Multiple endocrine neoplasia type 1 with Zollinger-Ellison syndrome: clinicopathological analysis of a Japanese family with focus on menin immunohistochemistry.

Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of multiple epithelial neuroendocrine tumors (NETs) and non-NETs in various organs. MEN1 encodes a 610-amino acid-long tumor suppressor protein, menin. The optimal treatment for multiple tumors, identification of the most critical tumors for patient prognosis, and menin immunohistochemistry findings remain controversial. Therefore, we aimed to elucidate these issues through a histological analysis of tumors and tumor-like lesions in a Japanese family, comprising a father and his two sons, who had MEN1 with Zollinger-Ellison syndrome (ZES). Patients and methods: All family members had a germline alteration in exon 10, c.1714-1715 del TC of MEN1, and exhibited multiple synchronous and metachronous tumors. The patients had pulmonary NETs, hyperparathyroidism, hypergastrinemia, pituitary adenomas, pancreaticoduodenal NETs, adrenocortical adenoma with myelolipoma, nodular goiter of the thyroid, lipomas, and angiofibroma. Most tumors were resected and histologically examined. We compared their clinical courses and tumor histology, and conducted menin immunohistochemistry (IHC). Results: Two patients died of pulmonary NET G2. One patient who underwent pancreaticoduodenectomy was cured of ZES; however, the two other patients who did not undergo pancreaticoduodenectomy suffered persistent ZES despite treatment with octreotide. Menin IHC revealed varying NET intensities, ranging from positive to negative stains. Conclusion: Pancreaticoduodenectomy is the most effective treatment for ZES. Long-term follow-up is essential for pulmonary NET G2 owing to the risk of distant metastasis and/or multiplicity. Moreover, the variability of menin IHC in MEN1-related tumors may indicate the pattern of tumor formation rather than the diagnostic utility of menin in MEN1.

A case report of anaplastic thyroid carcinoma transformed from small papillary carcinoma successfully detected by ultrasonography in its early stage with review of literature.

An 82-year-old woman was referred to our hospital because of a suspicious thyroid nodule. She was diagnosed with papillary microcarcinoma with a maximum diameter of 9 mm based on ultrasonography and fine-needle aspiration (FNA) cytology. She preferred observation without surgery. Her papillary carcinoma grew gradually and reached a maximum diameter of 19 mm after 23 months. At that time, ultrasonography showed an apparent change in the shape of the nodule as well as in its diameter. At the initial ultrasound examination, papillary microcarcinoma was demonstrated as a hypoechoic solid nodule with an irregular shape. No punctuate microcalcifications were shown. After 23 months, the preexisting nodule had expanded toward the common carotid artery. The expanded portion was round and well demarcated. FNA revealed that the expanded portion consisted of anaplastic thyroid carcinoma. She underwent hemithyroidectomy and lymph node dissection of the central compartment. She remained in good health for 18 months after surgery. Anaplastic thyroid carcinoma is generally found as an aggressive large tumor, and the ultrasound appearance of small anaplastic thyroid carcinoma is poorly understood at present. We successfully detected anaplastic transformation in the early period by ultrasonography and FNA. When observation is indicated for small papillary thyroid carcinoma, the change in the shape of the nodule as well as in its diameter should be carefully monitored by ultrasonography. FNA should be performed at a proper site on the nodule to avoid overlooking anaplastic transformation, as resection following the early detection of anaplastic transformation might bring a favorable prognosis.

Successful Control of Hypercalcemia with Sorafenib, Evocalcet, and Denosumab Combination Therapy for Recurrent Parathyroid Carcinoma.

Parathyroid carcinoma (PC) is a rare type of endocrine cancer. Recurrence and metastasis are common after surgery, and refractory hypercalcemia often leads to a poor prognosis. However, there are currently no specific strategies for PC recurrence. We herein report a 61-year-old Japanese man with metastatic PC who was treated with sorafenib, a multikinase inhibitor. In this case, the serum calcium level was under control for 10 months after the initiation of sorafenib. This case suggests that combination therapy with sorafenib, evocalcet, and denosumab may be an alternative, stronger management option for refractory hypercalcemia in recurrent PC.

