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Background: Dermatologic phenotypes in PTEN hamartoma tumor syndrome (PHTS) are heterogeneous and poorly documented., Objective: To characterize dermatologic findings among PHTS and conduct an analysis of genotype-dermatologic phenotype associations., Methods: Mucocutaneous findings were reviewed in a multicenter cohort study of PHTS. Genotype-dermatologic phenotype associations were tested using multivariable regression., Results: A total of 201 patients were included. Children were significantly less likely than adults to have oral papillomas, vascular malformations, benign follicular neoplasms, and acral keratoses. There were no cases of skin cancer among children. Basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma developed in 5%, 2%, and 1% of White adults, respectively. After adjusting for age, missense mutations were associated with 60% lower odds of developing cutaneous papillomatous papules (odds ratio: 0.4; 95% confidence interval [0.2, 0.7]), oral papillomas (0.4; 95% confidence interval [0.2, 0.9]), and vascular malformations (0.4; 95% confidence interval [0.2, 0.8])., Limitations: Partly retrospective data., Conclusion: Children are less likely than adults to have certain dermatologic findings, likely due to age-related penetrance. The risk of pediatric melanoma and the lifetime risk of nonmelanoma skin cancer in PHTS may not be elevated. Missense variants may be associated with the development of fewer dermatologic findings but future validation is required., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD)., Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS., Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023., Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews., Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population., Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001)., Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks., Methods: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses., Results: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%., Conclusions: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Cowden syndrome (CS) is an autosomal-dominant hereditary disorder caused by a germline PTEN variant and characterized by multiple hamartomas and a high risk of cancers. However, no detailed data on CS in Asian patients nor genotype-phenotype correlation have been reported., Methods: We performed the first Japanese nationwide questionnaire survey on CS and obtained questionnaire response data on 49 CS patients., Results: Patients included 26 females (median age 48 years). The incidence of breast, thyroid, endometrium, and colorectal cancer was 32.7%, 12.2%, 19.2% (among females), and 6.1%, respectively. The incidence of any cancers was relatively high among all patients (46.9%, 23/49), and particularly female patients (73.1%, 19/26), compared with previous reports from Western countries. Gastrointestinal (GI) polyps were more frequently found throughout the GI tract compared with previous studies. PTEN variants were detected in 95.6% (22/23) of patients; 12 in the N-terminal region (11 in phosphatase domain) and 10 in the C-terminal (C2 domain) region. The incidence of cancer in the C2 domain group was significantly higher than in the N-terminal region (phosphatase) group. All female patients with C2 domain variant had breast cancer., Conclusion: Our data suggest that Japanese patients with CS, particularly female patients and patients with C2 domain variant may have a high risk of cancers., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Goals and Background: Phosphatase and tensin homolog hamartoma tumor syndrome (PHTS) is an inherited disorder that increases the risk for cancer in multiple organ systems, including breast, endometrial, thyroid, and the gastrointestinal tract. Surveillance is recommended however there lacks data to describe the change in polyposis phenotype and cancer incidence over surveillance. Our aim is to describe the polyposis phenotype and cancer incidence in PHTS patients undergoing endoscopic surveillance., Study: PHTS patients, ages 17 through 89, who underwent at least 2 esophagogastroduodenoscopy (EGDs) or colonoscopies were identified. Number and sizes of polyps were noted, from which 5 categories were recreated. Incidence of colorectal and gastric cancer was evaluated., Results: Seventy patients were included. Patients were clustered and classified into 1 of 5 categories: no polyps, few small polyps (<1 cm, < 10 polyps), few large polyps (≥1 cm, < 10 polyps), many small polyps (<1 cm, ≥10 polyps), many large polyps (≥1 cm, ≥10 polyps). There was no significant difference in polyp number or size on EGD (P=0.47 and 0.83, respectively) or colonoscopy (P=0.49 and 0.10, respectively) over the surveillance period (4.8±3.9 y for stomach and 5.6±4.4 y for colon). The average interval between endoscopies was 28±24 months for EGDs and 29±23 months for colonoscopies. A stage II transverse colon adenocarcinoma and stage IV gastric adenocarcinoma were identified. Standardized incidence rates for gastric and colon cancers were 5427 (P=0.0002) and 353 (P=0.002), respectively., Conclusions: PTHS individuals can be classified into polyposis phenotypes which do not change over an endoscopic surveillance period. Two cancers were associated with a large size polyp phenotype. Surveillance intervals should be determined by polyp size ≥1 cm and pathology., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Context: Thyroid ultrasound screening is recommended in children with PTEN hamartoma tumor syndrome (PHTS) due to increased risk of thyroid neoplasia, but the natural history of thyroid disease in children with PHTS is unclear., Objective: Determine the prevalence and natural history of thyroid disease in children with PHTS., Methods: Retrospective cohort study (1998-2019) in an academic pediatric hospital of individuals with genetically confirmed PHTS diagnosed before age 19 years. Clinical, thyroid ultrasound, and laboratory characteristics are described. Primary outcomes were the prevalence of thyroid nodules ≥10 mm diameter and time course and risk factors for nodule development assessed by Cox regression analysis. Secondary outcomes included thyroid nodule requiring biopsy, other ultrasound findings, and prevalence of autoimmune thyroid disease., Results: Among 64 subjects with PHTS, 50 underwent thyroid ultrasound. A thyroid nodule ≥10 mm was diagnosed in 22/50 (44%) subjects at median (range) age 13.3 (7.0-22.9) years. Nodules were diagnosed earlier in females than in males (10.8 [7.0-17.9] vs 14.2 [9.9-22.9] years, P = .009). In multivariate analysis, risk of thyroid nodules was significantly associated with female sex (hazard ratio 2.90, 95% CI 1.16-7.27, P = .02) and inversely associated with the presence of neurologic findings of PHTS (HR 0.27, 95% CI 0.10-0.69, P = .007). Abnormal-appearing lymph nodes with echogenic foci were observed by ultrasound in 20% of subjects, but these were not associated with malignancy. Autoimmune thyroid disease was present in 10/33 (30.3%) of subjects in whom it was assessed., Conclusion: Thyroid disease is common in children with PHTS. This study supports current consensus recommendations for ultrasound screening., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

