Hereditary Non-polyposis Colorectal Carcinoma Syndrome (HNPCC)

Definition

• Autosomal dominant syndrome characterized by germ line mutation of DNA mismatch repair enzymes resulting in an increased incidence of colorectal and other neoplasms

Alternate/Historical Names

• Cancer family syndrome
• DNA mismatch repair deficiency
• DNA replication errors (RER) syndrome
• Lynch syndrome
• Muir-Torre syndrome (if sebaceous neoplasms present)
• Nucleotide instability
• Turcot syndrome (if CNS neoplasms present)

Covered separately

• Colorectal adenocarcinoma NOS
• Medullary colorectal adenocarcinoma
• Mucinous colorectal adenocarcinoma
• Sessile serrated adenoma / polyp

Diagnostic Criteria

• Current definition requires evidence of dysfunctional germ line mutations in DNA mismatch repair enzymes
  • We prefer to evaluate both PCR based microsatellite repair instability (MSI) / stability (MSS) and intact / absent immunohistochemical expression of DNA mismatch repair enzymes
    • Genetic counseling should be offered before genetic or immunohistologic testing is performed
    • See Supplemental Studies at left
• Prior Amsterdam and Bethesda criteria are no longer definitional but retain some use for helping to decide who should be tested
• The following pathologic features in colorectal adenocarcinoma are suggestive of microsatellite instability
  • Intraepithelial T lymphocytes, ≥3 per HPF
    • Other proposed limits include ≥2 per HPF and >5% of total cells (suggestive) and >10% (highly specific)
    • Must be intraepithelial, not in fibrovascular septa
  • Crohn-like response at edge of carcinoma
    • B cell lymphoid aggregates or follicles with or without germinal centers, not associated with a lymph node
    • ≥3 aggregates per section is proposed
  • Mucinous or signet ring carcinoma component
  • Medullary carcinoma
  • Less specific criteria
    • Right side location
    • Well or poorly differentiated histology
    • Lack of dirty necrosis
• Above pathologic features and evidence of DNA mismatch repair deficiency may be seen in both germ line and somatically mutated carcinomas
  • 15% of colorectal adenocarcinomas have evidence of somatic mutations in MMR enzymes, nearly always MLH1
    • Nearly all are probably associated with sessile serrated adenomas
    • These are non-hereditary
  • 2-3% of colorectal adenocarcinomas have evidence of germline mutations in MMR enzymes, usually MLH1 or MSH2
    • These constitute HNPCC cases
• Diagnosis of any of the following before age 50 or at any age in a patient with a family or personal history of any of the following should raise the question of HNPCC
• Colorectal adenocarcinoma
• Endometrial carcinoma
• Gastric adenocarcinoma
• Small intestine adenocarcinoma
• Glioblastoma
• Ureter and renal pelvis carcinoma
• Sebaceous cutaneous neoplasms
• Muir-Torre syndrome
  • Originally defined as a genetic syndrome characterized by cutaneous sebaceous neoplasms, keratoacanthomas and internal malignancy
  • Now recognized as a variant of HNPCC
• Turcot syndrome includes two distinct syndromes
• HNPCC with glioblastoma
• Familial adenomatous polyposis with brain tumors, usually medulloblastoma
• Homozygous and compound heterozygous mutations lead to cancers in children and young adults (first 3 decades)
  • Colorectal and endometrial carcinoma
  • CNS, various types
  • Leukemias and lymphomas, various types
• Adenomas may be moderately increased but not markedly
• Frequently have a villous component
• Increased frequency of high grade dysplasia suggests rapid transformation to carcinoma

