Cowden Syndrome Research Articles

Metachronous ovarian endometrioid carcinomas in a patient with a PTEN variant: case report of incidentally detected Cowden syndrome

BackgroundSomatic PTEN mutation occurs in a proportion of ovarian endometrioid carcinomas. However, these cancers have seldom been reported in diseases associated with germline PTEN variants, such as Cowden syndrome (CS).Case presentationThe present case was a 39-year-old woman with a left ovarian carcinoma who demonstrated a germline splice variant of PTEN (c.1026 + 1G > T) following genome-wide whole exome sequencing of her germline DNA. Histology of her resected tumor revealed endometrioid carcinoma of the same type as a right ovarian cancer resected eight years previously. These tumors showed null immunostaining for PTEN. She was genetically diagnosed with CS. Despite her clinical examinations had demonstrated several characteristic findings of CS, including mammary fibroma, esophageal and skin papilloma, colonic hamartoma, uterine myoma, and lipoma, the clinicians could not approach this diagnosis.ConclusionOvarian endometrioid carcinoma is generally thought to develop from endometrial tissue menstruated from the uterus and implanted on the ovary. To date, ovarian cancers have not been listed as CS-related cancers; however, ovarian endometrioid cancer can have a potential association with CS in endometriosis cases.

Toward Systems Pathology for PTEN Diagnostics.

Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline PTEN mutation. Furthermore, outside of the familial setting, somatic variants of PTEN occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnostics, incorporating clinical and molecular pathology data with the goal of improving the clinical management of patients with a PTEN mutation. Detection of a germline PTEN mutation can inform cancer surveillance and in the case of somatic mutation, have value in predicting disease course. Given that PTEN functions in the PI3K/AKT/mTOR pathway, identification of a PTEN mutation may highlight new therapeutic opportunities and/or inform therapeutic choices.

PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature.

PTEN hamartoma tumor syndrome (PHTS) is a highly variable autosomal dominant condition associated with intellectual disability, overgrowth, and tumor predisposition phenotypes, which often overlap. PHTS incorporates a number of historical clinical presentations including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome, and a macrocephaly-autism/developmental delay syndrome. Many reviews in the literature focus on PHTS as an adult hamartoma and malignancy predisposition condition. Here, we review the current literature with a focus on pediatric presentations. The review starts with a summary of the main conditions encompassed within PHTS. We then discuss PHTS diagnostic criteria, and clinical features. We briefly address rarer PTEN associations, and the possible role of mTOR inhibitors in treatment. We acknowledge the limited understanding of the natural history of childhood-onset PHTS as a cancer predisposition syndrome and present a summary of important management considerations.

1474 Cowden and MAP Syndrome: The Untold Story of a Screening Colonoscopy—Case Report

INTRODUCTION: Cowden syndrome is a rare autosomal dominant condition associated with PTEN gene mutation. MUTYH-associated polyposis (MAP) is inherited by autosomal recessive fashion. Cowden syndrome presents with multiple hamartomas in a variety of tissues, oral fibromas, and punctate palmoplantar keratoses, and an increased risk of breast, endometrial, thyroid, kidney and colorectal cancers. MAP syndrome is associated with adenomatous polyps and colon cancer predisposition. CASE DESCRIPTION/METHODS: 51-year-old female underwent screening colonoscopy and was found to have multiple polyps throughout the colon. Biopsy showed ganglioneuromas and hamartomous polyps. Medical history was significant for hypothyroidism and hypoparathyroidism secondary to thyroidectomy for a goiter, bilateral mastectomy for a ductal carcinoma in situ, hysterectomy for fibroids, palmar keratosis and oral papillomatosis. Family history was relevant for breast cancer in her mother at age 50. Genetic analysis revealed mosaicism for a loss of function variant in PTEN and autosomal recessive pathogenic single MUTYH variant which confirmed Cowden Syndrome and carrier state for MAP syndrome. Appropriate cancer surveillance was arranged for our patient according to the National Cancer Center Network Guidelines through multidisciplinary approach. DISCUSSION: PTEN gene is a tumor suppressor responsible for regulating the cell cycle. Because of her mutation, our patient is susceptible for an array of different malignancies. Her genetic profile showed mosaicism for PTEN genetic variant. Adequate cancer surveillance for colon cancer, renal cell carcinoma and recurrence of breast cancer were discussed with our patient. MUTYH variant mutation was found in this patient. However, she inherited only one single copy of this recessive gene expecting not to develop clinical MAP syndrome. Risks associated with a single variant in MUTYH are unclear. There are some reports that suggest an inconsistent increased risk of colon, endometrial, and breast cancer. National Cancer Center Network Guidelines has created surveillance guidelines for individuals with a single MUTYH variant but cautioned that these guidelines are likely to change over time. Uniquely, extracolonic neoplastic complications were detected before the diagnosis of Cowden in our patient. High clinical suspicion and early diagnosis of this condition is crucial for effective prevention of colonic and extracolonic malignancies that these individuals are at high risk for.

