Initiation of Patients onto Long-Acting Somatostatin Analogue Therapy for Neuroendocrine Tumors: A Single-Center Review of Practice

Objective: Neuroendocrine tumors (NETs) are being seen increasingly frequently, and recent data show that long-acting somatostatin analogues have become a major initial treatment, regardless of whether the tumors are functioning or not. However, test dosing with subcutaneous (sc) octreotide is usually advised to assess longer-term tolerability, although this advice is mainly based on results with functioning tumors. The aim of the study was to assess the value of an initiating test dose of sc octreotide on the prediction of subsequent adverse events after treatment with the long-acting analogue.Methods: In a single, large Centre of Excellence for NETs, a first cohort of patients (n = 24) was admitted overnight after an sc injection of octreotide, and then administered the analogue; a subsequent group (n = 53) had the test dose performed on an outpatient basis. Side effects were recorded after the test dose and subsequent treatment with the long-acting analogue.Results: The test dose injection was of little value in predicting adverse events following the long-acting somatostatin analogue.Conclusion: Unless there are serious symptoms associated with a functioning NET, it is unnecessary to carry out a test dose; a change to this procedure will improve resource allocation and should enhance early initiation onto maintenance therapy.Abbreviations:CLARINET = Controlled study of lanreotide antiproliferative response in neuroendocrine tumorsLAR = long-acting repeatableNET = neuroendocrine tumorPROMID = Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with meta-static neuroendocrine midgut tumors     

Prognostic Utility of 24-Hour Urinary 5-Hiaa Doubling Time in Patients With Neuroendocrine Tumors

Objective: New clinical prognostic tools are needed to select the population of patients with neuroendocrine tumors (NETs) that have a high risk of disease progression and disease-specific mortality (DSM). Biochemical biomarker doubling time (DT) is used clinically for prognosis prediction in several solid malignancies. The aim of the current study was to determine whether 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) level DT has any prognostic utility in patients with NETs.Methods: Patients with NETs were enrolled in a prospective study with comprehensive biochemical analysis. The current analysis included 90 subjects with increasing 5-HIAA levels in two consecutive measurements. DT was calculated using the Schwartz equation. The primary outcome measures were DSM and disease progression.Results: 5-HIAA DT of <434 days was associated with a higher rate of DSM (P =.02), with positive and negative predictive values for DSM of 75 and 77%, respectively. The difference in DSM was accounted for mainly by patients with small intestine or unknown primary NET (P =.01). In addition, a shorter 5-HIAA DT in patients with small intestine or unknown primary NET was associated with a higher risk of disease progression both in univariate (P =.001) and multivariable analyses (hazard ratio, 15.8; 95% confidence interval, 1.3 to 198.0; P =.03).Conclusion: 5-HIAA DT may be used as a risk stratification tool in patients with small intestine NET or NET of unknown primary after it is validated in an independent cohort and can assist in identifying patients with a high risk for disease progression and DSM.Abbreviations: CT = computed tomography; DSM = disease-specific mortality; DT = doubling time; 5-HIAA = 5-hydroxyindoleacetic acid; MRI = magnetic resonance imaging; NET = neuroendocrine tumor; NETUP = neuroendocrine tumor of unknown primary; PET = positron emission tomography; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumor; ROC = receiver operating characteristic; SINET = small-intestine neuroendocrine tumor     

Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment (Elect): A Randomized,Double-Blind,Placebo-Controlled Trial

