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A 36-year-old male patient initially presented with hypertension, tinnitus, bilateral carotid masses, a right jugular foramen, and a periaortic arch mass with an elevated plasma dopamine level but an otherwise normal biochemical profile. On surveillance MRI 4 years after initial presentation, he was found to have a 2.2-cm T2 hyperintense lesion with arterial enhancement adjacent to the gallbladder, which demonstrated avidity on 68Ga-DOTATATE PET/CT and retrospectively on 18F-FDOPA PET/CT but was non-avid on 18F-FDG PET/CT. Biochemical work-up including plasma catecholamines, metanephrines, and chromogranin A levels were found to be within normal limits. This lesion was surgically resected and was confirmed to be a paraganglioma (PGL) originating from the gallbladder wall on histopathology. Pheochromocytoma (PHEO) and PGL are rare tumors of the autonomic nervous system. Succinate dehydrogenase subunit D (SDHD) pathogenic variants of the succinate dehydrogenase complex are usually involved in parasympathetic, extra-adrenal, multifocal head, and neck PGLs. We report an unusual location of PGL in the gallbladder associated with SDHD mutation which could present as a potential pitfall on 18F-FDOPA PET/CT as its normal excretion occurs through biliary system and gallbladder. This case highlights the superiority of 68Ga-DOTATATE in comparison to 18F-FDOPA and 18F-FDG in the detection of SDHD-related parasympathetic PGL. ClinicalTrials.gov Identifier: NCT00004847 .

BACKGROUND: There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer. METHODS: We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P =.04) and had a greater rate of T1 disease (P =.019), lymph node metastasis (P =.002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (P = .04), had a lesser female-to-male ratio (P=.04), and had a greater rate of lymph node metastasis (P =.009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P =.003) but not in those diagnosed by screening ultrasonography (P =.58). CONCLUSION: Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first-degree relatives affected.

Background Approximately 10% of patients with primary hyperparathyroidism (PHPT) have hereditary disease. Hereditary PHPT may be syndromic (MEN1, 2, and 4 and hyperparathyroidism-jaw tumor syndrome) or non-syndromic (familial isolated PHPT). There are limited data on the probability of testing positive for genetic mutation based on clinical presentation. The aim of this study was to determine potential associations between clinical and biochemical features and mutation in susceptibility genes for PHPT in patients with a family history of PHPT. Study Design A retrospective analysis of 657 patients who had an initial parathyroidectomy for PHPT at a tertiary referral center. Logistic regression analyses were performed in 205 patients with a family history of PHPT to identify factors associated with a positive genetic test. Results Of 657 patients, 205 (31.2%) had a family history of PHPT. Of those 205 patients, 123 (60%) had a germline mutation detected (91 MEN1 , 14 CDC73 , and 18 GCM2 ). In univariate analysis, younger age (45 years and younger), male sex, multigland disease, and parathyroid carcinoma were associated with positive germline mutation; biochemical cure after an initial parathyroidectomy was less frequent in patients with familial PHPT (96.2% vs 89.2%; p = 0.005). In multivariable analysis, age 45 years and younger, male sex, and multigland disease were independent factors associated with positive genetic testing. Conclusions In addition to a family history of PHPT, male sex, age 45 years and younger, and presence of multigland disease, should prompt physicians to offer the opportunity for genetic counseling and testing, as it could influence the management of patients with PHPT.

Background Our knowledge of the susceptibility genes for pheochromocytomas/paragangliomas has increased; however, data on its impact on surgical decision-making has not been described. The aim of this study was to determine the effect of routine preoperative genetic testing on the operative intervention in patients with pheochromocytomas/paragangliomas. Methods One-hundred-eight patients diagnosed with pheochromocytomas/paragangliomas who underwent 118 operations had preoperative genetic testing for 9 known pheochromocytoma/paraganglioma susceptibility genes. A retrospective analysis of a prospective database was performed to evaluate clinical factors associated with the surgical approach selected and the outcome of the surgical intervention. Results In 51 patients (47%), a germline mutation was detected and one-third had no family history of pheochromocytoma/paraganglioma. In 77 operations (65%), it was the first operative intervention for the disease site (60 laparoscopic, 17 open), and 41 (35%) were reoperative interventions (36 open, 5 laparoscopic). For initial operations, variables associated with whether an open or laparoscopic approach was used were tumor size (P = .009) and presence of germline mutation (P = .042). Sixty-eight adrenal operations were performed (54 total, 14 cortical-sparing). Variables significantly associated with a cortical-sparing adrenalectomy being performed were the presence of germline mutation (P = .006) and tumor size (P = .013). Conclusion Preoperative knowledge of the germline mutation status affects the surgical approach and extent of adrenalectomy.

