Cowden Syndrome

Overview

Definition

Cowden syndrome is an autosomal dominant genodermatosis caused by a mutation in the PTEN gene and characterized by multiple benign hamartomas in any location of the body, mucocutaneous lesions, and macrocephaly.

Epidemiology

• 1 in 200,000 people are affected.
• Most common phenotype of the PTEN gene mutation spectrum
• Some studies suggest that women are more commonly affected. 
• Most patients are white.

Etiology

• Autosomal dominant inherited mutations in a tumor suppressor gene
• Mutation is in the PTEN gene on arm 10q23.
• PTEN is a lipid phosphatase that removes phosphate groups from signaling molecules.
• When PTEN is mutated, cells are allowed to proliferate.

Pathophysiology

• The PTEN protein:
  • Promotes cell death by restricting growth and survival signals, allowing for normal cell death
  • Negatively controls the pathway for regulating cell growth and survival (phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway)
• The PTEN gene is lost by a “2nd hit” mutation → PTEN is not expressed
• Normal downregulation of the mTOR pathway is lost →  loss of control of apoptosis → overproliferation of cells occurs → hamartomatous growths → neoplasms develop

Clinical Presentation

History

• Usually presents in patients’ 20s
• Patients report appearance of lesions on the skin and mucous membranes first.
• Women may complain of menstrual abnormalities due to uterine leiomyomas.
• Hamartomatous polyps in the GI tract can cause pain and bleeding.

Physical examination

• Head: macrocephaly
• Oral cavity: papillomas
• Skin: trichilemmoma (yellow-brown, warty papules), multiple seborrheic keratoses
• Soft tissue: hamartomas, lipomas, or angiolipomas
• Neck: goiter, thyroid cancer
• Breast (in both women and men): breast masses, breast cancer
• Rectal exam: positive hemoccult

Diagnosis

Diagnostic criteria

• Diagnosis depends on the fulfillment of 1 of 4 sets of criteria: 
  1. Pathognomonic criteria
  2. At least 2 major criteria
  3. 1 major and 3 minor criteria
  4. 4 minor criteria
• Pathognomonic criteria: mucosal and skin lesions
• Major criteria:
  • Macrocephaly
  • Thyroid cancer
  • Breast cancer
  • Endometrial cancer
• Minor criteria:
  • Genitourinary tumors or malformations
  • Lipomas
  • Fibromas
  • Mental retardation
  • Fibrocystic disease of the breast
  • GI hamartomas
  • Thyroid lesion (i.e., goiter)
  • Uterine fibroids

Laboratory tests

• CBC
• Thyroid function test (thyroid-stimulating hormone (TSH), FT4)
• Stool for occult blood
• Urinalysis
• PTEN gene mutation testing

Diagnostic imaging

• Based on complaint
• Abdominal CT scan
• Abdominal MRI
• Ultrasound of uterus for leiomyomas
• Mammography

Management

Surveillance

• Management is centered around more frequent cancer screenings.
• Education regarding the signs and symptoms of cancer
• Monthly breast self-exams for women
• Annual history and physical examinations including:
  • Thyroid ultrasound
  • Uterine screening for women
  • Skin checks
  • Kidney screening (urinalysis)
• Colonoscopy starting at age 35 years:
  • Colonoscopy every 5 years
  • More frequently if symptomatic or polyps found
• Mammogram, starting at age 30 for women

Complications

• Neoplasms:
  • Skin (in 90%–100% of cases)
  • Mucosa
  • GI tract
  • Bones
  • CNS
  • Eyes
  • Genitourinary tract
  • Thyroid (in 66% of cases)
• Gastric polyps
• Desmoid tumors 
• Thyroid tumors and disorders

Prognosis

• Patients may have close-to-normal life expectancies.
• Frequent cancer screening and prompt diagnosis improve outcomes. 
• Morbidity and mortality are associated with ↑ frequency of malignant tumors
• Benign tumors can cause significant morbidity.
• At least 40% of patients have a minimum of 1 malignant primary tumor.

Differential Diagnosis

• Hereditary nonpolyposis colon cancer (HNPCC): also known as Lynch syndrome, an autosomal dominant disorder caused by mutations in the mismatch repair (MMR) genes, which ultimately leads to the development of colorectal cancer in 1st-degree relatives. Management is with prophylactic colectomy and frequent endoscopy for surveillance. 
• Juvenile polyposis: an autosomal dominant condition characterized by the growth of hyperplastic, hamartomatous polyps in the colon. The condition is commonly associated with mutations in the SMAD4 and BMPR1A genes. Diagnosis is made by visualizing > 5 polyps on colonoscopy, or any number plus a positive family history. Management is surgical in order to reduce the likelihood of GI bleeding and obstruction. 
• Colorectal cancer (CRC): the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease, arising from genetic and epigenetic abnormalities, with influence from environmental factors. Almost all cases of CRC are adenocarcinoma. Most cases are asymptomatic, so screening is important. Diagnosis is by colonoscopy. Management is primarily surgical.
• Thyroid cancer: malignancy of the thyroid gland cells, which can arise from the thyroid follicular cells or the calcitonin-producing C cells. Exposure to ionizing radiation and iodine deficiency are also considered risk factors. Diagnostic is with TSH, ultrasound, and biopsy. Management is mainly surgical.
• Uterine leiomyomas: also known as uterine fibroids; benign tumors arising from smooth muscle cells in the uterine myometrium. Uterine leiomyomas present with abnormal bleeding and pelvic pain. Fibroids are hypoechoic, well-circumscribed, round masses on pelvic ultrasound. Depending on patient symptoms and preference, treatment for leiomyomas may include surgical resection or medical options to reduce bleeding or bulk.