CONDITIONS - Hereditary Colorectal Cancer

This page is divided into 2 sections - Familial Adenomatous Polyposis and Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Familial Adenomatous Polyposis (FAP)

Background

Most common adenomatous polyposis syndrome.
Autosomal dominant inheritance.
Affects around 1:10000 births and is responsible for 1% of colorectal cancers.
Diagnosis by colonoscopy, family history and genetic screening for mutation in APC gene in patients with a family history.
30% of patients are new mutations (i.e. no family history).

Genetics

Due to a germline mutation in the adenomatous polyposis coli (APC) gene. The APC gene is a tumor suppressor gene which is located on chromosome 5. The normal APC protein promotes apoptosis (programmed cell death) of colonic cells. Abnormal APC protein prevents apoptosis resulting in uninhibited cell growth and the development of hundreds of colonic adenomas. By the age of 40 all will have developed malignancy. For those with an APC mutation screening by colonoscopy should begin in the early teens.

Pathology

FAP is characterized by the onset of multiple colonic polyps during the teenage years. If left untreated, they result in colonic malignancy by the age of 40. There is also an increased risk for the development of other malignancies (e.g. thyroid, gastric, pancreatic). The second most common malignancy in patients with FAP is adenocarcinoma of the duodenum and the ampulla of Vater (overall risk ~ 4% but up to 25% if severe duodenal polyposis present). Even if patients undergo subtotal colectomy, regular screening with upper GI endoscopy is indicated.

FAP is also associated with desmoid tumors. They are benign fibrous neoplasms which may involve intra-abdominal organs and vessels causing intestinal obstruction and constriction of vessels or ureters. They may affect up to 20% of patients with FAP, even after surgical intervention.

Other Extracolonic manifestations
1. Turcot syndrome : FAP + CNS tumors (i.e.Medulloblastoma)
2. Gardner's Syndrome : FAP+ osteomas (commonly skull)+dental abnormalities + soft tissue tumors.
3. In the eye congenital hypertrophy of the retinal pigment epithelium (CHRPE) may be seen.
Diagnosis/Clinical Features
Commonly diagnosed by screening children of affected individuals.
In patients without any family history, the presenting complaint is loose stools or bleeding per rectum in late teens or early twenties.
Management
Prophylactic surgery:
1. Subtototal colectomy with ileorectal anastomosis Requires surveillance of rectum (younger patients especially men, so that there is no risk to autonomic nerves supplying bladder and penis)
2. Proctocolectomy and ileal pouch anal anastomosis.
Follow up needed to make sure no tumour forms in remaining mucosa in upper anal canal.

Even after surgery the duodenum needs to be inspected regularly in order to identify and remove any adenomas.

Medical treatment: Polyps may develop in the ileoanal pouch and often in the stomach and duodenum. NSAIDs such as sulindac or COX-2 inhibitors such as celecoxib may slow polyp development/progression and also be used to control desmoids tumours in the abdomen (surgery exacerbates these tumours and they grow causing obstruction of the bowel and other abdominal structures).

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

Background

Also known as Lynch syndrome
Affects around 1:5000 people and accounts for 3-10% of all colorectal cancer cases.
In affected individuals colorectal cancer tends to occur earlier than sporadic cases, usually between 40 and 50 years of age.

Genetics

Due to mutations in the DNA mismatch repair (MMR) genes.
Lead to microsatellite instability- Hallmark of HNPCC.
Autosomal dominant inheritance.

Pathology

80% lifetime risk of colon cancer.
Women have a 50% lifetime risk of endometrial cancer.
Also increased risk of other malignancies (e.g. gastric, small bowel)
Diagnosis/clinical features
Diagnosed by family history criteria "Amsterdam Criteria":
At least three relatives with an hereditary nonpolyposis colorectal cancer (HNPCC)-associated cancer [colorectal cancer, endometrial, stomach, ovary, ureter/renal pelvis, brain, small bowel, hepatobiliary tract, and skin (sebaceous tumors)]:
1. One is a first-degree relative of the other two;
2. At least two successive generations affected;
3. At least one of the syndrome-associated cancers should be diagnosed at <50 years of age;
4. FAP should be excluded in any colorectal cancer cases;
5. Tumors should be verified whenever possible.

Genetic testing is offered to individuals with a family history of HNPCC or strong family history of colorectal cancer.

Management

Regular colonoscopic examinations and polypectomies should be offered to individuals affected by HNPCC. Prophylactic colectomy or hysterectomy is another option but is controversial and should always be discussed with an expert.
Further reading:
Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications