Cerebral dural arteriovenous fistulas in patients with PTEN-related hamartoma tumor syndrome.

Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in PTEN-related hamartoma tumor syndrome (PHTS). However, PHTS-associated DAVF remain an underexplored field of the PHTS clinical landscape. Here, we studied cases with a PTEN pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34-year-old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21-year-old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case-by-case basis.

Giant cell collagenomas associated with Cowden syndrome: A case report.

Storiform collagenoma, also known as sclerotic fibroma, is a relatively rare benign cutaneous tumor consisting of a proliferation of fibroblasts that shows increased production of type I collagen. It may appear as a solitary, sporadic lesion, or, especially when multiple, associated with Cowden syndrome. Giant cell collagenoma has a histopathologic appearance similar to that of storiform collagenoma with the addition of floret-type giant cells. Herein, we report the finding of multiple giant cell collagenomas arising in an individual with Cowden syndrome. In a review of the published literature, this histopathologic variant appears to be rarely observed in association with Cowden syndrome.

Arteriovenous malformations as a presenting sign of PTEN hamartoma tumor syndrome: A case series.

High-flow vascular malformations have been associated with multiple syndromes including capillary malformation-arteriovenous malformation (CM-AVM) syndrome, hereditary hemorrhagic telangiectasia syndrome, and less commonly, phosphatase and tensin homolog hamartoma tumor syndrome (PHTS). We present a series of three patients with clinically challenging complex AVMs who were found to have underlying PHTS. In all patients, diagnosis was delayed, and the presence of the AVM prompted sampling and genetic testing for PHTS in the absence of other clinical features of the condition. This series highlights the importance of screening for PHTS in the setting of high-flow vascular malformations.

[Cowden syndrome in a male patient with metachronous triple cancers and various clinical features:a case report].

A 66-year-old male patient with a thyroid and nasopharyngeal cancer history visited our hospital because of a positive fecal occult blood test. Total colonoscopy detected sessile or subpedunculated polyps in the ascending colon, sigmoid colon, and rectum. These polyps were endoscopically resected, and the rectal polyp was pathologically diagnosed as adenocarcinoma in adenoma and the others as adenomas. Additionally, multiple sessile lesions were revealed in the sigmoid colon and rectum. A complete gastrointestinal tract examination revealed multiple foci of glycogenic acanthosis in the esophagus, multiple sessile lesions in the stomach, multiple sessile lesions, clubbings (rod-shaped lesions), and venous malformations in the small bowel. Mucocutaneous examination indicated hemangiomas on the body trunk, patchy pigmentation on the glans penis, and keratotic papules in the inguinal region. The National Comprehensive Cancer Network diagnostic criteria for Cowden syndrome were used in this case. The patient met four major and two minor criteria;thus, Cowden syndrome was diagnosed. Moreover, the patient was had phosphatase and tensin homolog deleted on chromosome 10 gene mutation. This is the first reported case of metachronal triple cancers in a male patient with Cowden syndrome, and our results indicate the importance of cancer surveillance.

Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

Characterizing dermatologic findings among patients with PTEN hamartoma tumor syndrome: Results of a multicenter cohort study.

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.

Diverse imaging findings of Lhermitte-Duclos disease.

AIM: To evaluate the diverse clinical and imaging features of Lhermitte-Duclos disease (LDD) and its subgroup comparison. MATERIALS AND METHODS: Clinical data from 21 patients with LDD were collected, including eight patients with LDD without other tumours and 13 LDD with other tumours. Redefined diagnostic criteria are used to evaluate Cowden Syndrome. Imaging indicators were analysed retrospectively to extract typical and atypical features. Imaging findings and preoperative diagnostic accuracy were compared between the subgroups. RESULTS: None of these patients met the redefined diagnostic criteria. The typical "tiger stripe sign" was seen in most LDD lesions (13/29, 61.9%), with lower density (29.66 ± 2.51 versus 37.81 ± 2.76 HU, p<0.001) and higher apparent diffusion coefficient (ADC) value (1.04 ± 0.05 × 10-3 versus 0.74 ± 0.03 × 10-3 mm2/s, p<0.001) than that of the normal cerebellum. Atypically, some lesions showed abnormal vessels (8/21, 38.1%), intratumoural calcification (3/21, 14.29%), intratumoural haemorrhage (4/21, 19.05%), peritumoural oedema (6/21, 28.57%), and heterogeneous enhancement (5/21, 23.81%). The typical "tiger stripe sign" was more common in LDD with other tumours (84.62% versus 25%, p=0.018). Although LDD without other tumours was more common with abnormal vessels (75% versus 15.38%, p=0.018), intratumoural calcification (37.5% versus 0, p=0.042), intratumoural haemorrhage (50% versus 0, p=0.012), peritumoural oedema (62.5% versus 7.69%, p=0.014) and heterogeneous enhancement (50% versus 7.69%, p=0.047). Preoperative diagnostic accuracy was higher in LDD with other tumours than LDD without other tumours (76.92% versus 25%, p=0.032). CONCLUSION: The "tiger stripe sign" of LDD is characteristic, but not unique. With or without other tumours, it may be associated with the imaging diversity. Combining typical and atypical signs can improve the imaging assessment of LDD.

Coexisting lipomatous meningioma and glioblastoma in Cowden syndrome: A unique tumor association.

Cowden syndrome (CS) is a rare hereditary hamartoma-cancer disorder related to germline mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) gene. Association of CS with intracranial tumors, apart from Lhermitte-Duclos disease (LDD), is not well recognized. We present an exceptional instance of concomitant meningioma and glioblastoma in CS, the first case ever reported. Following a new-onset seizure, a 62-year-old male harboring the PTEN gene germline mutation c.334C > G was diagnosed with multiple brain tumors, which were erroneously thought to correspond to metastases. Because no primary cancer was found, an operation was proposed for histopathological diagnosis. Examination of surgical specimens obtained from the two lesions removed, one extra-axial and the other intracerebral, demonstrated a metaplastic meningioma with a lipomatous appearance and an isocitrate dehydrogenase wild-type glioblastoma, respectively. Loss of the PTEN gene expression was demonstrated immunohistochemically in both lesions, a finding that supports their relation to CS. A thorough literature review revealed only 25 additional CS patients with intracranial tumors other than LDD. All of them corresponded to primary lesions, with meningiomas accounting for 76% of the cases (19 patients), followed by pituitary tumors (three cases) and glioblastomas (two patients from the same family). Our report and literature review highlight the association between CS and primary brain tumors rather than metastasis. For judicious management of a CS patient with multiple intracranial tumors, different primary brain pathological entities should also be suspected first before considering metastasis. Close neurological monitoring and brain magnetic resonance imaging are advocated as part of the cancer screening in CS patients, particularly in cases with a family history of intracranial tumors.

Lhermitte-Duclos disease with concomitant KCNT2 gene mutation: report of an extremely rare combination.

Lhermitte-Duclos disease (LDD) refers to cerebellar dysplastic gangliocytoma, a slow-growing tumor. Pathogenic variants of voltage-gated potassium channels have been associated with epilepsy of variable severity. These include the sodium-activated potassium channel subfamily T member 2 (KCNT2) gene, which encodes for pore-forming alpha subunits. KCNT2 gene mutations have been recently described to cause developmental and epileptic encephalopathies (DEEs). The purpose of the present article is to describe an extremely rare case of a young child who has both LDD and KCNT2 mutation. Our patient is an 11-year-old boy who presented with an absence episode, and his investigations revealed electroencephalography (EEG) abnormalities, LDD, and a heterozygous KCNT2 mutation. Regarding LDD patients, epileptic seizures have been reported in very few cases. Reports of patients with mutated KCNT2 variants are also extremely rare. It is for sure that LDD and KCNT2 mutation is an extremely rare combination. Although further follow-up is mandatory in order to draw safe conclusions for our case, the available data support that our patient is either the first reported case of a subclinical KCNT2 mutation or the first case of its clinical expression in late childhood so far.

Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S. Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

Cancer risk and genotype-phenotype correlation in Japanese patients with Cowden syndrome.

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.

Dysplastic gangliocytoma of the cerebellum in a cat.

A 2.5-year-old cat presented with progressive ataxia and lethargy. Magnetic resonance imaging (MRI) showed enlargement of the cerebellum and herniation of cerebellar vermis. Postmortem examination confirmed the MRI findings, and histopathology showed numerous large dysplastic neurons populating and displacing the Purkinje cell layer and extending into the molecular and granular layers of the cerebellum. The lesion was diagnosed as dysplastic gangliocytoma of the cerebellum. In humans, this tumor is often associated with Cowden syndrome, a genetic disorder characterized by multiple hamartomas and an increased risk of developing certain neoplasms, known to be linked to a germline mutation of the phosphatase and tensin homolog (PTEN) gene. Reduction in PTEN nuclear and cytoplasmic immunohistochemical labeling of dysplastic neurons in this case suggested a possible PTEN mutation involved in the tumorigenesis. This report provides a detailed pathology description of the tumor and the use of neuronal and PTEN markers which will help guide pathologists presented with this rare condition in the future.

Formation of a de novo intracranial arteriovenous fistula in a child with PTEN hamartoma tumor syndrome.

PURPOSE: Dural arteriovenous fistulae (dAVF) are an uncommon feature of PTEN hamartoma tumor syndrome (PHTS). We report a case of an adolescent male diagnosed with PHTS following the treatment of multiple intracranial dAVF to emphasize the association of vascular anomalies with this disorder and discuss potential implications. CASE REPORT: An adolescent male presented with bilateral proptosis secondary to intracranial venous hypertension. Workup revealed the presence of a complex intracranial dAVF which was treated with several embolization procedures. Following treatment, a de novo dAVF was identified on surveillance imaging. A genetic workup revealed a pathogenic mutation in PTEN consistent with a diagnosis of PHTS. CONCLUSIONS: Recognition that PHTS may be associated with dAVF, and potentially delayed spontaneous formation of dAVF, is critically important due to the potential for devastating yet preventable neurologic sequelae.

A progressive and refractory case of breast cancer with Cowden syndrome.

BACKGROUND: Cowden syndrome is a rare autosomal-dominant disease with a high risk of malignant tumors of the breast, commonly caused by germline mutations in the PTEN gene. Most breast cancers related to Cowden syndrome showed typically a slow-growing and favorable clinical course. Here, we report a progressive case of triple-negative breast cancer in a patient who was diagnosed with Cowden syndrome. CASE PRESENTATION: A 35-year-old female with breast cancer was referred to our hospital. Histopathological examination of the tumor showed that it was triple-negative breast cancer with high proliferation marker. Preoperative positron emission tomography-computed tomography showed abnormal uptake in the left cerebellar hemisphere in addition to the right breast and axillary lymph node. Brain T2-weighted magnetic resonance imaging revealed hyperintense bands in the left cerebellar hemisphere lesion, which demonstrated a "tiger-stripe" appearance. The patient's mother had died of endometrial cancer. Subsequently, she underwent genetic testing, leading to a diagnosis of Cowden syndrome with a pathogenic variant c.823_840del.18 at exon 8 in PTEN. She was treated with neoadjuvant chemotherapy of eribulin and cyclophosphamide followed by adriamycin and cyclophosphamide. However, her tumors increased after these treatments. She was immediately surgically treated and received adjuvant chemotherapy of capecitabine. Unfortunately, the cancer recurred in the lung nine months after surgery. We then administered paclitaxel and bevacizumab therapy, but the disease rapidly progressed. Consequently, the patient died due to breast cancer about three months after recurrence. CONCLUSION: We report an aggressive case of cancer with Cowden syndrome which was resistant to standard chemotherapy. Alteration of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway due to inactivating PTEN protein may be associated with chemoresistance and serves as a candidate for therapeutic intervention in PTEN-related cancers.

AMBRA1 p.Gln30Arg Mutation, Identified in a Cowden Syndrome Family, Exhibits Hyperproliferative Potential in hTERT-RPE1 Cells.

Cowden syndrome (CS) is a rare autosomal dominant disorder associated with multiple hamartomatous and neoplastic lesions in various organs. Most CS patients have been found to have germline mutations in the PTEN tumor suppressor. In the present study, we investigated the causative gene of CS in a family of PTEN (phosphatase and tensin homolog deleted on chromosome 10) -negative CS patients. Whole exome sequencing analysis revealed AMBRA1 (Autophagy and Beclin 1 Regulator 1) as a novel candidate gene harboring two germline variants: p.Gln30Arg (Q30R) and p.Arg1195Ser (R1195S). AMBRA1 is a key regulator of the autophagy signaling network and a tumor suppressor. To functionally validate the role of AMBRA1 in the clinical manifestations of CS, we generated AMBRA1 depletion and Q30R mutation in hTERT-RPE1 (humanTelomerase Reverse Transcriptase-immortalized Retinal Pigmented Epithelial cells) using the CRISPR-Cas9 gene editing system. We observed that both AMBRA1-depleted and mutant cells showed accumulation in the S phase, leading to hyperproliferation, which is a characteristic of hamartomatous lesions. Specifically, the AMBRA1 Q30R mutation disturbed the G1/S transition of cells, leading to continuous mitotic entry of mutant cells, irrespective of the extracellular condition. From our analysis of primary ciliogenesis in these cells, we speculated that the mitotic entry of AMBRA1 Q30R mutants could be due to non-functional primary cilia that lead to impaired processing of extracellular sensory signals. Additionally, we observed a situs inversus phenotype in ambra1-depleted zebrafish, a developmental abnormality resulting from dysregulated primary ciliogenesis. Taken together, we established that the AMBRA1 Q30R mutation that we observed in CS patients might play an important role in inducing the hyperproliferative potential of cells through regulating primary ciliogenesis.

