RARE DISEASE
Cowden syndrome
Cowden syndrome
Cowden syndrome
Synonyms: Cowden disease, Multiple hamartoma syndrome
Synonyms: Cowden disease, Multiple hamartoma syndrome
Synonyms: Cowden disease, Multiple hamartoma syndrome
Drug discovery
249
papers
On emerging therapies
Overview
Cowden syndrome is an autosomal dominant disorder caused by PTEN gene mutations, characterized by widespread hamartomas and elevated lifetime risks of breast (85%), thyroid (35%), endometrial (28%), and other cancers [1][6][7]. Clinical features include mucocutaneous lesions (e.g., trichilemmomas), macrocephaly, and Lhermitte-Duclos disease [12][14]. Diagnosis relies on NCCN criteria integrating major/minor clinical features and confirmed by genetic testing [7][12]. Management emphasizes early cancer surveillance and multidisciplinary care [3][6][16].
Burden
Cancer risk: 89% lifetime cancer risk; 25-48% develop multiple malignancies [9][12][19].
Morbidity: 40% experience intellectual disability/autism; recurrent surgeries for benign/malignant lesions [1][9][12].
Economic: High costs from lifelong screenings, genetic counseling, and cancer treatments [4][19].
Therapies
Surveillance: Annual breast MRI/mammography (age 30+), thyroid ultrasound (age 7+), biennial renal imaging, and colonoscopy (age 35+) [6][12][19].
Surgical: Prophylactic mastectomy/thyroidectomy for high-risk patients; tumor resection [3][6][18].
Pharmacologic: mTOR inhibitors (e.g., rapamycin) under investigation for hamartoma regression [8][14].
Categories: rare developmental anomalies during embryogenesis, rare gastroenterological diseases, rare genetic diseases, rare neoplastic diseases, rare skin diseases, rare transplant-related disorders
Research Papers
249 drug discovery papers about Cowden syndrome. Recent publications:
249 drug discovery papers about Cowden syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-08-07 | Cutaneous Adnexal Neoplasms: A Clinical, Dermoscopic, and Histopathological Study
structureless area and yellowish keratin with a few arborizing vessels at periphery, suggestive of keratoacanthoma (Fig. 1B).Excision was done considering keratoacanthoma, trichoblastoma and lobular capillary hemangioma as differentials.Histopathology revealed a well-circumscribed, ulcerated tumor exhibiting parakeratosis, acanthosis, and lobules of cells having round, uniform nuclei with moderate eosinophilic cytoplasm, many showing clearing of cytoplasm, separated by thin fibrous septa (Figs 1C and D).A few keratin pearls and squamous eddies were also seen.The tumor margins were free.The features were suggestive of a trichilemmoma. IntroductIonCutaneous adnexa comprise sweat glands, sebaceous glands, and pilosebaceous units.Skin adnexal tumors (SATs) arise from the multipotent undifferentiated stem cells, forming a large and diverse group of benign and malignant neoplasms, which exhibit morphological differentiation toward one of the different types of adnexal epithelium present in normal skin, sometimes exhibiting mixed differentiation, hence posing difficulty in precise diagnosis.Adnexal tumors present as asymptomatic papules or nodules, sometimes associated with pain depending on the site of involvement.SATs are more often excised and diagnosed based on histopathology.Local complete excision is often curative, as most of them are benign.Diagnosing adnexal tumors has important implications, as they might be markers for syndromes associated with internal malignancies, such as trichilemmomas in Cowden syndrome and sebaceous tumors in Muir-Torre syndrome.[1][2][3] Herein, we present seven cases of adnexal tumors with varied clinical, dermoscopic, and histopathological features. case descrIptIons Case 1A 13-year-old male presented to dermatology outpatient department with a painless, solitary swelling, gradually increasing in size with occasional bleeding over the scalp for 3 months.Examination revealed a solitary, sessile, nontender nodule 5 × 5 cm in size with central crater containing crust and bleeding over the midline of scalp (Fig. 1A).Dermoscopy revealed a central crater with a whitish, 1-
2026-05-12 | Management and outcomes of fertility preservation in rare Cowden syndrome-associated endometrial carcinoma: a case series.
Cowden syndrome-associated endometrial carcinoma (CS-EC) is rare, and data on fertility-preserving treatment for young patients remain limited. This series describes the diagnosis and management of three patients with CS-EC who underwent fertility-sparing treatment. We also report the subsequent pregnancy outcome for one of these individuals. These cases provide a clinical reference for the individualized management of such patients. Three patients (aged 29, 31, and 28 years) with germline Phosphatase and tensin homolog (PTEN) pathogenic variants and stage IA endometrial carcinoma underwent individualized fertility-sparing treatment. Case 1 (PTEN p.R189Qfs*9) failed levonorgestrel-releasing intrauterine system (LNG-IUS) treatment at 19 months. Eight cycles of GnRH agonist (GnRH-a) plus letrozole (LE) subsequently induced a complete response. A recurrence was successfully managed with twelve additional cycles of this regimen. Case 2 (PTEN p.R173C) attained remission after six months of megestrol acetate (MA). Case 3 (PTEN p.R335*) responded to MA over nine months, then developed complex mucinous papillary metaplasia during LNG-IUS maintenance, which resolved with ethinylestradiol/cyproterone acetate (EE/CPA). She subsequently conceived and delivered a live birth through Intracytoplasmic sperm injection (ICSI). During the follow-up period, all patients were administered maintenance therapy using a LNG-IUD. Fertility-sparing therapy may serve as a potentially feasible option for highly selected patients with stage IA CS-EC, and could lead to relatively favorable pregnancy outcomes. The clinical feasibility of this strategy relies heavily on strict patient selection, timely molecular diagnosis, and standardized continuous multidisciplinary management.
2026-04-16 | Remarkable response of metaplastic breast cancer to a novel targeted AKT inhibitor TAS-117 in a Cowden syndrome patient: a case report.
PTEN hamartoma tumour syndrome (PHTS) is characterized by a germline PTEN mutation and a substantial increase in lifetime breast cancer risk to 85% with lower age at first diagnosis. Despite the availability of agents targeting PTEN-regulated PI3K/AKT/mTOR pathway, there are currently no approved treatments for PHTS patients with cancer. This is the first report of a patient with triple-negative metaplastic breast cancer and PHTS in the literature. We present an exceptional response of this aggressive stage IV tumour in a 34-year-old woman with PHTS to treatment with the novel AKT1-3 inhibitor, TAS-117. Despite previous rapid progression and resistance to multi-agent chemotherapy and radiotherapy, disease stabilisation was ongoing at 3.8 years. Cell-free DNA analysis of blood samples at baseline and during treatment with TAS-117 revealed a complete marker response to treatment. Therapy has been well tolerated, and the patient continues the therapy without severe adverse events, dose reduction, or treatment interruptions. These findings support further investigation of targeted interventions for malignancies developing in the context of PHTS.
