hereditary colon cancer predisposition syndromes: …
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
Syndrome Colon cancers
Lynch syndrome 3-5%
Familial adenomatous polyposis 1%
MUTYH-associated polyposis <1%
Juvenile polyposis syndrome <1%
Peutz-Jeghers syndrome <1%
PTEN hamartoma tumor syndrome (Cowden syndrome) <1%
Colon cancer
Chromosomal instability/ microsatellite stable (MSS)
High-level microsatellite instability (MSI-H)
85% 15%
Sporadic Lynch syndrome
80% 20%
MLH1 promoter methylation
Germline mutation in MLH1, MSH2 >>
MHS6, PMS2
Mismatch repair-deficient colorectal cancers
Sporadic Lynch syndrome
Older adults (mean 70 yrs) Younger adults (mean 50 yrs) F > M F = M
Right colon Anywhere in colon Often arise from sessile
serrated polyps Arise from conventional
adenomas Distinctive histology Distinctive histology Favorable prognosis Favorable prognosis
Poor response to 5-FU Poor response to 5-FU
Special Subtypes of Colon Cancer
• Mucinous adenocarcinoma (10-15%): extracellular mucin pools
• 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
Features of MSI-H Colon Cancers • Right colon • Well-differentiated • Mucinous differentiation • Signet-ring-cell differentiation • Medullary differentiation • Marked intratumoral heterogeneity • Tumor-infiltrating lymphocytes • Crohn’s-like reaction • Expansile (well-circumscribed) border
Lynch syndrome
Lynch syndrome
Well-differentiated
Mucinous adenocarcinoma
Signet-ring-cell carcinoma
Signet-ring-cell carcinoma
Medullary carcinoma
Medullary carcinoma
Tumor-infiltrating lymphocytes
Tumor-infiltrating lymphocytes
Crohn’s-like reaction
Expansile border
Intratumoral heterogeneity
Colonic adenocarcinoma – microsatellite stable
Colonic adenocarcinoma – microsatellite stable
Clinical Significance of MSI-H
• Screening for Lynch syndrome • Heightened CRC screening • Significant risk of other tumor types
(especially endometrial CA) • Counseling and genetic testing for family
members • Improved prognosis compared to
microsatellite-stable CRC • Poor (or no) response to 5-fluorouracil-
based chemotherapy
Tumors associated with Lynch syndrome
Tumor type
Colorectal adenocarcinoma Endometrial adenocarcinoma
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
PMS2 are essentially all Lynch syndrome
Hereditary polyposis syndromes
Adenomatous polyposis syndromes
Hamartomatous polyposis syndromes
Familial adenomatous polyposis Juvenile polyposis
Attenuated familial adenomatous polyposis Peutz-Jeghers syndrome
MUTYH-associated polyposis Cowden syndrome
Familial adenomatous polyposis (FAP)
• Incidence: 1:10,000
• Autosomal dominant
• Germline mutation in APC
• New mutation in 20-30%
• Complete penetrance
• Variable risk of extracolonic manifestations
Familial adenomatous polyposis (FAP)
• Patients begin to develop colorectal adenomas in 2nd decade
• Hundreds or thousands by 4th decade
• Nearly 100% colorectal adenocarcinoma by 50 yrs without prophylactic total proctocolectomy
• Upper endoscopic surveillance important to detect early duodenal/ ampullary adenocarcinomas
FAP
Gastrointestinal manifestations
Colorectal adenomas
Duodenal adenomas
Ampullary adenomas
Gastric fundic gland polyps
Familial adenomatous polyposis
FAP Extra-gastrointestinal manifestations
(Gardner syndrome) Desmoid-type fibromatosis
Epidermoid cysts
Dental abnormalities
Osteomas of jaw and skull
Congenital hypertrophy of retinal pigment epithelium (CHRPE)
Hepatoblastoma Medulloblastoma (Turcot)
Thyroid carcinoma (cribriform-morular)
Mesenteric desmoid fibromatosis
Desmoid fibromatosis
Desmoid fibromatosis
β-catenin
Papillary thyroid carcinoma, cribriform-morular variant
Courtesy of Dr. Justine Barletta