Objective: To evaluate the efficacy and safety of lanreotide depot/autogel 120 mg for the control of carcinoid syndrome (CS) symptoms in patients with neuroendocrine tumors (NETs).Methods: This was a 16-week, randomized, double-blind, phase 3 trial (Clinicaltrials.gov: NCT00774930). Patients with/without prior somatostatin analog (SSA) use were randomized to lanreotide depot/autogel 120 mg or placebo every 4 weeks, with access to short-acting octreotide as rescue medication. The primary endpoint was the percentage of days in which short-acting octreotide was used, which was assessed from daily diaries using an analysis of covariance including the stratification variables baseline short-acting octreotide use and frequency of diarrhea/flushing. The proportions of patients experiencing treatment success was a supportive analysis. Adverse events were recorded at all visits.Results: A total of 115 patients were enrolled (lanreotide, n = 59; placebo, n = 56). The adjusted mean (95% confidence interval [CI]) percentage of days with rescue octreotide use (primary endpoint) was significantly lower in the lanreotide (33.7%; 95% CI, 25.0%–42.4%) versus the placebo group (48.5%; 95% CI, 39.6%–57.4%), representing an absolute difference of -14.8% (95% CI, -26.8% to -2.8%; P = .017). The odds ratio of full/partial treatment success (≤3 days short-acting octreotide use weeks 12 to 15) was significantly greater with lanreotide than placebo (2.4; 95% CI, 1.1–5.3; P = .036). No new safety concerns were identified, and lanreotide was well tolerated.Conclusion: Lanreotide depot/autogel is effective for the control of CS symptoms in patients (SSA-naïve or experienced) with NETs.Abbreviations:AE = adverse eventBMI = body mass indexCS = carcinoid syndromeELECT = Evaluating Lanreotide Efficacy and safety as a Carcinoid-syndrome TreatmentHRQoL = health-related quality of lifeLTOLE = long-term open-label extensionNET = neuroendocrine tumorOL = open labelSSA = somatostatin analog     

A case of heterotopic pancreas mimicking an intestinal neuroendocrine tumor in 18F-DOPA PET-CT and a review of the literature

18-Fluoro-L-dihydroxyphenylalanine positron emission tomography/computed tomography (18F-DOPA PET-CT) is a nuclear medicine imaging modality indicated for the diagnosis and staging of neuroendocrine tumors (NETs), particularly for the midgut tumors, due to its excellent sensitivity and specificity. Its performance for the detection of foregut-derived NETs (duodenopancreas and proximal jejunum) and for the detection of hindgut-derived NETs is poor and inferior to PET somatostatin receptor imaging such as DOTATOC PET-CT and even inferior to somatostatin analog scintigraphy (octreoscan). There are few studies in the literature on heterotopic pancreas (HP) which is a rare entity, and which can be in some cases a false positive in 18F-DOPA PET-CT. We report a case of HP showing focal uptake on 18F-DOPA PET-CT mimicking an intestinal NET. This case suggests that HP should be included as a possible false positive on 18F-DOPA PET-CT.     

Biochemical Responses in Symptomatic and Asymptomatic Patients with Neuroendocrine Tumors: Pooled Analysis of Two Phase 3 Trials

Objective: Neuroendocrine tumors (NETs) are associated with elevated 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels. This study aimed to analyze relationships between urinary 5-HIAA and plasma CgA levels and clinical outcomes.Methods: Centrally assessed biomarker levels and correlations with progression-free survival (PFS) and carcinoid syndrome (CS) symptom control were evaluated in a pooled analysis of CLARINET (96-week randomized, double-blind, placebo-controlled) and ELECT (16-week randomized, double-blind, placebo-controlled, 32-week initial open label and ≥2 year long-term extension open label) studies of adults with NETs, with (ELECT) or without (CLARINET) CS at 97 institutions. Patients were treated with subcutaneous lanreotide depot 120 mg monthly.Results: Of 319 pooled patients, 86% and 95% had baseline 5-HIAA and CgA data, respectively, with 47% and 74% having levels greater than the upper limit of normal (ULN). PFS was longer among patients who experienced a decrease in biomarker levels at week 12, with statistical significance reached in the CgA cohort (not reached vs. 14.4 months; P<.0001). A large proportion (87%) of patients without symptoms of CS in the CLARINET study had detectable levels of 5-HIAA (48% >ULN). In ELECT, patients with CS who received lanreotide and experienced a biochemical response (≥50% decrease from baseline) achieved greater symptom control.Conclusion: This pooled analysis of two randomized, placebo-controlled trials demonstrated that 5-HIAA and CgA are secreted as biochemical biomarkers in many patients with NETs, regardless of clinical syndromes. Significant biochemical response was associated with improved clinical outcomes, as measured by improved PFS or improved CS symptom control.Abbreviations: 5-HIAA = 5-hydroxyindoleacetic acid; CgA = chromogranin A; CI = confidence interval; CLARINET = Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors; CS = carcinoid syndrome; ELECT = Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment; HR = hazard ratio; ITT = intention-to-treat; NET = neuroendocrine tumor; PanNET = pancreatic NET; PFS = progression-free survival; PPI = proton pump inhibitor; SSA = somatostatin analogue; ULN = upper limit of normal     