2026-03-09 | A Successful Live Birth After Double Fertility Preservation With Embryo Cryopreservation and MPA Therapy Combined With Hysteroscopic Resection for Metachronous Breast and Endometrial Cancer in Women With Cowden Syndrome: A Case Report.
Cowden syndrome is an autosomal-dominantly inherited rare condition caused by germline pathogenic variants of the PTEN gene. Multiple tumor development at a younger age in this syndrome may warrant different modalities of fertility preservation. Here we report that women with this syndrome gave successful live birth with frozen-thaw embryo transfer that was cryopreserved before the start of chemotherapy for breast cancer. This woman also suffered from endometrial cancer that developed during hormonal treatment with GnRH agonist and tamoxifen for breast cancer. The lesion was well controlled with oral MPA therapy and hysteroscopic resection. She could receive fertility preservation for breast cancer and endometrial cancer before fertility treatment and pregnancy. This is the first report of live births after multiple fertility preservation therapy for metachronous breast and uterine cancer in Cowden syndrome. Appropriate genetic counseling may help the patient's decision making. The treatment plan should be discussed with diverse professionals such as oncologists, reproductive physicians, perinatologists, geneticists, and genetic counselors.
2026-02-13 | Hereditary Endometrial Cancer: Lynch Syndrome, Mismatch Repair Deficiency, and Emerging Genetic Predispositions-A Comprehensive Review with Clinical and Laboratory Guidelines.
Endometrial cancer is the most common gynaecologic malignancy in high-income countries, with a rising incidence largely driven by reproductive factors, obesity, and prolonged exposure to unopposed oestrogens. Although most cases are sporadic, approximately 2-5% are associated with hereditary cancer syndromes, of which Lynch syndrome represents the most important contributor. Lynch syndrome results from germline mutations in DNA mismatch repair (MMR) genes and is associated with a substantially increased lifetime risk of endometrial cancer, reaching up to 71% in carriers of MutS homologue 6 (MSH6) mutations. Hereditary cancer predisposition typically follows an autosomal dominant inheritance pattern and may be suspected based on clinical warning signs such as early disease onset, multiple primary malignancies, a strong family history, or the presence of microsatellite instability in tumour tissue. In addition to Lynch syndrome, rarer genetic conditions-including Cowden syndrome (PTEN), Li-Fraumeni syndrome (TP53), polymerase proofreading-associated polyposis (POLE/POLD1), and hereditary breast and ovarian cancer syndromes (BRCA1/2)-also contribute to hereditary endometrial cancer risk. Recognition of these genetic backgrounds is essential for accurate diagnosis, personalised surveillance, and the implementation of targeted preventive and therapeutic strategies. Despite major advances in molecular diagnostics, hereditary endometrial cancer remains frequently underdiagnosed, leading to missed opportunities for cancer prevention among affected individuals and their families. This comprehensive review summarises current evidence on hereditary predispositions to endometrial cancer, with a particular emphasis on Lynch syndrome, and discusses underlying genetic mechanisms, inheritance patterns, diagnostic strategies, and clinical implications for screening, genetic counselling, and treatment optimisation.
oligonucleotides
2025-10-09 | Paired DNA/RNA testing uncovers a deep intronic PTEN pathogenic variant associated with clinical Cowden Syndrome: a case report
Identification of a deep intronic PTEN pathogenic variant, which was not detected by standard DNA-targeted panel sequencing but was uncovered by targeted PTEN RNA sequencing using CaptureSeq technology, illustrates the added value of concurrent DNA and RNA analyses in risk assessment for PTEN Hamartoma Tumor Syndrome (PHTS) and in patients given the diagnosis of clinical Cowden Syndrome (CS). These findings have significant clinical implications, including providing the rationale for testing patients meeting clinical criteria for PHTS/CS with concurrent DNA and RNA testing. It also supports reevaluation of patients who test negative by DNA testing alone but with a clinical diagnosis of PHTS/CS with subsequent RNA testing to identify and clinically interpret previously undetected deep intronic PTEN variants. Where cancer treatment and prevention decisions hinge on correct diagnoses, concurrent DNA and RNA testing rather than stepwise testing can permit faster, more accurate results and earlier clinical actionability.
2025-05-28 | Paired DNA/RNA genetic testing to uncover cryptic pathogenic variants (PV) associated with PTEN hamartoma tumor syndrome (PHTS) and hereditary cancer (CA).
e22598 Background: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PTHS) is a family of related genetic disorders including Cowden Syndrome (CS), Bannayan-Riley-Ruvalcaba Syndrome (BRRS), and Proteus Syndrome (PS) associated with distinct phenotypes and increased CA risk. Germline PTEN PVs remain unidentified in many patients (pts), including 40% w/BRRS, 80% w/PS, and 15% w/CS. Standard DNA testing may fail to identify clinically relevant deep intronic PTEN PVs detectable by comprehensive testing that includes RNA analysis. Using a commercial laboratory database, we identify pts tested by DNA/RNA and found to harbor deep intronic PVs associated with alternative RNA splicing of PTEN and predicted to cause PHTS. Methods: Pts tested by paired DNA/RNA testing (2019-2024, Ambry Genetics) and found to have a deep intronic PV leading to a splice site variant were identified. DNA/RNA results were linked to clinical data from a test requisition form. RNA was isolated using standard methodology and converted to cDNA by RT-PCR. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes followed by PCR and NGS. Absence or presence of RNA transcripts meeting quality thresholds is incorporated as evidence towards classification of DNA variants. Study was IRB reviewed (FCCC IRB #24-9030/Ambry WCG IRB exempt). Results: Index case: 64 yo F w/hx of breast CA (42 & 53) and thyroidectomy for nodules and papillary thyroid CA was referred for genetic counseling following colonoscopy showing extensive ganglioneuromatosis. Exam found macrocephaly (59.5 cm), tongue papules, likely facial trichilemmomas, and axillary acrochordons. RNA testing identified a deep intronic PV at c.209+2047A>G resulting in alternative PTEN splicing. In the combined DNA/RNA testing database (n=489,960), 17 additional individuals/families undergoing PTEN testing were identified with a deep intronic PV/LPV (n=14) or suspicious VUS (n=3). In total, 12 probands reported CA (9 <50 yrs) including cases of early breast (n=4, 38-63 yrs), thyroid (n=1, 25 yrs), salivary (n=1, 31 yrs), uterine (n=1, 46 yrs), bladder (n=1, 29 yrs), prostate (n=1, 66 yrs) and ovary CA (n=3, 28-32 yrs). Other PHTS features reported in probands/families: macrocephaly (n=7), colon ganglioneuromas and/or polyposis (n=7), goiter/thyroid nodules (n=6), penile freckling (n=2), skin findings (n=3), and intellectual disability (n=2). Potentially clinically relevant co-occurring variants were detected in NF1 (x3), GALNT12 (x2), BRCA2 and SDHC . Conclusions: Deep intronic PTEN PVs missed by DNA sequencing but detectable by RNA testing and associated with early-onset CA explain a portion of negative results in pts meeting clinical criteria for CS and/or manifesting phenotypic features of PHTS.
