Red flags for early recognition of adult patients with PTEN Hamartoma Tumour Syndrome.

Patients with PTEN Hamartoma Tumour Syndrome (PHTS) are at increased risk of developing cancer. Many adult PHTS patients are not recognized as such and do not receive the cancer surveillance they need. Our aim was to define phenotypic characteristics that can easily be assessed and manifest by early adulthood, and hence could serve as red flags (i.e. alerting signals) for early recognition of adult patients at high risk of PHTS. Phenotypic characteristics including macrocephaly, multinodular goitre (MNG), and oral features were examined in 81 paediatric and 86 adult PHTS patients by one of two medical experts during yearly surveillance visits at our Dutch PHTS expert centre between 1997 and 2020. MNG was defined as signs of thyroid nodules and/or goitre. Oral features included gingival hypertrophy, high palate (adults only) and oral papillomas. Based on the characteristics' prevalence in different age groups, combinations of phenotypic characteristics were defined and evaluated on their potential to recognize individuals with PHTS. Macrocephaly was present in 100% of paediatric and 67% of adult patients. The prevalence of MNG was ∼50% in paediatric and gradually increased to >90% in adult patients. Similar percentages were observed for any of the oral features. Scoring two out of three of these characteristics yielded a sensitivity of 100% (95%CI 94-100%) in adults. The presence of the combination macrocephaly, MNG, or multiple oral features could serve as a red flag for general practitioners, medical specialists, and dentists to consider further assessment of the diagnosis PHTS in adults. In this way, recognition of adult PHTS patients might be improved and cancer surveillance can be offered timely.

PTEN Mouse Models of Cancer Initiation and Progression.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of the most frequently mutated, deleted, and functionally inactivated tumor suppressor genes in human cancer. PTEN is found mutated both somatically and in the germline of patients with PTEN hamartoma tumor syndrome (PHTS). PTEN encodes a dual lipid and protein phosphatase that dephosphorylates the lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3), in turn negatively regulating the oncogenic PI3K-AKT pathway, a key proto-oncogenic player in cancer development and progression. Because of importance of PTEN in tumorigenesis, a large number of sophisticated genetically engineered mouse models (GEMMs) has been designed to elucidate the underlying mechanisms by which the "PTEN pathway" promotes tumorigenesis, while simultaneously providing a well-tailored system for the identification of novel therapies and offering platforms for new drug discoveries. This review summarizes the major cancer mouse models through which the PTEN pathway has been genetically deconstructed, and outlines the rapid development of GEMMs toward more detailed functional and tissue-specific analysis.

PTEN-opathies: from biological insights to evidence-based precision medicine.

The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the "PTEN-opathies." Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.

Increased 18F-FDG Uptake in Lhermitte-Duclos Disease With Cowden Syndrome Revealed by PET-MRI.

A 62-year-old woman, with the history of breast and colorectal cancer, presented intermittent diplopia. A cerebellar lesion was revealed by F-FDG PET-MRI without post-gadolinium enhancement, but with increased perfusion and strong F-FDG uptake. The diagnosis of Cowden syndrome with PTEN gene mutation, linked to higher risk of neoplasia and occurrence of hamartomatous lesions characteristic of the Lhermitte-Duclos disease (LDD), was confirmed by genetic investigation.

Intranodal meningothelial proliferation in a patient with Cowden syndrome: a case report.

Ectopic meningothelial proliferations are rare and can occur in a multitude of extracranial/spinal anatomic locations. Perineurioma is another uncommon entity that shares similar histological characteristics to those found in meningothelial proliferations. These include bland spindle cells with thin, bipolar nuclei; eosinophilic cytoplasm; and indistinct cell borders, arranged in short fascicles with whorl formation. Given their uncommon occurrence and shared histological and immunohistochemical features, their distinction can present a diagnostic challenge. Immunohistochemical studies can provide guidance when attempting to distinguish between these 2 lesions. Here, we present an unusual case of a patient with Cowden syndrome who was discovered to have a meningothelial proliferation within an axillary lymph node. To the best of our knowledge, this is the first case in which a meningothelial proliferation has been identified in a lymph node. Furthermore, the occurrence in a patient with Cowden syndrome is intriguing and raises the possibility of a pathogenetic link.

