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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

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
    • 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
  • 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
  • Gastric pyloric gland adenomas have been described (Lee 2014)

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

Original posting/last update : 1/31/10, 3/26/14

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
Immunohistologic and Genetic Differences between Familial and Sporadic Cases
  Familial Sporadic
Immunohistologic loss of MLH1 and PMS2 May occur Virtually all
Immunohistologic loss of MSH2 or MSH6 May occur Very rare
MSI-H Yes Yes
Germline mismatch gene mutation Yes No
MLH1 genetic defect Most are nonsense or frame shifts Most are promoter methylation
BRAF mutation Rare Yes

 

Differential Diagnosis

HNPCC Sporadic MSI-H Colorectal Adenocarcinoma
May have family history of associated neoplasms No family history of associated neoplasms
Mean age 45 Mean age >60
Not associated with sessile serrated adenomas Associated with sessile serrated adenomas (may not always be identifiable)
Germline mutation in mismatch repair enzymes No germline mutation

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

HNPCC / Lynch Syndrome Familial Adenomatous Polyposis
May have family history of characteristic associated neoplasms Family history of early onset of colorectal polyps
Duodenal adenoma and carcinoma rare Personal or family history of duodenal adenoma common, carcinoma may occur
Adenomas if present are only moderately increased ≥100 adenomas in classic cases
Genetic and immunohistologic evidence of mismatch repair deficiency No evidence of mismatch repair deficiency
APC mutation not present APC mutation detectable in 80%
Attenuated FAP may be very difficult to distinguish from HNPCC as it has fewer adenomas and later presentation and frequent right sided carcinoma

 

MUTYH Associated Polyposis HNPCC
Family history of polyps and colorectal carcinoma only May have family history of characteristic associated neoplasms
Duodenal adenoma in 18% Duodenal adenoma rare
Germline mutation detected in MUTYH gene No MUTYH mutation
No evidence of mismatch repair deficiency Genetic and immunohistologic evidence of mismatch repair deficiency
Autosomal recessive Autosomal dominant
MUTYH associated polyposis may be very difficult to distinguish clinically from HNPCC as it has fewer adenomas and later presentation and frequent right sided carcinoma

 

Serrated Polyposis (Hyperplastic Polyposis) Hereditary Nonpolyposis Colorectal Cancer
Multiple serrated polyps (most are SSA) Polyps are not increased
Not associated with extra-GI cancers Associated with carcinomas of the endometrium, small intestine, ureter and renal pelvis
Associated with sporadic, non-familial colorectal adenocarcinoma Familial colorectal adenocarcinoma and other neoplasms
Two different pathways to MSI high colorectal carcinoma

 

HNPCC Peutz-Jeghers Syndrome
No mucocutaneous hyperpigmentation Mucocutaneous hyperpigmentation
Infrequent polyps are all adenomatous Hamartomatous polyps with arborizing smooth muscle bundles
Polyps rare in small intestine Most polyps in small intestine
Dysfunctional germ line mutations in DNA mismatch repair enzymes STK11 mutations in 50-90%
Both may be associated with carcinomas of the large intestine, breast and endometrium, as well as a number of other sites.

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.
  • Lee SE, Kang SY, Cho J, Lee B, Chang DK, Woo H, Kim JW, Park HY, Do IG, Kim YE, Kushima R, Lauwers GY, Park CK, Kim KM. Pyloric Gland Adenoma in Lynch Syndrome. Am J Surg Pathol. 2014 Feb 10. [Epub ahead of print] PubMed PMID: 24518125.
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