68 Ga-DOTATATE PET/CT imaging in endogenous hyperinsulinemic hypoglycemia: A tertiary endocrine centre experience.

OBJECTIVE: Literature regarding utility of 68 Ga-DOTATATE PET/CT in insulinoma localization across various subgroups [benign/malignant/multiple endocrine neoplasia-1 (MEN-1) syndrome associated] remains scarce. In this study, the performance of 68 Ga-DOTATATE PET/CT was compared with contrast-enhanced computed tomography (CECT) and 68 Ga-NODAGA-Exendin-4 PET/CT (whenever available) in an endogenous hyperinsulinemic hypoglycemia (EHH) cohort. DESIGN: Retrospective audit. PATIENTS: EHH patients [N = 36, lesions (n) = 49, final diagnosis: benign sporadic insulinoma (BSI) (N = 20), malignant insulinoma (N = 4, n = 14), MEN-1 syndrome associated insulinoma (N = 9, n = 15), Munchausen syndrome (N = 2) and drug-induced hypoglycemia (N = 1)] having both preoperative imaging modalities (CECT and 68 Ga-DOTATATE PET/CT). MEASUREMENTS: Per-lesion sensitivity (Sn) and positive predictive value (PPV) for histopathological diagnosis of insulinoma. RESULTS: Sn and PPV of 68 Ga-DOTATATE PET/CT were 67.3% and 89.2%; 55% and 100%; 85.7% and 100%; and 66.7% and 77% for overall EHH, BSI, malignant, and MEN-1 syndrome associated insulinoma cohorts respectively. Despite having comparatively lower sensitivity in BSI cohort, 68 Ga-DOTATATE PET/CT localized a pancreatic tail lesion missed by other modalities. 68 Ga-DOTATATE PET/CT had comparatively higher sensitivity in malignant insulinoma than BSI cohort. 68 Ga-DOTATATE PET/CT also paved the way for successful response to 177 Lu-based peptide receptor radionuclide therapy (PRRT). In MEN-1 cases, lower PPV as compared with BSI was due to uptake in non-insulinoma pancreatic neuroendocrine tumours (Pan-NET). CONCLUSIONS: 68 Ga-DOTATATE PET/CT has supplemental role in selected cases of BSI with negative and/or discordant results with CECT and 68 Ga-NODAGA-Exendin-4 PET/CT. In malignant insulinoma, 68 Ga-DOTATATE-PET/CT has an additional theranostic potential. Interference due to uptake in non-insulinoma Pan-NET in MEN-1 syndrome may hinder insulinoma localization with 68 Ga-DOTATATE-PET/CT.

Extra-endocrine phenotypes at infancy in multiple endocrine neoplasia type 2B: A case series of six Japanese patients.

Multiple endocrine neoplasia type 2B (MEN2B) is an extremely rare disease, most often caused by a de novo p.Met918Thr RET mutation. Medullary thyroid carcinoma of MEN2B has a good prognosis if diagnosed by one year of age. However, diagnosis of MEN2B within the first year of life is markedly challenging owing to its high de novo occurrence and lack of clarity in terms of extra-endocrine symptoms that could aid early diagnosis. Herein, we present six cases of Japanese children with MEN2B harboring the p.Met918Thr RET variant. Exploratory data extraction was conducted using a questionnaire. The patients underwent thyroidectomy at a median age of 11 yr (range, 6-19 yr). Four of the six patients underwent neonatal hospitalization at birth without complications, and three tested positive for neuroblastoma screening at infancy. The patients presented at least one MEN2B-associated symptom before one year of age, including ganglioneuromas, pseudo-Hirschsprung disease, alacrima, bumpy lips, sucking disability, or decreased muscle tone, along with other suspected comorbidities, such as Williams or Prader-Willi syndrome. This case series demonstrates that MEN2B manifests through several extra-endocrine symptoms by the age of one year.