Morphologic characterization of hamartomatous gastrointestinal polyps in Cowden syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome.

The morphologic features of the gastrointestinal polyps in hamartomatous polyposis syndromes are poorly defined. Our aim was to better characterize the gastrointestinal hamartomas in these syndromes. A blinded review was performed regarding many histologic features for every polyp. The study included 15 Cowden syndrome, 13 Peutz-Jeghers (PJS), 12 juvenile polyposis (JuvPS) patients, and 32 cases of sporadic hamartomatous polyps. A total of 375 polyps were examined. Cowden syndrome polyps were characteristically colonic, sessile, small, without surface erosion, and showing mildly inflamed fibrotic lamina propria with smooth muscle proliferation and lymphoid follicles. They showed the least degree of cystic glands and had no thick mucin. Uncommon but specific features were ganglion cells and nerve fibers within the lamina propria and mucosal fat. PJS polyps were typically of small or large bowel origin, often exophytic, seldom eroded, with inflamed edematous and fibrotic lamina propria and dilated cystic glands filled with often thick mucin. All PJS polyps showed smooth muscle proliferation, frequently widespread. The polyps of JuvPS were typically colonic, large, exophytic, eroded, with strikingly edematous, fibrotic markedly inflamed lamina propria, cystic glands filled with frequently thick mucin, and the least degree of smooth muscle proliferation. Nonsyndromic hamartomatous polyps were similar to JuvPS polyps; however, they were more often colonic, were smaller, showed more widespread smooth muscle proliferation, and were less likely to contain thick mucin. In conclusion, we were able to define the characteristic hamartomatous polyp for each hamartomatous polyposis syndrome. Awareness to these features may aid in the diagnosis of these rare syndromes.

A Hyalinized Trichilemmoma of the Eyelid in a Teenager.

A 16-year-old African American male, the youngest patient to date, presented with a well-circumscribed upper eyelid lesion. On excision, the dermal nodule was contiguous with the epidermis, displayed trichohyalin-like bodies in an expanded outer root sheath, and was composed chiefly of small cellular clusters separated by a prominent network of periodic acid Schiff -positive hyaline bands of basement membrane material. The tumor cells were positive for high molecular weight cytokeratins (CK) 5/6, CK14, and CK34ßE12 and were negative for CK7, carcinoembryonic antigen and epithelial membrane antigen. Negative S100, glial fibrillary acidic protein, and smooth muscle actin immunoreactions ruled out a myoepithelial lesion. The Ki-67 proliferation index was <10%. The diagnosis was a hyalinized trichilemmoma, contrasting with the more common lobular type. As an isolated lesion, trichilemmoma does not portend Cowden syndrome.

Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer.

Cancer-predisposing genes associated with inherited cancer syndromes help explain mechanisms of sporadic carcinogenesis and often inform normal development. Cowden syndrome (CS) is an autosomal-dominant disorder characterized by high lifetime risks of epithelial cancers, such that ∼50% of affected individuals are wild-type for known cancer-predisposing genes. Using whole-exome and Sanger sequencing of a multi-generation CS family affected by thyroid and other cancers, we identified a pathogenic missense heterozygous SEC23B variant (c.1781T>G [p.Val594Gly]) that segregates with the phenotype. We also found germline heterozygous SEC23B variants in 3/96 (3%) unrelated mutation-negative CS probands with thyroid cancer and in The Cancer Genome Atlas (TCGA), representing apparently sporadic cancers. We note that the TCGA thyroid cancer dataset is enriched with unique germline deleterious SEC23B variants associated with a significantly younger age of onset. SEC23B encodes Sec23 homolog B (S. cerevisiae), a component of coat protein complex II (COPII), which transports proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. Interestingly, germline homozygous or compound-heterozygous SEC23B mutations cause an unrelated disorder, congenital dyserythropoietic anemia type II, and SEC23B-deficient mice suffer from secretory organ degeneration due to ER-stress-associated apoptosis. By characterizing the p.Val594Gly variant in a normal thyroid cell line, we show that it is a functional alteration that results in ER-stress-mediated cell-colony formation and survival, growth, and invasion, which reflect aspects of a cancer phenotype. Our findings suggest a different role for SEC23B, whereby germline heterozygous variants associate with cancer predisposition potentially mediated by ER stress "addiction."