PTEN hamartoma tumour syndrome is a diverse multi-system disorder predisposing to the development of hamartomatous growths, increasing risk of breast, thyroid, renal cancer, and possibly increasing risk of endometrial cancer, colorectal cancer and melanoma. There is no international consensus on cancer surveillance in PHTS and all current guidelines are based on expert opinion. A comprehensive literature review was undertaken and guidelines were developed by clinicians with expertise from clinical genetics, gynaecology, endocrinology, dermatology, radiology, gastroenterology and general surgery, together with affected individuals and their representatives. Recommendations were put forward for surveillance for breast, thyroid and renal cancers. Limited recommendations were developed for other sites including endometrial, colon and skin. The proposed cancer surveillance recommendations for PHTS require a coordinated multidisciplinary approach and significant patient commitment. The evidence base for cancer surveillance in this guideline are limited, emphasising the need for prospective evaluation of the effectiveness of surveillance in the PHTS population.

PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1-weighted and 9 diffusion-weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high-angular resolution diffusion MRI (HARDI) tractography analyses. Mega-corpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto-occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS., (© 2020 Wiley Periodicals, Inc.)

Introduction: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) comprises a collection of clinical features characterized by constitutional variants in PTEN. Several guidelines recommend thyroid screening, beginning at the pediatric age at the time of PHTS diagnosis; however, the benefits of early surveillance has not been well defined., Methods: We conducted a retrospective investigation of patients followed up at the Children's Hospital of Philadelphia with a diagnosis of PHTS between January 2003 and June 2019. In total, 81 patients younger than 19 years were identified., Results: The most common clinical feature at presentation was macrocephaly (85.1%), followed by impaired development (42.0%), skin/oral lesions (30.9%), and autism spectrum disorder (27.2%). A total of 58 of 81 patients underwent thyroid surveillance, with 30 patients (51.7%) found to have a nodule(s). Ultimately, 16 patients underwent thyroidectomy, with 7.4% (6/81) diagnosed with thyroid cancer. All thyroid cancer patients were older than 10 years at diagnosis, and all displayed low-invasive behavior. Of the patients younger than 10 years at the time of thyroid ultrasound (US) surveillance, 71.4% (15/21) had a normal US. The remaining 6 patients had thyroid nodules, including 4 undergoing thyroid surgery with benign histology., Discussion/conclusion: Patients with macrocephaly, impaired cognitive development and thyroid nodules, and/or early-onset gastrointestinal polyps should undergo constitutional testing for PHTS. There does not appear to be a clinical advantage to initiating thyroid US surveillance before 10 years of age. In PHTS patients with a normal physical examination, thyroid US surveillance can be delayed until 10 years of age., (© 2021 S. Karger AG, Basel.)

Basal cell carcinoma (BCC), the most frequent skin cancer, has been increasing in incidence. However, the characteristics of multiple BCC have not been clarified in Japan. Therefore, we conducted a retrospective study to elucidate the features of multiple BCC compared with solitary BCC. The study population consisted of 327 patients with histopathologically proven BCC who were referred to the Department of Dermatology in Tottori University Hospital between November 2006 and April 2016. Of the 327 patients, 304 (93.0%) had solitary BCC and 23 (7.0%) had multiple BCC. The mean age of the patients with solitary BCC was 74.7 years (range, 31-102) and that of patients with multiple BCC was 79.3 years (range, 63-91). There was a significant difference in mean age between the two groups (P = 0.01). Approximately four-fifths of the BCC were located on the head or neck in the total study population. In the group of patients with multiple BCC, the incidence of lesions on the head and neck was lower and that on the trunk was higher than those in patients with solitary BCC. There was a significant difference in the tumor site between the two groups (P < 0.0001). With respect to tumor histopathology, the ratio of superficial BCC was significantly higher in the group of patients with multiple BCC than in the group of patients with solitary BCC (P < 0.0001). In conclusion, we demonstrated that older age, truncal location and superficial histopathological type of tumor are features of multiple BCC in Japanese subjects., (© 2018 Japanese Dermatological Association.)

Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes ( APC and MUTYH ), juvenile polyposis coli ( BMPR1A and SMAD4 ), Peutz-Jeghers Syndrome ( STK11 / LKB1 ), and PTEN hamartoma tumor syndrome (PHTS; PTEN ), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107-e14. ©2017 AACR See all articles in the online-only CCR Pediatric Oncology Series ., (©2017 American Association for Cancer Research.)

PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord-stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended. Clin Cancer Res; 23(12); e76-e82. ©2017 AACR See all articles in the online-only CCR Pediatric Oncology Series., (©2017 American Association for Cancer Research.)

Male breast cancer is a rare disease, accounting for only 1% of breast cancer diagnoses in the USA. The current literature suggests that genetic factors including BRCA2 mutations, family history, age, androgen/estrogen imbalance, and environmental exposures may predispose to male breast cancer. In this manuscript, we will review known and possible risk factors for male breast cancer, as well as describe the clinical patterns of the disease.

Cowden syndrome (CS) is a genetic disorder characterized by multiple benign tissue growths (i.e., hamartomas) and an increased risk of developing specific cancers, such as breast, thyroid, kidney, endometrial, or colorectal cancer (Genetics Home Reference, 2012). This genetic syndrome was named after a person diagnosed with the disorder (Lloyd & Dennis, 1963). CS is part of a larger syndrome called PTEN hamartomatous syndrome, which also includes Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and Proteus-like syndrome (Eng, 2014).

