Neoplasms: Small and Large Bowel - Mackinnon

Question 1

Name (4) major risk factors for small intestine adenocarcinoma

Answer 1

• Crohn’s disease
• Adenomas
• Celiac disease
• Familial adenomatous polyposis (FAP)

Question 2

What is the most common soft tissue tumor of the GI tract?

What cell population does it arise from?

Where is this type of tumor most often found?

What tends to be the most useful first-line therapy for this type of tumor? Why? What other key disease is this therapy used for?

Answer 2

GIST (gastrointestinal stromal tumor)

Arises from **Interstitial Cells of Cajal **(pacemaker cells of the GI tract)

Stomach (60%) and small intestine (30%)

Imatinib (Gleevec) - active against c-kit mutations (85% of GISTs have a mutation). Also used for CML

Question 3

Name (3) immunohistochemical markers that are highly specific for GIST. Which is the most specific?

Answer 3

• CD117 (c-kit gene product) -> 90-100%
• DOG1 (“Detected on GIST 1”) -> most specific marker
• CD34 -> 85-95%

Muscle markers such as actin (25%), desmin (10%), and S-100 (5%) might be helpful but are fairly non-specific

Question 4

On c-kit, which receptor domain is most often mutated in GIST?

Besides c-kit, what other tyrosine kinase receptor type might underly GIST (5-10% of the time)

Answer 4

juxtamembrane domain (exon 11) -> 60-70%

PDGFRA

Question 5

Give (4) presenting symptoms of carcinoid syndrome

What is the most common elevated neuroendocrine finding in carcinoid tumors?

Hisologically, how might a carcinoid tumor be described?

Answer 5

• Vasomotor disturbances
• Intestinal hypermotility
• Wheezing
• Hepatomegaly
• Cardiac involvement

Elevated serotonin (5-HT or 5-HIAA) is the most common neuroendocrine finding

Histo:

• Submucosal nodule (often confused for a polyp grossly)
• Organized into nests of neuroendocrine cells pushing up the overlying mucosa

Question 6

Name the two major morphological classifications of intestinal polyps

Answer 6

Pudunculated -> mushroom-shaped

Sessile -> flat

Question 7

Are hamartomas benign or malignant?

Describe them histologically

Answer 7

Benign

Composed of mature, histologically normal local tissue growing in a disorganized manner

Question 8

In contrast to a hamartoma, what might you call the ‘wrong’ type of local tissue growing in an organized fashion?

Answer 8

choristoma

Question 9

Who gets hamartomatous polyps?

Describe them

Answer 9

Children < 5 y.o.

• 80% occurring in the rectum
• Pedunculated, 1-3cm (large)
• Expanded lamina propria (bulk of the polyp) with variable inflammation
• Abundant cystically dilated, tortuous glands
• Non-neoplastic

Question 10

What is Juvenile Polyposis Syndrome?

What genetic defects are responsible for it?

Describe the relative cancer risks of this syndrome

Answer 10

Syndrome of multiple juvenile polyps (>5, 50-100 or more)

Genetic defects: SMAD4 (20%), BMPR1A (20%), PTEN

Significantly increased risk of adenomas with 10-50% lifetime incidence of GI cancers

Question 11

What is the genetic defect in Peutz-Jeghers symdrome? Describe this syndrome.

Are Peutz-Jeghers polyps malignant? Describe them.

Answer 11

STK11 (autosomal dominant)

• Multiple GI polyps
• Hyperpigmentation of the mouth mucosa and fingertips
• Increased risk of intussiception
• Increased risk of pancreatic, breast, lung, ovary, and uteral cancers

The polyps have no malignant potential. However, the syndrome carries a 50% lifetime risk of cancer

• Large and pedunculated
• Connective tissue and smooth muscle extending into the polyp stalk
• Abundant glands a goblet cells

Question 12

Name the syndrome is characterized by:

• hamartomatous polyps with no malignant potential
• Skin lesions of the nose and lips (facial trichilemmomas, oral papillomas, and acral keratoses)
• Increased risk of tyroid and breast cancer

Autosomal dominant or autosomal recessive?

Answer 12

Cowden syndrome

Autosomal dominant

Question 13

Name the non-hereditary syndrome characterized by:

• GI hamartomatous polyps
• Nail atrophy and alopecia

Answer 13

Cronkhite-Canada

Question 14

What is a pseudopolyp?

Answer 14

An inflammatory polyp consisting of regenerating mucosa adjaced to ulceration (often seen in severe IBD)

Question 15

What is a lymphoid polyp?

Answer 15

A mucosal bump caused by intramucosal follicles. These are normal.

Question 16

Name the two classes of serrated polyp. Which is more common?

