Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant condition which predisposes to a host of malignancies, including colorectal cancer. It is considered the most frequent form of hereditary colorectal cancer. Diagnosis requires evaluation using clinical criteria (see: Amsterdam criteria for HNPCC).

Terminology

Historically a distinction was made between Lynch I and Lynch II syndromes, referring respectively to families affected only by colorectal cancer, and those affected by extracolonic malignancies in addition to colorectal cancer, but this distinction is no longer routinely made ⁷.

Epidemiology

Lynch syndrome is the most common cancer syndrome, affecting 1 in 400 persons ³. Typically, HNPCC patients present in their forties and fifties with colorectal cancer ², or with one of the associated malignancies. It is 5 times more common than familial adenomatous polyposis syndromes (FAP) ⁶. It is the most common hereditary cause of endometrial cancer ⁹.

Pathology

HNPCC is due to mutations in DNA mismatch repair (MMR) genes ², resulting most frequently in colorectal cancer (10-82% lifetime risk ⁹) as well as extracolonic malignancies, including ^1,2:

• genitourinary tract malignancies

  • endometrial cancer: 15-60% lifetime risk ⁹, most often endometrioid type

    • more than half of women with Lynch syndrome will first present with endometrial cancer rather than colorectal cancer ¹¹

  • ovarian tumour: 4-12% lifetime risk ⁹

  • prostate cancer: 30% lifetime risk ⁹

  • urothelial tract cancer: 1-7% lifetime risk ⁹

• small bowel cancer: ~5% lifetime risk ⁴

  • duodenum 45%

  • jejunum 29%

  • ileum 12%

  • not specified 14%

• gastric cancer: 6-13% lifetime risk ⁹

• hepatobiliary tract malignancies: 1-4% lifetime risk ⁹

• pancreatic malignancies: 1-6% lifetime risk ⁹

• CNS tumours: most often glioblastoma

There is a described association with breast malignancy, although the relationship is inconsistent ⁹. The MMR genes most commonly affected are MLH1, MSH2 (these two 70-85% of cases, MSH6, and PMS2 or EPCAM, an upstream gene in MSH2 expression ³.

Variants

• Muir-Torre syndrome: HNPCC-variant with sebaceous tumours and keratoacanthocytomas

Radiographic features

Radiographic features are related to the underlying conditions:

• colorectal cancer: more frequently right sided (70% proximal to the splenic flexure) ⁶. Despite the name, colorectal cancers arise from adenomatous polyps. Diffuse polyposis is characteristically absent.

• small bowel adenocarcinoma: most commonly duodenal

• endometrial carcinoma

• ovarian tumours

• urinary tract malignancies

Treatment and prognosis

The high risk of colorectal cancer, and the relatively rapid progression from adenoma to carcinoma in these patients, warrants screening of the colon every 1 to 2 years starting from 25-40 years of age ^2,3 and may require colectomy. With close surveillance and resection of any adenomas which develop, the risk of colorectal cancer can be reduced by 60% ³.

Due to the risk of endometrial and ovarian cancer, transvaginal ultrasound screening and serum CA-125 can be considered in women's early 30s ². In those post childbearing or over 40 years, prophylactic hysterectomy and bilateral salpingo-oophorectomy should be offered ⁹.

History and etymology

Lynch syndrome was first described by Aldred Scott Warthin (1866-1931) ⁸, an American pathologist, from University of Michigan in Ann Arbor, Michigan, in 1913, after research into a family with several members with cancers. In the mid 1960s, Henry T Lynch (1928-2019) ¹⁰, an American oncologist, published further detailed painstaking work on the same family studied by Warthin, shedding further light on these apparently hereditary cancers ⁷. The condition was later renamed after Lynch who doggedly pursued the then heterodoxy that cancer could be hereditary.