Clinical Guidelines for Diagnosis and Management of Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in Children and Adults-Secondary Publication

Abstract

Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.

Keywords: Cowden syndrome; PTEN hamartoma tumor syndrome; cancer; colorectal polyp.

Figure 1.

Oral mucosal lesions. a. The lower gingiva is irregularly thickened and elevated, covering part of the tooth. b. Slightly white papillomatous lesions arranged in a paving stone pattern on the lower gingiva and similar lesions with mild change on the mucosal side of the lower lip.

Figure 2.

Small keratotic papules on the face and hands and multiple trichilemmomas on the face. a. Numerous normal-colored papules on the dorsum and wings of the nose from the medial cheek area. b. Scattered verrucous, keratotic papules on the dorsum of the hands and fingers. c. Multiple trichilemmomas: scattered keratotic pits on the forehead and eyebrows of an older patient, some clustered. d. Histopathology of trichilemmomas (histopathology of one of the trichilemmomas in c, hematoxylin and eosin staining): epidermal thickening composed of bright cells with hyperkeratosis is prominent.

Figure 3.

Breast cancer. a. Mammography shows an irregularly shaped mass in the breast. b. CT image shows an irregular mass in the left mammary gland. c. Gross examination of the surgically removed specimen reveals a whitish mass. d. Histopathological examination revealed ductal carcinoma of the breast. Enlarged image with black frame.

Figure 4.

Multiple nodular goiter. a. CT image. A mass-like lesion approximately 20 mm in size with relatively clear borders is observed in the right lobe of the thyroid gland. b. CT images. CT MRP images show heterogeneity within the mass. c. Ultrasound image. The mass in the right lobe of the thyroid gland is hypoechoic with well-defined borders, and a small cyst is observed inside. d. Ultrasound image. The left lobe shows a cyst with a septum. In the present case, puncture aspiration of the mass in the right lobe was performed; however, no cells suggestive of malignancy were observed.

Figure 5.

Colorectal polyps. a. Colonoscopy showing a reddish pedunculated polyp 8 mm in size in the transverse colon. b. NBI observation does not show appearance of neoplastic vessels on the surface. c. Loupe image of excised polyp. d. Higher magnification of the black square in c. The histological findings are consistent with those of a hamartomatous polyp.

Figure 6.

Gastric polyp. a. Gastroscopy shows a reddish pedunculated polyp in the pylorus. b. NBI observation shows slightly rich vascularity, but no tumor-like findings. c. Loupe image of excised polyp. d. Higher magnification of the black square in c. The histological findings are consistent with those of a hamartomatous polyp.

Figure 7.

Glycogenic acanthosis of the esophagus. a. Endoscopic examination of the esophagus reveals numerous white elevations. b. Diagnosis of glycogenic acanthosis due to the presence of an increased number of spinous cells with bright and abundant cytoplasm. The inset is the magnified black square image.