PTEN hamartoma tumor syndrome (PHTS): Clinical characteristics, onco-phenotype, and molecular analysis.

Abstract

1510 Background: Germline mutations of the PTEN gene are associated with a spectrum of clinical syndromes such as Cowden's syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and the adult Lhermitte-Duclos disease (LDD). CS is the most common amongst these, and results in an increased risk of benign and malignant tumors. We sought to characterize the malignancies that develop in patients with PHTS. Methods: Patients at the Mayo Clinic Rochester, with a clinical diagnosis of PHTS, CS, BRRS, PS, and LDD were retrospectively identified from 1980 to 2009. Only patients that met the NCCN consortium criteria for diagnosis were included. The onco-pathology and molecular studies were reviewed, and relevant clinical information retrospectively obtained. Results: Forty six(23 M) patients met the consortium criteria for diagnosis of CS or related disorders. 37 had CS (80.4%), 6 had BRRS (13%) and 3 had LDD (6%). 16 of 20 patients tested had detectable genetic abnormalities; 14 missense/nonsense mutations and 2 deletions. Invasive malignancy was documented as follows: thyroid cancer (n = 7, 15%) (6 papillary, 1 follicular), breast (n = 6, 13%) (1 bilateral), renal cell (n = 6, 13%), colon (n = 2), and one each with endometrial and ovarian cancer. Regarding breast malignancies, 5 of 6 (83%) were triple negative (ER-/PR-/HER2-), and 5 of 6 patients had metastatic disease within 2 years of diagnosis. Unique neoplasms included pituitary macroadenoma (1), vaginal adenocarcinoma (1), rectal cancer (1), bronchioalveolar carcinoma (1), breast lymphoma (1), and perineal squamous cell carcinoma (1). 27 patients had benign thyroid lesions (58.6%), 11 had benign breast disease (23%), 9 had tricholemmomas (19.5%), 8 had acral keratoses (17%), 8 had cutaneous papillomas (17%), 4 had meningiomas (8%), 4 had AV malformations (8%) and 2 had colonic ganglioneuromas (4%). Conclusions: Patients with PHTS can present with a diverse oncological spectrum, highlighting the importance of intense surveillance. Breast cancer in PHTS tends to be aggressive, triple negative, with a high rate of metastases. Contrary to published literature, papillary cancers of thyroid occur more commonly than follicular neoplasms. No significant financial relationships to disclose.