is VHL?
von Hippel Lindau- the protein forms a complex that functions as ubiquitin ligase. Lack of it prevents degradation of HIF1 and is associated with increased levels of angiogenic GF.
What does mutational activation of WT1 cause?
Wilms Tumor, a pediatric kidney cancer.
The protein activates genes involved in real and gonadal differentiatidon.
What do cadherins do?
Act as glues between epithelial cells.
Loss of caherins -> metastases.
What cancer is BCL2 related to?
B-Cell-Lymphoma, follicular. 14.
How does BCL2 affect the cell?
Anti-apoptotic, works through the mitochondrial pathway,
What does MYC do?
Triggers proliferation.
What is microsatellite instability?
Microsatellites are tandem repeats, that are fixed for life and are the same in every tissue.
Microsatellite instability is a hallmark of defective mismatch repair.
What is Xeroderma Pigmentosum?
Inhertied disorder, defective DNA repair genes (Nucleotide Excision Repair).
Patients are at increased risk for develipment of cancers of the skin when exposed to UV rays.

Assoc: Pigmentosum!
What checkpoint are BRCA1/2 involved with?
G1/S
What do extra-shortened telomers activate?
p53
Two methods by which neovascularization has an effect on tumor growth?
1. Perfusion, duh.
2. Endothelial cells stimulate the growth of adjacent tumor cells by secreting polypeptide GF (such as PDGF and insulin-like GF).
Two methods by which matrix degradation has an effect on tumor growth?
1. Create a path for invasion by tumor cells.
2. Cleavage products of matrix components have growth-promoting, angiogenic and chemotactic activities.
What translocation and gene are involved in Burkitt's lymphoma?
8:14, overexpression of c-MYC.
What translocation and genes are involved in CML?
9:22, philadellphia BCR-ABL, constitutive tyrosine-kinase (*non*-receptor).
What do promoters do?
Induce tumors in initiated cells, but aren't tumorigenic by themselves- do not affect DNA directly and are reversible.
What are some properties of initiators?
Highly reactive electrophiles.
Can be direct/indirect (require metabolic conversion, to produce ultimate carcinogen).
Who metabolizes most of the known carcinogens?
Cytochrome P-450!
What is Ames test?
A test that uses the ability of a chemical to induce mutations in the bacterium Salmonella Typhimurium (70%-90% of known carcinogens score positive!).
What does Aflatoxin B1 do?
Cause HCC, by mutating p53.
(HBV helps)
What are direct-acting alkylating agents?
Weak carcinogens.
Used as anticancer drugs (by interacting and damaging DNA).
What are Polycyclic Aromatic Hydrocarbons?
The most potent carcinogens known!
Require metabolic activation.
(cigarette smoking)
What are aromatic amines and azo dyes?
Food coloring! Require metabolism with P450.
HCC, bladder cancer.
What do Nitrosamines and amides cause?
Stomach cancer.
What does asbestos cause?
Meotheliomas, bronchogenic carcinomas, GI cancers.
What does Vinyl Chloride cause?
The extremely rare HemangioSarcoma of the liver.
Name a few promoters
Exogenous: Viral infections and cigarette smoking (cause tissue damage and reactive hyperplasia).
Endogenous: Hormones and bile salts (fatty food increases synthesis of bile acids).
How does UVB light damage DNA?
Related to formation of pyrimidine dimers.
Fixed by NER, which is faulty in Xeroderma.
What is the hierarchy of vulnerability of different tissue to radiation induced cancers?
1. LEUKEMIAS (except for CLL).
2. Thyroid, in the young.
Last- skin, bone, GI tract.
Where is the HPV genome in benign neoplasms? Malignant?
Benign: episomal.
Malignant: Integrated.
Is HPV an initiator or promoter?
Initiator!
What is present in 100% of nasopharyngial carcinoma?
EBV!
What is the major immune defense mechanism against tumors?
CTLs (CD8).
What functions as tumor antigens?
1. Products of mutated oncogenes and tumor suppressor genes.
2. Products of other mutated genes.
3. Overexpressed cellular proteins.
4. Aberranly expressed cellular proteins (not in this tissue, only early in development).
What role do machrophages have in antitumor mechanisms?
The machanisms are similar to those used to kill microbes, like ROS.
Activated because IFN-gamma is produced by T and NK cells.
Ways for tumors to avoid immune system?
1. Selective outgrowth of antigen-negative variants.
2. Loss/reduced expression of MHC class I (but then NK rise up).
3. Lack of costimulation (also makes T cells anergic, or worse- apoptotic).
3. Immunosuppression (TGF-beta, immunosuppressor, is secreted by many).
4. Antigenic masking.
5. Cause apoptosis of T cells- by expressing FAS ligand.
Why are benign tumors manifest more by elaboration of hormones?
Hormone secretion requires a decent level of differentiation.
What is cachexia?
"Wasting syndrome"- progressive loss of body fat and muscle.
What causes cachexia?
Cytokines secreted by the tumor/host.
What is the most common paraneoplastic syndrome?
Hypercalcemia, either by osteloysis induced by cancer or by the production of calcemic humoral substances by extraosseous neoplasms.
What is PTHRP?
PTH-Related Protein.
Which tissues produce PTHRP?
Many normal tissues, in small amounts (in cancer, amounts go large).
What is T0 in staging?
Carcinoma in-situ.
What is CEA?
Tumor marker.
Substance normally produced in embryonic tissue. Not very specific or sensitive.
What does a rising CEA level indicate?
Reccurance.
What is AFP?
Tumor marker.
Synthesized normally early in fetal life.
What do elevations of AFP level indicate?
HCC and germ-cell tumors of the testis.
What is the maximal size for a tumor unless before angiogenic switch?
1-2mm.