2023-10-12 | PTEN, PTENP1, microRNAs, and ceRNA Networks: Precision Targeting in Cancer Therapeutics
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a well characterised tumour suppressor, playing a critical role in the maintenance of fundamental cellular processes including cell proliferation, migration, metabolism, and survival. Subtle decreases in cellular levels of PTEN result in the development and progression of cancer, hence there is tight regulation of the expression, activity, and cellular half-life of PTEN at the transcriptional, post-transcriptional, and post-translational levels. PTENP1, the processed pseudogene of PTEN, is an important transcriptional and post-transcriptional regulator of PTEN. PTENP1 expression produces sense and antisense transcripts modulating PTEN expression, in conjunction with miRNAs. Due to the high sequence similarity between PTEN and the PTENP1 sense transcript, the transcripts possess common miRNA binding sites with the potential for PTENP1 to compete for the binding, or 'sponging', of miRNAs that would otherwise target the PTEN transcript. PTENP1 therefore acts as a competitive endogenous RNA (ceRNA), competing with PTEN for the binding of specific miRNAs to alter the abundance of PTEN. Transcription from the antisense strand produces two functionally independent isoforms (PTENP1-AS-α and PTENP1-AS-β), which can regulate PTEN transcription. In this review, we provide an overview of the post-transcriptional regulation of PTEN through interaction with its pseudogene, the cellular miRNA milieu and operation of the ceRNA network. Furthermore, its importance in maintaining cellular integrity and how disruption of this PTEN-miRNA-PTENP1 axis may lead to cancer but also provide novel therapeutic opportunities, is discussed. Precision targeting of PTENP1-miRNA mediated regulation of PTEN may present as a viable alternative therapy.
2022-08-09 | Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants.
Germline PTEN variants (PTEN hamartoma tumor syndrome [PHTS]) confer up to 85% lifetime risk of female breast cancer (BC). BCs arising in PHTS are clinically distinct from sporadic BCs, including younger age of onset, multifocality, and an increased risk of second primary BCs. Yet, there is no previous investigation into the underlying genomic landscape of this entity. We sought to address the hypothesis that BCs arising in PHTS have a distinct genomic landscape compared to sporadic counterparts. We performed and analyzed exome sequencing data from 44 women with germline PTEN variants who developed BCs. The control cohort comprised of 497 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. We demonstrate that PHTS-derived BCs have a distinct somatic mutational landscape compared to the sporadic counterparts, namely second somatic hits in PTEN, distinct mutational signatures, and increased genomic instability. The PHTS group had a significantly higher frequency of somatic PTEN variants compared to TCGA (22.7% versus 5.6%; odds ratio [OR] 4.93; 95% confidence interval [CI] 2.21 to 10.98; p < 0.001) and a lower mutational frequency in PIK3CA (22.7% versus 33.4%; OR 0.59; 95% CI 0.28 to 1.22; p = 0.15). Somatic variants in PTEN and PIK3CA were mutually exclusive in PHTS (p = 0.01) but not in TCGA. Our findings have important implications for the personalized management of PTEN-related BCs, especially in the context of more accessible genetic testing.
2013-02-12 | Utility of PTEN protein dosage in predicting for underlying germline PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes.
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. 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. 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)). We assessed the utility of PTEN protein levels in predicting germline PTEN mutations. 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). 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.
antibodies
2026-08-24 | Solid papillary carcinoma of the breast: A clinicopathological study with emphasis on unusual immunohistochemical and genetic features.
To characterize the clinicopathological spectrum of solid papillary carcinoma (SPC) in our institutional cohort and to attempt to interpret unusual findings observed during routine diagnostic workup. We retrospectively analyzed the clinicopathological features of 20 cases of SPC from our institution. All 20 patients were women, aged 45-79 years (mean, 66.4 years; median, 69.5 years). Among these, 18 cases were detected by the patients themselves, one was detected during routine examination, and the remaining patient presented with bloody nipple discharge. Imaging showed that most tumors were well‑defined solid or complex cystic and solid nodules. On microscopic examination, the tumors exhibited solid nests with delicate fibrovascular cores. The tumor cells were morphologically diverse, generally showing mild atypia and rare mitotic figures. Necrosis, hemorrhage, mucin deposition, and lymphocytic infiltration were observed in the stroma. Some cases showed unusual immunohistochemical patterns, including negativity for GATA binding protein 3 (GATA3) and synaptophysin (Syn). Transcriptional repressor GATA binding protein 1 (TRPS1) and insulinoma‑associated protein 1 (INSM1) may aid in the diagnosis of such cases. Furthermore, 1 patient exhibited chromosome 17 polysomy on human epidermal growth factor receptor 2 (HER2) fluorescence in situ hybridization (FISH) analysis. Moreover, using immunohistochemistry and FISH analyses, two patients with concomitant thyroid lesions were found to demonstrate loss of phosphatase and tensin homolog (PTEN) expression, suggestive of possible Cowden syndrome. SPC of the breast is a rare tumor and generally carries a favorable prognosis. However, some cases may show unusual immunohistochemical expression patterns; in particular, the clinical significance of chromosome 17 polysomy detected using HER2 FISH remains unclear. In addition, occasional cases may be associated with Cowden syndrome, which warrants further investigation through genetic testing.
2025-12-29 | Genetic and immunohistochemical studies identify recurrent ACTB mutations and PTEN alterations in tubular adenomas of the breast.
