Lynch Syndrome/Hereditary Nonpolyposis Colon Cancer (HNPCC)

Johnathan W. Cain, DO
The Operative Review of Surgery. 2023; 1:112-117.

Download PDF

Table of Contents

Pathophysiology
Extracolonic Manifestations
Diagnosis and Screening
Surgical Management

Other Colorectal Cancer and Polyposis Syndromes
References

Pathophysiology

Colorectal Cancer

  • The Most Common Cause of Hereditary Colorectal Cancer 1
  • Lifetime Risk: 20-80% Depending Mutation & Associated Risk Factors 2
  • Accounts for 3-5% of All Colorectal Cancers 2,3
  • Cancer Occurs at a Younger Age than Sporadic Cancers 4
    • Average Age 45-60 Years 5
  • Most Common in the Right Colon (Sporadic Cancers are Most Common on the Left) 5
  • Propensity for Synchronous and Metachronous Colorectal Cancers 5

Genetic Mutations

  • Autosomal Dominant
  • Mutation in DNA Mismatch Repair (MMR) Genes
    • Include: MLH1, MSH2, MSH6, or PMS2 6,7
      • MLH1 and MSH2 are the Most Common (60-80%) 5
    • Can Also Be Caused by Deletions in the Non-MMR EpCAM Gene – Causes Epigenetic Silencing of MSH2 5
  • Cause Microsatellite Instability (Genetic Hypermutability) 2,5
  • Incidence: 1/279 Births 8
  • 20% are Sporadic Mutations

Types

  • Type I: Colorectal Cancer with No Extracolonic Malignancy
  • Type II: Colorectal Cancer with Extracolonic Malignancy

Tumor-Infiltrating Lymphocytes, Suggestive of Microsatellite Instability (MSI) as Seen in Lynch Syndrome 9

Extracolonic Manifestations

Endometrial Cancer

  • Most Common Extracolonic Malignancy (40-60%) 2
  • Accounts for 5% of All Endometrial Cancers 10
  • Median Age of Diagnosis: 48 Years 11
  • Endometrioid Adenocarcinoma is the Most Common Type (92%) 12

Ovarian Cancer

  • Incidence: 1-38% 2
  • Earlier Age of Onset: 42-49 Years 13

Other Less Common Associations 2,14

  • Urinary Tract Cancers (Kidney, Ureter, Bladder) (1-18%)
  • Stomach Cancer (1-13%)
  • Small Bowel Cancers (1-6%)
  • Pancreatic Cancer (1-6%)
  • Hepatobiliary Cancer (1-4%)
  • Brain Tumors (1-3%)
  • Breast Cancer
  • Skin Cancers

Diagnosis and Screening

Diagnosis

  • Clinical Diagnosis Suspected Based on the Amsterdam Criteria
  • Diagnosis Confirmed by Genetic Screening

Amsterdam Criteria (1990) 15

  • Criteria:
    • ≥ 3 Relatives with Histologically Verified Colorectal Cancer, One of Whom is a First-Degree Relative of the Other Two
    • ≥ 2 Generations are Involved
    • ≥ 1 Cancer Case Was Diagnosed Before Age 50
    • FAP Must Be Excluded
  • *Criteria are Remembered as the “3-2-1 Rule”
  • Sensitivity 61% and Specificity 67% 16

Amsterdam II Criteria (1999) 17

  • Criteria:
    • ≥ 3 Relatives with Histologically Verified Lynch Syndrome-Associated Cancer, One of Whom is a First-Degree Relative of the Other Two
    • ≥ 2 Generations are Involved
    • ≥ 1 Cancer Case Was Diagnosed Before Age 50
    • FAP Must Be Excluded
  • *Criteria are Remembered as the “3-2-1 Rule”
  • Sensitivity 78% (Increased) and Specificity 61% 16

Revised Bethesda Criteria 18

  • Criteria Used to Determine the Need to Test Colorectal Tumors for MMR Deficiency and/or MSI
  • Criteria:
    • Colorectal Cancer Diagnosed in a Patient Who is < 50 Years of Age
    • Presence of Synchronous, Metachronous Colorectal, or Other HNPCC-Associated Tumors, Regardless of Age
    • Colorectal Cancer with the MSI-H Histology Diagnosed in a Patient Who is < 60 Years of Age
    • Colorectal Cancer Diagnosed in One or More First-Degree Relatives with an HNPCC-Related Tumor, with One of the Cancers Being Diagnosed Under Age 50 Years
    • Colorectal Cancer Diagnosed in Two or More First- or Second-Degree Relatives with HNPCC-Related Tumors, Regardless of Age
  • Sensitivity 94% and Specificity 25% 16
  • Has Largely Been Replaced by Universal Screening for MMR Deficiency and/or MSI in Colorectal and Endometrial Cancers

Screening 19

  • High-Quality Colonoscopy Starting at Age 20-25
    • Repeat Every 1-2 Years
  • Upper Endoscopy Starting at Age 30-40
    • Repeat Every 2-4 Years
  • Consider Endometrial Biopsy Starting at Age 30-35
    • Repeat Every 1-2 Years
    • *No Proven Benefit to Endometrial or Ovarian Cancer Screening 19

Surgical Management

Therapeutic Colectomy

  • Indications: Colorectal Cancer or Unresectable Adenomas
  • Colon Cancer: Total Abdominal Colectomy with Ileorectal Anastomosis (TAC/IRA) is Generally Preferred 20
    • May Consider Segmental Colectomy in Select Circumstances
    • Requires Surveillance with Flexible Proctoscopy or Repeat Colonoscopy Every Year 21
  • Rectal Cancer: Consider Total Proctocolectomy vs Segmental Resection
    • Total Proctocolectomy Done with End Ileostomy or Ileal Pouch Anal Anastomosis (IPAA)
    • Segmental Resections: Low Anterior Resection (LAR) and Abdominoperineal Resection (APR)