Context: RASAL1 has recently been identified as an important tumor suppressor for sporadic thyroid tumorigenesis, particularly for follicular thyroid cancer (FTC) and anaplastic thyroid cancer. Thyroid cancer is an important component of Cowden syndrome (CS). Patients with germline PTEN mutations have an overrepresentation of FTC over other histological subtypes., Objective: To determine the prevalence of germline RASAL1 mutations in PTEN mutation-positive and wild type CS patients., Setting and Design: We reviewed our prospective database of more than 3000 CS/CS-like patients and retrospectively identified a subset of patients who presented with thyroid cancer for RASAL1 mutation analysis. We reviewed data from The Cancer Genome Atlas (TCGA) sporadic papillary thyroid cancer (PTC) database with germline data for RASAL1 mutations to determine the prevalence of germline RASAL1 mutations in CS-related thyroid cancer patients., Results: We scanned 155 CS/CS-like patients with thyroid cancer for germline RASAL1 mutations. Of the 155 patients, 39 had known germline pathogenic PTEN mutations (PTEN(mut+)) and 116 were PTEN mutation negative (PTEN(WT)). Among these 155 patients, we identified RASAL1 germline alterations suspected as being deleterious in two patients. Both were patients with PTEN(WT) who had FTC (2/48, 4.1%). This was in contrast to patients with PTEN(mut+) who had thyroid cancer (0/39). Of 339 sporadic patients with PTC from the TCGA study, 62 (18%) had germline RASAL1 variants predicted to be deleterious. TCGA patients with follicular-variant PTC were statistically overrepresented (21/62, 34%) among patients with deleterious RASAL1 variants compared with those without (57/277, 21%)., Conclusions: Germline RASAL1 alterations are uncommon in patients with CS but may not be infrequent in patients with apparently sporadic follicular-variant PTC.

Objective: To formally study the prevalence and histologic classification of renal cell carcinoma (RCC) in a series of patients with PTEN hamartoma tumor syndrome (PHTS)., Methods: We evaluated prevalence of RCC within a prospectively-accrued series of 219 patients found to have pathogenic germline PTEN mutations. Clinical data including pathology reports were requested for all participants. Slides and tumor blocks were requested for central pathology re-review and immunohistochemistry (IHC) analysis., Results: Nine patients were identified with RCC. Based on Surveillance Epidemiology and End Results (SEER) data 0.28 RCC cases were expected for the group, giving an overall age-adjusted Standardized Incidence Ratio (SIR) of 31.7 (95% CI 15.4-58.1, P < 0.001) with a higher sex-adjusted SIR for females (46.7 vs 21.6 for males). Reported histology of each mutation positive patient's RCC was variable. However, on central pathology re-review of eight patients, six examined lesions were determined to be of papillary subhistology (pRCC), with the other two patients' tumors consistent with the initial report of chromophobe RCC (chRCC). IHC demonstrated complete loss of PTEN protein in all PTEN mutation positive patients' pRCCs and patchy positivity in one chRCC., Conclusion: PHTS is a hereditary syndrome newly associated with pRCC, and PTEN IHC may be a helpful screening tool to identify pRCC patients with PHTS. Physicians caring for PHTS patients should note the >31-fold increased risk for RCC and have a low threshold for investigating possible RCC in patients with relevant complaints. Renal ultrasound is not sensitive for detecting pRCC and so PHTS patients should have alternate renal imaging (CT or MRI)., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Basal cell carcinoma (BCC) is the commonest cancer in humans. Predisposing factors reflect common genetic variations and environmental influences in most cases. However, an underlying Mendelian disorder should be suspected in a specific subset of patients, namely those with multiple, early onset lesions. Some specific conditions, including Gorlin, Bazex-Dupré-Christol and Rombo syndromes, and Xeroderma Pigmentosum, show BCC as a prominent feature. In addition, BCC may represent a relatively common, although less specific, finding in many other genodermatoses. These include disorders of DNA replication/repair functions (Bloom, Werner, Rothmund-Thomson and Muir-Torre syndromes), genodermatoses affecting the folliculo-sebaceus unit (Brooke-Spiegler, Schöpf-Schulz-Passarge and Cowden syndromes), immune response (cartilage-hair hypoplasia and epidermodysplasia verruciformis) and melanin biosynthesis (oculocutaneous albinism and Hermansky-Pudlak syndrome), and some epidermal nevus syndromes. Further conditions occasionally associated with BCCs exist, but the significance of the association remains to be proven.