Tubular adenoma of the breast (TAB) is a rare and understudied neoplasm, initially thought to represent a fibroadenoma (FA) variant. Recently, it has been shown that TABs lack MED12 mutations indicating a distinct pathogenesis, and an association between multiple TABs and Cowden syndrome (CS) has been described. We sought to evaluate PTEN status in TABs with immunohistochemistry (IHC) and identify other potential molecular alterations. Forty-nine TABs from 43 patients (3 with CS, 40 without known CS) were retrieved. All patients were female, and ages ranged from 15 to 54 years old (median: 25). All TABs were well circumscribed and composed of closely packed, bilayered tubules with minimal intervening stroma. CS patients had multiple, bilateral TABs. PTEN IHC showed loss of expression in the luminal cells in TABs from all CS patients while the expression was retained in sporadic/non-CS TABs. Whole exome and/or Sanger sequencing was performed on 34 sporadic TABs and identified somatic missense mutations at codon 95 of the beta-actin gene, ACTB, in 19 cases (56%). No pathogenic MED12 mutations were identified in 29 TABs with next-generation sequencing results. Overall, our findings highlight recurrent somatic ACTB mutations in more than half of sporadic TABs. CS-associated TABs but not sporadic TABs showed loss of PTEN expression. The presence of bilateral and/or multiple TABs should prompt PTEN IHC to rule out the possibility of CS.
2025-11-03 | The Value of Punching It Out: Patient With Cowden Syndrome and MALT Lymphoma of the Lung.
Cowden syndrome (CS) is a phenotypic representation of PTEN hamartoma tumor syndrome. CS is the result of dysregulation of the MTOR pathway contributing to cellular proliferation, which leads to an increased risk for the development of benign and malignant tumors of the breast, thyroid, endometrium, and kidney. There are scarce reports of patients with this condition developing lymphomas. We present an African American female with a history of MALT lymphoma of the right lung diagnosed at age 41 treated with Rituxan who then presented at age 48 with a triple-negative cancer of the right breast. Physical exam showed macrocephaly, thyromegaly, and palmar pits. Family history was notable for a sister deceased from ovarian cancer at age 21 and a mother deceased from colon cancer at age 61. Genetic testing via peripheral blood identified a heterozygous PTEN pathogenic variant p.R130Q consistent with a molecular diagnosis of CS. Skin biopsy was coordinated given concern the MALT lymphoma could have contributed to spurious results and confirmed the same pathogenic PTEN mutation. Lymphomas have rarely been reported with this condition although activation of the PTEN pathway has been previously reported as a contributing factor in B cell lymphoma. Skin biopsies may offer the best specimen for patients with hematologic malignancy.
2025-10-01 | S3870 Colonic Ganglioneuromas in Older Adults: A Case Series Highlighting Potential Associations With Malignancy and Genetic Risk
Introduction: Colonic ganglioneuromas are rare, benign neurogenic tumors composed of ganglion cells, Schwann cells, and nerve fibers. Often found incidentally during colonoscopy, they may resemble hyperplastic or adenomatous polyps. These lesions are typically diagnosed in children or young adults and are associated with genetic syndromes such as multiple endocrine neoplasia type 2B (MEN2B), neurofibromatosis type 1, and Cowden syndrome. Their significance in older adults, particularly those with cancer or genetic risk, remains unclear. We present the cases of 4 patients, all above the age of 50 years, with ganglioneuromas found on colonoscopy. Case Description/Methods: In case 1, a 65-year-old man with stage 3 chronic kidney disease, hypertension, and intermittent constipation. Colonoscopies: 2006 (2 3-mm sessile polyps), 2017 (tubular adenoma and ganglioneuroma), 2020 (2 hyperplastic polyps), and 2025 (8-mm hyperplastic polyp). Case 2 is a 64-year-old woman with breast cancer treated in 2022 and prior grade 3 cervical intraepithelial neoplasia. Colonoscopies: 2012 (diverticulosis), 2019 (5 mm tubular adenoma), 2024 (multiple small polyps and a 5-mm sigmoid lesion—biopsy-confirmed ganglioneuroma) with 4-month recall (5-mm pedunculated ganglioneuroma). Case 3 is a 60-year-old woman with hypothyroidism, migraines, endometrial cancer, BARD1 gene mutation, family history of uterine and colon cancer, and longstanding bloating and constipation. Colonoscopies: 2020 (tortuous colon, no polyps), 2025 (10-mm pedunculated sigmoid polyp—ganglioneuroma). Case 4 is a 53-year-old man with alcoholic cirrhosis and liver failure. No family history of colonic issues. Colonoscopies: Polyps as a child and in teen years with normal follow-ups, 2023 (5 polyps, polypoid ganglioneuroma, polypoid with features of mucosal Schwann cell hamartoma) 3-year recall and genetic testing. Discussion: All patients were older than 50 years, challenging the view that colonic ganglioneuromas are exclusively pediatric or young adult findings. Lesions ranged from sessile to pedunculated, which demonstrates the continued need to evaluate lesions by pathology. Colonic ganglioneuromas may be underrecognized in older adults and could be associated with malignancy and genetic risk. This case series supports the need for further investigation into their natural history and clinical implications, especially in high-risk populations.
