Biology Disease

Familial Adenomatous Polyposis (FAP) Syndrome

Familial Adenomatous Polyposis Syndrome Inheritance pattern

- autosomal dominant inheritance

- APC gene is on chromosome 5q21
- APC gene plays a role in the WNT pathway in the degradation of the beta-catenin

- beta-catenin role is to turn on transcription factors in the nucleus that lead to cell cycle progression
-mutations in the APC leads to absence of b-catenin degradation and signal independent tranlocation into the nucleus where it turns on the cell cycl

Familial Adenomatous Polyposis Syndrome Clinical Presentation

- two types of clinical presentations:

Classic Familial Adenomatous Polyposis

- minimum of 100 colonic polyps

- polyps in ampulla of Vater - this leads to a prophylactic colectomy in siblings and first-degree relatives which are at risk

Attenuated Familial Adenomatous Polyposis

- patients tend to develop fewer polyps (average 30), and most of the polyps are located in the proximal colon

- lifetime risk of cancer development is usually around 50%

Gardner syndrome

- polyps identical to those in classic FAP
- multiple osteomas (particularly of the mandible, skull, and long bones)
- epidermal cysts
- fibromatosis - desmoid tumors
- less frequent are abnormalities of dentition, such as unerupted and supernumerary teeth
- higher frequency of duodenal and thyroid cancer

Turcot syndrome

- combination of adenomatous colonic polyposis and tumors of the CNS
2/3 have  have APC gene mutations and develop brain medulloblastomas

- 1/3 have mutations in one of the genes associated with HNPCC and develop brain glioblastomas

Gross Features of Familial Adenomatous Polyposis

-hundreds to thousands of adenomas evenly distributed through colorectum  and appendix
- adenomas range from microscopic to 1cm in diameter with larger adenomas found in the rectosigmoid
- rectum occasionally spared, especially in the attenuated FAP
- colorectal carcinomas may be multifocal

Microscopic Features of Familial Adenomatous Polyposis

- histologically identical to sporadic adenomas
- normal intervening mucosa

- adenomas evolve from single adenomatous crypts

Symptoms and Management

- patients may be asymptomatic before puberty
- initial symptoms are  rectal bleeding and diarrhea
- carcinomas start about 6 years after first symptoms
- 100%  colon cancer without intervention
- treatment is prophylactic total colectomy
- following colectomy, the most common cause of death is periampullary cancer in 20%

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome, also known as Lynch syndrome, is a rare colorectal syndrome that can lead to cancer of the colon.

Hereditary Nonpolyposis Colorectal Cancer Syndrome Inheritance pattern
- autosomal dominant
- syndromal patients have only one functional allele and cancer occurs through loss of heterozygosity (LOH)
- mutations occur in mismatch repair genes (MLH1, MSH 2, MSH6, PMS 1, PMS 2)
- mutations lead to microsatellite instability which are mostly repeats in intronic regions

What to look for?

- you can look for the loss of the genes themselves

- you can look at particular microsatellite loci and see how many have instability
- 0/5 - stable
- 1/5 - low frequency instability
- 2 or greater/5  - high frequency of instability - MSI-H
- microsatellite instability is NOT specific to HNPCC, as it is seen in 10-15 % of sporadic colorectal carcinomas. Sporadic tumors arise in older patients who lack a family history. The activity of the mismatch repair genes in sporadic tumors is lost through hypermethylation

Diagnostic criteria is through the Amsterdam II criteria

Clinical presentation

- development of multiple cancers at an early age, including cancer of the colon, endometrium, renal pelvis and ureter, small bowel, ovary, brain, hepatobiliary tract and sebaceous tumors 

Muir -Torre Syndrome

- sebaceous tumors along with HNPCC type of internal malignancy

Turcot Syndrome

- tumors of the CNS (usually gliobalstomas) and multiple colorectal tumors

Gross Appearance

- predilection for right colon and cecum all the way to the transverse colon
- usually polypoid in appearnace rather than diffuse

Microscopic Appearance

- sporadic tumors have the same features as tumors associated with HNPCC

- proximally located mucinous type of colorectal adenocarcinomas +/- tumor infiltrating lymphocytes

- proximally located, poorly differentiated medullary or undifferentiated colorectal adenocarcinomas - these are well circumscribed and lacking abundant desmoplastic stroma and may contain tumor infiltrating lymphocytes

- adenomas - many have a villous morphology and high grade dysplasia, with rapid progression to carcinoma