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.

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.

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.

[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.

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.

Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel CDC73 mutation.

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant hereditary tumor syndrome characterized by synchronous or metachronous occurrence of primary hyperparathyroidism (PHPT), ossifying fibroma of the maxilla and/or mandible, renal tumor and uterine tumors. Early diagnosis of this syndrome is essential because it is associated with increased risk of parathyroid cancer. A 30-year-old man with urolithiasis had severe hypercalcemia (15.0 mg/dL after correction) induced by inappropriate parathyroid hormone (PTH) secretion (intact PTH 1390 pg/mL), indicating severe PHPT. An underlying parathyroid tumor was surgically removed and was histologically confirmed to be an adenoma. However, PHPT due to another parathyroid tumor reoccurred two years after the surgery. Although no HPT-JT-associated manifestations other than PHPT were detected, HPT-JT was strongly suspected based on the exclusion of multiple endocrine neoplasia (MEN) and the young age of disease occurrence. Genetic analysis revealed a novel nonsense mutation (p.Arg91X; c.271C>T) in exon 3 of the causative gene, CDC73, which encodes the tumor suppressor protein parafibromin. The residual parathyroid glands were all removed without autotransplantation of parathyroid gland taking into consideration prospective parathyroid carcinogenesis. The resected parathyroid tumor was also an adenoma. The present case highlights that HPT-JT should be considered and CDC73 mutation analysis should be performed, especially in cases of early-onset PHPT, recurrent PHPT, PHPT with polyglandular parathyroid involvement, and PHPT presenting with severe hypercalcemia even if there is no positive family history.

A newly identified missense mutation in RET codon 666 is associated with the development of medullary thyroid carcinoma.

A 38-year-old woman with a thyroid nodule measuring approximately 2 cm was suspected to have medullary thyroid carcinoma (MTC) because of markedly elevated serum calcitonin and carcinoembryonic antigen levels. There were no signs of pheochromocytoma, whereas primary hyperparathyroidism was suspected based on the findings of inappropriate hypersecretion of parathyroid hormone although no parathyroid tumor was detected with imaging studies. RET mutation analysis revealed a novel germline missense mutation in codon 666, c.1997A>G (p.K666R). She underwent total thyroidectomy with lymphadenectomy and simultaneous total parathyroidectomy with autotransplantation of parathyroid tissue. She was given calcium lactate and alfacalcidol to prevent postoperative hypocalcemia. Pathological findings of the thyroid tumor were compatible with MTC, but the resected parathyroid glands were intact. To our knowledge, c.1997A>G (p.K666R) is a new RET mutation. This is a minor variant, but it is significant because of the possible pathogenicity in tumor formation. It is often difficult to determine whether MTC is generated as part of MEN2-related disease or familial MTC when it is a unique manifestation. In addition, it is still unclear whether all missense mutations in this codon reported previously will lead to the same clinical course and prognosis. Further careful observations of clinical presentation are required to determine the clinical features associated with this variant.

Pheochromocytoma as the first manifestation of MEN2A with RET mutation S891A: report of a case.

We report a rare case with pheochromocytoma as the first manifestation of multiple endocrine neoplasia type 2A with RET mutation S891A. Bilateral pheochromocytomas were identified in a 54-year-old woman. Screening for RET revealed a rare S891A mutation located in the intracellular tyrosine kinase domain. This mutation was previously recognized as one of the mutations only in cases manifesting solely medullary thyroid carcinomas (MTCs). Since calcitonin stimulation test indicated positive result, total thyroidectomy was performed 1 year after the bilateral adrenalectomy, and C-cell hyperplasia was diagnosed by histopathological examination. Our report suggests that cases with S891A mutation, akin to those with other RET mutations, require screening for pheochromocytoma. In addition, it is indicated that calcitonin stimulation test should be performed even in the unaffected elder cases with S891A mutation although the mutation is classified as lowest risk group on MTC in guidelines.

Thymic neuroendocrine tumour in multiple endocrine neoplasia type 1: female patients are not rare exceptions.

OBJECTIVE: Thymic neuroendocrine tumour (Th-NET) occurs in 2-5% of patients with MEN1 and has high malignant potency accompanying recurrence and distant metastasis. While Th-NET is recognized to develop predominantly in men and heavy smokers, a number of female patients have been reported in the literature. The objective of this study is to clarify the clinical features of MEN1 patients with Th-NET using database analysis. DESIGN/PATIENTS: Clinical data of patients with Th-NET were extracted and analysed from a recently constructed database of Japanese MEN1 patients. RESULTS: Among 560 registered cases, Th-NET was seen in 28 (5·0%) patients. Of note, 36% of patients (10/28) were women; only one patient among those was a smoker and another six patients were non-smokers. Age at diagnosis of Th-NET and MEN1, tumour size, prevalence of other MEN1-related tumours did not differ between male and female patients, and 10-year survival probability was 0·271 ± 0·106. CONCLUSIONS: Although the prevalence of Th-NET in women (3·2%) is significantly lower than that in men (7·6%), a considerable proportion of female patients develop Th-NET. Given that Th-NET is a major determinant of life expectancy of patients, our results alert clinicians who treat patients with MEN1 that surveillance of Th-NET is essential even for female patients without a smoking habit.