JNETS clinical practice guidelines for gastroenteropancreatic neuroendocrine neoplasms: diagnosis, treatment, and follow-up: a synopsis.

Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters-diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel-Lindau (VHL) disease-and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of "neuroendocrine tumor" (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published.

Preoperative prediction of parathyroid carcinoma in an Asian Indian cohort.

BACKGROUND: Parathyroid carcinoma (PC) requires preoperative prediction for appropriate surgical management. Differentiation from symptomatic primary hyperparathyroidism (sPHPT) cohort is difficult. METHODS: Patients with sPHPT from a tertiary-care center, Western India, including Cohort-A (n = 19 [10/M; 9/F]) with PC and Cohort-B (n = 93 [33/M; 60/F] with benign parathyroid lesions) were compared to derive predictors for differential diagnosis. RESULTS: There were no differences in clinical or biochemical parameters between the two cohorts. Comparison of CECT parameters showed that irregular shape, tumor heterogeneity, infiltration, short/long-axis ratio >0.76, and long-diameter >30 mm had high negative-predictive value and intratumoral calcification had 100% positive-predictive value to diagnose PC; whereas there were no differences in contrast-enhancement patterns. Long diameter, short/long-axis ratio, and heterogeneity were significant predictors on multivariate analysis. CONCLUSION: It is difficult to predict diagnosis of PC in an Indian sPHPT cohort based on clinical and biochemical parameters, whereas CECT parathyroid-based parameters can aid in diagnosis.

HLA-B*39:01:01 is a novel risk factor for antithyroid drug-induced agranulocytosis in Japanese population.

Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is characterized by severe reduction of circulating neutrophils. Immune-mediated responses have been proposed as a possible mechanism for the pathogenesis of ATD-induced agranulocytosis. Although it has been reported that the HLA class II allele (HLA-DRB1*08:03) was associated with ATD-induced agranulocytosis in multiple populations, the entire HLA region have not been explored in Japanese. Therefore, we performed HLA sequencing for 10 class I and 11 class II genes in 87 patients with ATD-induced agranulocytosis and 384 patients with GD who did not show ATD-induced agranulocytosis. By conducting case-control association studies at the HLA allele and haplotype levels, we replicated the association between HLA-DRB1*08:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10-7, odds ratio = 2.80), and identified HLA-B*39:01:01 as an independent risk factor (P = 1.4 × 10-3, odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B*39:01:01, we reanalyzed allele frequency data for HLA-B*39:01:01 from previous case-control association studies. The association of HLA-B*39:01:01 was significantly replicated in Chinese (P = 9.0 × 10-3), Taiwanese (P = 1.1 × 10-3), and European populations (P = 5.2 × 10-4). A meta-analysis combining results from the previous and current studies reinforced evidence of the association between HLA-B*39:01:01 and ATD-induced agranulocytosis (Pmeta = 1.2 × 10-9, pooled OR = 3.66, 95% CI; 2.41-5.57). The results of this study will provide a better understanding of the pathogenesis of ATD-induced agranulocytosis in the context of HLA-mediated hypersensitivity reactions.

MicroRNA 200b promotes mesenchymal-to-epithelial transition in anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) remains a cancer with one of the worst prognoses, despite novel targeted therapies. The median survival rate has not improved for decades. Epithelial-to-mesenchymal transition (EMT) is a crucial step in physiological processes and in cancer progression, but the underlying mechanisms are not yet fully understood. The current study examined the role of microRNA (miR)-200b in mesenchymal-to-epithelial transition in ATC. Total RNA and miR isolation were performed from ATC cell lines transfected with a miR-200b mimic. After miR-200b mimic transfection, expression levels of E-cadherin, vimentin and zinc finger E-box binding homeobox 1 (ZEB1) were confirmed by reverse transcription-quantitative PCR and western blotting. Additionally, cell migration was evaluated using miR-200b mimic and scrambled negative control-transfected cells. A total of 14 human ATC and 15 non-cancerous human thyroid tissues were immunohistochemically stained and scored as controls for E-cadherin, vimentin and ZEB1. In ATC tissues and cell lines, the mesenchymal marker ZEB1 was significantly upregulated and the epithelial marker E-cadherin was significantly downregulated. Additionally, the mesenchymal marker vimentin was significantly upregulated in ATC tissues and in one ATC cell line. MiR-200b mimic transfection significantly increased vimentin and ZEB1 expression, but E-cadherin expression remained below the measurement sensitivity. Furthermore, miR-200b overexpression decreased cell migration. The current study suggested that miR-200b may regulate the expression levels of mesenchymal markers such as vimentin and ZEB1 in ATC and may promote mesenchymal-to-epithelial transition.

Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study.

OBJECTIVE: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases. DESIGN AND METHODS: An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017. RESULTS: Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4-1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis. CONCLUSIONS: Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.

A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1.

A novel therapeutic approach is urgently needed for patients with anaplastic thyroid cancer (ATC) due to its fatal and rapid progress. We recently reported that ATC highly expressed MYC protein and blocking of MYC through its selective inhibitor, JQ1, decreased ATC growth and improved survival in preclinical models. One of the important roles of MYC is regulation of L-neutral amino acid transporter 1 (LAT1) protein and inhibition of LAT1 would provide similar anti-tumor effect. We first identified that while the human ATC expresses LAT1 protein, it is little or not detected in non-cancerous thyroidal tissue, further supporting LAT1 as a good target. Then we evaluated the efficacy of JPH203, a LAT1 inhibitor, against ATC by using the in vitro cell-based studies and in vivo xenograft model bearing human ATC cells. JPH203 markedly inhibited proliferation of three ATC cell lines through suppression of mTOR signals and blocked cell cycle progression from the G0/G1 phase to the S phase. The tumor growth inhibition and decrease in size by JPH203 via inhibition of mTOR signaling and G0/G1 cell cycle associated proteins were further confirmed in xenograft models. These preclinical findings suggest that LAT1 inhibitors are strong candidates to control ATC, for which current treatment options are highly limited.

[Multiple Endocrine Neoplasia].

Multiple endocrine neoplasia(MEN)is an autosomal dominantly inherited tumor syndrome which develop tumors in multiple endocrine organs and its subtype, MEN1 and MEN2, are well known. The causative gene for MEN1 is the MEN1 gene located on chromosome 11q13. Primary hyperparathyroidism, pancreatic gastroduodenal neuroendocrine tumor, pituitary tumor, adrenal cortical hyperplasia, or thymic neuroendocrine tumor are the typical features of MEN1 patients. Pathogenic variant of the MEN1 gene is distributed in exons 2-10. The causative gene for MEN2 is the RET gene located on chromosome 10q11.2. MEN2 is characterized by medullary thyroid carcinoma, pheochromocytoma and primary hyperparathyroidism. MEN2 is divided into two clinical phenotypes, 2A and 2B. Pathogenic variant of the RET gene concentrated on exons 10, 11, 13-16 and there are strong association of the location of the pathogenic variant with disease phenotype. Recently, it is reported that the pathogenic variant of the CDKN1B gene located on chromosome 12p13 is the cause of MEN4. In this syndrome, MEN1- associated tumors of hyperparathyroidism, pituitary adenomas and neuroendocrine tumors of the pancreas or digestive tract with other endocrine tumors are found. The onset age is relatively high and it shows greater diversity of the tumors compared to MEN1.

Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study.

BACKGROUND: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING: None.

Development of a functional thyroid model based on an organoid culture system.

The low turnover rate of thyroid follicular cells and the lack of a long-term thyroid cell culture system have hampered studies of thyroid carcinogenesis. We have now established a thyroid organoid culture system that supports thyroid cell proliferation in vitro. The established mouse thyroid organoids performed thyroid functions including thyroglobulin synthesis, iodide uptake, and the production and release of thyroid hormone. Furthermore, transplantation of the organoids into recipient mice resulted in the formation of normal thyroid-like tissue capable of iodide uptake and thyroglobulin production in vivo. Finally, forced expression of oncogenic NRAS (NRASQ61R) in thyroid organoids established from p53 knockout mice and transplantation of the manipulated organoids into mouse recipients generated a model of poorly differentiated thyroid cancer. Our findings suggest that this newly developed thyroid organoid culture system is a potential research tool for the study of thyroid physiology and pathology including thyroid cancer.