Esophageal cancer in a family with hamartomatous tumors and germline PTEN frameshift and SMAD7 missense mutations.

Germline mutations in the PTEN tumor-suppressor gene cause autosomal-dominant conditions such as Cowden and Bannayan-Riley-Ruvalcaba syndromes with variable presentations, including hamartomatous gastrointestinal tumors, dermatologic abnormalities, neurologic symptoms, and elevated cancer risk. We describe a father and son with extensive hamartomatous gastrointestinal polyposis who both developed early-onset esophageal cancer. Exome sequencing identified a novel germline PTEN frameshift mutation (c.568_569insC, p.V191Sfs*11). In addition, a missense mutation of SMAD7 (c.115G>A, p.G39R) with an allele frequency of 0.3% in the Exome Variant Server was detected in both affected individuals. Fluorescence in situ hybridization for PTEN in the resected esophageal cancer specimen demonstrated no PTEN copy loss in malignant cells; however, results of an immunohistochemical analysis demonstrated a loss of PTEN protein expression. While the risks of many cancers are elevated in the PTEN hamartoma tumor syndromes, association between esophageal adenocarcinoma and these syndromes has not been previously reported. Esophageal adenocarcinoma and extensive polyposis/ganglioneuromatosis could represent less common features of these syndromes, potentially correlating with this novel PTEN frameshift and early protein termination genotype. Alternatively, because simultaneous disruption of both the PTEN and TGF-ß/SMAD4 pathways is associated with development of esophageal cancer in a mouse model and because SMAD4 mutations cause gastrointestinal hamartomas in juvenile polyposis syndrome, the SMAD7 mutation may represent an additional modifier of these individuals' PTEN-mutant phenotype.

Dysplastic cerebellar gangliocytoma lhermitte-duclos disease imaging and magnetic resonance spectroscopy.

Lhermitte-Duclos disease (LDD) is a rare, benign, slow-growing, unilateral mass of the cerebellar cortex. Our case is that of a 71-year-old male with a superior cerebellar lesion consistent with LDD on imaging and Magnetic Resonance Spectroscopy (MRS). It has been reported that MRS can be a valuable diagnostic addition, as it allows for a non-invasive diagnosis and analysis to distinguish a benign lesion, such as an intraparenchymal lesion, and in our case, from a true neoplastic lesion.

Oral manifestations of phosphatase and tensin homolog hamartoma tumor syndrome: a report of three cases.

BACKGROUND: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) encompasses several rare disorders linked to mutations of the PTEN gene, including Cowden disease (CD) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). The authors present a case series involving patients with characteristic periodontal features. CASE DESCRIPTIONS: The authors assessed three patients, two of whom already had been diagnosed with BRRS: a 60-year-old man and his 33-year-old daughter, both of whom had pathognomonic oral and cutaneous manifestations, and a 26-year-old man affected by multiple micropapillomatous and keratotic periodontal lesions, through which the diagnosis of CD was made. All three patients were referred to the oral medicine unit of the authors' institution because of asymptomatic lesions of the oral mucosa, and two of them underwent incisional biopsy. CONCLUSIONS: This series of cases emphasizes that oral health care workers always should perform a more careful visual inspection of the oral cavity without neglecting a macroscopic analysis of the gingival pattern. The knowledge of these diseases and their clinical features, associated with a multidisciplinary approach, allows clinicians to achieve remarkable diagnostic success. PRACTICAL IMPLICATIONS: Gingival manifestations may represent one of the primary clinically detectable manifestations of these rare systemic diseases, in respect of which an early diagnosis could decrease the associated mortality and morbidity.

