Histopathological phenotyping of cancers in PTEN Hamartoma Tumor Syndrome for improved recognition: A single‐center study

• Published in: International journal of cancer Vol. 155; no. 9; pp. 1567 - 1576
• Main Authors: Schei‐Andersen, Ane J., Hendricks, Linda A. J., Post, Rachel S., Mensenkamp, Arjen R., Schieving, Jolanda, Adank, Muriel A., Duijkers, Floor, Jong, Mirjam, Jongemans, Marjolijn C. J., Hest, Liselotte P., Ierland, Yvette, Kleefstra, Tjitske, Leter, Edward M., Nielsen, Maartje, Schuurs‐Hoeijmakers, Janneke H. M., Hoogerbrugge, Nicoline, Vos, Janet R.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.11.2024; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Age; Age of Onset; Aged; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cohort analysis; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Cowden syndrome; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Female; Germ-Line Mutation; Hamartoma Syndrome, Multiple - genetics; Hamartoma Syndrome, Multiple - pathology; hereditary cancer; histopathology; human genetics; Humans; Male; Middle Aged; Neoplasia; Neoplasms - genetics; Neoplasms - pathology; Pathology; Phenotype; Phenotyping; PTEN; PTEN Phosphohydrolase - genetics; PTEN protein; Thyroid cancer; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Tumors; Young Adult; Cowden syndrome; PTEN; histopathology; human genetics; hereditary cancer
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.35049

PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition. Genetic testing results and pathology reports were collected for patients tested for germline PTEN variants between 1997 and 2020 from the diagnostic laboratory and the Dutch nationwide pathology databank (Palga). The cancer spectrum and age of onset were assessed in patients with (PTENpos) and without (PTENneg) a germline PTEN variant. Histopathological cancer characteristics were assessed in a nested cohort. 341 PTENpos patients (56% females) and 2882 PTENneg patients (66% females) were included. PTENpos patients presented mostly with female breast (BC, 30%), endometrial (EC, 6%), thyroid (TC, 4%) or colorectal cancer (4%). PTENpos were significantly younger at cancer onset (43 vs. 47 years) and had more often (46% vs. 18%) a second BC than PTENneg. PTEN detection rates were highest for BC <40 years (9%), TC <20 years (15%) and EC <50 years (28%), and dropped to 6%, 4%, and 15% by age 60. Histopathological characteristics were similar between groups. No histopathological cancer characteristics were distinctive for PHTS. However, PTENpos were significantly younger at cancer onset. Therefore early‐onset BC, EC, or TC warrants consideration of PHTS diagnostics either through a pre‐screen for other PHTS features or direct germline testing. What's new? PTEN hamartoma tumor syndrome (PHTS) is a rare condition caused by a germline variant in PTEN. Although PHTS is associated with increased cancer risk, patients may go unrecognized. In this study, the authors assessed the cancer spectrum, age of onset, and histopathology in a Dutch clinic‐based cohort. Germline PTEN variants presented significantly more often with early‐onset cancer, second primary breast cancer and bilateral breast cancer. In particular, PTEN detection rates were highest among patients diagnosed with breast cancer before age 40, thyroid cancer before age 20, and endometrial cancer before age 50. Such patients should be referred for germline PTEN testing.