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
- We prefer to evaluate both PCR based microsatellite repair instability (MSI) / stability (MSS) and intact / absent immunohistochemical expression of DNA mismatch repair enzymes
- 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
- Intraepithelial T lymphocytes, ≥3 per HPF
- 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
- 15% of colorectal adenocarcinomas have evidence of somatic mutations in MMR enzymes, nearly always MLH1
- 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
- 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
