Intro to Clinical Oncology; Dx and Staging of Cancer

Question 1

What are the two general pathways leading to cancer development?

Answer 1

One pathway involves tumor suppressor genes and the other one involves oncogenes

Question 2

What is the function of a tumor suppressor gene?

Answer 2

Tumor suppressor genes function to regulate cell growth and proliferation (they’re on all the time and function like a brake pedal for cell growth)

Question 3

What is Knudson’s “Two-Hit” theory of cancer causation (with respect to tumor suppressor genes)? (hint: if you get hit twice that’s how you get broken)

Answer 3

Knudson’s theory basically describes that one needs to mutation events to render the retinoblastoma gene ineffective. (see below)

***

Study found two different variants of patients with retinoblastoma:

One group had hereditary retinoblastoma so that’s how they developed the disease, and the other group had sporadic retinoblastoma (so no family history of disease)

Retinoblastoma results from a mutation in a tumor suppressor gene. Two “events” required to make the gene inactive/mutated (so almost like two mutations/mutation in each alleles of the gene/recessive allele)

Question 4

There are many functions of tumor suppressor genes. Name four.

Answer 4

Cell cycle regulation

Cell cycle regulation coupled with DNA damage

Assist with cell adhesion/prevent metastasis

DNA repair: BRCA, HNPCC, MEN1

Question 5

What are 3 important dna repair proteins?

Answer 5

BRCA

HNPCC

MEN1

Question 6

What is the most well known tumor suppressor gene? Does this gene fit Knudson’s two hit theory of cancer causation?

Answer 6

p53!!

No, it doesn’t. In fact,p53 mutation can function as double negative (only one mutation needed to render the gene inactive)

**Genetic syndrome: Li-Fraumeni syndrome (pts can develop cancer early in life and multiple cancers in life)**

Question 7

Which cellular pathways are affected by p53?

Answer 7

Cell cycle arrest (p21)

DNA repair (GADD45)

Apoptosis (FAS/APO-1)

Angiogenesis (BAI1)

Auto-regulation (MDM2

Question 8

Describe the function of an oncogene

Answer 8

When mutated, oncogenes promote cell growth and proliferation

(example pathways: RAS, WNT, Bcr-Abl etc)

Question 9

What are 3 methods to activation of oncogenes?

Answer 9

Mutation within regulatory region (e.g. mutation in promoter region resulting in increased protein activity/loss of growth regulation)

Increased protein concentration (increase in protein expression thru misregulation, ↑ in mRNA stability, gene duplication)

Chromosomal translocations (relocate a proto-oncogene to a new chromosomal site leading to ↑ expression, fusion between a proto-oncogene and a 2nd gene)

Question 10

Describe how Chronic myelogenous leukemia develops?

Answer 10

CML is an example of a cancer arising from chromosomal translocations

Basically, the cancer results from the translocation between chromosomes 9 and 22 >> Bcr-Abl protein >> “always on” tyrosine kinase so translocation = uncontrolled cell proliferation

Rx: Gleevac/imatinib - tyrosine kinase inhibitor

Question 11

Describe the presentation of solid tumors/cancers

Answer 11

You can have local symptoms (at site of originating organ), which develop when the cancer interferes with normal organ function or if there’s extension into nearby organs

There’s also symptoms of metastatic disease (at site distant from originating organ)

Question 12

Just study this slide

Answer 12

Question 13

Also just study this slide

Answer 13

Question 14

Fill in the blanks

Answer 14

Question 15

What are 3 ways to get samples for cancer work up?

Answer 15

Fine needle aspiration - collects single cells

Core needle biopsy

Excisional biopsy

Question 16

Describe how cancer cells undergo invasion/metastasis

Answer 16

Detachment of cells from each other via loss of E cadherins/other cadherins >> expression of basement membrane receptors/ECM proteins >> dissolution of basement membrane + connective tissue matrix >> expression of matrix metalloproteinases (creation of passage for migration)

Question 17

Describe how cancer cells undergo metastasis

Answer 17

Migration through degraded extracellular matrix >> penetration of vascular basement membrane >> formation of tumor embolus >> adhesion to endothelium >> extravasation and homing >> angiogenesis (mediated by VEGF)

Question 18

What is the definition of metastasis?

