Neoplasms: Small and Large Bowel - Mackinnon Flashcards
Name (4) major risk factors for small intestine adenocarcinoma
- Crohn’s disease
- Adenomas
- Celiac disease
- Familial adenomatous polyposis (FAP)
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?
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
Name (3) immunohistochemical markers that are highly specific for GIST. Which is the most specific?
- 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
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)
juxtamembrane domain (exon 11) -> 60-70%
PDGFRA
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?
- 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
Name the two major morphological classifications of intestinal polyps
Pudunculated -> mushroom-shaped
Sessile -> flat
Are hamartomas benign or malignant?
Describe them histologically
Benign
Composed of mature, histologically normal local tissue growing in a disorganized manner
In contrast to a hamartoma, what might you call the ‘wrong’ type of local tissue growing in an organized fashion?
choristoma
Who gets hamartomatous polyps?
Describe them
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
What is Juvenile Polyposis Syndrome?
What genetic defects are responsible for it?
Describe the relative cancer risks of this syndrome
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
What is the genetic defect in Peutz-Jeghers symdrome? Describe this syndrome.
Are Peutz-Jeghers polyps malignant? Describe them.
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
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?
Cowden syndrome
Autosomal dominant
Name the non-hereditary syndrome characterized by:
- GI hamartomatous polyps
- Nail atrophy and alopecia
Cronkhite-Canada
What is a pseudopolyp?
An inflammatory polyp consisting of regenerating mucosa adjaced to ulceration (often seen in severe IBD)
What is a lymphoid polyp?
A mucosal bump caused by intramucosal follicles. These are normal.
Name the two classes of serrated polyp. Which is more common?
Why are they called ‘serrated’?
Where are they generally found?
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
Which carries greater malignant potential: hyperplastic or sessile serrated polyps?
Describe the migration/proliferation pattern of the neoplastic cells in each
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
What genetic abnormalities are seen in sessile serrated polyps?
BRAF V600E mutations
Hypermethylation of tumor suppressor genes
microsatellite instability
Name the 3 architectural types of adenomatous polyps
Tubular adenoma
Villous Adenoma
Tubulovillous adenoma
Tubular adenomas: describe the morphology
- Tubular glands
- Often small, pedunculated, single or multiple
- Smaller (rarely >2.5cm)
- Dysplastic epithelium with elongated, pseudo-stratified, hyperchromatic nuclei
- Loss of mucin production
Villius adenomas: describe the morphology
What about the morphology of this architecture contributes to its increased invasiveness?
- 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
Describe characteristics of an adenomatous polyp that contribute to increased cancer risk
- 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)
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
- 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
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?
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%)
Give 2 broad explanations for why we see greater incidence of death from colorectal cancer in the US, Australia, NZ, and Eastern Europe.
- Dietary practices (low fiber, red meat, high calories, etc)
- Obesity and physical inactivity
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?
Right side
In the setting of colorectal carcinoma, cancer located on which side of the colon most often presents with obstructive symptoms?
Left side
What is an ‘apple core sign’ on plain-film x-ray with barium swallow?
The apple core sign indicates an annular (napkin ring) constriction in the colon. It is most often associated with cancers of the left colon.
Describe the order of mutations in the adenoma-carcinoma sequence
“AK-53 sequence” - multi-hit hypothesis
- APC
- K-RAS
- p53
Infiltrative colorectal cancer is often associated with what other disorder of the bowel?
Ulcerative colitis
Explain the following elements of the TNM tumor staging system:
- T
- Tis
- T1
- T2
- T3
- T4
- N
- Nx
- N1
- N2
- M
- Mx
- M1
- 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
In terms of the TNM system, what is stage?
Describe stages 0-4
stage = T + N + M
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)
What is the single most important prognostic indicator we have for colorectal carcinoma?
stage
Stage 1: 93.2%
Stage 4: 8.1%
Give 3 of the most common sites of metastasis for colorectal carcinoma.
Is the spread generally lymphatic or hematogenous? How common is metastasis?
- liver
- lungs
- bones
Mets: usually lymphatic spread. 25-30% of patients already have mets at the time of presentation.
What are biomarkers used for during cancer treatment?
Prognosis- provides information about outcome and cancer aggressivity
Predictive- provides information on how effective a particular treatment might be
What is EGFR?
Why is EGFR mutation so prevalent in tumors?
A tyrosine kinase receptor
Activates a large number of pathways controlling proliferation, angiogenesis, invasion, and metastasis
What three pathways are activated downstream of EGFR?
What treatments are aimed at treating EGFR mutations in cancer?
PI3K, RAS/RAF/MAPK, and PLC-gamma
Monoclonal antibodies (cetuximab, panitumumab)
What determines the effectiveness of anti-EGFR antibody therapy?
What mutations correspond to poor response to anti-EGFR therapy?
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
What is Familial Adenomatous polyposis?
What gene is involved?
How is it inherited?
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
When does FAP typically present?
What variants of FAP can be seen?
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
What is MYH associated polyposis?
How does it compare to FAP?
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
What is Lynch syndrome?
What gene defect causes lynch syndrome?
How is Lynch syndrome diagnosed?
A disease the increases the risk of colon, endometrial, and urinary cancers
Defect in gene repair: MLH1, PMS2, MSH2, MSH6
Microsatellite Instability pathway
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?
Muir-Torre Syndrome
Colonoscopy to check for colon cancer
Full skin exam to check for sebaceous adenomas and carcinomas
How is a patient with a family history of Lynch syndrome diagnosed?
How is a patient without a family history of Lynch syndrome diagnosed?
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
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?
Adjuvant chemotherapy
The microsatellite instability makes it unlikely that the tumor is the only mutation. Adjuvant chemo increases long-term survival.
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?
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.
What tumors can be seen in the appendix?
What complication can arise from cancer of the appendix?
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!)