Follicular thyroid cancer in children and adolescents: clinicopathologic features, long-term survival, and risk factors for recurrence.

Children and adolescents represent 1-1.5% of all patients with thyroid cancer (TC). The vast majority of TC in children and adolescents is papillary TC; follicular TC (FTC) is exceedingly rare. In this study, we evaluate the clinical and pathological features of FTC in children and adolescents. We also report the risk factors for post-operative tumor recurrence and the associated outcomes. Twenty children and adolescents (under 21 years old) with FTC have been treated and followed at Noguchi Thyroid Clinic and Hospital Foundation since 1946. All patients underwent surgery (lobectomy, 11; subtotal thyroidectomy, 8; and total thyroidectomy, 1), and 8 patients received postoperative external beam radiation therapy. The incidence of FTC in children and adolescents was 1.9% among all FTC patients treated in our hospital. Histopathology revealed vascular and capsular invasion in 9 and 20 patients, respectively. The tumor recurrence rate in FTC with vascular invasion is significantly higher than in those without it (p = 0.038). No other factors were significant. Patients with recurrences were treated with completion thyroidectomy and ¹³¹I radioactive iodine therapy. There were no significant differences in the rates of disease-free survival or cause-specific survival when pediatric/adolescent FTC patients were compared to adults with FTC. FTC is very rare among children and adolescents, but the outcomes are similar to those observed among adults. Vascular invasion is poor prognostic indicator in pediatric/adolescent FTC patients.

A Case of medullary thyroid carcinoma with de novo V804M RET germline mutation.

Many cases of RET proto-oncogene mutations of hereditary medullary thyroid carcinoma (MTC) have been reported in Korea. However, MTC with V804M RET proto-oncogene germline mutations have not been reported in Korea. A 33-yr-old man was diagnosed with a 0.7-cm sized thyroid nodule. Laboratory testing revealed serum calcitonin was elevated. The patient underwent total thyroidectomy with central compartment neck dissection for the thyroid tumor. RET gene analysis was performed in both the index patient and his family. There were no V804M RET mutation and abnormal laboratory findings within his family except the index patient. Therefore, this patient was a de novo V804M RET germline mutation.

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.

Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is less well recognized in Asian countries, including Japan, than in the West. The clinical features and optimal management of MEN1 have yet to be clarified in Japan. The aim of this study was to clarify the clinical features of Japanese patients with MEN1. DESIGN/PATIENTS: We established a MEN study group designated the 'MEN Consortium of Japan' in 2008, and asked physicians and surgeons to provide clinical and genetic information on patients they had treated. Of 680 registered patients, 560 were analysed. MEASUREMENTS: Clinical and genetic features of Japanese patients with MEN1 were examined. RESULTS: Primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumours (GEPNET), and pituitary tumours were seen in 94·4%, 58·6% and 49·6% of patients, respectively. The prevalence of insulinoma was higher in the Japanese than in the West (22%vs 10%). In addition, 37% of patients with thymic carcinoids were women, while most were men in western countries. The MEN1 mutation positive rate was 91·7% in familial cases and only 49·3% in sporadic cases. Eight novel mutations were identified. Despite the availability of genetic testing for MEN1, the application of genetic testing, especially presymptomatic diagnosis for at-risk family members appeared to be insufficient. CONCLUSIONS: We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them.

Clinical features, treatment, and long-term outcome of papillary thyroid cancer in children and adolescents without radiation exposure.

BACKGROUND: Cancer of the thyroid gland is rare in children and adolescents. A history of neck irradiation is a well-established risk factor for tumor development, and most previous reports focused on cases that were induced by radiation exposure. We present here a retrospective review of the clinical features, treatment, and long-term outcome of children and adolescents with papillary thyroid cancer (PTC) without a history of radiation exposure who were treated at our institution over a period of ~50 years. METHODS: We retrospectively investigated 142 PTC patients without an irradiation history who were younger than 20 years of age when treated from 1961 to 2005 (17 males and 125 females; mean age = 16.3 ± 2.7 years; follow-up = 21.8 ± 12.0 years). The clinicopathological results were evaluated using the medical records. Disease-free survival (DFS) and cause-specific survival (CSS) were assessed with the Kaplan-Meier method and compared with the log-rank test. Parametric analyses were performed using Student's t test and nonparametric analyses were performed using the Mann-Whitney U test. RESULTS: At diagnosis, three patients had distant lung metastasis and 33 had gross neck lymph node (LN) metastasis. All patients were treated with surgery (hemi/partial thyroidectomy in 45 patients, subtotal thyroidectomy in 85, total thyroidectomy in 12, no LN dissection in 50, central compartment dissection in 20, and modified radical neck dissection in 72), and postoperative external beam radiation therapy was administered to 59. Postoperative ablative therapy using I(131) was not performed in this series. Recurrence was found for regional LN (n = 25), lung (n = 9), remnant thyroid (n = 5), and others (n = 4). DFS and CSS at 40 years were 74.1 and 97.5%, respectively. DFS was significantly worse in patients aged <16 years with a family history of thyroid cancer, preoperative neck gross LN metastasis, maximum tumor diameter, and extrathyroidal invasion. Preoperative gross neck LN metastasis and distant metastasis at diagnosis were significant factors for CSS. No other factors contributed to DFS and CSS. When the clinical features of children and adolescents were compared, the incidence of preoperative gross neck LN metastasis and distant metastasis at diagnosis and tumors with a maximum diameter >10 mm were significantly higher in the children group than in the adolescent group. DFS was significantly shorter in the children group than in the adolescent group, but no significant difference was found in CSS between these two groups. CONCLUSIONS: The prognosis of PTC in children and adolescents is excellent, regardless of the extent of thyroidectomy and LN dissection. We recommend that only children or adolescents with preoperative gross neck LN metastasis and distant metastasis at diagnosis should be subjected to postoperative ablative therapy.

