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