1591 Melanosis Coli Aids Endoscopic Differentiation of Polyp Histology in Cowden Syndrome

INTRODUCTION: Cowden syndrome is a rare disorder related to germline mutations in the PTEN gene. Although considered a hamartomatous polyposis syndrome, emerging evidence has shown colorectal polyposis with mixed histologic types (including adenomas) to be most common. This can make endoscopic surveillance difficult. Melanosis coli is characterized by dark pigmentation of the colon. Adenomatous and hyperplastic polyps remain pale in this setting and are easily visualized, but there are no published reports on the appearance of hamartomatous polyps. CASE DESCRIPTION/METHODS: A 55-year-old man with intellectual disability was referred to our institution for consideration of colectomy due to colorectal polyposis. He was then referred to GI Genetics clinic for further evaluation prior to surgery. His history included innumerable colon polyps on previous colonoscopies. Available pathology included multiple colon polyp types including tubulovillous and tubular adenoma, serrated adenoma, hyperplastic and inflammatory polyps. His family history included twin brother with brain tumor, mother with breast cancer and stomach cancer and father with brain cancer. Examination showed macrocephaly with head circumference of 62 cm. Cowden syndrome was suspected and genetic testing was performed. This showed a pathogenic mutation in the PTEN gene and confirmed the diagnosis. Surveillance colonoscopy was performed. This showed diffuse melanosis and polyposis of the colon. There were 4 colon polyps that were pale and visually consistent with adenomas. These were resected and returned as 3 tubular adenomas and a serrated adenoma with minimally apparent melanosis on histologic assessment. There were multiple diminutive polyps throughout the colon that were dark and appeared visually consistent with hamartomas. Many of these were sampled and were consistent with hamartomatous polyps with prominent melanosis histologically. Given the ability to endoscopically differentiate between neoplastic and benign polyp histologies, ongoing surveillance colonoscopy was recommended and colectomy was avoided. DISCUSSION: Polyposis with mixed polyp histology is common in Cowden syndrome and complicates endoscopic surveillance. In our patient with melanosis coli, hamartomatous polyps remained dark and matched the surrounding mucosa while adenomas and serrated adenomas were pale and easily distinguishable. This is the first report of the appearance of hamartomas in the setting of melanosis to our knowledge.

1677 Few Bumps in the Road Led to Surgical Prophylaxis: Cowden’s Syndrome

INTRODUCTION: PTEN syndrome is caused by a germline mutation in phosphatase and tensin homolog (PTEN) gene. As a syndrome, it has different clinical manifestations, Cowden syndrome being one of them. We present the case of a 41-year-old female found to have multiple polyps throughout the large and small bowel. Biopsy showed hamartomous type polyps and ganglioneuromas. Genetic testing revealed de novo PTEN mutation. CASE DESCRIPTION/METHODS: 41-year-old female presented with acute diarrhea to the emergency department. Medical history was relevant for hypothyroidism secondary to thyroidectomy for goiter and multiple skin tags. Colonoscopy showed the small and large bowel carpeted with polyps and biopsies were taken. Pathology showed hamartomatous-type polyps and ganglioneuromas. Genetic testing was positive for PTEN de novo mutation. A multidisciplinary team was involved in the case for cancer surveillance. Estrogen/progesterone receptor positive and HER2-negative invasive lobular carcinoma was found after bilateral prophylactic mastectomy. Follow up endoscopy showed small esophageal nodules and multiple gastroduodenal polyps found to be hyperplastic on pathology. Hysterectomy is planned with subsequent Arimidex as adjuvant therapy. DISCUSSION: First reported in 1963, Cowden syndrome has a prevalence of 1 in 200,000–250,000 with 20–34% of individuals having germline PTEN mutation. PTEN acts as a tumor suppressor. A mutation of this gene leads to an increased prevelance of a variety of malignancies (colorectal, breast, thyroid, renal, endometrial skin, and brain) and non-neoplastic growths (trichilemmoma, papules, acral keratosis). The purpose of bringing attention to this very rare polyposis syndrome is increase awareness about the multidisciplinary approach needed for cancer surveillance. Annual physical exam should be performed starting at age 18; baseline screening colonoscopy at age 35 with follow up screening earlier than 5 years. Annual urinalysis and cytology to screen for renal cancer is recommended to start at age 35. Surveillance for thyroid cancer includes baseline thyroid ultrasound starting at age 18, and then annual thyroid exams thereafter. Women with PTEN mutations should have annual breast cancer screening starting at age 25. Our patient was advised to undergo appropriate cancer surveillance according to the National Cancer Center Network guidelines.