Context Patients with von Hippel–Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types. Objective To define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype. Design A prospective natural history study. Setting The National Institutes of Health clinical center. Patients Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations. Intervention In-silico prediction of VHL mutation via five computational prediction models. Patients with >80% prediction for disease-causing mutations in all models [high predicted risk (HPR)] were compared with others [low predicted risk (LPR)]. Main Outcome Measure Rates of metastases, surgical intervention, and disease progression. Results Sixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the HPR group (n = 13) had a higher rate of disease progression than the LPR group (n = 43) in multivariable analysis (hazard ratio 3.6; 95% confidence interval, 1.1 to 11.9; P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) than other patients. Conclusions Computational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.

ObjectiveTo determine the association between neuroendocrine tumor (NET) biomarker levels and the extent of disease as assessed by68Ga DOTATATE PET/CT imaging.DesignA retrospective analysis of a prospective database of patients with NETs.MethodsFasting plasma chromogranin A (CgA), neuron-specific enolase (NSE), gastrin, glucagon, vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP), and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were measured. Correlation between biomarkers and total68Ga-DOTATATE-avid tumor volume (TV) was analyzed.ResultsThe analysis included 232 patients. In patients with pancreatic NETs (n = 112),68Ga-DOTATATE TV correlated with CgA (r = 0.6,P = 0.001, Spearman). In patients with multiple endocrine neoplasia type 1 (n = 39),68Ga-DOTATATE TV correlated with glucagon (r = 0.5,P = 0.01) and PP levels (r = 0.5,P = 0.049). In patients with von Hippel–Lindau (n = 24), plasma VIP (r = 0.5,P = 0.02) and PP levels (r = 0.7,P 68Ga-DOTATATE TV. In patients with small intestine NET (SINET,n = 74),68Ga-DOTATATE TV correlated with CgA (r = 0.5,P = 0.02) and 5-HIAA levels (r = 0.7,P P = 0.001).68Ga-DOTATATE TV in patients with NET of unknown primary (n = 16) and those with NET of other primary location (n = 30) correlated with 5-HIAA levels (r = 0.8,P = 0.002 andr = 0.7,P = 0.02 respectively).ConclusionsOur data supports the use of specific NET biomarkers based on the site of the primary NET and the presence of hereditary syndrome-associated NET. High urinary 5-HIAA levels indicate the presence of metastatic disease in patients with SINET.

Context: Insulinomas are usually due to a solitary tumor, but they can be challenging to localize. Case Description: A 66-year-old woman presented with a 1-year history of episodic neuroglycopenic hypoglycemia and was suspected of having an insulinoma. On a supervised fast, she was found to be hypoglycemic at 39 mg/dL, with an insulin of 40 μU/mL 26 hours into the fast and a proinsulin of 35 pmol/L. Contrast-enhanced computed tomography and magnetic resonance imaging did not localize a pancreatic lesion. Intra-arterial calcium stimulation testing showed a step-up of venous insulin levels at injection of the superior mesenteric artery and proximal and mid-splenic artery, and a 68Ga-DOTATATE positron emission tomography/computed tomography showed focal uptake in the neck of the pancreas with a standardized uptake value of 12. Despite negative intraoperative pancreatic palpation and ultrasound, the patient underwent an extended distal pancreatectomy with normalization of biochemical levels and resolution of ...

PURPOSE: It has been proposed that rebound hyperglycemia after resection of insulinoma indicates a biochemical cure. However, there is scant objective data in the literature on the rate and need for intervention in hyperglycemia in patients undergoing resection of insulinoma. The goal of our study was to evaluate the rate of postoperative hyperglycemia, any predisposing factors, and the need for intervention in a prospective cohort study of all patients undergoing routine glucose monitoring. METHODS: A retrospective analysis of 33 patients who had an insulinoma resected and who underwent routine postoperative monitoring of blood glucose (every hour for the first six hours then every four hours for the first 24 h) was performed. Hyperglycemia was defined as glucose greater than 180 mg/dL (10 mmol/l). RESULTS: Twelve patients (36%) developed hyperglycemia within 24 h (range 1–16 h). In patients with hyperglycemia, the mean maximum plasma glucose level was 221.5 mg/dL (range 97–325 mg/dL) (12.3 mmol/l), and four (33%) patients were treated with insulin. There was no significant difference in age, gender, body mass index (BMI), tumor size, biochemical profile, or surgical approach and extent of pancreatectomy between patients who developed hyperglycemia and those who did not. Pre-excision and post-excision intraoperative insulin levels were evaluated in 14 of 33 patients. The percentage decrease of the intraoperative insulin levels was not significantly different between patients who developed hyperglycemia and those who did not. All patients with postoperative hyperglycemia had normalization of their glucose levels, and none were discharged on anti-hyperglycemic agents. CONCLUSIONS: Hyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.

Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation-positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism.We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism.Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2-associated primary hyperparathyroidism (239 ± 394 vs 136 ± 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P .001 and 5% vs 0%, P = .04, respectively), but the biochemical cure rate was less in the GCM2 group (86% vs 99%, P .001).GCM2-associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2-associated familial isolated hyperparathyroidism.

Context: Reliable localization of insulinoma is critical for successful treatment. Objective: This study compared the accuracy of 68Gallium DOTA-(Tyr3)-octreotate (Ga-DOTATATE) positron emission tomography (PET)/computed tomography (CT) to anatomic imaging modalities, selective arterial secretagogue injection (SASI), and intraoperative ultrasound (IO ultrasound) and palpation for localizing insulinoma in patients who were biochemically cured. Design, Setting, and Patients: We conducted a retrospective analysis of 31 patients who had an insulinoma. The results of CT, magnetic resonance imaging (MRI), ultrasound, IO ultrasound, 68Ga-DOTATATE PET/CT, SASI, and operative findings were analyzed. Intervention, Main Outcome Measures, and Results: The insulinomas were correctly localized in 17 out of 31 (55%) patients by CT, in 17 out of 28 (61%) by MRI, in 6 out of 28 (21%) by ultrasound, and in 9 out of 10 (90%) by 68Ga-DOTATATE. In 29 of 31 patients (93.5%) who had IO ultrasound, an insulinoma was successfully localized. Thirty patients underwent SASI, and the insulinoma was regionalized in 28 out of 30 patients (93%). In 19 out of 23 patients (83%), manual palpation identified insulinoma. In patients who had all 4 noninvasive imaging studies, CT was concordant with 68Ga-DOTATATE in 6 out of 9 patients (67%), MRI in 8 out of 9 (78%), ultrasound in 0 out of 9; the lesion was only seen by 68Ga-DOTATATE in 1 out of 9 (11%). Conclusions 68Ga-DOTATATE PET/CT identifies most insulinomas and may be considered as an adjunct imaging study when all imaging studies are negative and when a minimally invasive surgical approach is planned.

Adrenal neoplasms are common and are most commonly detected incidentally. The prevalence of adrenal neoplasms/incidentaloma ranges from 1 % to up to 8.7 % depending on patient age and the use of anatomic imaging studies. The estimated incidence is 2–8 cases per 100,000 individuals per year. Although the vast majority of adrenal neoplasms discovered incidentally are benign and nonfunctioning, work up to exclude functioning tumors and malignant disease is necessary. Long-term follow up is also important in patients with benign and nonfunctioning tumors as their natural history is not always innocuous. The main risk factor for developing adrenal neoplasms is a family history due to inherited mutations in susceptibility genes. We review the epidemiology of adrenal neoplasms to underscore the important elements that need to be considered when making management decisions regarding patients who have adrenal neoplasms identified on clinical presentation and those that are discovered incidentally.

