Gastroenterology and Endoscopy News - Inherited Colon and Rectal Cancer

"In Part 1 of this four-part series, we examine the clinical pathology and molecular biology of (Lynch Syndrome) hereditary nonpolyposis colorectal cancer (HNPCC). In Part 2, we will discuss screening and treatment, and the roles of the epidemiologist, the diagnostician and the surgeon."

An estimated 150,000 Americans may be carriers of the (Lynch Syndrome) HNPCC mutation(s) and have a 90% lifetime risk for developing some type of cancer. (MSH2/MSH6/MLH1/PMS2)



Understanding the Disease:
Clinical Pathology HNPCC is divided into Lynch I and Lynch II. Muir-Torre Syndrome and Familial Colorectal Cancer Type X are also members of the HNPCC group. Muir-Torre Syndrome is not commonly seen in the clinical setting. These diseases are often discovered by the pathologist postoperatively, on finding certain pathologic features during the examination of a resected surgical specimen.

Lynch I is a type of HNPCC in which the most commonly observed malignancy is colorectal cancer. The lifetime risk for colorectal cancer in an individual with Lynch I syndrome is 80%. The average age at diagnosis is 44 years, compared with 64 years in patients with sporadic forms of colon cancer. Multiple generations are usually affected. Most of the neoplasms in Lynch I are poorly differentiated and located proximal to the splenic flexure. Synchronous lesions occur in 7% of cases compared with 1% in sporadic cases. Metachronous lesions are found in 45% of patients with Lynch I compared with 5% of patients with sporadic colon cancer, signaling a possible mismatch repair defect. Colorectal cancer occurring in the absence of a visible polyp or polyposis is the final phenotypic expression of the MMR mutation. It is important to note that a polyp, whether visible or occult, is the precursor lesion of the colorectal cancer.

Lynch II describes the association of colorectal cancer with extracolonic malignancies. In women with Lynch II, there is a 50% to 70% lifetime risk for endometrial cancer, with the average age at diagnosis being 46 years.4 Other malignancies observed in patients with Lynch II are ovarian cancer (3%-13%), gastric cancer (2%-13%), transitional cell carcinoma of the ureter and renal pelvis (1%-12%), small bowel cancer (4%-7%; occurring most commonly in the duodenum and jejunum), central nervous system tumors (1%-4%; most often glioblastomas) and hepatobiliary cancer (2%).5

Muir-Torre Syndrome is a rare syndrome consisting of multiple benign and malignant neoplasms. It may be a variant of Lynch II. Sebaceous gland adenomas are the most common marker of the disease and are often found on the head. Keratoacanthomas, which may begin as a red nodule and progress to a shiny nodule with telangiectasia and a central crust, are located on the face and dorsum of the hands. Visceral carcinomas are frequent, occurring in one-half of patients with Muir-Torre. The colonic neoplasms are the most frequent malignancies found in Muir-Torre Syndrome and are usually located proximal to the splenic flexure. Genitourinary tumors are the second most common malignancy.6

Familial Colorectal Cancer Type X is a category of HNPCC in which affected patients meet the clinical criteria of HNPCC but do not exhibit mutations in MMR genes that are typically observed in patients with Lynch syndrome. The risk for developing colorectal cancer or extracolonic neoplasia is lower than that in patients with other forms of HNPCC, and the age at diagnosis of colon cancer is older than that in patients with Lynch syndrome. Colonic malignancies are not predominantly right-sided as in patients with Lynch syndrome. Unlike patients with Lynch II syndrome, these individuals do not have a propensity to develop malignancies in other organ systems.7