Purpose: Age-adjusted cancer incidence and age-related penetrance studies have helped guide cancer risk assessment and management. PTEN hamartoma tumor syndrome (PHTS) is a term encompassing subsets of several clinical syndromes with germline mutations in the PTEN tumor suppressor gene. We conducted the first prospective study to clarify corresponding cancer risks to shed biologic insights on human germline PTEN mutations, and to better inform current surveillance recommendations on the basis of expert opinion., Experimental Design: A series of 3,399 individuals meeting relaxed International Cowden Consortium PHTS criteria were prospectively recruited; 368 individuals were found to have deleterious germline PTEN mutations. Age-adjusted standardized incidence ratio (SIR) calculations and genotype-phenotype analyses were carried out., Results: Elevated SIRs were found for carcinomas of the breast [25.4, 95% confidence interval (CI), 19.8-32.0], thyroid (51.1, 38.1-67.1), endometrium (42.9, 28.1-62.8), colorectum (10.3, 5.6-17.4), kidney (30.6, 17.8-49.4), and melanoma (8.5, 4.1-15.6). Estimated lifetime risks were, respectively, 85.2% (95% CI, 71.4%-99.1%), 35.2% (19.7%-50.7%), 28.2% (17.1%-39.3%), 9.0% (3.8%-14.1%), 33.6% (10.4%-56.9%), and 6% (1.6%-9.4%). Promoter mutations were associated with breast cancer, whereas colorectal cancer was associated with nonsense mutations., Conclusion: Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer, and melanoma, are increased in patients with PTEN mutations. The genotype-phenotype associations here may provide new insights on PTEN structure and function. We propose a comprehensive approach to surveillance of patients with PTEN mutations., (©2011 AACR.)

Context: Thyroid cancer is believed to be an important component of Cowden syndrome (CS). Germline PTEN and SDHx mutations and KLLN epimutation cause CS and CS-like phenotypes. Despite the established association, little is known about the incidence and clinical features of thyroid cancer found in CS/CS-like patients., Objective: The aim of the study was to compare incidence, clinical, and histological characteristics of epithelial thyroid cancers in CS/CS-like individuals, in the context of PTEN, SDHx, and KLLN status., Design and Participants: The study encompassed a 5-yr, multicenter, prospective accrual of 2723 CS and CS-like patients, all of whom had comprehensive PTEN analysis. SDHx mutation analysis occurred in those without PTEN mutations/variations and elevated manganese superoxide dismutase (MnSOD) levels. KLLN epimutation analysis was performed in the subset without any PTEN or SDHx mutation/deletion/ variant/polymorphism., Main Outcome Measures: Gene-specific thyroid cancer histologies, demographic and clinical information, and adjusted standardized incidence rates were studied., Results: Of 2723 CS/CS-like patients, 664 had thyroid cancer. Standardized incidence rates for thyroid cancer were 72 [95% confidence interval (CI), 51-99; P < 0.001] for pathogenic PTEN mutations, 63 (95% CI, 42-92; P < 0.001) for SDHx variants, and 45 (95% CI, 26-73; P < 0.001) for KLLN epimutations. All six (16.7%) diagnosed under age 18 yr carried pathogenic PTEN mutations. Follicular thyroid cancer was overrepresented in PTEN mutation-positive cases compared to those with SDHx and KLLN alterations. PTEN frameshift mutations were found in 31% of patients with thyroid cancer compared to 17% in those without thyroid cancer., Conclusions: CS/CS-like patients have elevated risks of follicular thyroid cancer due to PTEN pathogenic mutations and of papillary thyroid cancer from SDHx and KLLN alterations. Children presenting with thyroid cancer should be tested for PTEN mutations.

We report a case of pulmonary arterial hypertension (PAH) occurring in a patient with Cowden syndrome with a mutation in the phosphatase and tensin (PTEN) tumor suppressor gene, in the context of exposure to the appetite suppressant dexfenfluramine. Anorexigen exposure is known to be a risk factor for PAH. However, the role of PTEN in cell function and the development of pulmonary vascular remodeling and histopathologic signs of PAH in mice with a Pten depletion in smooth muscle cells suggest that the association of PAH and Cowden syndrome may be relevant. In this case report, we hypothesize that PTEN mutations may be a predisposing factor for the development of PAH, with anorexigen exposure as a potential trigger.