1586 A Classic Presentation of Cowden Syndrome

INTRODUCTION: Cowden syndrome (CS) is a rare autosomal dominant hereditary multiple hamartoma syndrome characterized by benign and malignant tumors. CS is one of the four subtypes of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS). The National Comprehensive Cancer Network utilizes consensus diagnostic criteria, where one must have ≥3 major criteria or 2 major plus 3 minor criteria. Major criteria include breast cancer, endometrial cancer, follicular thyroid cancer, GI hamartomas including ganglioneuromas, Lhermitte-Duclos disease, macrocephaly, macular pigmentation of the glans penis, and multiple mucocutaneous lesions. Minor criteria include autism, colon cancer, esophageal glycogenic acanthoses, lipomas, intellectual disability, renal cell carcinoma, testicular lipomatosis, papillary thyroid cancer, thyroid structural lesions, and vascular anomalies. CASE DESCRIPTION/METHODS: A 59-year-old male with macrocephaly presented for a screening colonoscopy. He was found to have 30 polyps ranging in size from 3-15 mm. Pathology revealed serrated adenomas, hyperplastic polyps and moderately differentiated invasive adenocarcinoma arising in a tubular adenoma. Subsequent PET/CT revealed marked enlargement and heterogeneity in the thyroid gland. He underwent a total colectomy with ileorectal anastomosis and ultimately a total thyroidectomy. The resected colon showed adenomatous polyps, multiple lipomas, and a ganglioneuroma. Pathology from the thyroid revealed a 2.5 cm nodule with follicular carcinoma and a 6 mm nodule with papillary micro-carcinoma, follicular variant. Our patient met 3 major criteria (macrocephaly, GI hamartomas including ganglioneuromas, follicular thyroid carcinoma) and 1 minor criterion (colon cancer). The clinical presentation prompted genetic testing. DISCUSSION: Early onset colorectal cancer has been reported in patients with CS due to malignant transformation of adenomatous and hamartomatous polyps. Management includes annual thyroid ultrasound, renal ultrasound at age 40 every 1-2 years, dermatologic assessment, and discussion regarding risk to relatives. Colonoscopy is recommended at age 35 and then at least every 5 years; more frequent in patients who are symptomatic, have family history of colon cancer, personal history of polyps or colon cancer. Recognition of pertinent medical history, family history and physical manifestations are critical for accurate diagnosis, risk assessment, genetic testing and medical management.

1857 Not the Average Pseudopolyp

INTRODUCTION: Polyposis syndromes are rare and often undiagnosed or misdiagnosed in clinical practice. Presented here is a case of Cowden syndrome initially misdiagnosed as an atypical presentation of ulcerative colitis. CASE DESCRIPTION/METHODS: A 62-year-old male presented to the gastroenterology clinic for routine annual surveillance colonoscopy. He had undergone numerous colonoscopies for the past decade demonstrating pseudopolyps throughout the colon. Pathology revealed normal colonic mucosa, hyperplastic features, and inflammatory polyps. He denied a history of diarrhea or hematochezia, or a family history of inflammatory bowel disease. The patient was ultimately diagnosed with ulcerative colitis, placed on oral mesalamine treatment, and advised to undergo annual colonoscopy for dysplasia surveillance. On the date of encounter a thyroidectomy scar was noted on physical exam. The patient had undergone total thyroidectomy in the 1990’s for an unknown reason. Chronic lesions resembling papillomas were present on his buccal mucosa. Although he did not have a formal diagnosis of autism, the patient displayed several characteristics of the disorder throughout the encounter. The patient’s son had also been diagnosed with numerous non-adenomatous colon polyps and his father had passed from renal cell carcinoma. Given clinical suspicion for Cowden syndrome, an upper endoscopy was added to the annual colonoscopy demonstrating significant esophageal glycogenic acanthosis and extensive duodenal hamartomas. Colonoscopy again demonstrated numerous hamartomas throughout the colon. Genetic sequencing demonstrating a frame shift mutation in the PTEN gene was performed by Athena Diagnostics, diagnostic of Cowden syndrome. Subsequently his mesalamine was discontinued, his colonoscopy surveillance interval was increased to every five years, and annual screening for renal cell carcinoma screening was initiated. His son was advised to undergo genetic testing as well due to the syndrome’s autosomal dominant inheritance pattern. DISCUSSION: This case showcases the utility of highlighting rare clinical entities. The prevalence of Cowden syndrome is estimated to be only 1 in 200,000 to 250,000 individuals. Clinicians are proficient at diagnosing more common disease presentations; however, rare disorders such as polyposis syndromes can be unrecognized unless they are consistently reviewed outside of daily practice.

