HEREDITARY COLON CANCER PREDISPOSITION SYNDROMES: WHAT DO WE NEED TO KNOW? Jason L Hornick, MD, PhD Director of Surgical Pathology Director of Immunohistochemistry Brigham and Women’s Hospital Associate Professor of Pathology Harvard Medical School Boston, MA, USA
68
Embed
HEREDITARY COLON CANCER PREDISPOSITION SYNDROMES: …
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
HEREDITARY COLON CANCER PREDISPOSITION SYNDROMES: WHAT DO WE NEED TO KNOW?
Jason L Hornick, MD, PhD Director of Surgical Pathology
Director of Immunohistochemistry Brigham and Women’s Hospital
Associate Professor of Pathology Harvard Medical School
Boston, MA, USA
Objectives • To describe the contribution of various
hereditary predisposition syndromes to colorectal carcinoma
• To describe the histologic features associated with MSI-H colorectal carcinoma
• To explain the various screening methods for Lynch syndrome
• To describe the features of the most common hereditary polyposis syndromes
Colon cancers attributable to hereditary predisposition syndromes
• Signet-ring-cell carcinoma (5%): diffuse infiltrative cords and sheets; cells with intracytoplasmic mucin vacuoles, often compressing nuclei to periphery
• Medullary carcinoma (1%): sheets of large epithelioid cells with vesicular nuclei, prominent nucleoli, sometimes admixed with numerous lymphocytes
Significance of Special Subtypes of Colon Cancer
• Mucinous, signet-ring-cell, and medullary phenotypes predictive of microsatellite instability (MSI-H) – either sporadic or Lynch syndrome
• Medullary phenotype strongest correlation
• Signet-ring-cell histology associated with worse prognosis
Urothelial carcinoma (upper tract) Small bowel adenocarcinoma
Gastric adenocarcinoma
Sebaceous adenoma/carcinoma (Muir-Torre) Astrocytoma and glioblastoma
Screening for Lynch Syndrome I • Screening of colorectal adenocarcinoma • Variable practice among institutions • Some use age cut-off <50 yrs • Many have universal screening • 4 antibody immunohistochemistry panel:
• MLH1, MSH2, PMS2, MSH6 • MLH1/PMS2 and MSH2/MSH6 heterodimers:
in most cases, proteins are lost together • PCR-based microsatellite instability
analysis
Immunohistochemistry for MMR proteins
Sporadic Lynch syndrome
80% 20%
MLH1 promoter methylation
MLH1 mut
MSH2
mut MSH6
mut PMS2
mut
Loss of MLH1/PMS2
Loss of MSH2/MSH6
Loss of MSH6
or MSH2/MSH6
Loss of PMS2
or MLH1/PMS2
MLH1
Conventional adenocarcinoma
MLH1
Lynch syndrome-associated adenocarcinoma
Screening for Lynch Syndrome II
• Adenomas can be tested by IHC or MSI • 50-70% of adenomas in patients with
Lynch syndrome will show loss of MMR protein expression and MSI
• Highly specific for Lynch syndrome • Not practical or cost-effective as screening • In select cases (high index of suspicion
owing to personal or family history), testing adenomas is reasonable
MSH2
Lynch syndrome-associated adenoma
Microsatellite analysis
Normal
Tumor
Screening for Lynch Syndrome III • Most MLH1/PMS2-deficient CRC are
sporadic • Reflex MLH1 promoter methylation or BRAF
V600E sequencing can help triage patients • If either are found, then sporadic (no need for
germline testing) • Sensitivity of MLH1 promoter methylation for
sporadic etiology almost 100% • Rarely somatic mutations are responsible
• Sensitivity of BRAF V600E sequencing ~70% • MSH2/MSH6-deficient and isolated MSH6 or
• Much less often exhibit extra-intestinal manifestations
Attenuated familial adenomatous polyposis
MUTYH-associated polyposis (MAP) • Autosomal recessive inheritance • Mutations in DNA base excision repair
gene MUTYH • Patients typically have similar adenoma
burden as attenuated FAP (30-100) • Some patients may have 10 or fewer
adenomas • Adenomas typically found in proximal
colon • Subset of patients with duodenal
adenomas and fundic gland polyps
MUTYH-associated polyposis (MAP)
• 25-30% of APC-negative polyposis patients with 10-100 adenomas
• 15% of APC-negative polyposis patients with >100 adenomas
• Some patients have serrated polyposis • Risk of duodenal adenocarcinoma 5% • Sebaceous tumors 2% • CHRPE 5% • Lifetime risk extra-intestinal cancer 38% • Colon cancer histology similar to MSI-H
• Mutations in SMAD4, BMPR1A, or ENG in 50%; genetic cause unknown in 50%
• Half of affected patients have no family history (likely new mutation)
• Diagnostic criteria: • 3 to 5 or more colorectal juvenile polyps • Juvenile polyps throughout GI tract • Any juvenile polyps with family history
Juvenile polyposis syndrome • Patients present in childhood or young
adulthood with hematochezia, anemia, or abdominal pain
• Rare severe variant presents in infancy with diarrhea, malabsorption; rapidly fatal (germline deletion on chromosome 10q involving both BMPR1A and PTEN)
• Significant risk of colon cancer • Smaller risk of upper GI tract, pancreatic
cancer
Juvenile polyposis syndrome
Courtesy of Dr. Amitabh Srivastava
Juvenile polyposis syndrome
Hornick JL in Fletcher CDM, ed. Diagnostic Histopathology of Tumors
Hornick JL in Fletcher CDM, ed. Diagnostic Histopathology of Tumors