2025-10-01 | MON-383 NF1 and PHTS Co-Occurrence: A Unique Case and Management Challenges
Abstract Disclosure: A. Razzeto: None. H. Mejia: None. N.A. Borja: None. Z.C. Hannoush: None. Introduction: Neurofibromatosis type 1 (NF1) and PTEN Hamartoma Tumor Syndrome (PHTS) are autosomal dominant disorders that predispose to various neoplasms. NF1, affecting 1 in 3,000, has been linked to subclinical hypothyroidism and rarely to thyroid nodules/cancer, primary hyperparathyroidism, and pheochromocytoma/paraganglioma. PHTS, affecting 1 in 200,000 individuals, is associated with an increased incidence of benign thyroid nodules and differentiated thyroid cancer. The co-occurrence of these syndromes has not been previously reported, and this case highlights the complexities of managing a patient with both. Case Presentation: A 33-year-old Eastern European male with NF1 and a history of multiple neurofibroma resections, optic nerve gliomas, history of metastatic testicular cancer, lung teratoma, and colonic polyposis presented with an incidental thyroid mass in surveillance CT. He denied compressive neck symptoms and was clinically and biochemically euthyroid (TSH 2.35 mcIU/mL). Physical exam demonstrated macrocephaly, diffuse neurofibromas, café-au-lait macules, and a large left thyroid mass. Thyroid ultrasound revealed a bilateral goiter with multiple hypoechoic nodules (largest 4.8 cm, left lobe). Laboratory evaluation revealed normal calcium, calcitonin, metanephrine and normetanephrine levels. Further genetic testing revealed he was heterozygous the pathogenic variants NF1 c.1381C>T (p.Arg461*) and PTEN c.253+1G>T. Due to the significantly elevated lifetime risk of follicular and papillary thyroid cancer associated with PHTS ranging between 3% and 14%, the patient was counseled regarding FNA/thyroidectomy but opted for close surveillance. Most recently, he developed PTH-dependent hypercalcemia (Ca 11.3 mg/dL, corrected Ca 10.7 mg/dL; PTH 95 pg/mL) with normal GFR. Further workup for primary hyperparathyroidism is pending. Conclusion: This is the first reported case of co-occurring NF1 and PHTS. The patient's multinodular goiter, prior malignancy, and increased risk for thyroid cancer and other endocrine disorders due to his dual genetic diagnoses require individualized management. Despite declining intervention, close surveillance is crucial. Presentation: Monday, July 14, 2025
small molecules
2026-08-07 | Cutaneous Adnexal Neoplasms: A Clinical, Dermoscopic, and Histopathological Study
structureless area and yellowish keratin with a few arborizing vessels at periphery, suggestive of keratoacanthoma (Fig. 1B).Excision was done considering keratoacanthoma, trichoblastoma and lobular capillary hemangioma as differentials.Histopathology revealed a well-circumscribed, ulcerated tumor exhibiting parakeratosis, acanthosis, and lobules of cells having round, uniform nuclei with moderate eosinophilic cytoplasm, many showing clearing of cytoplasm, separated by thin fibrous septa (Figs 1C and D).A few keratin pearls and squamous eddies were also seen.The tumor margins were free.The features were suggestive of a trichilemmoma. IntroductIonCutaneous adnexa comprise sweat glands, sebaceous glands, and pilosebaceous units.Skin adnexal tumors (SATs) arise from the multipotent undifferentiated stem cells, forming a large and diverse group of benign and malignant neoplasms, which exhibit morphological differentiation toward one of the different types of adnexal epithelium present in normal skin, sometimes exhibiting mixed differentiation, hence posing difficulty in precise diagnosis.Adnexal tumors present as asymptomatic papules or nodules, sometimes associated with pain depending on the site of involvement.SATs are more often excised and diagnosed based on histopathology.Local complete excision is often curative, as most of them are benign.Diagnosing adnexal tumors has important implications, as they might be markers for syndromes associated with internal malignancies, such as trichilemmomas in Cowden syndrome and sebaceous tumors in Muir-Torre syndrome.[1][2][3] Herein, we present seven cases of adnexal tumors with varied clinical, dermoscopic, and histopathological features. case descrIptIons Case 1A 13-year-old male presented to dermatology outpatient department with a painless, solitary swelling, gradually increasing in size with occasional bleeding over the scalp for 3 months.Examination revealed a solitary, sessile, nontender nodule 5 × 5 cm in size with central crater containing crust and bleeding over the midline of scalp (Fig. 1A).Dermoscopy revealed a central crater with a whitish, 1-
2026-05-12 | Management and outcomes of fertility preservation in rare Cowden syndrome-associated endometrial carcinoma: a case series.
Cowden syndrome-associated endometrial carcinoma (CS-EC) is rare, and data on fertility-preserving treatment for young patients remain limited. This series describes the diagnosis and management of three patients with CS-EC who underwent fertility-sparing treatment. We also report the subsequent pregnancy outcome for one of these individuals. These cases provide a clinical reference for the individualized management of such patients. Three patients (aged 29, 31, and 28 years) with germline Phosphatase and tensin homolog (PTEN) pathogenic variants and stage IA endometrial carcinoma underwent individualized fertility-sparing treatment. Case 1 (PTEN p.R189Qfs*9) failed levonorgestrel-releasing intrauterine system (LNG-IUS) treatment at 19 months. Eight cycles of GnRH agonist (GnRH-a) plus letrozole (LE) subsequently induced a complete response. A recurrence was successfully managed with twelve additional cycles of this regimen. Case 2 (PTEN p.R173C) attained remission after six months of megestrol acetate (MA). Case 3 (PTEN p.R335*) responded to MA over nine months, then developed complex mucinous papillary metaplasia during LNG-IUS maintenance, which resolved with ethinylestradiol/cyproterone acetate (EE/CPA). She subsequently conceived and delivered a live birth through Intracytoplasmic sperm injection (ICSI). During the follow-up period, all patients were administered maintenance therapy using a LNG-IUD. Fertility-sparing therapy may serve as a potentially feasible option for highly selected patients with stage IA CS-EC, and could lead to relatively favorable pregnancy outcomes. The clinical feasibility of this strategy relies heavily on strict patient selection, timely molecular diagnosis, and standardized continuous multidisciplinary management.
2026-04-16 | Remarkable response of metaplastic breast cancer to a novel targeted AKT inhibitor TAS-117 in a Cowden syndrome patient: a case report.
PTEN hamartoma tumour syndrome (PHTS) is characterized by a germline PTEN mutation and a substantial increase in lifetime breast cancer risk to 85% with lower age at first diagnosis. Despite the availability of agents targeting PTEN-regulated PI3K/AKT/mTOR pathway, there are currently no approved treatments for PHTS patients with cancer. This is the first report of a patient with triple-negative metaplastic breast cancer and PHTS in the literature. We present an exceptional response of this aggressive stage IV tumour in a 34-year-old woman with PHTS to treatment with the novel AKT1-3 inhibitor, TAS-117. Despite previous rapid progression and resistance to multi-agent chemotherapy and radiotherapy, disease stabilisation was ongoing at 3.8 years. Cell-free DNA analysis of blood samples at baseline and during treatment with TAS-117 revealed a complete marker response to treatment. Therapy has been well tolerated, and the patient continues the therapy without severe adverse events, dose reduction, or treatment interruptions. These findings support further investigation of targeted interventions for malignancies developing in the context of PHTS.
2026-03-09 | A Successful Live Birth After Double Fertility Preservation With Embryo Cryopreservation and MPA Therapy Combined With Hysteroscopic Resection for Metachronous Breast and Endometrial Cancer in Women With Cowden Syndrome: A Case Report.