1552 A Tale of Two Ganglioneuromas

INTRODUCTION: Ganglioneuromas are rare benign tumors of nerve fibers, ganglion cells, and supportive cells that rarely occur in the GI tract. GI ganglioneuromas come in three forms including solitary polypoid ganglioneuroma, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. These classifications are vital to recognize as some are associated with genetic syndromes which require close cancer surveillance. Here we present two cases of ganglioneuromas: one as a solitary ganglioneuroma and the other as part of a hereditary syndrome. CASE DESCRIPTION/METHODS: Patient 1 was a 61 yo man with hypertension. Screening colonoscopy revealed a 1.3 cm pedunculated polyp in the ascending colon. Path revealed spindle cell proliferation expressing S-100, consistent with ganglioneuroma. EGD was normal. After confirmation of complete removal, he will proceed with standard screening intervals. Patient 2 was a 52 yo man with OSA and skin lipomas. Screening colonoscopy revealed polyps too numerous to count dispersed throughout. Biopsies showed a mix of ganglioneuromas, tubular adenomas, and hyperplastic polyps consistent with ganglioneuromatous polyposis. Genetic testing identified a PTEN mutation confirming Cowden Syndrome. He was then scheduled for an EGD, repeat colonoscopy in 6 months, and cancer screening per ACG Hereditary Cancer Guidelines. DISCUSSION: While both patients had ganglioneuromas, the management was significantly different. Patient 1 had a solitary ganglioneuroma, which is often found incidentally. Due to their benign nature, solitary ganglioneuromas do not necessitate more frequent screening. Ganglioneuromatous polyposis, as seen in patient 2, is associated with Cowden syndrome and diagnosed by a PTEN mutation. Patients have multiple types of polyps, including ganglioneuromas. They must get regular cancer screening of the colon, breast, thyroid, skin and kidney. Current recommendations are to repeat colonoscopies usually every 2 years depending on findings. Diffuse ganglioneuromatosis often appears as thickening of the bowel with involvement of the myenteric plexus. This is associated with MENIIB and more rarely Neurofibromatosis type 1. This may be handled conservatively but if obstruction results then resection of the involved bowel may need to be considered. Recognition of these presentations takes careful consideration including detailed history and physical exam to ensure correct diagnosis, which may tailor future cancer surveillance programs for patients diagnosed with polyposis syndromes.

3043 Not All Bumps Are Equal, Mucosal Schwann Cell Hamartoma a Rare Subtype

INTRODUCTION: Benign mesenchymal polyps are an interesting group of colonic polyps. There has been a surge in the number of these polyps identified since legislation modified Medicare and began reimbursement for screening colonoscopy in patients at an average risk for colorectal carcinoma. It is important to differentiate between the different types of mesenchymal polyps given that some have correlation with hereditary diseases. CASE DESCRIPTION/METHODS: 66 year old male patient with history of hypertension presents for routine colorectal cancer screening colonoscopy. He is asymptomatic and has no family history of cancer including colon cancer. During the colonoscopy a small 5 mm polyp was found in the rectosigmoid which was removed using cold forceps polypectomy. The pathology was read as a benign mesenchymal polyp. Further staining with S-100 and CD 68 was done which revealed that this polyp was in fact a Schwann cell hamartoma. DISCUSSION: There has been 10 reported cases of mucosal schwann cell hamartoma in literature. Using immunohistochemistry for S100 highlights tissue with neural differentiation expanding the lamina propria of the colonic biopsy and CD68 highlights muciphages. These polyps resemble spindle cell proliferation and other neuronal tumors and are usually limited to the mucosa of the colon with no submucosal extension. They are usually solitary and patients do not have symptoms though a couple of cases reported finding them in the process of workup for diarrhea. Gibson and Hornick supplied the necessary name in 2009 in an attempt to differentiate it from other Schwann cell proliferation which is seen in entities like neurofibroma and ganglioneuroma. The importance of this entity is its lack of association with hereditary cancer syndromes, specifically neurofibromatosis type 1 (NF1) and multiple endocrine neoplasia 2B (RET) which is seen with neurofibromas. Also ganglioneuromatous polyposis and diffuse ganglioneuromatosis are seen in Cowden syndrome, Juvenile polyposis syndrome, MEN2B and NF1 however solitiary ganglioneuroma are not associated with hereditary diseases. It is important to differentiate this entity from others to prevent unnecessary and aggressive testing and treatment. Pathologists should include this differential as part of S 100 positive spindle cell proliferative lesions and gastroenterologists should be aware of the benign nature of this pathology.

