Lynch Syndrome and Cowden Syndrome

Lynch Syndrome (HNPCC)

Overview

Genetic Basis

Cancer Risks

• Colorectal cancer: 53-69% lifetime risk; average age of diagnosis in the early 60s. Tumors predominate in the right (proximal) colon, are often flat adenomas (usually <10 polyps), and show infiltrating lymphocytes, mucinous histology with signet ring cells, and poor differentiation. Despite poor differentiation, prognosis is paradoxically better than stage-matched sporadic CRC - but MMR-deficient tumors respond poorly to 5-FU-based adjuvant chemotherapy.
• Endometrial cancer: Most common extracolonic malignancy - occurs in ~54% of women with LS. Women with LS are also at increased risk for ovarian cancer.
• Other cancers: Gastric, pancreatic, biliary tract, urinary tract (urothelial), brain (glioblastoma), and emerging data suggest increased breast cancer risk.
• Men with LS have a higher CRC risk than women with LS.
• Patients have a 3-5% annual cumulative rate of metachronous colorectal tumors, supporting consideration of more extensive resection (subtotal colectomy) when a LS-related CRC is diagnosed.

Muir-Torre Syndrome

Diagnosis

1. Three or more relatives with LS-associated tumors, one of whom is a first-degree relative of the other two (and FAP excluded)
2. Cancers across at least two successive generations
3. At least one cancer diagnosed before age 50

1. CRC diagnosed before age 50
2. Synchronous or metachronous Lynch-associated tumors
3. MSI-H features on histology regardless of age
4. CRC in a first-degree relative of an LS patient, diagnosed before age 50

• Immunohistochemistry (IHC) of tumor tissue for MMR protein expression (loss of MLH1, MSH2, MSH6, or PMS2)
• MSI testing by PCR (5-locus mononucleotide panel)
• If MLH1 protein lost: check BRAF V600E mutation or MLH1 promoter hypermethylation (these indicate sporadic cause, not LS)
• If no sporadic cause: germline sequencing of MMR genes from blood

Surveillance

• Colonoscopy every 1-2 years starting at age 20-25 (or 2-5 years before youngest affected relative)
• Annual endometrial sampling + transvaginal ultrasound for women starting at age 30-35
• Upper endoscopy for gastric/duodenal surveillance in high-risk families
• Urinalysis for urinary tract surveillance

Cowden Syndrome (PTEN Hamartoma Tumor Syndrome)

Overview

Genetic Basis

Clinical Features

• Trichilemmomas (benign follicular outer root sheath tumors): multiple facial papules, especially around the nose, cheeks, and orifices; present in ~86% of CS patients, average onset age 22
• Acral keratoses: verrucous hyperkeratosis on extensor extremities (28%) and palmoplantar translucent keratoses (20%)
• Oral papillomas/mucosal lesions: >80% of patients, multiple anatomic sites (buccal and gingival mucosa), can coalesce into a cobblestone pattern (in 40%)
• Macrocephaly: head circumference >97th percentile (>63 cm in males, >60 cm in females) - a major diagnostic criterion

Cancer Risks

• Breast carcinoma (25-50% of females)
• Endometrial carcinoma (~6%)
• Follicular thyroid carcinoma (<10%)
• Renal cell carcinoma
• Colorectal cancer (modest risk compared to Lynch syndrome)

Diagnosis

Surveillance

• Annual clinical breast exam + mammography/MRI from age 30-35
• Annual thyroid ultrasound from time of diagnosis
• Annual endometrial sampling from age 30-35
• Consideration of colonoscopy beginning at age 35
• Annual renal ultrasound/imaging from age 40

Side-by-Side Comparison

Familial Adenomatous Polyposis (FAP)

Overview

• ~75% of cases are inherited; 20-30% arise from de novo mutations (no family history)
• Penetrance is very high - nearly 100% lifetime risk of CRC if untreated

Genetic Basis

• The APC protein, together with glycogen synthase kinase-3β (GSK-3β) and axin, forms a destruction complex that phosphorylates cytoplasmic β-catenin, targeting it for ubiquitin-mediated proteasomal degradation
• When APC is lost, β-catenin escapes degradation, accumulates in the nucleus, and binds LEF/TCF transcription factors
• This drives constitutive, ligand-independent Wnt target gene transcription, upregulating genes involved in proliferation (e.g., cyclin D1, c-Myc)
• Following Knudson's two-hit hypothesis, the germline APC mutation is the "first hit"; somatic loss of the second allele is required for tumor formation

• Over 1,700 germline variants identified - most are small frameshifts or nonsense variants creating truncated proteins
• Two hotspots account for ~25% of all variants: codons 1061 (~10%) and 1309 (~15%)
• ~30% of additional variants cluster between these two sites
• The location of the germline variant influences the type of somatic second hit and disease phenotype (genotype-phenotype correlations)
• Gross rearrangements detected by MLPA