Hyperparathyroidism-jaw Tumor Syndrome Confirmed by Preoperative Genetic Testing.

We herein report the case of a young woman who was diagnosed with primary hyperparathyroidism and in whom genetic testing confirmed a diagnosis of hyperparathyroidism-jaw tumor syndrome. Familial hyperparathyroidism was suspected based on the patient's young age at the onset of the disease. Thus, genetic testing was performed. It showed a germline mutation in the HRPT2/CDC73 gene and confirmed the diagnosis of hyperparathyroidism-jaw tumor syndrome. Total parathyroidectomy was performed to prevent recurrence. In patients with early-onset hyperparathyroidism, genetic testing should be considered to facilitate the selection of a proper surgical procedure based on the consideration of future life expectancy.

Composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2B: A case report.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal-dominant cancer syndrome with major components of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. MEN2B is the most aggressive and rarest of the MEN2 variants. Pheochromocytoma in MEN2 is virtually always located in the adrenal medulla, but MEN2-associated extra-adrenal pheochromocytomas (paraganglioma) are rare. A 59-year-old man who has been diagnosed with MEN2B consulted our hospital for surgical treatment of a 10-mm left adrenal mass and a 30-mm retroperitoneal mass. He had paroxysmal elevations in blood pressure and in urinary metanephrine and vanillylmandelic acid values. Laparoscopic excision of the left adrenal gland and retroperitoneal mass was performed. We experienced an extremely rare case of composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with MEN2B.

Age- and Gender-Specific Risk of Thyroid Cancer in Patients With Familial Adenomatous Polyposis.

CONTEXT: The cribriform-morula variant of papillary thyroid carcinoma (CMV-PTC) is a rare variant of PTC and is associated with familial adenomatous polyposis (FAP). However, the incidence and the nature of CMV-PTC among FAP patients have not been well characterized. OBJECTIVE: The aim of this study was to determine the incidence and characteristics of thyroid cancer screened by neck ultrasonography for FAP patients. Design, Patients, and Intervention: A total of 129 FAP patients were included in this study. Neck ultrasonography was performed using a 12.0-MHz transducer probe. Germline APC gene mutation was examined for by the protein truncation test or DNA sequencing methods. DESIGN, PATIENTS, AND INTERVENTION: A total of 129 FAP patients were included in this study. Neck ultrasonography was performed using a 12.0-MHz transducer probe. Germline APC gene mutation was examined for by the protein truncation test or DNA sequencing methods. RESULTS: Twenty-one patients (16.3%) had solid nodules, and 24 patients (18.6%) had benign cystic nodules. In total, PTC was found in 11 patients (16% of the women and 0% of the men), 8 of which were CMV-PTC and the rest were classical PTC. In 17 female patients with thyroid nodules, CMV-PTC occurred in 8 of 9 patients who were 35 years age or younger but in none of the 8 patients who were older than 35 (P = .0004 by Fisher's exact test). The APC germline mutations in 8 patients with CMV-PTC were present at the 5' side of the profuse type of FAP region (codons 1249-1330). CONCLUSIONS: The prevalence of CMV-PTC in FAP patients was higher than previously reported and this type of tumor was found preferentially in younger (under age 35) female patients with FAP in this cohort.

Multiple endocrine neoplasia type 1 syndrome: single centre experience from western India.