Background: The incidence of multiple basal cell carcinomas (BCCs) is not well documented., Objectives: To calculate the cumulative risks, rates and risk factors for the development of subsequent histologically confirmed BCCs., Methods: For this cohort study the Dutch nationwide network and registry of histopathology and cytopathology (PALGA) was used. The first 2483 patients diagnosed with a first histologically confirmed BCC in the year 2004 were followed for 5years. Multifailure survival models were used to study whether gender or age affected the risk of developing subsequent tumours., Results: During our observational period, the 2483 patients developed a total of 3793 histologically confirmed BCCs. The 5-year cumulative risk of developing one or more subsequent BCCs was 29·2%. Incidence rates were 25,318 per 100,000person-years in the first 6months after first BCC diagnosis, decreasing to 6953 per 100,000person-years after 5years of follow-up. Males compared with females had a 30% [adjusted hazard ratio (HR) 1·30, 95% CI (confidence interval) 1·11-1·53] higher risk of developing multiple BCCs and those aged 65-79years had more than 80% (adjusted HR 1·81, 95% CI 1·37-2·41) higher risk of having subsequent tumours compared with patients younger than 50years., Conclusions: The high incidence rate of subsequent BCCs among patients with a first BCC is highest in the first months after diagnosis of the first BCC but persists long term, indicating that patients with BCC should undergo full-body skin examinations at first presentation and subsequent follow-up visits. Special attention should be paid to males and persons of older age at index lesion., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Background & Aims: Germline phosphatase and tensin homolog (PTEN) mutations cause Cowden syndrome (CS), associated with breast and thyroid cancers. Case reports found 35%-85% of CS patients had gastrointestinal (GI) hamartomas. The association of benign and malignant GI neoplasias with CS remains debatable. Our goal is to describe the GI phenotype in a prospective series of PTEN mutation carriers., Methods: Patients who met relaxed International Cowden Consortium criteria (N = 2548) or with 5 or more GI polyps, 1 or more of which was hyperplastic or hamartomatous (N = 397), were prospectively recruited. Germline PTEN mutation/deletion analysis was performed. Of the 2945 patients, 127 (123 of 2548 and 4 of 397, respectively) patients having clear pathogenic PTEN mutations were eligible for this study. Esophagogastroduodenoscopy, colonoscopy, and pathology reports were reviewed. The Fisher 2-tailed exact test, unpaired t tests, and age- and sex-adjusted standardized incidence ratio were calculated., Results: Of 127 PTEN mutation carriers, 69 underwent 1 or more endoscopies with 64 (93%) having polyps. Of the 64, half had hyperplastic polyps. There were one to innumerable polyps in the colorectum, ileum, duodenum, stomach, and/or esophagus, with 24 subjects having both upper and lower GI polyps. Nine (13%) subjects had colorectal cancer, all younger than the age of 50. The adjusted standardized incidence ratio was 224.1 (95% confidence interval, 109.3-411.3; P < .0001)., Conclusions: PTEN-associated CS should be considered a mixed polyp syndrome, with hyperplastic polyps most prevalent, with a risk of early onset colorectal cancer. Routine colonoscopy should be considered in PTEN-associated CS, especially in the context of hyperplastic and/or adenomatous polyps., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Cowden syndrome is a familial cancer predisposition syndrome associated with an increased risk for breast, thyroid, and endometrial cancers and benign manifestations. With early detection and appropriate therapeutic treatment, many of its associated tumors and cancers are treatable. By better understanding mutations such as Cowden syndrome, additional targeted therapies can be developed and delivered.

Cowden disease (CD) is an autosomal dominant syndrome characterized by multiple hamartomatous lesions and an increased risk for malignancies. Recent evidence has indicated that the PTEN gene, encoding a protein tyrosine phosphatase, is the CD susceptibility gene. However, another line of evidence has suggested that CD might be genetically heterogeneous. Clinical features of CD are variable, and there are interfamilial differences in the expression of skin lesions. Therefore, information on PTEN mutations in CD patients should be accumulated to clarify the genotype-phenotype correlation. In the present study, we found heterozygous germline mutations of PTEN in all of three Japanese patients with CD examined, indicating no genetic heterogeneity among our patients. The mutations included two non-sense mutations of R335X and R130X, and a mis-sense mutation of C136R. To the best of our knowledge, the C136R mutation has not previously been reported in CD patients. This novel mutation was located outside the core motif of the phosphatase domain of PTEN protein, where most of the missense mutations previously reported in CD patients were clustered. Mucocutaneous manifestations were far fewer in the patient with this mutation than in the patients with nonsense mutations. Whether the phenotypic difference in mucocutaneous features was due to the different mutations remains unclear.