Why are they called ‘serrated’?

Where are they generally found?

Answer 16

Hyperplastic (60-90%) and Sessile Serrated (10-30%)

The lumina of the glands look jagged (instead of smooth and round) and have increased numbers of goblet cells

Question 17

Which carries greater malignant potential: hyperplastic or sessile serrated polyps?

Describe the migration/proliferation pattern of the neoplastic cells in each

Answer 17

Sessile serrated polyps have high malignant potential. Hyperplastic have no malignant potential.

Migration:

• Hyperplastic: grows ‘up’ from crypts to the tips of polyp
• Sessile serrated: grows ‘up’ to the tips **and **‘down’ to the crypts

Question 18

What genetic abnormalities are seen in sessile serrated polyps?

Answer 18

BRAF V600E mutations

Hypermethylation of tumor suppressor genes

microsatellite instability

Question 19

Name the 3 architectural types of adenomatous polyps

Answer 19

Tubular adenoma

Villous Adenoma

Tubulovillous adenoma

Question 20

Tubular adenomas: describe the morphology

Answer 20

• Tubular glands
• Often small, pedunculated, single or multiple
• Smaller (rarely >2.5cm)
• Dysplastic epithelium with elongated, pseudo-stratified, hyperchromatic nuclei
• Loss of mucin production

Question 21

Villius adenomas: describe the morphology

What about the morphology of this architecture contributes to its increased invasiveness?

Answer 21

• Villus projections, often large and sessile (flat, 10cm or more in diameter)
• Most commonly found in older people
• Most commonly found in the rectosigmoid colon

Close proximity to the colon wall means invasion can proceed directly into the deeper tissues - higher malignant potential

Question 22

Describe characteristics of an adenomatous polyp that contribute to increased cancer risk

Answer 22

• Large size (>1cm)
• Sessile, villous (risk approaches 40% in >4cm)
• High-grade dysplasia (more often found in villous areas, but can be found in any type of polyp)

Question 23

Discuss the clinical significance/approach of:

• Intramucosal carcinoma
• Invasive carcinoma in a pedunculated adenoma (i.e. through muscularis mucosa)
• Invasive carcinoma in a sessile polyp

Answer 23

• If it only invades the lamina propria, there is not yet any metastatic potential
• Endoscopic removal is feasible if:
  
  • resection margins negative
  • no apparent vascular or lymphatic invasion
  • carcinoma is well or moderately differentiated
• Requires partial colectomy (endoscopic removal inadequate)

** Regardless: the only adequate treatment for any of these is complete resection

Question 24

Approximately what percent of all cancer deaths in the US are attributable to colorectal cancer?

What is the most common type?

What is the peak incidence age of colorectal cancer?

What is the most common anatomical site for colorectal cancer? What is the next most common site?

Answer 24

9% of all cancer deaths in the US

Adenocarcinoma (98%)

Peak incidence: 90% diagnosed after age 50

Rectosigmoid colon (55%), Cecum and ascending colon (22%)

Question 25

Give 2 broad explanations for why we see greater incidence of death from colorectal cancer in the US, Australia, NZ, and Eastern Europe.

Answer 25

1. Dietary practices (low fiber, red meat, high calories, etc) 2. Obesity and physical inactivity

Question 26

In the setting of colorectal cancer, which side of the colon most commonly presents with fatigue, weakness, iron deficiency anemia, and other non-obstructive symptoms?

Answer 26

Right side

Question 27

In the setting of colorectal carcinoma, cancer located on which side of the colon most often presents with obstructive symptoms?

Answer 27

Left side

Question 28

What is an 'apple core sign' on plain-film x-ray with barium swallow?

Answer 28

The apple core sign indicates an annular (napkin ring) constriction in the colon. It is most often associated with cancers of the left colon.

Question 29

Describe the order of mutations in the adenoma-carcinoma sequence

Answer 29

"AK-53 sequence" - multi-hit hypothesis 1. APC 2. K-RAS 3. p53

Question 30

Infiltrative colorectal cancer is often associated with what other disorder of the bowel?

Answer 30

Ulcerative colitis

Question 31

Explain the following elements of the TNM tumor staging system: * T * Tis * T1 * T2 * T3 * T4 * N * Nx * N1 * N2 * M * Mx * M1

Answer 31

* T * Tis - carcinoma in situ * T1 - submucosa invasion * T2 - muscularis propria invasion * T3 - subserosa invasion * T4 - direct invasion of other organs or structures * N - regional lymph nodes * Nx - regional lymph nodes cannot be assessed * N0 - no regional mets * N1 - mets to 1 to 3 nodes * N2 - mets to 4 or more nodes * M - distant metastasis * Mx - cannot be assessed * M0 - no distant mets * M1 - distant mets

Question 32

In terms of the TNM system, what is **stage**? Describe stages 0-4

Answer 32

stage = T + N + M ## Footnote Stage 0: in situ carcinoma Stage 1: T1 or T2, N0, M0 Stage 2: T3 or T4 N0 M0 Stage 3: any T, positive nodes (N1 or N2), M0 Stage 4: any T, any N, M1 (distant mets)

Question 33

What is the single most important prognostic indicator we have for colorectal carcinoma?