American Association of Clinical Endocrinology Disease State Clinical Review on the Evaluation and Management of Adrenocortical Carcinoma in an Adult: a Practical Approach

Objective: The aim of this Disease State Clinical Review is to provide a practical approach to patients with newly diagnosed adrenocortical carcinoma, as well as to follow-up and management of patients with persistent or recurrent disease.Methods: This is a case-based clinical review. The provided recommendations are based on evidence available from randomized prospective clinical studies, cohort studies, cross-sectional and case-based studies, and expert opinions.Results: Adrenocortical carcinoma is a rare malignancy, often with poor outcomes. For any patient with an adrenal mass suspicious for adrenocortical carcinoma, the approach should include prompt evaluation with detailed history and physical exam, imaging, and biochemical adrenal hormone assessment. In addition to adrenal-focused imaging, patients should be evaluated with chest-abdomen-pelvis cross-sectional imaging to define the initial therapy plan. Patients with potentially resectable disease limited to the adrenal gland should undergo en bloc open surgery by an expert surgeon. For patients presenting with advanced or recurrent disease, a multidisciplinary approach considering curative repeat surgery, local control with surgery, radiation therapy or radiofrequency ablation, or systemic therapy with mitotane and/or cytotoxic chemotherapy is recommended.Conclusion: As most health care providers will rarely encounter a patient with adrenocortical carcinoma, we recommend that patients with suspected adrenocortical carcinoma be evaluated by an expert multidisciplinary team which includes clinicians with expertise in adrenal tumors, including endocrinologists, oncologists, surgeons, radiation oncologists, pathologists, geneticists, and radiologists. We recommend that patients in remote locations be followed by the local health care provider in collaboration with a multidisciplinary team at an expert adrenal tumor program.Abbreviations: ACC = adrenocortical carcinoma; ACTH = adrenocorticotropic hormone; BRACC = borderline resectable adrenocortical carcinoma; CT = computed tomography; DHEAS = dehydroepiandrosterone sulfate; EDP = etoposide, doxorubicin, cisplatin; FDG = ¹⁸F-fluorodeoxyglucose; FNA = fine-needle aspiration; HU = Hounsfield units; IVC = inferior vena cava; LFS = Li-Fraumeni syndrome; MEN1 = multiple endocrine neoplasia type 1; MRI = magnetic resonance imaging; OAC = oncocytic adrenocortical carcinoma; PC = palliative care; PET = positron emission tomography     

Lanreotide Therapy in Carcinoid Syndrome: Prospective Analysis of Patient-Reported Symptoms in Patients Responsive To Prior Octreotide Therapy And Patients Naïve To Somatostatin Analogue Therapy in The Elect Phase 3 Study