Papillary thyroid carcinoma, cribriform-morular variant
β-catenin
FAP Tumor type Relative risk Absolute risk
Desmoid 850 15%
Duodenal CA 330 3-5% Thyroid CA 7.6 2%
Medulloblastoma 7 2%
Ampullary CA 125 1.7%
Pancreatic CA 4.5 1.7%
Hepatoblastoma 850 1.6%
Courtesy of Dr. Amitabh Srivastava
Attenuated familial adenomatous polyposis (AFAP)
• Patients have fewer adenomas (30-100)
• Typical the rectum is spared
• Colon cancer at older age
• Duodenal adenomas, fundic gland polyps
• 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
Juvenile polyposis syndrome • Autosomal dominant inheritance
• 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
Juvenile polyp
Peutz-Jeghers syndrome • Incidence 1:50,000 – 1:200,000 • Autosomal dominant inheritance • Germline mutations in STK11 (LKB1) • Characteristic mucocutaneous
pigmentation (lips, perioral) • Distinctive hamartomatous polyps • “Adenoma malignum” (uterine cervix) • Sex cord tumor with annular tubules
(ovary) • Sertoli cell tumor of testis
Juvenile polyps and polyposis Association Diagnostic
criteria Inheritance Genetics Risk of cancer
Sporadic <3 polyps; no family history None None None
Juvenile polyposis of
infancy
Diarrhea, protein-losing enteropathy, polyps from
stomach to rectum
None
De novo germline
deletion of 10q
(BMPR1A and PTEN)
Fatal <2 yrs from
complications
Juvenile polyposis
coli
≥ 3 polyps; any polyps with family history
Autosomal dominant
BMPR1A, PTEN, or
ENG mutation
30-68% colon cancer
Generalized juvenile
polyposis
Polyps throughout stomach, small
bowel, colon (50-200)
Autosomal dominant
SMAD4 > BMPR1A mutation
At least 55% GI cancers,
including 20% upper tract
Peutz-Jeghers polyps • Small intestine (60-95%) • Colon (60%) • Stomach (20-50%)
• Distinctive arborizing smooth muscle • Best developed in small intestine • Gastric and colonic polyps may
contain little smooth muscle (difficult to recognize)
Peutz-Jeghers polyp
Peutz-Jeghers polyp
Cowden syndrome (PTEN hamartoma tumor syndrome)
• Autosomal dominant; PTEN mutation • Bilateral fibrocystic disease of breast,
multinodular goiter common • Other features: glycogenic acanthosis/
papillomatosis of esophagus, cutaneous trichilemmomas, dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos syndrome)
• Diverse GI hamartomatous polyps: juvenile, ganglioneuromatous, lipomatous, fibroblastic, lymphoid
Cowden syndrome
Ganglioneuromatous polyposis
Ganglioneuromatous polyp
Cowden syndrome
Juvenile and lymphoid polyps
Courtesy of Dr. Amitabh Srivastava
Cowden syndrome
Colonic polyp with subtle expansion of lamina propria
Cowden syndrome
Glycogenic acanthosis/papillomatosis
Courtesy of Dr. Amitabh Srivastava
Cowden syndrome
Courtesy of Dr. Justine Barletta
Multiple adenomatous nodules of thyroid
PTEN
Other hereditary polyposis syndromes
Syndrome Other clinical features
Histologic features of
colonic polyps Genetics Risk of
cancer
Peutz-Jeghers
syndrome
Mucocutaneous pigmentation
Arborizing smooth muscle
scaffold
STK11 (LKB1)
mutation
Colon: 39% Pancreas: 36% Stomach: 29% Breast: 54%
Cowden syndrome
Mucocutaneous lesions
(trichilemmomas, oral papillomas),
glycogenic acanthosis,
fibrocystic breast disease,
multinodular goiter
Juvenile polyps, ganglioneural,
lipomatous, fibroblastic,
lymphoid
PTEN mutation
Breast: 25-50% Thyroid: 3-10% Colon: 10-15%
Practice points • Lynch syndrome (germline mutations in
mismatch repair genes) most common hereditary colorectal carcinoma predisposition syndrome
• Universal screening by IHC becoming common
• Adenomatous and hamartomatous polyposis syndromes variable cancer risk
• Be aware of distinctive features of polyps and other clinical/pathologic features to suggest syndromes to clinical colleagues