Hereditary Nonpolyposis Colorectal Cancer typically presents in a younger demographic than sporadic colorectal cancer, hallmarked by germline mutations in DNA mismatch repair genes MLH1 and MSH2 and a characteristic propensity for proximal colon cancer.
Description
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant genetic condition associated with high risk for colorectal cancer and endometrial cancer. It’s part of a family of hereditary cancer syndromes and is the most common inherited cause of colorectal cancer. Despite the name, colorectal cancers arise from adenomatous polyps. Diffuse polyposis is characteristically absent.
Pathogenesis
The pathogenesis of HNPCC involves mutations in the DNA mismatch repair (MMR) genes, particularly MLH1 and MSH2. These genes are responsible for the repair of errors that occur during DNA replication. Mutations in these genes lead to an accumulation of errors in the DNA, resulting in genomic instability and increased susceptibility to cancer.
Subtypes
There are no recognised subtypes of HNPCC. However, there are several related syndromes depending on the specific MMR gene involved:
- Lynch Syndrome I: Site-specific colorectal cancer
- Lynch Syndrome II: Associated with other malignancies such as endometrial, ovarian, and gastric cancer.
Epidemiology, Risk Factors & Associations
- Most commonly associated with colorectal and endometrial cancer (70% and 40-60% lifetime risk respectively)
Other associated extracolonic malignancies include:
- Genitourinary tract malignancies:
- Endometrial cancer (most commonly endometrioid type)
- Ovarian tumour
- Prostate cancer
- Urothelial tract cancer
- Small bowel cancer (most commonly affecting duodenum, then jejunum, ileum and stomach)
- Hepatobiliary tract and pancreatic malignacies
- CNS tumours (most commonly glioblastoma)
- Skin cancer
Clinical Features
The most common clinical features of HNPCC include:
- Early onset of colorectal cancer (before age 50)
- Proximal colon often involved
- Multiple synchronous or metachronous colorectal cancers
- Family history of colorectal cancer or other associated malignancies
Complications
The main complication of HNPCC is the development of cancer, especially colorectal and endometrial cancer. There is no increased risk of malignant transformation in non-malignant tissue.
Pathological Features
Histopathology
- Macroscopic: Often appear as protruded or polypoid, rather than annular or ulcerative.
- Microscopic: Tumours are often poorly differentiated, with mucinous or signet ring cell histology.
Serology
- Genetic testing reveals mutations in the DNA MMR genes, especially MLH1 and MSH2.
Biochemistry
No specific biochemical markers are associated with HNPCC.
Radiological Features
General Features
- Characteristically demonstrates colorectal and endometrial tumours
- Frequent proximal/right-sided colon involvement (70% arise proximal to splenic flexure).
CT
- Non-contrast: Colorectal polyps and tumours may be visualised, appearing as soft tissue density masses, either pedunculated or sessile. Mass effect on adjacent structures may be observed in advanced cases.
- C+ Arterial: Enhancement of tumours
- C+ Venous: Continued enhancement of tumours
MRI
- T1: Tumours are generally hypointense or isointense compared to muscle
- T2: Tumours appear hyperintense, while desmoplastic reaction and fibrosis appear hypointense
- DWI/ADC: Restricted diffusion in malignant tumours
- T1 Gad+: Enhancement of tumours is seen post gadolinium administration, which helps in differentiating tumour tissue from normal tissue
NM
- PET FDG: Can be used in the staging and follow-up of colorectal cancer
Grading and Staging
Grading and staging of detected cancers follows the TNM staging system.
Diagnosis
Diagnosis of HNPCC is based on the Amsterdam II criteria or revised Bethesda guidelines, in addition to genetic testing.
Differential Diagnosis
- Familial Adenomatous Polyposis: Typically younger age of onset, characterised by numerous (>100) colorectal adenomas.
- Sporadic colorectal cancer: Typically older age of onset, often distal colon involvement, no or minimal family history.
Management
Management involves regular screening for colorectal and endometrial cancer, genetic counselling, and prophylactic surgery in some cases. Typically every 1 to 2 years from 25 to 40 years of age. Colorectal cancer treatment follows standard guidelines, usually involving surgery (colectomy), chemotherapy, and radiation therapy.