What is the recommended evaluation and management for a patient with suspected Cowden syndrome, particularly with a family history of breast, thyroid, or other cancers?

Cowden Syndrome: Evaluation and Management

For patients with suspected Cowden syndrome and a family history of breast, thyroid, or other cancers, immediately pursue comprehensive PTEN genetic testing if they meet specific clinical criteria, followed by intensive multi-organ cancer surveillance starting at age 18 or earlier based on family history. 1

Diagnostic Evaluation and Genetic Testing Criteria

Who Should Undergo PTEN Testing

Comprehensive PTEN testing (including full sequencing, gene deletion/duplication analysis, and promoter analysis) should be performed in individuals meeting any of the following criteria: 1

Major Criteria include: 1

• Breast cancer
• Endometrial cancer (epithelial)
• Follicular thyroid cancer
• Macrocephaly (≥97th percentile: ≥58 cm for women, ≥60 cm for men)
• Multiple gastrointestinal hamartomas or ganglioneuromas (≥3)
• Adult Lhermitte-Duclos disease
• Macular pigmentation of glans penis
• Multiple mucocutaneous lesions (≥3 trichilemmomas with ≥1 biopsy-proven, multiple palmoplantar keratoses, multiple oral mucosal papillomatosis, or multiple cutaneous facial papules)

Testing Thresholds: 1

• 2 or more major criteria with 1 being macrocephaly
• 3 or more major criteria without macrocephaly
• 1 major criterion plus 3 minor criteria
• 4 or more minor criteria alone

Minor Criteria include: 1

• Autism spectrum disorder (without macrocephaly)
• Colon cancer
• Esophageal glycogenic acanthosis (≥3)
• Lipomas
• Mental retardation (IQ ≤75)
• Papillary or follicular variant of papillary thyroid cancer
• Thyroid structural lesions (adenoma, nodules, goiter)
• Renal cell carcinoma
• Single gastrointestinal hamartoma or ganglioneuroma
• Testicular lipomatosis
• Vascular anomalies (including multiple intracranial developmental venous anomalies)

At-Risk Family Members

First-degree relatives of affected individuals should undergo PTEN testing if they have: 1

• Any 1 major criterion, OR
• 2 or more minor criteria

Initial Clinical Assessment

Perform a targeted physical examination focusing on: 1

• Skin and oral mucosa (looking for trichilemmomas, palmoplantar keratoses, oral papillomas, facial papules)
• Breast examination
• Thyroid palpation and assessment
• Head circumference measurement
• Neurologic examination

Cancer Surveillance and Management for Confirmed Cases

Breast Cancer Surveillance (Women)

Women with Cowden syndrome face a cumulative lifetime breast cancer risk of 77-85%, with average diagnosis age of 38-46 years. 1

Implement the following breast surveillance protocol: 1

• Breast awareness: Begin at age 18
• Clinical breast examination: Every 6-12 months starting at age 25 (or 5-10 years before youngest family breast cancer diagnosis)
• Annual mammography AND breast MRI: Begin at age 30-35 (or individualized based on earliest family onset)
• Risk-reducing mastectomy: Discuss on case-by-case basis, though no specific outcome data exist for this population 1

Thyroid Cancer Surveillance (Both Sexes)

Lifetime thyroid cancer risk is 35-38% (compared to 1% in general population), with standardized incidence ratios of 43.2 for women and 199.5 for men. 1

Thyroid surveillance protocol: 1

• Annual thyroid ultrasound: Begin at age 18 (or 5-10 years before earliest known family thyroid cancer diagnosis)
• Careful thyroid assessment during annual comprehensive physical examination

Endometrial Cancer Surveillance (Women)

Women face a 28-48.7% lifetime risk of endometrial cancer. 1

Endometrial surveillance protocol: 1

• Patient education regarding endometrial cancer symptoms with prompt response to any symptoms
• Consider annual random endometrial biopsies and/or transvaginal ultrasound: Begin at age 30-35
• Note: Oophorectomy is NOT indicated for Cowden syndrome alone 1

Colorectal Cancer Surveillance

Colorectal cancer risk is elevated (9-16% lifetime risk, with 13% presenting before age 50). 1

Colonoscopy protocol: 1

• Begin at age 35
• Repeat every 5-10 years (more frequently if symptomatic or polyps found)

Renal Cell Carcinoma Surveillance

Lifetime renal cancer risk is 30.6-34%. 1

Renal surveillance protocol: 1

• Renal ultrasound: Begin at age 40
• Repeat every 1-2 years thereafter

Additional Surveillance and Management

Annual comprehensive physical examination: Begin at age 18 (or 5 years before youngest family cancer diagnosis) 1

Annual dermatologic examination for management of mucocutaneous lesions 1

Psychomotor assessment in children at diagnosis (due to mental retardation risk) 1

Brain MRI only if localizing neurologic signs or symptoms present 1

Critical Management Pitfalls

Common diagnostic errors to avoid: 1, 2

• Misdiagnosing as Peutz-Jeghers syndrome when gastrointestinal polyposis is prominent
• Failing to recognize subtle mucocutaneous lesions that are pathognomonic
• Not measuring head circumference in adults (macrocephaly is a key criterion)
• Overlooking the syndrome in patients presenting with isolated breast or thyroid cancer without recognizing other features

Testing considerations: 1

• Patients who received allogeneic bone marrow transplant should NOT have genetic testing via blood or buccal samples due to donor DNA contamination; use fibroblast culture DNA if available
• If no PTEN mutation found but clinical suspicion remains high, consider testing for other hereditary breast cancer syndromes 1

The penetrance of PTEN mutations is approximately 80%, and cumulative lifetime risk for any cancer is 85-89%. 1 Early identification through recognition of mucocutaneous lesions and family history is crucial before malignancy develops. 3