Prophylactic Colectomy

  • Prophylactic Colectomy Generally Not Performed
  • Possible Prophylactic Indications: 21
    • Colon Technically Difficult to Navigate
    • Unable to Comply with Screening Recommendations
    • Severe Psychological Distress Due to Fear of Developing Colorectal Cancer
    • Families with Early Onset or Severe Penetrance of Colorectal Cancer
    • Females Already Undergoing Hysterectomy for Uterine Cancer

Prophylactic Total Hysterectomy and Bilateral Salpingo-Oophorectomy (TH-BSO)

  • Effective at Preventing Endometrial and Ovarian Cancers
  • Indicated for Females After Age 40 or Once Childbearing is Complete 22

Other Prophylactic Measures

  • Aspirin – May Reduce the Incidence of Colorectal Cancer 23,24
  • Oral Contraceptives – Used to Prevent Gynecologic Cancers (Debated) 25

Other Colorectal Cancer and Polyposis Syndromes

Syndromes

  • Familial Adenomatous Polyposis (FAP)
  • Lynch Syndrome
  • Juvenile Polyposis Syndrome (JPS)/Familial Juvenile Polyposis
  • MUT Y Homolog (MUTYH)-Associated Polyposis (MAP)
  • Peutz-Jeghers Syndrome (PJS)
  • Serrated Polyposis Syndrome (SPS)
  • PTEN Hamartoma Tumor Syndromes: (PHTS)

Comparisons

References

  1. Lynch Syndrome. CDC. 2022
  2. Lynch Syndrome. Cancer.Net. 2021.
  3. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev 2017;26:404-412.
  4. Møller P, Seppälä T, Bernstein I, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 2017;66:464-472.
  5. Sinicrope FA. Lynch Syndrome-Associated Colorectal Cancer. N Engl J Med. 2018 Aug 23;379(8):764-773.
  6. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110:223-262.
  7. Boland CR, Lynch HT. The history of Lynch syndrome. Fam Cancer. 2013;12:145-157.
  8. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2017;26:404-412.
  9. Nephron, Wikimedia Commons. (License: CC BY-SA 3.0)
  10. Meyer LA, Broaddus RR, Lu KH. Endometrial cancer and Lynch syndrome: clinical and pathologic considerations. Cancer Control. 2009 Jan;16(1):14-22.
  11. Vasen HF, Watson P, Mecklin JP, et al. The epidemiology of endometrial cancer in hereditary nonpolyposis colorectal cancer. Anticancer Res. 1994;14(4B):1675–1678.
  12. Boks DE, Trujillo AP, Voogd AC, et al. Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer. 2002;102(2):198–200.
  13. Nakamura K, Banno K, Yanokura M, Iida M, Adachi M, Masuda K, Ueki A, Kobayashi Y, Nomura H, Hirasawa A, Tominaga E, Aoki D. Features of ovarian cancer in Lynch syndrome (Review). Mol Clin Oncol. 2014 Nov;2(6):909-916.
  14. Bansidhar BJ. Extracolonic manifestations of lynch syndrome. Clin Colon Rectal Surg. 2012 Jun;25(2):103-10.
  15. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991 May;34(5):424-5.
  16. Syngal S, Fox EA, Eng C, Kolodner RD, Garber JE. Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet. 2000 Sep;37(9):641-5.
  17. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999 Jun;116(6):1453-6.
  18. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004 Feb 18;96(4):261-8.
  19. Familial Adenomatous Polyposis. Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2022. National Comprehensive Cancer Network (NCCN).
  20. Herzig DO, Buie WD, Weiser MR, You YN, Rafferty JF, Feingold D, Steele SR. Clinical Practice Guidelines for the Surgical Treatment of Patients With Lynch Syndrome. Dis Colon Rectum. 2017 Feb;60(2):137-143
  21. Baucom RB, Wise PE. Endoscopic and surgical management of hereditary nonpolyposis colorectal cancer. Clin Colon Rectal Surg. 2012 Jun;25(2):90-6.
  22. Schmeler KM, Lynch HT, Chen LM, Munsell MF, Soliman PT, Clark MB, Daniels MS, White KG, Boyd-Rogers SG, Conrad PG, Yang KY, Rubin MM, Sun CC, Slomovitz BM, Gershenson DM, Lu KH. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006 Jan 19;354(3):261-9.
  23. Serrano D, Patrignani P, Stigliano V, Turchetti D, Sciallero S, Roviello F, D’Arpino A, Grattagliano I, Testa S, Oliani C, Bertario L, Bonanni B. Aspirin Colorectal Cancer Prevention in Lynch Syndrome: Recommendations in the Era of Precision Medicine. Genes (Basel). 2022 Mar 3;13(3):460.
  24. Burn J, Sheth H, Elliott F, Reed L, Macrae F, Mecklin JP, Möslein G, McRonald FE, Bertario L, Evans DG, Gerdes AM, Ho JWC, Lindblom A, Morrison PJ, Rashbass J, Ramesar R, Seppälä T, Thomas HJW, Pylvänäinen K, Borthwick GM, Mathers JC, Bishop DT; CAPP2 Investigators. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet. 2020 Jun 13;395(10240):1855-1863.
  25. Stoffel EM, Walsh C. Chemoprevention of endometrial cancer in Lynch syndrome: a step forward. Cancer Prev Res (Phila). 2013 Aug;6(8):755-9.