Stat5 regulates the phosphatidylinositol 3-kinase/Akt1 pathway during mammary gland development and tumorigenesis.

Stat5 (signal transducer and activator of transcription 5) is an essential mediator of cytokine receptor signaling and plays important roles in the proliferation of alveolar progenitors and the survival of functionally differentiated epithelial cells in the mammary gland. A deregulated expression and activation of Stat5 leads to precocious alveolar development in the absence of pregnancy hormones, impaired mammary gland remodeling following the cessation of lactation, and mammary tumor formation. We reported previously that Stat5 induces the transcription of the Akt1 gene from a novel promoter. In this report, we provide experimental evidence that Akt1 is an essential mediator for the biological function of Stat5 as a survival factor. Additionally, Stat5 controls the expression of the regulatory and catalytic subunits of the phosphatidylinositol 3-kinase (PI3K) (p85α and p110α), thereby greatly augmenting signaling through the prosurvival PI3K/Akt pathway. In agreement with this model, we observed that the constitutive activation of Stat5 cooperates with the loss of function of the tumor suppressor PTEN by accelerating the formation of preneoplastic lesions and mammary tumors. The mammary gland-specific ablation of Stat5 is sufficient to prevent mammary carcinogenesis in a genuine mouse model for Cowden syndrome. Therefore, targeting the Jak2/Stat5 pathway might be a suitable strategy to prevent breast cancer in patients that carry a mutant PTEN allele.

Lhermitte-Duclos disease. A case report.

Lhermitte-Duclos disease is a rare pathologic condition consisting of a dysplastic gangliocytoma of the cerebellum. Its association with phacomatosis and an autosomal dominant neoplastic syndrome, Cowden's syndrome is also known. Modern neuroimaging contributes to a correct diagnosis and pre- and postoperative evaluation. Here we describe the morphologic and metabolic aspects of the disease as shown by conventional MRI, diffusion imaging and spectroscopy in a 31-year-old woman. In addition, the specific neuroradiologic characteristics are presented and discussed in the light of the main pathologic and clinical features, such as hypertrophy of the cerebellar folia associated with white matter atrophy.

mTOR signaling in neural stem cells: from basic biology to disease.

The mammalian target of rapamycin (mTOR) pathway is a central controller of growth and homeostasis, and, as such, is implicated in disease states where growth is deregulated, namely cancer, metabolic diseases, and hamartoma syndromes like tuberous sclerosis complex (TSC). Accordingly, mTOR is also a pivotal regulator of the homeostasis of several distinct stem cell pools in which it finely tunes the balance between stem cell self-renewal and differentiation. mTOR hyperactivation in neural stem cells (NSCs) has been etiologically linked to the development of TSC-associated neurological lesions, such as brain hamartomas and benign tumors. Animal models generated by deletion of mTOR upstream regulators in different types of NSCs reproduce faithfully some of the TSC neurological alterations. Thus, mTOR dysregulation in NSCs seems to be responsible for the derangement of their homeostasis, thus leading to TSC development. Here we review recent advances in the molecular dissection of the mTOR cascade, its involvement in the maintenance of stem cell compartments, and in particular the implications of mTOR hyperactivation in NSCs in vivo and in vitro.

Utility of PTEN protein dosage in predicting for underlying germline PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes.