Cowden syndrome is an autosomal-dominantly inherited rare condition caused by germline pathogenic variants of the PTEN gene. Multiple tumor development at a younger age in this syndrome may warrant different modalities of fertility preservation. Here we report that women with this syndrome gave successful live birth with frozen-thaw embryo transfer that was cryopreserved before the start of chemotherapy for breast cancer. This woman also suffered from endometrial cancer that developed during hormonal treatment with GnRH agonist and tamoxifen for breast cancer. The lesion was well controlled with oral MPA therapy and hysteroscopic resection. She could receive fertility preservation for breast cancer and endometrial cancer before fertility treatment and pregnancy. This is the first report of live births after multiple fertility preservation therapy for metachronous breast and uterine cancer in Cowden syndrome. Appropriate genetic counseling may help the patient's decision making. The treatment plan should be discussed with diverse professionals such as oncologists, reproductive physicians, perinatologists, geneticists, and genetic counselors.
2026-02-13 | Hereditary Endometrial Cancer: Lynch Syndrome, Mismatch Repair Deficiency, and Emerging Genetic Predispositions-A Comprehensive Review with Clinical and Laboratory Guidelines.
Endometrial cancer is the most common gynaecologic malignancy in high-income countries, with a rising incidence largely driven by reproductive factors, obesity, and prolonged exposure to unopposed oestrogens. Although most cases are sporadic, approximately 2-5% are associated with hereditary cancer syndromes, of which Lynch syndrome represents the most important contributor. Lynch syndrome results from germline mutations in DNA mismatch repair (MMR) genes and is associated with a substantially increased lifetime risk of endometrial cancer, reaching up to 71% in carriers of MutS homologue 6 (MSH6) mutations. Hereditary cancer predisposition typically follows an autosomal dominant inheritance pattern and may be suspected based on clinical warning signs such as early disease onset, multiple primary malignancies, a strong family history, or the presence of microsatellite instability in tumour tissue. In addition to Lynch syndrome, rarer genetic conditions-including Cowden syndrome (PTEN), Li-Fraumeni syndrome (TP53), polymerase proofreading-associated polyposis (POLE/POLD1), and hereditary breast and ovarian cancer syndromes (BRCA1/2)-also contribute to hereditary endometrial cancer risk. Recognition of these genetic backgrounds is essential for accurate diagnosis, personalised surveillance, and the implementation of targeted preventive and therapeutic strategies. Despite major advances in molecular diagnostics, hereditary endometrial cancer remains frequently underdiagnosed, leading to missed opportunities for cancer prevention among affected individuals and their families. This comprehensive review summarises current evidence on hereditary predispositions to endometrial cancer, with a particular emphasis on Lynch syndrome, and discusses underlying genetic mechanisms, inheritance patterns, diagnostic strategies, and clinical implications for screening, genetic counselling, and treatment optimisation.
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2025-10-09 | Paired DNA/RNA testing uncovers a deep intronic PTEN pathogenic variant associated with clinical Cowden Syndrome: a case report
Identification of a deep intronic PTEN pathogenic variant, which was not detected by standard DNA-targeted panel sequencing but was uncovered by targeted PTEN RNA sequencing using CaptureSeq technology, illustrates the added value of concurrent DNA and RNA analyses in risk assessment for PTEN Hamartoma Tumor Syndrome (PHTS) and in patients given the diagnosis of clinical Cowden Syndrome (CS). These findings have significant clinical implications, including providing the rationale for testing patients meeting clinical criteria for PHTS/CS with concurrent DNA and RNA testing. It also supports reevaluation of patients who test negative by DNA testing alone but with a clinical diagnosis of PHTS/CS with subsequent RNA testing to identify and clinically interpret previously undetected deep intronic PTEN variants. Where cancer treatment and prevention decisions hinge on correct diagnoses, concurrent DNA and RNA testing rather than stepwise testing can permit faster, more accurate results and earlier clinical actionability.
2025-05-28 | Paired DNA/RNA genetic testing to uncover cryptic pathogenic variants (PV) associated with PTEN hamartoma tumor syndrome (PHTS) and hereditary cancer (CA).
e22598 Background: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PTHS) is a family of related genetic disorders including Cowden Syndrome (CS), Bannayan-Riley-Ruvalcaba Syndrome (BRRS), and Proteus Syndrome (PS) associated with distinct phenotypes and increased CA risk. Germline PTEN PVs remain unidentified in many patients (pts), including 40% w/BRRS, 80% w/PS, and 15% w/CS. Standard DNA testing may fail to identify clinically relevant deep intronic PTEN PVs detectable by comprehensive testing that includes RNA analysis. Using a commercial laboratory database, we identify pts tested by DNA/RNA and found to harbor deep intronic PVs associated with alternative RNA splicing of PTEN and predicted to cause PHTS. Methods: Pts tested by paired DNA/RNA testing (2019-2024, Ambry Genetics) and found to have a deep intronic PV leading to a splice site variant were identified. DNA/RNA results were linked to clinical data from a test requisition form. RNA was isolated using standard methodology and converted to cDNA by RT-PCR. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes followed by PCR and NGS. Absence or presence of RNA transcripts meeting quality thresholds is incorporated as evidence towards classification of DNA variants. Study was IRB reviewed (FCCC IRB #24-9030/Ambry WCG IRB exempt). Results: Index case: 64 yo F w/hx of breast CA (42 & 53) and thyroidectomy for nodules and papillary thyroid CA was referred for genetic counseling following colonoscopy showing extensive ganglioneuromatosis. Exam found macrocephaly (59.5 cm), tongue papules, likely facial trichilemmomas, and axillary acrochordons. RNA testing identified a deep intronic PV at c.209+2047A>G resulting in alternative PTEN splicing. In the combined DNA/RNA testing database (n=489,960), 17 additional individuals/families undergoing PTEN testing were identified with a deep intronic PV/LPV (n=14) or suspicious VUS (n=3). In total, 12 probands reported CA (9 <50 yrs) including cases of early breast (n=4, 38-63 yrs), thyroid (n=1, 25 yrs), salivary (n=1, 31 yrs), uterine (n=1, 46 yrs), bladder (n=1, 29 yrs), prostate (n=1, 66 yrs) and ovary CA (n=3, 28-32 yrs). Other PHTS features reported in probands/families: macrocephaly (n=7), colon ganglioneuromas and/or polyposis (n=7), goiter/thyroid nodules (n=6), penile freckling (n=2), skin findings (n=3), and intellectual disability (n=2). Potentially clinically relevant co-occurring variants were detected in NF1 (x3), GALNT12 (x2), BRCA2 and SDHC . Conclusions: Deep intronic PTEN PVs missed by DNA sequencing but detectable by RNA testing and associated with early-onset CA explain a portion of negative results in pts meeting clinical criteria for CS and/or manifesting phenotypic features of PHTS.
