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 carcinoma. It is considered the most frequent form of hereditary colorectal cancer. Diagnosis requires evaluation using clinical criteria (see: Amsterdam criteria for HNPCC).
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.
HNPCC is due to mutations in DNA mismatch repair (MMR) genes 2, resulting most frequently in colorectal carcinoma (10-82% lifetime risk 9) as well as extracolonic malignancies, including 1,2:
- genitourinary tract malignancies
- small bowel cancer: ~5% lifetime risk 4
- gastric cancer: 6-13% lifetime risk 9
- hepatobiliary tract malignancies: 1-4% lifetime risk 9
- pancreatic malignancies: 1-6% lifetime risk 9
- CNS tumors: 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.
- Muir-Torre syndrome: HNPCC-variant with sebaceous tumors and keratoacanthocytomas
Radiographic features are related to the underlying conditions:
- colorectal carcinoma (CRC): 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 tumors
- urinary tract malignancies
Treatment and prognosis
The high risk of colorectal carcinoma 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 CRC can be reduced by 60% 3.
Due to a high number of extracolonic tumors, various screening programs have been instituted. Examples include transvaginal ultrasound screening of the uterus and ovaries (in post-menopausal women 9, at the clinician's discretion) and serum CA-125 2. One follow up regimen recommends annual transvaginal ultrasound and endometrial biopsy 3, although screening should be individualized 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-fl.2019), 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.
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- 4. Schulmann K, Engel C, Propping P et-al. Small Bowel Cancer risk in Lynch Syndrome. Gut. 2008;doi:10.1136/gut.2007.140657 - Pubmed citation
- 5. Shinagare AB, Giardino AA, Jagannathan JP et-al. Hereditary cancer syndromes: a radiologist's perspective. AJR Am J Roentgenol. 2011;197 (6): W1001-7. doi:10.2214/AJR.11.6465 - Pubmed citation
- 6.Dahnert, Wolfgang, author. Radiology review manual I Wolfgang Dahnert, M.D., Department of Radiology, Aurora BayCare Medical Center, Green Bay, Wisconsin. - Seventh Edition.
- 7. Boland CR, Lynch HT. The history of Lynch syndrome. (2013) Familial cancer. 12 (2): 145-57. doi:10.1007/s10689-013-9637-8 - Pubmed
- 8. Lynch HT. Classics in oncology. Aldred Scott Warthin, M.D., Ph.D. (1866-1931). (1985) CA: a cancer journal for clinicians. 35 (6): 345-7. Pubmed
- 9. Chung SH, Woldenberg N, Roth AR, Masamed R, Conlon W, Cohen JG, Joines MM, Patel MK. and Beyond: Comprehensive Image-rich Review of Hereditary Breast and Gynecologic Cancer Syndromes. (2020) Radiographics : a review publication of the Radiological Society of North America, Inc. 40 (2): 306-325. doi:10.1148/rg.2020190084 - Pubmed