Hereditary nonpolyposis colorectal cancer pathophysiology

Hereditary nonpolyposis colorectal cancer is an autosomal dominant genetic disease characterized by an early onset of colon cancer, endometrial cancer, and other malignant tumors. Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations. The genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer include: MSH-2, MLH-1, MSH-6, PMS-2 , PMS-1, TGF-BR2, and MLH-3. This syndrome occurs most commonly in the proximal colon (60% to 80%). Endometrial cancer is the most common sentinel cancer among female patients with hereditary nonpolyposis colorectal cancer.

• Hereditary nonpolyposis colorectal cancer results from a defect in the DNA mismatch repair mechanism that leads to microsatellite instability (MSI), which is a hallmark of the disease.
• Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine.^[1]
• Microsatellite instability (MSI) is a surrogate marker for DNA mismatch repair gene dysfunction.^[2][3]
• In hereditary nonpolyposis colorectal cancer, colon malignancies usually occur from a single or multiple adenomas, and mostly in the proximal colon.

• Hereditary nonpolyposis colorectal cancer is inherited in an autosomal dominant manner.
• Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations.^[4]
• Most mutations (90%) that cause hereditary nonpolyposis colorectal cancer are found in the MLH1 or MSH2 genes.^[5]
• MSH6 and PMS2 account for the other 10% of mutations.^[6]
• Endometrial cancer is the most common distant cancer among female patients with hereditary nonpolyposis colorectal cancer.
• MSH2 mutations have an increased risk of urothelial carcinoma relative to MLH1 and MSH6 mutations.^[7]

• Colorectal carcinoma
• Endometrial carcinoma
  • Non-endometrioid endometrial carcinoma^[8][9]
  • Endometrioid endometrial carcinoma^[10]

• Stomach carcinoma (intestinal type)^[11][12]
• Biliary tree carcinoma^[11]
• Pancreatic carcinoma
• Urinary system carcinoma

• On gross pathology, there are no characteristic findings of hereditary nonpolyposis colorectal cancer.^[4]

• On microscopic histopathological analysis, hereditary nonpolyposis colorectal cancer is more likely to be poorly differentiated, abundant in extracellular mucin, and distinguished by a lymphoid (peritumoral lymphocytes) host response to the tumor.^[4]
• Three major groups of MSI-H cancers can be recognized by histopathological criteria, which include:^[13][14]
  • Right-sided poorly differentiated cancers
  • Right-sided mucinous cancers
  • Adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte

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