There are 3 pathways of tumor spread: ___ is metastasis via the lymphatics, hematogenous metastasis is ___ and ___ is penetration of malignant tumor into a natural open space (e.g. pleural or peritoneal space/any of the body cavities)

Answer 18

Metastasis is basically when the tumor implant (so the part of the tumor that’s spreading) is separated from the primary tumor

**

Lymph node METASTASIS via lymphatic channels

Hematogenous METASTASIS via blood vessels

Direct seeding – penetration of malignant tumor into a natural open space (peritoneal, pleural, or pericardial cavities or subarachnoid or joint spaces)

Question 19

___ (type of cancer) metastasize to the lymph nodes first then move hematogenously

Answer 19

Carcinomas (and melanoma) metastasize to the lymph nodes first then move hematogenously

Question 20

Which type of tumor metastasizes almost always hematogenously?

Answer 20

Sarcomas (usually metastasize to the lungs)

Question 21

What are the 2 pathological ways of diagnosing tumors?

Answer 21

Cytology: fine needle aspiration, scrape/brush (e.g. for Pap smear), body fluid cytology (e.g. CSF)

Surgical pathology: biopsy

Question 22

Explain the TNM staging system

Answer 22

T - primary Tumor

N - regional lymph Node

M - Metastases

**

In general:

T1 -T4: increasing size of primary Tumor; T0 (Tis) = tumor is in situ

N0 - no lymph node involvement, N1 - N3 - increasing number and range of lymph nodes

M0 - no distant metastases, M1 - metastasis

p for pathologic tumor stage – the most definitive

Question 23

Another type of tumor grading is based on differentiation. What grade is assigned to well differentiated vs poorly differentiated tumors?

What grade is assigned to de-differentiated tumors?

Answer 23

Well differentiated tumors: Grade ½

Poorly differentiated tumors: high grade/grade 3-4

De-differentiated tumors: high grade 3-4 (hard to classify and very aggressive)

Question 24

What is the significance of a tumor that’s cytokeratin positive?

Answer 24

Cytokeratin is used when you don’t know of what origin the tumor is so you use it since its a marker of epithelial origin (tells you that the tumor is an epithelial malignancy

Question 25

___ is a non-specific tumor marker that can be used to screen colorectal, pancreatic and gastric/breast carcinomas

Answer 25

CEA is a non-specific tumor marker that can be used to screen colorectal, pancreatic and gastric/breast carcinomas

**note that this marker lacks the sensitivity and specificity needed for early detection**

Question 26

___ is a glycoprotein tumor marker that is synthesized early in fetal life and raised serum levels of this marker indicate the presence of hepatocellular carcinoma and germ cell tumors of the testis/ovary

Answer 26

AFP (alpha fetal protein) is a glycoprotein tumor marker that is synthesized early in fetal life and raised serum levels of this marker indicate the presence of hepatocellular carcinoma and germ cell tumors of the testis/ovary

**note that this marker is also non-specific and can be elevated in non-neoplastic conditions**

Question 27

Besides hepatocellular carcinoma and testicular/ovarian tumors, what 2 other conditions might be on your differential if you see elevated levels of AFP?

Answer 27

Liver disease: cirrhosis, toxic liver injury, hepatitis

Pregnancy, esp with high neural tube/abdominal wall defects

Question 28

What tumor marker is elevated in pts with bone and liver metastases, as well non-cancerpus conditions involving those same organs?

Answer 28

Alkaline phosphatase is elevated in pts with liver or bone metastasis but also in patients with non-neoplastic liver and bone disease

Question 29

Which tumor marker can be elevated in pregnancy and is ass’d with germ cell tumors?

Answer 29

hCG (elevated in germ cell tumors, gestational trophoblastic disease (choriocarcinoma, hydatidiform mole) )

Question 30

___ is a tumor marker that is elevated in prostate cancer, as well as non-cancerous conditions such as chronic prostatitis and BPH

Answer 30

PSA is a tumor marker that is elevated in prostate cancer, as well as non-cancerous conditions such as chronic prostatitis and BPH

Question 31

__ is a marker for ovarian tumors, ___ is for pancreatic cancers and chromogranin is for ___ tumors

Answer 31

CA-125 is a marker for ovarian tumors, CA19-9 is for pancreatic cancers and chromogranin is for neuroendocrine tumors