2729 An Unusual Location of a Mucosal Schwann Cell Hamartoma

INTRODUCTION: Nerve sheath tumors are rarely found in the gastrointestinal tract andhave been seen only in association with inherited syndromes such as neurofibromatosis type I (NF-1), multiple endocrine neoplasia type 2B (MEN 2B) and Cowden syndrome. Mucosal Schwann cell hamartoma (MSCH) is a new entity described by Gibson et al. in 2009 and has mostly been described in the colorectal area. CASE DESCRIPTION/METHODS: A 59-year-old man with no pertinent past medical history visited the gastroenterology clinic as a scheduled appointment for a long-standing history of GERD. He denied any nausea, vomiting, early satiety, abdominal pain or unintentional weight loss. His diagnosis was made on a clinical basis, and for this reason, an EGD was recommended. The EGD showed no abnormalities and esophageal mucosa was not erythematous (Figure 1). Multiple biopsies were taken. Pathology results showed mucosal Schwann cell hamartoma features in the antral biopsies (Figure 2). DISCUSSION: The exact incidence of MSCH is not known but it is mostly seen in female patients. MSCH has specific histological characteristics: lack of circumscription, absence of peripheral lymphoid cuff, crypt entrapment and strong positive stain for S-100. It is important to differentiate it from other spindle cell tumors since this will affect the management, prognostication and monitoring of possible associated complications. Differential diagnosis includes gastrointestinal stromal tumors (GISTs), carcinoid tumor, leiomyoma, schwannoma, mucosal neuroma, neurofibroma and ganglioneuroma. GISTs are the most common spindle cell tumors in the GI tract, however they have immunoreactivity to C-KIT and CD 117. GI schwannomas are mostly found in the stomach, but these have peripheral lymphoid cuffs and Antoni-A and Antoni –B regions. MSCH presents as a polypoid lesion in the colon and patients are typically asymptomatic. However, they can also present with rectal bleeding when the tumor is located in the colorectal area. This tumor follows a benign course and there is no need for treatment or extraction. Given its recent discovery and rarity, there is only one case report in the literature describing gastric affectation of the MSCH tumors. We describe this case due its unusual location as this is the 2nd case in the literature describing gastric affectation. Furthermore, a correct histological characterization is recommended since it will be crucial for the management and prognostication of these patients.

1535 A Rare Case of Rectosigmoid Mucosal Schwann Cell Hamartoma

INTRODUCTION: Colorectal polyps of mesenchymal origin are rare. Mucosal Schwann cell hamartomas have a pure proliferation of Schwann cells in the lamina propria and show immunoreactivity to S-100 protein. To our knowledge, only 11 cases have been reported in the literature since it was first described in 2009. CASE DESCRIPTION/METHODS: We present a case of a 50-year-old African-American female who presented to us for routine screening colonoscopy. Her past medical history was only significant for a prolactinoma for which she was on cabergoline. The patient had no personal or family history of neural lesions or inherited syndromes such as NF1, Cowden syndrome or MEN 2B. The colonoscopy revealed a 2 mm polyp in the cecum and a 3 mm sized rectosigmoid polyp which were resected and sent to pathology. The cecal polyp showed a tubular adenoma. The pathology report for the rectosigmoid polyp was consistent with spindle-shaped lesional cells with immunohistochemical staining strongly positive for S-100. They did not have immunoreactivity for epithelial membrane antigen (EMA). Hence, supporting the diagnosis for Schwann cell hamartoma. The patient was made aware of pathology findings and reassured. DISCUSSION: Mucosal Schwann Cell Hamartoma is a rare and benign lesion that forms in the colon. It usually arises in older adults. The specific risk factors of Mucosal Schwann Cell Hamartoma are unknown. Most patients are asymptomatic however rectal schwannoma may cause symptoms such as obstruction, bleeding, and tenesmus. They are often found incidentally in the distal colon during a colonoscopy. These tumors are poorly circumscribed, with short fascicles of uniform spindle cells replacing the colonic lamina propria, especially the superficial lamina propria, and separating and entrapping the crypts. These tumors involve the mucosa but never the submucosa. Although the histological differential diagnosis of a mucosal Schwann-cell hamartoma can include a gastrointestinal stromal tumor (GIST), neurofibroma, mucosal neuroma, ganglioneuroma, or mucosal schwannoma, a mucosal Schwann-cell hamartoma is composed of single Schwann cells without other cells, such as axons or fibroblasts, and is uniformly stained for S-100. These cells do not have immunoreactivity for c-Kit, CD34, glial fibrillary acidic protein, epithelial membrane antigen (EMA), smooth muscle actin, or neurofilament protein (NFP). Due to the benign nature of Mucosal Schwann Cell Hamartoma, they do not generally require any treatment.