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates : 1/31/10, 11/12/11

Supplemental studies

• Current definition requires evidence of dysfunctional germ line mutations in DNA mismatch repair enzymes
• We prefer to evaluate both PCR based microsatellite repair instability (MSI) / stability (MSS) and intact / absent immunohistochemical expression of DNA mismatch repair enzymes
• Genetic counseling should be offered before genetic or immunohistologic testing is performed
• PCR test evaluates 5 microsatellites in neoplastic vs. normal tissue
• If ≥2 are altered, designate as MSI-high (MSI-H)
• If one is altered, designate as MSI-low (MSI-L)
• If none altered, designate as MSS
• If more than 5 microsatellites evaluated, alter criteria proportionally
• Immunohistochemical test evaluates presence of mismatch repair enzymes
• It does not evaluate presence of functional enzyme
• Miss-sense mutations may result in an immunohistochemically positive result but a non-functional enzyme
• Most commonly evaluated enzymes are MLH1, MSH2 and PMS2 and may include MSH6
• PMS2 requires MLH1 expression, thus may be absent if MLH1 is lost
• MSH6 requires MSH2 expression, thus may be absent if MSH2 is lost
• Clear absence of an enzyme is abnormal

Differential Diagnosis

• Sporadic MSI-H colorectal adenocarcinoma
• Familial adenomatous polyposis
• MUTYH associated polyposis
• Serrated adenomatous polyposis (hyperplastic polyposis)
• Peutz Jeghers polyposis

See Supplemental Studies in left menu for differences in mismatch genes and expression

Clinical

• Genetic counseling should be offered before genetic or immunohistologic testing is performed
• Autosomal dominant with variable penetrance
• Increased overall survival for colorectal carcinoma
• Decreased response to 5FU chemotherapy
• Mean age at clinical diagnosis 45 years
• 35% of patients have multiple cancers
• Associated with a lifetime risk of cancer of 70%
• Colorectal adenocarcinoma 70-85%
• Endometrial adenocarcinoma 50-70%
• 3-15%
• Stomach
• Small intestine
• CNS glioblastoma (Turcot syndrome)
• <3%
• Ureter and renal pelvis
• Muir-Torre syndrome findings are present in 9% of HNPCC patients
• Sebaceous cutaneous neoplasms
• Keratoacanthomas
• Mutations in MLH1 and MSH2 result in classic HNPCC
• Mutations in PMS2 and MSH6 result in attenuated HNPCC
• Cancers develop 6-8 years later than in classic syndrome
• Homozygous and compound heterozygous mutations lead to cancers in children and young adults (first 3 decades)
• Colorectal and endometrial carcinoma
• CNS, various types
• Leukemias and lymphomas, various types

Bibliography

• Bosman FT, Carneiro F, Hruban RH, Thiese ND (Eds). WHO Classifiication of Tumors of the Digestive System, IARC, Lyon 2010
• Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, et al. The molecular basis of Turcot's syndrome. N Engl J Med. 1995 Mar 30;332(13):839-47.
• Greenson JK, Huang SC, Herron C, Moreno V, Bonner JD, Tomsho LP, Ben-Izhak O, Cohen HI, Trougouboff P, Bejhar J, Sova Y, Pinchev M, Rennert G, Gruber SB. Pathologic Predictors of Microsatellite Instability in Colorectal Cancer. Am J Surg Pathol. 2009 Jan;33(1):126-33.
• Desai TK, Barkel D. Syndromic colon cancer: lynch syndrome and familial adenomatous polyposis. Gastroenterol Clin North Am. 2008 Mar;37(1):47-72.
• Bandipalliam P. Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations. Fam Cancer. 2005;4(4):323-33.
• Boland CR, Koi M, Chang DK, Carethers JM. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside. Fam Cancer. 2008;7(1):41-52.
• Gatalica Z, Torlakovic E. Pathology of the hereditary colorectal carcinoma. Fam Cancer. 2008;7(1):15-26.
• South CD, Hampel H, Comeras I, Westman JA, Frankel WL, de la Chapelle A. The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst. 2008 Feb 20;100(4):277-81.
• Ponti G, Ponz de Leon M. Muir-Torre syndrome. Lancet Oncol. 2005 Dec;6(12):980-7.
• Bellizzi AM, Frankel WL. Colorectal cancer due to deficiency in DNA mismatch repair function: a review. Adv Anat Pathol. 2009 Nov;16(6):405-17.