[Ovarian Carcinosarcoma Associated with Cowden Syndrome-A Case Report].

Cowden syndrome is a rare autosomal dominant disorder characterized by multiple hamartomas in various tissues, including the skin, mucous membranes, and gastrointestinal tract. Germline mutations of the PTEN tumor suppressor gene are responsible for Cowden syndrome. Cowden syndrome is associated with an increased risk of breast, thyroid, renal and uterine cancers; however, ovarian cancer rarely develops in women with Cowden syndrome, although somatic PTEN mutation often occurs in some types of ovarian carcinomas. Herein we report the first case of ovarian carcinosarcoma that developed in a woman with Cowden syndrome. A 55-year-old woman with a history of breast cancer, thyroid goiter, and palatal papillomatosis presented with pelvic distention. CT scan revealed a pelvic tumor suggesting ovarian cancer. She underwent a total abdominal hysterectomy, a bilateral salpingo-oophorectomy, and an omentectomy, but the surgical cytoreduction was suboptima( l >2 cm residual disease). Pathological examination showed a mixed tumor composed of high-grade carcinoma and heterologous sarcoma. Immunohistochemically, tumor cells were positive for p53. She was diagnosed with stage ⅢC ovarian carcinosarcoma. Genetic testing detected a PTEN variant, confirming the diagnosis of Cowden syndrome. She received paclitaxel/ carboplatin chemotherapy. However, no response was observed and she died of disease 2 months postoperatively.

A review on age-related cancer risks in PTEN hamartoma tumor syndrome.

Patients with PTEN hamartoma tumor syndrome (PHTS, comprising Cowden, Bannayan-Riley-Ruvalcaba, and Proteus-like syndromes) are at increased risk of developing cancer due to pathogenic PTEN germline variants. This review summarizes age-, sex-, and type-specific malignant cancer risks for PHTS patients, which is urgently needed for clinical management. A PubMed literature search for Standardized Incidence Ratios or Cumulative Lifetime cancer risks (CLTRs) resulted in nine cohort studies comprising four independent PHTS cohorts, including mainly index cases and prevalent cancer cases. The median age at diagnosis was 36 years. Reported CLTRs for any cancer varied from 81% to 90%. The tumor spectrum included female breast cancer (CLTRs including sex-specific estimates at age 60-70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%). Although these estimates provide guidance for clinical care, discrepancies between studies, sample sizes, retrospective designs, strongly ascertained cases, and lack of pediatric research emphasizes that data should be interpreted with great caution. Therefore, more accurate and more personalized age-, sex-, and cancer-specific risk estimates are needed to enable counseling of all PHTS patients irrespective of ascertainment, and improvement of cancer surveillance guidelines.

Diagnosis and management of an endometrial cancer patient with Cowden syndrome.

Somatic PTEN alterations are common in endometrial carcinoma (EC), but in rare cases PTEN mutations are associated with inherited syndromes. Here, we present a case of Cowden syndrome-associated EC. We discuss clinical, pathologic and molecular features of her tumor and PTEN-mutated EC, inherited syndromes predisposing to EC and PTEN-targeted therapies.

Endometrial Endometrioid Carcinoma With Ovarian Metastasis Showing Morula-like Features in a Patient With Cowden Syndrome: A Case Report.

Cowden syndrome (CS) is a multiple hamartoma syndrome associated with the development of various tumors, including endometrial cancer. However, the histology of CS-associated endometrial cancer remains to be fully described. To our knowledge, this is the first report of a patient with CS having endometrial endometrioid carcinoma with ovarian metastasis demonstrating morula-like features. A 31-yr-old, nulliparous, Japanese woman presented with abnormal genital bleeding. Endometrial biopsy revealed endometrioid carcinoma with an extensive morular formation, partially resembling atypical polypoid adenomyoma (APAM). Moreover, she had a past history of bilateral breast cancer and a family history of juvenile breast cancer in her mother. Genetic testing revealed they shared the same pathogenic germline PTEN mutation. She underwent an abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node biopsy. Pathologic examination revealed endometrial endometrioid carcinoma with APAM-like histology. Furthermore, the solid components with morula-like morphology and immunophenotypes showed myometrial invasion and ovarian metastasis (FIGO stage IIIA/pT3aN0M0). The present case highlights the need for careful assessment of myometrial invasion and extrauterine spread for appropriate gynecologic treatment even if endometrial biopsy shows APAM-like histology. Moreover, characterization of CS-associated endometrial cancers is required.