Classic FAP

Colorectal Manifestations

• Diagnosis requires ≥100 synchronous adenomatous polyps (or fewer with positive family history)
• Polyps predominate in the left colon and rectum
• Polyps typically first appear in the second decade of life (present in ~15% by age 10, ~75% by age 20, and nearly all by age 35)
• GI symptoms (bleeding, diarrhea, abdominal pain, mucous discharge) emerge in the 3rd-4th decade
• CRC risk approaches 100% if untreated, typically developing ~15 years after polyp onset; median age of cancer ~40 years, nearly always by age 50

Upper GI / Extracolonic Intestinal Disease

• Duodenal adenomas: present in >95% of FAP patients, typically around the ampulla of Vater; develop ~15 years after colonic polyps
• Duodenal/periampullary cancer: in 5-10% of patients; second leading cause of FAP-associated death; mean age of diagnosis ~50 years
• Spiegelman staging system is used to guide surveillance intensity (Stage IV carries 36% cancer risk over 10 years)
• Fundic gland polyps (FGPs): hyperplastic, low malignant potential; in 30-90% of patients
• Gastric adenomas: 10-30% of patients; higher risk in Asian populations (Japanese/Korean patients have 3-4x higher gastric cancer risk)

Extraintestinal Manifestations

FAP Variants

Attenuated FAP (aFAP)

• Caused by APC mutations at the extreme ends of the gene (5' end, 3' end, or exon 9)
• 10-100 adenomas (vs. hundreds to thousands in classic FAP)
• Right colon predominance rather than left/pan-colonic distribution
• Later onset - CRC risk still up to 80% by age 70, but develops ~10 years later than classic FAP
• Some patients can be managed endoscopically (without colectomy) if polyps can be cleared

Gardner Syndrome

• APC gene mutations at a different location (largely codons 1310-2011) → same gene as FAP (allelic)
• Identical adenomatous polyposis with equivalent malignant potential
• Characterized by prominent extraintestinal features: soft tissue tumors (lipomas, sebaceous cysts, fibrosarcomas), osteomas (particularly mandibular), supernumerary teeth, desmoid tumors, mesenteric fibromatosis, CHRPE
• Whether a patient manifests Gardner vs. classic FAP is influenced by modifier genes and environmental factors, not only the APC variant
• Screening and treatment are the same as classic FAP

Turcot Syndrome

• Combination of colorectal polyposis + CNS malignancy
• Two-thirds caused by APC mutations → typically medulloblastoma
• One-third caused by MMR gene mutations (same as Lynch syndrome) → typically glioblastoma
• Also associated with ependymomas

MUTYH-Associated Polyposis (MAP)

• Gene: MUTYH (also called MYH), a base excision repair gene encoding a DNA glycosylase that excises adenine mismatched with 8-oxoguanine (a product of oxidative DNA damage)
• Failure of this repair leads to G:C → T:A transversions, accumulating mutations in APC and KRAS
• Most frequent variants: Y179C, G396D, E480X (in European populations)
• 0.4-0.7% of all CRC patients carry a homozygous MUTYH mutation
• Polyp count: usually fewer than 100 adenomas; sessile serrated and hyperplastic polyps also common
• CRC risk: ~80%; right-sided predominance; average age of onset 45-50 years
• Extracolonic features similar to FAP (CHRPE, duodenal polyps, osteomas) but less frequent; also breast, ovarian, bladder, and skin cancer risk
• Because of recessive inheritance, family history may not be obvious

Diagnosis

• APC gene sequencing (Sanger or NGS) + deletion/duplication analysis (MLPA)
• In index cases with negative APC testing, add MUTYH biallelic testing
• Multigene panel testing increasingly used

• FAP defined as ≥100 synchronous adenomas OR fewer than 100 with a positive family history or confirmed APC mutation

Surveillance and Management

• Colonoscopy (or flexible sigmoidoscopy) starting at age 10-12 years, then annually
• Once polyps detected, annual colonoscopy
• Upper endoscopy (EGD) starting at age ~20; frequency guided by Spiegelman score (Stage I: every 5 years → Stage IV: consider surgical intervention)
• Thyroid ultrasound annually
• In women: hepatoblastoma screening in infants of affected parents

• Prophylactic colectomy is the standard of care - prevents CRC
• Timing: typically in late teens to early 20s once polyps are confirmed, or when high-grade dysplasia is found
• Options:
  • Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) - preferred when rectal polyp burden is high
  • Colectomy with ileorectal anastomosis (IRA) - appropriate for aFAP or mild rectal disease; requires continued rectal surveillance
• Desmoid disease affects surgical planning (mesenteric desmoids may preclude IPAA)

• Sulindac (NSAID) reduces adenoma number and size, especially in the rectum
• COX-2 inhibitors (celecoxib) shown to reduce polyp burden; approved as adjunct therapy
• These do not eliminate cancer risk and are not a substitute for colectomy

Comparison with Related Syndromes