{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:09:21Z","timestamp":1793729361701,"version":"4.6.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Cowden syndrome (CS) is a multisystem disease with an elevated lifetime risk of internal malignancy. We aim to assess the role of PTEN immunostain as a screening test for CS in a variety of common CS-associated neoplasms, with a particular focus on cutaneous tumors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We retrospectively searched for patients meeting criteria for CS and\/or demonstrating germline PTEN mutation from 2008 to 2022. We then performed PTEN immunostains on tumors of these patients as well as control cases.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Our study included 30 patients with CS who had a total of 25 CS-associated malignancies (13 thyroid, 8 breast, and 4 endometrial carcinomas). Specifically, there were 11 patients with biopsy-confirmed CS-associated cutaneous neoplasms, including 1 patient with multiple trichilemmomas and 3 with multiple sclerotic fibromas. In total, 45 CS-associated tumors (6 trichilemmomas, 7 sclerotic fibromas, 5 thyroid carcinomas, 18 adenomatous thyroid nodules, 6 breast carcinomas, and 3 endometrial carcinomas) and 31 non-CS cases (9 trichilemmomas, 5 sclerotic fibromas, 8 adenomatous thyroid nodules, and 3 thyroid, 3 breast, and 3 endometrial carcinomas) were available for PTEN immunohistochemical staining. PTEN expression was lost in 43 (96%) of 45 CS-associated lesions and retained in 30 (97%) of 31 sporadic tumors. The overall sensitivity and specificity of PTEN loss of expression as a screening test for CS were 96% and 97%, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>PTEN immunohistochemistry on CS-associated tumors, especially trichilemmomas, can serve as a readily accessible and cost-effective screening test for CS.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ajcp\/aqad177","type":"journal-article","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T15:07:08Z","timestamp":1704985628000},"page":"490-500","source":"Crossref","is-referenced-by-count":12,"title":["Utilizing PTEN immunohistochemistry as a screening test for Cowden syndrome"],"prefix":"10.1093","volume":"161","author":[{"given":"Emily","family":"Hartsough","sequence":"first","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital , Boston, MA , US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia S","family":"DeSimone","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital , Boston, MA , US"},{"name":"Department of Pathology, Harvard Medical School , Boston, MA , US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayra E","family":"Lorenzo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School , Boston, MA , US"},{"name":"Department of Dermatology, Massachusetts General Hospital and Harvard Medical School , Boston, MA , US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1174-3972","authenticated-orcid":false,"given":"Dora","family":"Dias-Santagata","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital , Boston, MA , US"},{"name":"Department of Pathology, Harvard Medical School , Boston, MA , US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vania","family":"Nose","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital , Boston, MA , US"},{"name":"Department of Pathology, Harvard Medical School , Boston, MA , US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1406-7981","authenticated-orcid":false,"given":"Mai P","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital , Boston, MA , US"},{"name":"Department of Pathology, Harvard Medical School , Boston, MA , US"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,11]]},"reference":[{"key":"2024050205531422800_CIT0001","first-page":"1607","article-title":"Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria","volume-title":"J Natl Cancer Inst.","author":"Pilarski","year":"2013"},{"key":"2024050205531422800_CIT0002","first-page":"103","article-title":"The clinical spectrum of PTEN mutations","volume-title":"Annu Rev Med.","author":"Yehia","year":"2020"},{"key":"2024050205531422800_CIT0003","first-page":"844","article-title":"PTEN hamartoma tumor syndrome: a clinical overview","volume-title":"Cancers.","author":"Pilarski","year":"2019"},{"key":"2024050205531422800_CIT0004","first-page":"658842","article-title":"The skin in Cowden syndrome","volume-title":"Front Med","author":"Lim","year":"2021"},{"key":"2024050205531422800_CIT0005","first-page":"42","article-title":"A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands","volume-title":"Am J Hum Genet.","author":"Tan","year":"2011"},{"key":"2024050205531422800_CIT0006","article-title":"PTEN hamartoma tumor syndrome. 2001 Nov 29 [updated 2021 Feb 11]","volume-title":"GeneReviews","author":"Yehia","year":"1993-2023"},{"key":"2024050205531422800_CIT0007","first-page":"1505","article-title":"Immunohistochemical staining of thyroidectomy specimens for PTEN can aid in the identification of patients with Cowden syndrome","volume-title":"Am J Surg Pathol.","author":"Barletta","year":"2011"},{"key":"2024050205531422800_CIT0008","first-page":"77","article-title":"Synchronous bilateral breast carcinoma in a patient with Cowden syndrome: a case report with morphologic, immunohistochemical and genetic analysis","volume-title":"Breast J.","author":"Peir\u00f3","year":"2010"},{"key":"2024050205531422800_CIT0009","first-page":"493","article-title":"Trichilemmomas show loss of PTEN in Cowden syndrome but only rarely in sporadic tumors","volume-title":"J Cutan Pathol.","author":"Al-Zaid","year":"2012"},{"key":"2024050205531422800_CIT0010","first-page":"632","article-title":"Cowden