2023-10-12 | PTEN, PTENP1, microRNAs, and ceRNA Networks: Precision Targeting in Cancer Therapeutics
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a well characterised tumour suppressor, playing a critical role in the maintenance of fundamental cellular processes including cell proliferation, migration, metabolism, and survival. Subtle decreases in cellular levels of PTEN result in the development and progression of cancer, hence there is tight regulation of the expression, activity, and cellular half-life of PTEN at the transcriptional, post-transcriptional, and post-translational levels. PTENP1, the processed pseudogene of PTEN, is an important transcriptional and post-transcriptional regulator of PTEN. PTENP1 expression produces sense and antisense transcripts modulating PTEN expression, in conjunction with miRNAs. Due to the high sequence similarity between PTEN and the PTENP1 sense transcript, the transcripts possess common miRNA binding sites with the potential for PTENP1 to compete for the binding, or 'sponging', of miRNAs that would otherwise target the PTEN transcript. PTENP1 therefore acts as a competitive endogenous RNA (ceRNA), competing with PTEN for the binding of specific miRNAs to alter the abundance of PTEN. Transcription from the antisense strand produces two functionally independent isoforms (PTENP1-AS-α and PTENP1-AS-β), which can regulate PTEN transcription. In this review, we provide an overview of the post-transcriptional regulation of PTEN through interaction with its pseudogene, the cellular miRNA milieu and operation of the ceRNA network. Furthermore, its importance in maintaining cellular integrity and how disruption of this PTEN-miRNA-PTENP1 axis may lead to cancer but also provide novel therapeutic opportunities, is discussed. Precision targeting of PTENP1-miRNA mediated regulation of PTEN may present as a viable alternative therapy.
2022-08-09 | Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants.
Germline PTEN variants (PTEN hamartoma tumor syndrome [PHTS]) confer up to 85% lifetime risk of female breast cancer (BC). BCs arising in PHTS are clinically distinct from sporadic BCs, including younger age of onset, multifocality, and an increased risk of second primary BCs. Yet, there is no previous investigation into the underlying genomic landscape of this entity. We sought to address the hypothesis that BCs arising in PHTS have a distinct genomic landscape compared to sporadic counterparts. We performed and analyzed exome sequencing data from 44 women with germline PTEN variants who developed BCs. The control cohort comprised of 497 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. We demonstrate that PHTS-derived BCs have a distinct somatic mutational landscape compared to the sporadic counterparts, namely second somatic hits in PTEN, distinct mutational signatures, and increased genomic instability. The PHTS group had a significantly higher frequency of somatic PTEN variants compared to TCGA (22.7% versus 5.6%; odds ratio [OR] 4.93; 95% confidence interval [CI] 2.21 to 10.98; p < 0.001) and a lower mutational frequency in PIK3CA (22.7% versus 33.4%; OR 0.59; 95% CI 0.28 to 1.22; p = 0.15). Somatic variants in PTEN and PIK3CA were mutually exclusive in PHTS (p = 0.01) but not in TCGA. Our findings have important implications for the personalized management of PTEN-related BCs, especially in the context of more accessible genetic testing.
2013-02-12 | Utility of PTEN protein dosage in predicting for underlying germline PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes.
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. 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. 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)). We assessed the utility of PTEN protein levels in predicting germline PTEN mutations. 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). 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.
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2026-08-24 | Solid papillary carcinoma of the breast: A clinicopathological study with emphasis on unusual immunohistochemical and genetic features.
To characterize the clinicopathological spectrum of solid papillary carcinoma (SPC) in our institutional cohort and to attempt to interpret unusual findings observed during routine diagnostic workup. We retrospectively analyzed the clinicopathological features of 20 cases of SPC from our institution. All 20 patients were women, aged 45-79 years (mean, 66.4 years; median, 69.5 years). Among these, 18 cases were detected by the patients themselves, one was detected during routine examination, and the remaining patient presented with bloody nipple discharge. Imaging showed that most tumors were well‑defined solid or complex cystic and solid nodules. On microscopic examination, the tumors exhibited solid nests with delicate fibrovascular cores. The tumor cells were morphologically diverse, generally showing mild atypia and rare mitotic figures. Necrosis, hemorrhage, mucin deposition, and lymphocytic infiltration were observed in the stroma. Some cases showed unusual immunohistochemical patterns, including negativity for GATA binding protein 3 (GATA3) and synaptophysin (Syn). Transcriptional repressor GATA binding protein 1 (TRPS1) and insulinoma‑associated protein 1 (INSM1) may aid in the diagnosis of such cases. Furthermore, 1 patient exhibited chromosome 17 polysomy on human epidermal growth factor receptor 2 (HER2) fluorescence in situ hybridization (FISH) analysis. Moreover, using immunohistochemistry and FISH analyses, two patients with concomitant thyroid lesions were found to demonstrate loss of phosphatase and tensin homolog (PTEN) expression, suggestive of possible Cowden syndrome. SPC of the breast is a rare tumor and generally carries a favorable prognosis. However, some cases may show unusual immunohistochemical expression patterns; in particular, the clinical significance of chromosome 17 polysomy detected using HER2 FISH remains unclear. In addition, occasional cases may be associated with Cowden syndrome, which warrants further investigation through genetic testing.
2025-12-29 | Genetic and immunohistochemical studies identify recurrent ACTB mutations and PTEN alterations in tubular adenomas of the breast.
Tubular adenoma of the breast (TAB) is a rare and understudied neoplasm, initially thought to represent a fibroadenoma (FA) variant. Recently, it has been shown that TABs lack MED12 mutations indicating a distinct pathogenesis, and an association between multiple TABs and Cowden syndrome (CS) has been described. We sought to evaluate PTEN status in TABs with immunohistochemistry (IHC) and identify other potential molecular alterations. Forty-nine TABs from 43 patients (3 with CS, 40 without known CS) were retrieved. All patients were female, and ages ranged from 15 to 54 years old (median: 25). All TABs were well circumscribed and composed of closely packed, bilayered tubules with minimal intervening stroma. CS patients had multiple, bilateral TABs. PTEN IHC showed loss of expression in the luminal cells in TABs from all CS patients while the expression was retained in sporadic/non-CS TABs. Whole exome and/or Sanger sequencing was performed on 34 sporadic TABs and identified somatic missense mutations at codon 95 of the beta-actin gene, ACTB, in 19 cases (56%). No pathogenic MED12 mutations were identified in 29 TABs with next-generation sequencing results. Overall, our findings highlight recurrent somatic ACTB mutations in more than half of sporadic TABs. CS-associated TABs but not sporadic TABs showed loss of PTEN expression. The presence of bilateral and/or multiple TABs should prompt PTEN IHC to rule out the possibility of CS.