2568 A Unique Case Presentation of Small Bowel Intussusception

INTRODUCTION: Intussusception is a life-threatening condition and can cause ischemia of the small intestine if not intervened promptly. When present in adults, intussusception typically is caused by a neoplasm, adhesions of the small bowel, or resultant of weight loss surgeries. Below we describe a unique intervention provided to a case presentation of intussesception. CASE DESCRIPTION/METHODS: 21 y.o. year old female with a past medical history of chronic abdominal pain, PTSD, suicide attempts, gender dysphoria, gastroesophageal reflux disease, depression, presented to the emergency department with secondary to abnormally low hemoglobin, abdominal pain, nausea and vomiting. She described pain in the epigastric abdominal region. She had no known family history of colon cancer, colonic polyps or other malignancies. She was noted to have a hemoglobin of 4.4 with no overt bleeding. She was tested negative for celiac serologies. She was evaluated with a CT scan of the abdomen and pelvis with IV contrast which showed long segment of proximal jejunal intussusception with associated inflammatory changes. The surgical team approached the gastroenterology team to attempt to reduce the intussusception prior to surgical resection. As a result of which a push enteroscopy was performed where in a normal esophagus, with erythematous mucosa in the gastric fundus and gastric body were seen. The duodenum was normal. An intussusception was encountered after the C-loop of the duodenum, around the proximal jejunum. This was reduced with the scope. A vascular appearing jejunal mass was seen. Biopsy was not attempted given the vascular appearance. A tattoo was applied. The patient subsequently underwent jejunal resection with small bowel anastomosis. The pathology of the mass resulted as benign hamartomatous polyp with surface erosion and no dysplasia. The patient's symptoms and anemia resolved post operatively. In addition she was evaluated with an upper endoscopy and flexible sigmoidoscopy previously which were within normal limits. DISCUSSION: Hamartomatous polyps of the small intestine can be associated with Cowden syndrome, Bannayan-Riley Ruvalcaba syndrome (BRRS), and juvenile polyposis syndrome (JPS). The above mentioned patient is unique as she does not meet criteria for any of these syndromes. In addition the emergent symptom relief was provided by endoscopic reduction of the intussusception providing the surgeons for a planned elective procedure rather than an emergent procedure.

DIAGNOSTIC STRATEGIES FOR MULTIPLE PULMONARY NODULES

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Multiple pulmonary nodules are often challenging in terms of their workup. Having non-invasive diagnostic methods to exclude benign lesions such as pulmonary hamartomas is desirable and useful in avoiding risky invasive procedures. We present a case highlighting the non-invasive approach which we believe is under recognized. CASE PRESENTATION: A 49 year-old-female with an extensive smoking history was referred for known pulmonary nodules. Chest CT showed multiple ground glass opacities (GGO) within peripheral parenchyma of the lungs [Figures 1-3]. Given the patients history of smoking and the presence of GGO, malignancy was considered. CT imaging was evaluated for intranodular calcification or fat. No calcifications were observed but given the measured fat density of -124 HU a diagnosis of pulmonary hamartomas was made. Comparison with CTs from 15-years prior confirmed the stability and benign nature of the nodules. DISCUSSION: Pulmonary hamartomas are the most common benign neoplasms of the lung, representing 75% of non-malignant lung tumors. Most hamartomas are asymptomatic and are incidentally found on imaging within the peripheral parenchyma, however 10% are endobronchial. They are relatively stable with a volume doubling time over 400 days. Malignant transformation is rare thus observation is safe. However, studies have found an association with primary lung cancer. While typically solitary, pulmonary hamartomas have been observed in multiples, with one study showing an incidence of 3%. Extrapulmonary involvement, especially mucocutaneous and gastrointestinal locations, indicates Cowden disease. Characteristically, pulmonary hamartomas contain fat and/or “popcorn” calcifications, found in 60% and 5-50% of nodules respectively. Fat can be identified on CT with a Hounsfield values of -40 to -120 HU, and when found with smooth, sharply marginated nodules it provides a confident diagnosis of hamartoma. MRI is a less common imaging modality, but chemical-shift MRI shows potential in identifying intracellular lipid when CT is negative for intranodular fat. Additionally, CT texture mapping shows promise in classifying nodules via heterogeneity, something ordinarily reserved to histopathology of biopsied specimens. Lastly, PET-CT is available for characterizing intermediate to large pulmonary nodules, but increased FDG avidity of hamartomas can lead to misdiagnosis. CONCLUSIONS: Multiple pulmonary hamartomas can be diagnosed on chest CT by measuring fat density within nodules. Thin section CT is essential to avoid missing small foci of fat. When inconclusive, other imaging modalities such as chemical-shift MRI and CT texture mapping should be considered before invasive biopsy or PET-CT. Reference #1: Provenzale, James M., Rendon C. Nelson, and Emily N. Vinson, eds. Duke radiology case review: imaging, differential diagnosis, and discussion. Lippincott Williams & Wilkins; 2011. Reference #2: “Primary Lung Tumors Other than Bronchogenic Carcinoma: Benign and Malignant.” Grippi MA et al. Fishman's Pulmonary Diseases and Disorders, Fifth Edition. New York: McGraw-Hill; 2015. Reference #3: Ekinci, G. H., et al. "The frequency of lung cancer in patients with pulmonary hamartomas: An evaluation of clinical, radiological, and pathological features and follow-up data of 96 patients with pulmonary hamartomas.” Revista Portuguesa de Pneumologia (English Edition) 2017; 23(5): 280-286. DISCLOSURES: No relevant relationships by jayanth keshavamurthy, source=Web Response No relevant relationships by Matthew Potter, source=Web Response No relevant relationships by Varsha Taskar, source=Web Response No relevant relationships by Thomas Whitton, source=Web Response