CONTEXT: Thyroid cancer is a major component of Cowden syndrome (CS). CS patients with an underlying PTEN mutation (PTEN(mut+)) have a 70-fold increased risk of developing epithelial thyroid cancer. In contrast, less than 1% of sporadic epithelial thyroid cancer patients carry a germline PTEN mutation. Cost-efficient markers capable of shortlisting thyroid cancers for CS genetic testing would be clinically useful. OBJECTIVE: Our objective was to analyze the utility of patient blood phosphate and tensin homolog deleted on chromosome 10 (PTEN) protein levels in predicting germline PTEN mutations. DESIGN, SETTING, AND PATIENTS: We conducted a 5-yr, multicenter prospective study of 2792 CS and CS-like patients, all of whom had comprehensive PTEN analysis. Analysis of PTEN and downstream proteins by immunoblotting was performed on total protein lysates from patient-derived lymphoblast lines. We compared blood PTEN protein levels between PTEN(mut+) patients and those with variants of unknown significance or wild-type PTEN (PTEN(wt/vus)). MAIN OUTCOME MEASURES: We assessed the utility of PTEN protein levels in predicting germline PTEN mutations. RESULTS: Of 2792 CS/CS-like patients, 721 patients had thyroid cancer; 582 of them (81%) had blood PTEN protein analyzed. PTEN germline pathogenic mutations were present in 27 of 582 patients (4.6%). Ninety-six percent (26 of 27) of PTEN(mut+) patients had blood PTEN protein levels in the lowest quartile as compared with 25% (139 of 555) of PTEN(wt/vus) patients (P < 0.001). Low blood PTEN levels predicted for PTEN(mut+) cases with a 99.76% negative predictive value (95% confidence interval = 98.67-99.96) and a positive test likelihood ratio of 3.84 (95% confidence interval = 3.27-4.52). CONCLUSIONS: Our study shows that low blood PTEN protein expression could serve as a screening molecular correlate to predict for germline PTEN mutation in CS and CS-like presentations of thyroid cancer.

PTEN lipid phosphatase activity and proper subcellular localization are necessary and sufficient for down-regulating AKT phosphorylation in the nucleus in Cowden syndrome.

CONTEXT: Germline mutations in PTEN are associated with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) hamartoma tumor syndrome including Cowden syndrome (CS) and Cowden-like syndrome (CSL) that predisposes to high risks of benign and malignant tumors of thyroid and breast. OBJECTIVE: The objective of the study was to analyze the subcellular pattern of phosphorylated (P)-AKT expression in nonmedullary thyroid cancers from PTEN hamartoma tumor syndrome patients and to investigate whether the lack of PTEN in the nucleus and/or lack of proper PTEN function in the nucleus affect(s) nuclear AKT activity in CS patients. DESIGN: In all, 664 patients with CS/CSL were screened for PTEN germline mutations and nonmedullary thyroid cancers. Twenty-two patients who have both pathogenic PTEN germline mutations and nonmedullary thyroid cancers were selected. Thyroid samples from these patients were stained for PTEN and P-AKT. In our in vitro study, PTEN was knocked down or overexpressed in both thyroid cancer cells and breast cancer cells, and nuclear P-AKT was compared with the control. RESULTS: Loss of PTEN protein was found in thyroid adenomas and carcinomas from all 22 (100%) PTEN(Mut+) CS/CSL patients. AKT activation was identified in 17 of 22 (77.3%) thyroid adenoma/carcinoma specimens, and most patients (63.7%) have activated nuclear AKT. Knockdown of PTEN in cells containing wild-type PTEN enhanced nuclear P-AKT, whereas expression of wild-type PTEN, but not phosphatase-dead mutants (C124S or G129E), markedly reduced nuclear P-AKT in PTEN null cells. We also showed that in breast cancer but not thyroid cancer cells, PTEN suppresses nuclear P-AKT mainly through decreasing P-AKT nuclear translocation by reducing the PIP3/P-AKT reservoir in the cytoplasm. In thyroid cancer cells, PTEN suppresses phosphorylation of AKT already resident in the nucleus. CONCLUSIONS: PTEN is necessary and sufficient for inhibiting AKT activation in the nucleus through its intact lipid phosphatase activity and proper subcellular localization.