Multiple endocrine neoplasia type 1 syndrome (MEN1) is a rare autosomal dominant familial cancer syndrome affecting multiple endocrine glands. Published literature on MEN1 from Indian subcontinent is scarce. We report here a case series of MEN1 patients (n = 18) from 14 unrelated families. Retrospective study describing the clinical profile of MEN1 patients from endocrine unit of a tertiary care hospital from western India. Additionally clinical profile of primary hyperparathyroidism (PHPT) in MEN1 patients was compared with that of apparently sporadic PHPT cohort from our centre. Eighteen patients (10 males, 8 females) diagnosed as MEN1 were included. Mean age at diagnosis was 31.5 ± 10.6 years (range 17-54). Incidence of primary hyperparathyroidism (PHPT), pituitary adenoma (PA), and gastro-entero-pancreatic neuroendocrine tumor (GEP-NET) was 94.4, 72.2, and 72.2 %, respectively. GEP-NET was the commonest presenting lesion (33.3 %), followed by PA (27.7 %), PHPT (16.6 %), thymic carcinoid (5.5 %), while 16.6 % cases were identified on family screening. PHPT manifestations (clinical and biochemical) in MEN1 were less severe as compared to those of sporadic PHPT. Contrast enhanced computed tomography (CECT) and (68)Ga-DOTANOC PET/CT were equally sensitive (64.7 vs. 63.5 %) in identifying multiglandular parathyroid disease. Non functioning tumors (NFT) were the most common GEP-NET, followed by insulinoma (5/13, two were metastatic). (68)Ga-DOTANOC PET/CT had higher sensitivity in detecting GEP-NET lesions than CECT (100 vs. 62.5 %). The most common pituitary lesion was prolactinoma, and all were cabergoline responsive. Genetic analysis was available in 13 patients and 11 patients showed mutation in MEN1 gene. The clinical profile of MEN1 in Asian Indian patients is largely comparable to that reported in other cohorts. Peculiar findings of our cohort are predominance of GEP-NET as a presenting manifestation and relatively higher prevalence of insulinoma with higher occurrence of metastatic insulinoma. Clinical and biochemical profile of MEN1 associated PHPT is less severe than that of our sporadic PHPT.

An adolescent case of familial hyperparathyroidism with a germline frameshift mutation of the CDC73 gene.

A 13-yr-old boy who complained of persistent nausea, vomiting and weight loss had hypercalcemia and an elevated intact PTH level. Computed tomography confirmed two tumors in the thyroid gland. The tumors were surgically removed and pathologically confirmed as parathyroid adenoma. Because his maternal aunt and grandmother both had histories of parathyroid tumors, genetic investigation was undertaken for him, and a germline frameshift mutation of the CDC73 gene was identified. CDC73 gene analysis should be done on individuals who are at risk of familial hyperparathyroidism, including those who are asymptomatic, and they should be followed for potential primary hyperparathyroidism and associated disorders including resultant parathyroid carcinoma.

BRAF(V600E) mutation is highly prevalent in thyroid carcinomas in the young population in Fukushima: a different oncogenic profile from Chernobyl.

After the accident at the Fukushima Daiichi Nuclear Power Plant, the thyroid ultrasound screening program for children aged 0-18 at the time of the accident was started from October 2011. The prevalence of thyroid carcinomas in that population has appeared to be very high (84 cases per 296,253). To clarify the pathogenesis, we investigated the presence of driver mutations in these tumours. 61 classic papillary thyroid carcinomas (PTCs), two follicular variant PTCs, four cribriform-morular variant PTCs and one poorly-differentiated thyroid carcinoma were analysed. We detected BRAF(V600E) in 43 cases (63.2%), RET/PTC1 in six (8.8%), RET/PTC3 in one (1.5%) and ETV6/NTRK3 in four (5.9%). Among classic and follicular variant PTCs, BRAF(V600E) was significantly associated with the smaller size. The genetic pattern was completely different from post-Chernobyl PTCs, suggesting non-radiogenic etiology of these cancers. This is the first study demonstrating the oncogene profile in the thyroid cancers discovered by large mass screening, which probably reflects genetic status of all sporadic and latent tumours in the young Japanese population. It is assumed that BRAF(V600E) may not confer growth advantage on paediatric PTCs, and many of these cases grow slowly, suggesting that additional factors may be important for tumour progression in paediatric PTCs.