Clinical utility of multigene panel testing for diagnosis of hereditary tumor syndromes

Abstract Backgrounds Different hereditary tumor syndromes (HTS) sometimes have common phenotype as breast cancer among Hereditary Breast and Ovarian Cancer Syndrome (HBOC), Cowden Disease and Li-Fraumeni Syndrome. In these situations, it is difficult to decide which gene to be tested and may be useful to use next-generation sequencing (NGS) based multigene panel testing (MPT). However, little is known when the testing should be used. Methods From January 2017 to December 2018, we performed genetic counseling for 62 families of candidate HTS in Hamamatsu University Hospital and performed MPT for 24 families. For MPT, DNA was isolated from peripheral blood and the targeted germline mutation screening was performed utilizing two types of MPT, NCC oncopanel FC v2.0 performed in National Cancer Center Hospital and/or hamafamilial panel performed in Hamamatsu University School of Medicine, both of which are designed for DNA targeted captured sequencing (Agilent). All samples were sequenced on an Illumina HiSeq or Miseq sequencer. Results We detected pathogenic germline variants in six genes (APC in three families, BRCA2 in three families, CDH1 in one family, MLH1 in one family, MSH2 in one family, MEN1 in one family, and PTEN in one family) and variants of unknown significance (VUS) in three genes (RAD51D in one family, POLE in one family, and POLD1 in one family). In clinical practice, the MPT was especially useful when a proband has phenotype that is common with some types of HTS. However, we additionally needed Multiplex Ligation-dependent Probe Amplification (MLPA) to detect long insertion/deletion and targeted resequencing to detect mosaicism when a proband has typical phenotype of certain HTS but no pathogenic variants by MPT. Conclusions It is informative to use MPT but sometimes additional tools as MLPA or targeted resequencing should be needed for diagnosis of HTS.

Distinct Alterations in Tricarboxylic Acid Cycle Metabolites Associate with Cancer and Autism Phenotypes in Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome

Germline heterozygous PTEN mutations cause subsets of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS); these subsets are characterized by high risks of breast, thyroid, and other cancers and, in one subset, autism spectrum disorder (ASD). Up to 10% of individuals with PTENMUT CS, CS-like syndrome, or BRRS have germline SDHx (succinate dehydrogenase, mitochondrial complex II) variants, which modify cancer risk. PTEN contributes to metabolic reprogramming; this is a well-established role in a cancer context. Relatedly, SDH sits at the crossroad of the electron transport chain and tricarboxylic acid (TCA) cycle, two central bioenergetic pathways. Intriguingly, PTENMUT and SDHMUT individuals have reduced SDH catalytic activity, resulting in succinate accumulation; this indicates a common genotype-independent biochemical alteration. Here, we conducted a TCA targeted metabolomics study on 511 individuals with CS, CS-like syndrome, or BRRS with various genotypes (PTEN or SDHx, mutant or wild type [WT]) and phenotypes (cancer or ASD) and a series of 187 population controls. We found consistent TCA cycle metabolite alterations in cases with various genotypes and phenotypes compared to controls, and we found unique correlations of individual metabolites with particular genotype-phenotype combinations. Notably, increased isocitrate (p = 1.2 × 10−3), but reduced citrate (p = 5.0 × 10−4), were found to be associated with breast cancer in individuals with PTENMUT/SDHxWT. Conversely, increased lactate was associated with neurodevelopmental disorders regardless of genotype (p = 9.7 × 10−3); this finding was replicated in an independent validation series (n = 171) enriched for idiopathic ASD (PTENWT, p = 5.6 × 10−4). Importantly, we identified fumarate (p = 1.9 × 10−2) as a pertinent metabolite, distinguishing individuals who develop ASD from those who develop cancer. Our observations suggest that TCA cycle metabolite alterations are germane to the pathobiology of PTEN-related CS and BRRS, as well as genotype-independent ASD, with implications for potential biomarker and/or therapeutic value.