Delay in the diagnosis of multiple endocrine neoplasia type 1: typical symptoms are frequently overlooked.

The morbidity and mortality of individuals with multiple endocrine neoplasia type 1 (MEN1) can be reduced by early diagnosis of MEN1 and related endocrine tumors. To find factors contributing to early diagnosis, we collected clinical information on MEN1 patients through a MEN study group, "MEN Consortium of Japan" and analyzed the time of initial symptom-dependent detection of parathyroid tumors, gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) and pituitary tumors, and that of tumor detection-dependent MEN1 diagnosis in 560 patients. Main tumors were identified up to 7.0 years after symptoms appeared and there was no difference in age at the diagnosis of GEPNETs alone between probands and family members. In patients with typical symptoms (peptic ulcers, urolithiasis, fasting hypoglycemia, bone fracture/loss and amenorrhea), the mean interval between symptom manifestation and tumor detection was extended up to 9.6 years. In particular, 21.7% (5/23) of patients with amenorrhea were diagnosed with pituitary tumors in under one year. In patients with peptic ulcers (from parathyroid tumors or GEPNETs) and urolithiasis (from parathyroid tumors), the interval was positively correlated with age at tumor detection. The interval between tumor detection and MEN1 diagnosis was also prolonged to approximately four years in patients with fasting hypoglycemia (from GEPNETs) and amenorrhea. A substantial delay in the diagnosis of symptom-related tumors and subsequent MEN1 and inadequate screening of GEPNETs in family members were indicated. A greater understanding of MEN1 may assist medical practitioners to make earlier diagnoses, to share patients' medical information and to give family members sufficient disease information.

Clinical features of insulinoma in patients with multiple endocrine neoplasia type 1: analysis of the database of the MEN Consortium of Japan.

More than 50% of patients with multiple endocrine neoplasia type 1 (MEN1) develop gastroenteropancreatic neuroendocrine tumors (GEPNETs), and insulinoma is the second most common functioning GEPNET. Compared to other functioning and nonfunctioning GEPNETs in MEN1, insulinoma is considered to develop at a younger age. To clarify the clinical features of insulinoma developed in Japanese patients with MEN1, a recently constructed database of Japanese MEN1 patients was analyzed. Among 560 registered cases, insulinoma was seen in 69 patients and information on age at diagnosis was available for 54 patients. Tumors predominantly occurred in the body and tail of the pancreas. The mean age at diagnosis of insulinoma (34.8 ± 16.7 yrs) was significantly younger than that of gastrinoma (50.6 ± 14.3 yrs) and nonfunctioning tumor (44.7 ± 13.3 yrs) in patients with MEN1. Patients diagnosed as having insulinoma during middle-age (30 - 49 yrs) tended to have a long period from appearance of hypoglycemic symptoms to diagnosis of the tumor. Of note, 13 patients (24%) were diagnosed as having insulinoma before 20 yrs of age. Such young onset was not seen in other GEPNETs. Since the development of GEPNETs during adolescence is quite rare, insulinoma diagnosed before 20 yrs strongly suggests the presence of MEN1 and warrants further investigation, including MEN1 genetic testing. Also, clinicians should be aware that insulinoma can often be missed in middle-aged patients.

[Multiple endocrine neoplasia type 2 in Japan: large-scale analysis of data from the MEN consortium of Japan].

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal, dominantly inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism and is divided into types 2A and 2B. Familial medullary thyroid carcinoma (FMTC) is characterized by the presence of medullary thyroid carcinoma alone in family members and is considered to be one of the subtypes of MEN2. Clinical and genetic data on 505 Japanese patients from 275 MEN2 or FMTC families registered at 54 medical institutions were collected by the MEN Consortium of Japan. The diagnosis was MEN2A in 343 (67.9%) patients, MEN2B in 29 (5.7%), FMTC in 103 (20.4%), and unclassified in 30 (5.9%). Medullary thyroid carcinoma was found in 91.2% of patients (437/479), pheochromocytoma in 45.6% (212/465), and primary hyperparathyroidism in 8.1% (37/457). RET genetic testing was performed in 410 patients, and the germline RET mutation was found in 98.8% (397/402).

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.

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.

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.