About 5% of colorectal cancer cases are due to an autosomal dominant genetic predisposition with high penetrance. In this condition, the patient is carrier of a pathogenic gene mutation present in all body cells which can be transmitted to descendants, a so-called germ line mutation. The mutation is usually present in a tumour suppressor gene. Three subgroups of hereditary colorectal cancer can be distinguished on the basis of the clinical characteristics: (a) syndromes without polyposis (mostly hereditary non-polyposis colorectal carcinoma; HNPCC), (b) syndromes with adenomatous polyposis (mostly familial adenomatous polyposis; FAP) and (c) syndromes with hamartomatous polyposis. Recently, the main gene defects which underlie these syndromes were identified. Consequently, it is possible in approximately half the families with HNPCC or FAP in patients with colorectal cancer to demonstrate the causative gene defect and subsequently, by blood testing of healthy relatives to determine who is and is not a carrier of this hereditary condition. Thus, preventive measures can be directed toward family members with a demonstrable high risk of large bowel cancer.

Cowden syndrome (CS) is an autosomal dominant inherited syndrome characterised by hamartoma development in multiple organs and a risk of breast, thyroid and other cancers. The susceptibility gene for this syndrome was mapped to 10q22-23. Subsequently, germline mutations in PTEN, which encodes a dual specificity phosphatase, were found in individuals and families with CS. With the identification of the CS susceptibility gene, DNA-based predictive testing may be offered in theory. Somatic mutations in PTEN have been described in sporadic thyroid tumors, endometrial carcinomas, prostate carcinomas and glioblastoma multiforme. Although initial analyses suggest that the presence of somatic PTEN alterations appear to be associated with more advanced disease in carcinomas of the prostate and brain, this does not appear to be the case in epithelial thyroid tumors.

Cowden's disease, or multiple hamartoma syndrome, is an uncommon condition with characteristic mucocutaneous lesions associated with abnormalities of the breast, thyroid, and gastrointestinal tract. We describe a 32-year-old man with oral mucosal papillomatosis and plantar hyperkeratosis as a definite case of Cowden's disease according to the criteria proposed by Salem and Steck. The patient also had a thyroid mass and numerous gastrointestinal polyps endoscopically. Histologically the polyps were hamartomatous or hyperplastic polyps. The oral papillary lesions were fibroepithelial polyps and the thyroid mass was a follicular adenoma. We review the literature on this entity and summarize the pertinent findings. To the best of our knowledge, this is the first documented case of Cowden's disease in a Korean.

We describe a case of peripheral intrapulmonary hamartoma accompanied by a similar endotracheal lesion. A 70-year-old asymptomatic man had a polypoid lesion in the trachea and a nodular shadow in a peripheral lung area. A biopsy specimen from the trachea revealed a chondroid hamartoma, and the surgically resected tissue of the intrapulmonary tumor showed the same histologic findings. This is the second case of multiple hamartomas showing coexistence of tracheobronchial and parenchymal tumors.

Lhermitte-Duclos disease is a rare entity, and its pathological features are unique. Pathological findings are characteristic of the disease, with global hypertrophy of the cerebellum, coarse gyri, and the typical "inverted cortex" pattern. Several associated lesions were noted in many patients with Lhermitte-Duclos disease. It is only recently that an association between Lhermitte-Duclos disease and Cowden disease was reported. Cowden disease, or multiple hamartomas syndrome, is a familial disease associating breast cancer, cutaneomucous tricholemmomas, and various other tumoural and dysplasic conditions. A new case of Lhermitte-Duclos disease associated with Cowden disease is reported. A review of the literature found 72 cases of Lhermitte-Duclos disease; 26 had conditions suggesting Cowden disease and seven were definite cases of Cowden disease. The association of Lhermitte-Duclos disease and Cowden disease is probably underestimated. Cowden disease represents a new form of phakomatosis; Lhermitte-Duclos disease may occur as a sporadic disease, or as part of familial Cowden disease. The possibility of preneoplastic states in Cowden syndrome stresses the importance of a thorough screening when Lhermitte-Duclos disease is diagnosed.