Pathology

Question 1

What are biomarkers and where are they found?

Answer 1

Biomarkers are substances produced by tumor cells or other cells of the body in response to cancer or to a benign noncancerous condition Can be found in tissue, blood, urine, CSF

Question 2

What is the uses for biomarkers?

Answer 2

• Risk assessment– determine genetic risk - Screening– detect premalignant lesions or early cancer - Diagnostic– detect specific disease and improve staging - Prognostic– estimate disease course - Predictive– predict response to treatment - Monitor– detection of remission or recurrence

Question 3

How are biomarkers used in the assessment of breast cancer?

Answer 3

• IHC staining for ER, PR is diagnostic (NOT prognostic) and predicts response to chemo and hormone therapy - IHC staining for HER2/NEU is prognostic and predicts response to receptor blockade (Herceptin = trastuzumab)

Question 4

How are biomarkers used in the assessment of GIST (gastrointestinal stromal tumor)?

Answer 4

IHC staining for CD117 is diagnostic and predicts response to targeted therapy w/ imantinib

Question 5

How are biomarkers used in the assessment of B cell lymphoma?

Answer 5

IHC staining for CD20 is diagnostic (for non-Hodgkin’s lymphoma) Monoclonal Ab to CD20 (rituximab) used in various chemo regimens

Question 6

Why would you assess both EGFR and KRAS mutations prior to treatment of a patient w/ adenocarcinoma of the lung or colon?

Answer 6

If a patient has a mutation in EGFR you can use an inhibitor (antibody in colon, tyrosine kinase inhibitor in lung) to block the receptor and prevent cancer cell proliferation However, you should also test the patient for mutations in KRAS because this enzyme is downstream from EGFR– if KRAS is mutated, it doesn’t matter what treatment you give for the EGFR mutation, the pathway is not going to work anyways

Question 7

What type of study is needed to validate a biomarker?

Answer 7

Large, prospective control study

Question 8

Is there a uniform system for grading tumors?

Answer 8

NO, but there are multiple systems in place (Nottingham, Gleason, Bloom-richardson, etc.)

Question 9

How does grading classify cancer?

Answer 9

Grading classifies cancer in terms of how abnormal they look (ie - differentiation) and how quickly the tumor is likely to grow and spread.

Question 10

What are 3 variables used when attempting to grade a breast carcinoma?

Answer 10

1. Nuclear pleomorphism (differentiation)
2. Mitotic Count / mm²
3. Tubule Formation percentage (acini - glandular structures)

Question 11

What does TMN stand for in tumor staging?

Answer 11

• T = Tumor extent (size of tumor or invasion)
• N = Regional Lymph Node metastasis (present or absent?, Where, how many)
• M = Has it metastasized?

Question 12

In terms of TMN, what is the defining factor of Stage IV cancer.

Answer 12

It is has metastisized to other organs/parts of body.

Question 13

What information can cancer staging predict?

Answer 13

Probability of Survival

Question 14

What are the mechanisms of replicative immortality?

Answer 14

Telomerase lengthening of telomeres in cancer stem cells allows for the continued replication of neoplastic cells.

Question 15

What fuel metabolism changes occur in tumor cells?

Answer 15

• Proliferating cells increase glucose and glutamine uptake for energy needs and macromolecule biosynthesis
• Warburg effect: under aerobic conditions, cancer cells metabolize glucose by glycolysis rather than by oxidative phosphorylation, there is a shift in enzyme isotypes. In anerobic conditions, glutamine is used to drive the TCA cycle independently of glucose.

Question 16

Describe the roles of the tumor microenvironment in tumorigenesis.

Answer 16

Myofibroblasts/fibroblasts: tumor initiation, growth and tumor invasion by incorporation of alpha-smooth muscle actin fibers

Adipocytes: adipokines lead to increased tumor cell migration and tumor invasion by regulating expression and activation of MMPs

Tumor endothelial cells: leukocytes recruitement and tumor cell behavior and metastasis

Pericytes: stabilize blood vessels, inhibit endothelial cell proliferation, maintain capillary diameter, regulate blood flow, provide endothelial survival signals

Tumor associated macrophages: immune regulation, promote cell growth and promote tumor development

Dendritic cells: induce vascularity and involved in tumor immune-pathogenesis

Immune cells: promote growth and progression of cancer

Mast cells: promote tumor development by distributing the normal stroma-epithelial communication, facilitating tumor angiogenesis, releasing growth factors, and inducing state of immunosuppression

Question 17

What are some important proteins involved in the tumor microenvironment?

Answer 17

• Hyaluronic acid: ligand for CD44 which is expressed on invading tumor cells
• MMPs: remodel the ECM, fragments regulate invasion, angiogenesis, immune regulating, lymphangiogenesis, and metastasis

TIMPs: downregulated in cancers

Question 18

Describe the cellular mechanisms involved in the epithelial to mesenchymal transition (EMT).

Answer 18

Altered cell adhesion molecule expression (e.g. integrins, decrease in E-cadherin) causing a loss of cell polarity

Altered intermediate filaments (e.g. increased vimentin, decreased keratins)

Increased motility due to increased MMPs and increased fibronectin

EMT is promoted by EGF, FGF, HGF, collagen, MMPs, and TGFbeta

Question 19

Describe the cellular mechanisms that facilitate tumor cell invasion and metastasis.

Answer 19

• Individual cell migration (loss of cell adhesion) or collective cell migation (cell adhesion molecules present)
• Mediated by cell-cell and cell-ECM adhesion molecules, MMPs, and chemokine receptors, linked to cytoskeletal elements including actin