家族性大腸腺腫症，Peutz-Jeghers症候群，Cowden症候群，若年性ポリポーシスなどの消化管ポリポーシス研究グループの紹介

家族性大腸腺腫症，Peutz-Jeghers症候群，Cowden症候群，若年性ポリポーシスなどの消化管ポリポーシス研究グループの紹介

Lhermitte-Duclos Disease and Cowden Syndrome: A Case Report and Literature Review

AbstractLhermitte-Duclos disease (LDD), also known as dysplastic gangliocytoma of the cerebellum, is a rare, usually benign, slow-growing tumor, that commonly affects patients aged 30 to 50 years-old. The manifestations of dysplastic cerebellar gangliocytoma are nonspecific and are related both to the mass effect produced by its growth and to the location of the lesion. Cerebellar symptoms such as ataxia are often present. In 40% of cases, the tumor is associated with Cowden syndrome, which is part of a group of genetic disorders called polypoid hamartoma complex. In this case report, the patient presented expansive lesion in the posterior fossa, compatible with LDD, associated with macrocephaly. These findings are considered major criteria for Cowden syndrome. When together, they confirm the diagnoses. To our knowledge, this is the first report of the association of LDD and Cowden syndrome in Brazil.

The Clinical Spectrum of PTEN Mutations.

PTEN is a tumor suppressor gene that classically dampens the PI3K/AKT/mTOR growth-promoting signaling cascade. PTEN dysfunction causes dysregulation of this and other pathways, resulting in overgrowth. Cowden syndrome, a hereditary cancer predisposition and overgrowth disorder, was the first Mendelian condition associated with germline PTEN mutations. Since then, significant advances by the research and medical communities have elucidated how clinical phenotypic manifestations result from the underlying germline PTEN mutations. With time, it became evident that PTEN mutations can result in a broad phenotypic spectrum, causing seemingly disparate disorders from cancer to autism. Hence, the umbrella term of PTEN hamartoma tumor syndrome (PHTS) was coined. Timely diagnosis and understanding the natural history of PHTS are vital because early recognition enables gene-informed management, particularly as related to high-risk cancer surveillance and addressing the neurodevelopmental symptoms.

Clinical, Imaging, and Pathologic Features of Conditions with Combined Esophageal and Cutaneous Manifestations.

A variety of clinically significant conditions can affect both the esophagus and the skin. Esophageal and cutaneous manifestations may directly reflect the underlying disease process, as in infections such as herpes simplex virus, bullous diseases such as epidermolysis bullosa and mucous membrane pemphigoid, connective tissue diseases such as systemic sclerosis, and inflammatory diseases such as lichen planus. Alternatively, esophageal and cutaneous findings may result from conditions that are closely associated with and potentially pathognomonic for but distinct from the underlying disease process, as in genetic diseases such as Cowden syndrome or paraneoplastic syndromes such as acrokeratosis paraneoplastica. Other diseases such as Crohn disease may have cutaneous manifestations that directly reflect the same underlying inflammatory process that affects the gastrointestinal tract or cutaneous manifestations that represent reactive or associated conditions distinct from the underlying inflammatory process. The cutaneous manifestations of disease may precede, coincide with, or follow the esophageal manifestations of disease. The authors present the characteristic clinical features and imaging findings associated with common and uncommon conditions that have esophageal and cutaneous manifestations. Each condition is presented with a brief overview, discussion of salient clinical and cutaneous manifestations, and description of the typical esophageal imaging findings, with particular attention to implications for diagnosis, prognosis, and treatment. Recognition of potential associations between cutaneous lesions and esophageal imaging findings is important for establishing a specific diagnosis or generating a meaningful differential diagnosis.