Answer 33

stage Stage 1: 93.2% Stage 4: 8.1%

Question 34

Give 3 of the most common sites of metastasis for colorectal carcinoma. Is the spread generally lymphatic or hematogenous? How common is metastasis?

Answer 34

1. liver 2. lungs 3. bones Mets: usually lymphatic spread. 25-30% of patients already have mets at the time of presentation.

Question 35

What are biomarkers used for during cancer treatment?

Answer 35

Prognosis- provides information about outcome and cancer aggressivity Predictive- provides information on how effective a particular treatment might be

Question 36

What is EGFR? Why is EGFR mutation so prevalent in tumors?

Answer 36

A tyrosine kinase receptor Activates a large number of pathways controlling proliferation, angiogenesis, invasion, and metastasis

Question 37

What three pathways are activated downstream of EGFR? What treatments are aimed at treating EGFR mutations in cancer?

Answer 37

PI3K, RAS/RAF/MAPK, and PLC-gamma Monoclonal antibodies (cetuximab, panitumumab)

Question 38

What determines the effectiveness of anti-EGFR antibody therapy? What mutations correspond to poor response to anti-EGFR therapy?

Answer 38

If downstream target of EGFR are mutated to be constitutively active, anti-EGFR therapy will not be effective. It's effective when EGFR is over-expressed. BRAF and KRAS

Question 39

What is Familial Adenomatous polyposis? What gene is involved? How is it inherited?

Answer 39

A disorder where the patient is particularly prone to developing adenomas (at least 100 must be present for FAP) APC Autosomal dominant, but up to 25% of cases are sporadic

Question 40

When does FAP typically present? What variants of FAP can be seen?

Answer 40

Polyps start at 16, cancer arises in 30s or 40s * Attenuated FAP- fewer than 100 polyps * Gardner's Syndrome- polyps and osteomas, epidermoid cysts, and desmoid tumors * Turcot Syndrome- polyps and medulloblastoma

Question 41

What is MYH associated polyposis? How does it compare to FAP?

Answer 41

Mutation in MYH that results in mulitple adenomas MAP has autosomal recessive inheritance MAP is more similar to attenuated FAP MAP has mutations in DNA repair proteins while FAP has mutations in adhesion proteins

Question 42

What is Lynch syndrome? What gene defect causes lynch syndrome? How is Lynch syndrome diagnosed?

Answer 42

A disease the increases the risk of colon, endometrial, and urinary cancers Defect in gene repair: MLH1, PMS2, MSH2, MSH6 Microsatellite Instability pathway

Question 43

A patient comes in with a skin lesion. The dermatologist reports that they have a keratoacanthoma. What is the most likely underlying condition? What other tests should be investigated?

Answer 43

Muir-Torre Syndrome Colonoscopy to check for colon cancer Full skin exam to check for sebaceous adenomas and carcinomas

Question 44

How is a patient with a family history of Lynch syndrome diagnosed? How is a patient without a family history of Lynch syndrome diagnosed?

Answer 44

genetic testing for MLH1, PMS2, MSH2, MSH6 hypermethylation or mutation Immunohistochemistry staining is done on a tumor when it is removed and tests for microsatellite instability are done the genome

Question 45

A patient with Lynch syndrome presents with a stage 1 colon cancer. The cancer is excised with clean margins. What other treatment should be given?

Answer 45

Adjuvant chemotherapy The microsatellite instability makes it unlikely that the tumor is the only mutation. Adjuvant chemo increases long-term survival.

Question 46

A patient comes to genetic counselor and says that his genentic testing showed high levels of microsatellite instability, including BRAF mutations. What is his diagnosis?

Answer 46

Not Lynch syndrome For some reason, BRAF is never mutated in Lynch syndrome. You should definitely still be screening this guy consistently for cancer though.

Question 47

What tumors can be seen in the appendix? What complication can arise from cancer of the appendix?

Answer 47

Carcinoid, mucocele (not really a tumor), and a mucinous cystadenoma With a mucinous cystadenoma, you can get pseudomyxoma peritonei (AKA jelly belly: appendix mucus turns your omentum into a mucus crust!)