syndrome: report of two cases with immunohistochemical analysis for PTEN expression","volume-title":"Am J Dermatopathol.","author":"Zabetian","year":"2012"},{"key":"2024050205531422800_CIT0011","first-page":"637","article-title":"Phosphatase and tensin homolog immunohistochemical staining and clinical criteria for Cowden syndrome in patients with trichilemmoma or associated lesions","volume-title":"Am J Dermatopathol.","author":"Jin","year":"2013"},{"key":"2024050205531422800_CIT0012","first-page":"1201","article-title":"Phosphatase and tensin homologue status in sporadic and Cowden syndrome-associated trichilemmomas: evaluation of immunohistochemistry and fluorescence in situ hybridization","volume-title":"Br J Dermatol.","author":"Shon","year":"2014"},{"key":"2024050205531422800_CIT0013","first-page":"625","article-title":"Cowden syndrome: report of a case with immunohistochemical analysis and review of the literature","volume-title":"Oral Surg Oral Med Oral Pathol Oral Radiol Endod.","author":"Scheper","year":"2006"},{"key":"2024050205531422800_CIT0014","first-page":"1253","article-title":"Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast","volume-title":"Am J Pathol.","author":"Perren","year":"1999"},{"key":"2024050205531422800_CIT0015","first-page":"3577","article-title":"PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer","volume-title":"Clin Cancer Res.","author":"P\u00e9rez-Tenorio","year":"2007"},{"key":"2024050205531422800_CIT0016","first-page":"41","article-title":"Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations","volume-title":"Cancer Genet","author":"Sherman","year":"2015"},{"key":"2024050205531422800_CIT0017","first-page":"e5","article-title":"Upper and lower gastrointestinal findings in PTEN mutation-positive Cowden syndrome patients participating in an active surveillance program","volume-title":"Clin Transl Gastroenterol","author":"Levi","year":"2011"},{"key":"2024050205531422800_CIT0018","first-page":"1191","article-title":"Germline inactivation of PTEN and dysregulation of the Phosphoinositol-3-kinase\/Akt pathway cause human Lhermitte-Duclos disease in adults","volume-title":"Am J Hum Genet.","author":"Zhou","year":"2003"},{"key":"2024050205531422800_CIT0019","first-page":"114","article-title":"Localization of the gene for Cowden disease to chromosome 10q22-23","volume-title":"Nat Genet.","author":"Nelen","year":"1996"},{"key":"2024050205531422800_CIT0020","first-page":"828","article-title":"Will the real Cowden syndrome please stand up: revised diagnostic criteria","volume-title":"J Med Genet.","author":"Eng","year":"2000"},{"key":"2024050205531422800_CIT0021","first-page":"331","article-title":"Thyroid pathologic findings in patients with Cowden disease","volume-title":"Ann Diagn Pathol.","author":"Harach","year":"1999"},{"issue":"5","key":"2024050205531422800_CIT0022","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1001\/archderm.1972.01620140030010","article-title":"Multiple hamartoma syndrome (Cowden\u2019s disease)","volume":"106","author":"Weary","year":"1972","journal-title":"Arch Dermatol."},{"key":"2024050205531422800_CIT0023","first-page":"346","article-title":"Multiple sclerotic fibromas of the skin: a cutaneous marker of Cowden\u2019s disease","volume-title":"J Cutan Pathol.","author":"Requena","year":"1992"},{"key":"2024050205531422800_CIT0024","first-page":"840","article-title":"Storiform collagenoma as a clue for Cowden disease or PTEN hamartoma tumour syndrome","volume-title":"J Clin Pathol.","author":"Al-Daraji","year":"2007"},{"key":"2024050205531422800_CIT0025","first-page":"bcr2017221695","article-title":"Multiple sclerotic fibromas of the skin: an important clue for the diagnosis of Cowden syndrome","volume-title":"BMJ Case Rep.","author":"Kieselova","year":"2017"},{"key":"2024050205531422800_CIT0026","first-page":"30","article-title":"Inherited PTEN mutations and the prediction of phenotype","volume-title":"Semin Cell Dev Biol.","author":"Leslie","year":"2016"},{"key":"2024050205531422800_CIT0027","first-page":"104632","article-title":"Genotype-phenotype associations in a large PTEN hamartoma tumor syndrome (PHTS) patient cohort","volume-title":"Eur J Med Genet.","author":"Hendricks","year":"2022"},{"key":"2024050205531422800_CIT0028","first-page":"699","article-title":"Clinical assessment of PTEN loss in endometrial carcinoma: immunohistochemistry outperforms gene sequencing","volume-title":"Mod Pathol.","author":"Djordjevic","year":"2012"},{"key":"2024050205531422800_CIT0029","first-page":"756","article-title":"Cowden syndrome-affected patients with PTEN promoter mutations demonstrate abnormal protein translation","volume-title":"Am J Hum Genet.","author":"Teresi","year":"2007"},{"key":"2024050205531422800_CIT0030","first-page":"1985","article-title":"Biallelic NTHL1 mutations in a woman with multiple primary tumors","volume-title":"N Engl J Med.","author":"Rivera","year":"2015"},{"key":"2024050205531422800_CIT0031","first-page":"104533","article-title":"Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN hamartoma tumour syndrome and literature review","volume-title":"Eur J Med Genet.","author":"Hendricks","year":"2022"},{"key":"2024050205531422800_CIT0032","first-page":"11","article-title":"Precise definition of PTEN C-terminal epitopes and its implications in clinical oncology","volume-title":"NPJ Precis Oncol.","author":"Mingo","year":"2019"},{"key":"2024050205531422800_CIT0033","first-page":"1693","article-title":"Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors","volume-title":"Am J 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