2025-11-03 | The Value of Punching It Out: Patient With Cowden Syndrome and MALT Lymphoma of the Lung.
Cowden syndrome (CS) is a phenotypic representation of PTEN hamartoma tumor syndrome. CS is the result of dysregulation of the MTOR pathway contributing to cellular proliferation, which leads to an increased risk for the development of benign and malignant tumors of the breast, thyroid, endometrium, and kidney. There are scarce reports of patients with this condition developing lymphomas. We present an African American female with a history of MALT lymphoma of the right lung diagnosed at age 41 treated with Rituxan who then presented at age 48 with a triple-negative cancer of the right breast. Physical exam showed macrocephaly, thyromegaly, and palmar pits. Family history was notable for a sister deceased from ovarian cancer at age 21 and a mother deceased from colon cancer at age 61. Genetic testing via peripheral blood identified a heterozygous PTEN pathogenic variant p.R130Q consistent with a molecular diagnosis of CS. Skin biopsy was coordinated given concern the MALT lymphoma could have contributed to spurious results and confirmed the same pathogenic PTEN mutation. Lymphomas have rarely been reported with this condition although activation of the PTEN pathway has been previously reported as a contributing factor in B cell lymphoma. Skin biopsies may offer the best specimen for patients with hematologic malignancy.
2025-10-01 | S3870 Colonic Ganglioneuromas in Older Adults: A Case Series Highlighting Potential Associations With Malignancy and Genetic Risk
Introduction: Colonic ganglioneuromas are rare, benign neurogenic tumors composed of ganglion cells, Schwann cells, and nerve fibers. Often found incidentally during colonoscopy, they may resemble hyperplastic or adenomatous polyps. These lesions are typically diagnosed in children or young adults and are associated with genetic syndromes such as multiple endocrine neoplasia type 2B (MEN2B), neurofibromatosis type 1, and Cowden syndrome. Their significance in older adults, particularly those with cancer or genetic risk, remains unclear. We present the cases of 4 patients, all above the age of 50 years, with ganglioneuromas found on colonoscopy. Case Description/Methods: In case 1, a 65-year-old man with stage 3 chronic kidney disease, hypertension, and intermittent constipation. Colonoscopies: 2006 (2 3-mm sessile polyps), 2017 (tubular adenoma and ganglioneuroma), 2020 (2 hyperplastic polyps), and 2025 (8-mm hyperplastic polyp). Case 2 is a 64-year-old woman with breast cancer treated in 2022 and prior grade 3 cervical intraepithelial neoplasia. Colonoscopies: 2012 (diverticulosis), 2019 (5 mm tubular adenoma), 2024 (multiple small polyps and a 5-mm sigmoid lesion—biopsy-confirmed ganglioneuroma) with 4-month recall (5-mm pedunculated ganglioneuroma). Case 3 is a 60-year-old woman with hypothyroidism, migraines, endometrial cancer, BARD1 gene mutation, family history of uterine and colon cancer, and longstanding bloating and constipation. Colonoscopies: 2020 (tortuous colon, no polyps), 2025 (10-mm pedunculated sigmoid polyp—ganglioneuroma). Case 4 is a 53-year-old man with alcoholic cirrhosis and liver failure. No family history of colonic issues. Colonoscopies: Polyps as a child and in teen years with normal follow-ups, 2023 (5 polyps, polypoid ganglioneuroma, polypoid with features of mucosal Schwann cell hamartoma) 3-year recall and genetic testing. Discussion: All patients were older than 50 years, challenging the view that colonic ganglioneuromas are exclusively pediatric or young adult findings. Lesions ranged from sessile to pedunculated, which demonstrates the continued need to evaluate lesions by pathology. Colonic ganglioneuromas may be underrecognized in older adults and could be associated with malignancy and genetic risk. This case series supports the need for further investigation into their natural history and clinical implications, especially in high-risk populations.
2025-10-01 | MON-383 NF1 and PHTS Co-Occurrence: A Unique Case and Management Challenges
Abstract Disclosure: A. Razzeto: None. H. Mejia: None. N.A. Borja: None. Z.C. Hannoush: None. Introduction: Neurofibromatosis type 1 (NF1) and PTEN Hamartoma Tumor Syndrome (PHTS) are autosomal dominant disorders that predispose to various neoplasms. NF1, affecting 1 in 3,000, has been linked to subclinical hypothyroidism and rarely to thyroid nodules/cancer, primary hyperparathyroidism, and pheochromocytoma/paraganglioma. PHTS, affecting 1 in 200,000 individuals, is associated with an increased incidence of benign thyroid nodules and differentiated thyroid cancer. The co-occurrence of these syndromes has not been previously reported, and this case highlights the complexities of managing a patient with both. Case Presentation: A 33-year-old Eastern European male with NF1 and a history of multiple neurofibroma resections, optic nerve gliomas, history of metastatic testicular cancer, lung teratoma, and colonic polyposis presented with an incidental thyroid mass in surveillance CT. He denied compressive neck symptoms and was clinically and biochemically euthyroid (TSH 2.35 mcIU/mL). Physical exam demonstrated macrocephaly, diffuse neurofibromas, café-au-lait macules, and a large left thyroid mass. Thyroid ultrasound revealed a bilateral goiter with multiple hypoechoic nodules (largest 4.8 cm, left lobe). Laboratory evaluation revealed normal calcium, calcitonin, metanephrine and normetanephrine levels. Further genetic testing revealed he was heterozygous the pathogenic variants NF1 c.1381C>T (p.Arg461*) and PTEN c.253+1G>T. Due to the significantly elevated lifetime risk of follicular and papillary thyroid cancer associated with PHTS ranging between 3% and 14%, the patient was counseled regarding FNA/thyroidectomy but opted for close surveillance. Most recently, he developed PTH-dependent hypercalcemia (Ca 11.3 mg/dL, corrected Ca 10.7 mg/dL; PTH 95 pg/mL) with normal GFR. Further workup for primary hyperparathyroidism is pending. Conclusion: This is the first reported case of co-occurring NF1 and PHTS. The patient's multinodular goiter, prior malignancy, and increased risk for thyroid cancer and other endocrine disorders due to his dual genetic diagnoses require individualized management. Despite declining intervention, close surveillance is crucial. Presentation: Monday, July 14, 2025
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