Gallium-68 (Ga-68) DOTATATE is a radiolabeled peptide-imaging modality that targets the somatostatin receptor (SSTR), especially subtype 2 (SSTR2). Benign and malignant thyroid tumors have been observed to express SSTR. The aim of this study was to evaluate the frequency and clinical significance of incidental atypical thyroid uptake as detected by Ga-68 DOTATATE positron emission tomography/computed tomography (PET/CT).A retrospective analysis was conducted of a prospective study in which 237 patients underwent Ga-68 DOTATATE PET/CT as part of a work-up for metastatic and unknown primary neuroendocrine tumors. The types of uptake in the thyroid gland (focal/diffuse) and maximum standardized uptake value (SUVmax) levels were evaluated and compared with the background uptake in the liver and salivary glands.Of 237 patients, 26 (11%) had atypical thyroid uptake as detected by Ga-68 DOTATATE PET/CT. There were no significant clinical or biochemical variables associated with atypical thyroid uptake. Fourteen (54%) patients had positive focal uptake, and 12 (46%) patients had diffuse uptake. Of the 14 patients with atypical focal uptake, 10 (71%) had thyroid nodules on the corresponding side, as detected by anatomic imaging. Three of 10 patients (21%) were found to have papillary thyroid cancer, and seven (70%) had adenomatoid nodules. Of the 12 patients with diffuse increased uptake, six (50%) had a history of hypothyroidism, five (42%) had chronic lymphocytic thyroiditis, and one (8%) had nontoxic multinodular goiter.Patients with an incidental focal abnormal thyroid uptake on Ga-68 DOTATATE PET/CT scan should have further clinical evaluation to exclude a diagnosis of thyroid cancer.

Background & Aims Survival times vary among patients with neuroendocrine tumors (NETs)—even among those with the same site, stage, and grade of primary tumor. This makes it difficult to select treatment for patients with unresectable NETs, because some patients can survive decades without treatment. 68 Gallium-DOTATATE positron emission tomography with computed tomography ( 68 Ga-DOTATATE PET/CT) is a sensitive imaging technique for detection of NETs. We investigated the prognostic accuracy of 68 Ga-DOTATATE PET/CT analysis of tumor volume in patients with NETs. Methods We performed a prospective study of 184 patients with NETs (128 [69.6%] with metastases and 11 patients [6.0%] with locally advanced disease) at the National Institutes of Health Clinical Center from 2013 through 2017. All patients underwent 68 Ga-DOTATATE PET/CT image analysis and total 68 Ga-DOTATATE-Avid tumor volume ( 68 Ga-DOTATATE TV) was determined. We also measured fasting serum chromogranin A, neuron-specific enolase, gastrin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and 24-hour urinary 5-hydroxyindoleacetic acid levels in all patients. Disease progression was defined as a new lesion or a growth of a known lesion, during the interval between baseline 68 Ga-DOTATATE PET/CT scan and follow-up imaging (14.0±6.1 months; range 1–35 months). The primary outcomes were progression-free survival (PFS) and disease-specific mortality during a median follow-up time of 18 months (range 4–35 months). Results We found an inverse correlation between quartiles of 68 Ga-DOTATATE TV and PFS ( P =.001) and disease-specific survival ( P =.002). A 68 Ga-DOTATATE TV of 7.0 mL or more was associated with higher odds of disease progression (hazard ratio, 3.0; P =.04). A 68 Ga-DOTATATE TV of 35.8 mL or more was associated with increased risk of disease-specific death (hazard ratio, 10.6) in multivariable analysis ( P =.01), as well as in subgroup analysis of patients with pancreatic NETs. Conclusions In a prospective study, we demonstrated the prognostic utility of 68 Ga-DOTATATE TV in a large cohort of patients with NETs, in terms of PFS and disease-specific mortality.