hereditary colon cancer predisposition syndromes: …
TRANSCRIPT
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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
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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
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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%
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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
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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
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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
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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
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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
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Lynch syndrome
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Lynch syndrome
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Well-differentiated
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Mucinous adenocarcinoma
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Signet-ring-cell carcinoma
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Signet-ring-cell carcinoma
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Medullary carcinoma
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Medullary carcinoma
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Tumor-infiltrating lymphocytes
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Tumor-infiltrating lymphocytes
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Crohn’s-like reaction
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Expansile border
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Intratumoral heterogeneity
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Colonic adenocarcinoma – microsatellite stable
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Colonic adenocarcinoma – microsatellite stable
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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
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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
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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
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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
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MLH1
Conventional adenocarcinoma
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MLH1
Lynch syndrome-associated adenocarcinoma
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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
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MSH2
Lynch syndrome-associated adenoma
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Microsatellite analysis
Normal
Tumor
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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
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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
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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
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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
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FAP
Gastrointestinal manifestations
Colorectal adenomas
Duodenal adenomas
Ampullary adenomas
Gastric fundic gland polyps
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Familial adenomatous polyposis
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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)
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Mesenteric desmoid fibromatosis
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Desmoid fibromatosis
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Desmoid fibromatosis
β-catenin
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Papillary thyroid carcinoma, cribriform-morular variant
Courtesy of Dr. Justine Barletta
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Papillary thyroid carcinoma, cribriform-morular variant
β-catenin
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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
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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
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Attenuated familial adenomatous polyposis
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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
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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
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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
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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
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Juvenile polyposis syndrome
Courtesy of Dr. Amitabh Srivastava
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Juvenile polyposis syndrome
Hornick JL in Fletcher CDM, ed. Diagnostic Histopathology of Tumors
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Hornick JL in Fletcher CDM, ed. Diagnostic Histopathology of Tumors
Juvenile polyp
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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
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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
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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)
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Peutz-Jeghers polyp
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Peutz-Jeghers polyp
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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
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Cowden syndrome
Ganglioneuromatous polyposis
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Ganglioneuromatous polyp
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Cowden syndrome
Juvenile and lymphoid polyps
Courtesy of Dr. Amitabh Srivastava
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Cowden syndrome
Colonic polyp with subtle expansion of lamina propria
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Cowden syndrome
Glycogenic acanthosis/papillomatosis
Courtesy of Dr. Amitabh Srivastava
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Cowden syndrome
Courtesy of Dr. Justine Barletta
Multiple adenomatous nodules of thyroid
PTEN
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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%
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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