Objective: This ELECT prospective analysis examined lanreotide depot/autogel for carcinoid syndrome (CS) symptom control in patients with neuroendocrine tumors (NETs) who were responsive to prior octreotide (prior octreotide group) compared with patients who were naïve to prior somatostatin analogue treatment (de novo group).Methods: Adults with histopathologically confirmed NET and stable CS (diarrhea and/or flushing) were randomized to subcutaneous (SC) lanreotide 120 mg or placebo every 4 weeks for 16 weeks. Patients reported diarrhea and/or flushing symptom severity and frequency and short-acting SC octreotide rescue therapy daily using an Interactive Voice/Web Response System. To evaluate the efficacy of lanreotide compared with placebo, the novel primary endpoint of patient-determined use of SC octreotide rescue therapy for breakthrough symptoms was used as a surrogate for symptom control. Clinically meaningful patient-reported treatment benefit was examined using daily patient-reported symptoms of diarrhea and flushing.Results: Of the 115 randomized patients, 51 (n = 26 lanreotide, n = 25 placebo) were octreotide-naïve (de novo) and 64 (n = 33 lanreotide; n = 31 placebo) received prior octreotide. Lanreotide versus placebo patients had a lower mean percentage of days of SC octreotide rescue therapy in de novo and prior octreotide groups (least squares &lsqb;LS] mean difference -19.1, P = .0477 and -6.9, P = .4332, respectively). The mean percentage of days with moderate/severe diarrhea and/or flushing was lower in lanreotide versus placebo patients in de novo and prior octreotide groups (LS mean difference -14.6, P = .0140 and -10.9, P = .0746, respectively). The transition from octreotide to lanreotide was generally well-tolerated.Conclusion: Improvement in CS symptoms occurred with lanreotide treatment, regardless of prior octreotide use.Abbreviations:CI = confidence intervalCS = carcinoid syndromeDB = double blindELECT = Evaluation of Lanreotide depot/autogel Efficacy and safety as a Carcinoid-syndrome TreatmentIOL = initial open-labelIVRS/IWRS = interactive voice/web response systemLS = least squareNET = neuroendocrine tumorOR = odds ratioSC = subcutaneousSSA = somatostatin analogueSSTR = somatostatin receptorTEAE = treatment-emergent adverse event     

Systemic Treatment of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETS): Cuirrent Approaches and Future Options

ObjectiveTo describe recent advances in the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs).MethodsA review of the published English language literature on GEP-NET therapy with a focus on practice-changing clinical trials.ResultsSomatostatin analog (SSA) treatment remains a cornerstone of GEP-NET therapy, primarily for patients with hormonally functional tumors and midgut carcinoids. The biologic agents everolimus and sunitinib have similar tumor-stabilizing effects in pancreatic NETs and are both approved to treat progressive low-intermediate-grade tumors. Their role in nonpancreatic NETs remains controversial. Cytotoxic chemotherapy is effective against pancreatic NETs, but modern prospective data is lacking. Radiolabeled SSAs will likely become more widely available once phase III randomized studies are completed.ConclusionsNew treatment options for GEP-NETs have become available and highlight the necessity of developing predictive biomarkers that will allow for appropriate and individualized therapy selection. (Endocr Pract. 2014;20:167-175)     

Pheochromocytoma: A Genetic And Diagnostic Update

Objective: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathologic studies are performed to prove, localize, treat, and monitor disease progression. Improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (<1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment.Methods: This review outlines the most updated approach to PPGL patients and presents a new diagnostic protocol for physicians to increase earlier tumor identification and accurately assess metastatic behavior.Conclusion: We present the most recent advances in genetics, epigenetics, metabolomics, biochemical, and imaging diagnoses of this rare tumor to properly assess disease, decide treatment options, and manage follow-up. We also elaborate on new therapeutic perspectives in these very rare neoplastic entities.Abbreviations: ATRX = ATRX chromatin remodeler; ccRCC = clear cell renal cell carcinoma; c-MYC = MYC proto oncognene; CT = computed tomography; DOTATATE = DOTA-octreotate; EGLN1/2 = egl-9 family hypoxia inducible factor 1/2; EGLN2/PHD1 = egl-9 family hypoxia inducible factor 2; EPAS1/HIF2A = endothelial PAS domain protein 2/hypoxia-inducible factor 2α; ERK = extracellular signal-regulated kinase; HIFs = hypoxia-inducible factors; HIF-α = hypoxia-inducible factor alpha; HNPGLs = head and neck paragangliomas; ¹⁷⁷Lu-DOTATATE = lutetium octreotate; MAX = myc-associated factor X; MDH2 = malate dehydrogenase; MIBG = metaiodobenzylguanidine; MN = metanephrine; MRI = magnetic resonance imaging; mTOR = mammalian target of rapamycin; NETs = neuroendocrine tumors; NF1 = neurofibromin 1; NMN = normetanephrine; PHD = prolyl hydroxylase domain protein; PI3K = phosphoinositide 3-kinase; PPGLs = pheochromocytoma and paragangliomas; PRRT = peptide receptor radionuclide therapy; Pvhl = von Hippel-Lindau protein; RAS = rat sarcoma oncogene; RET = rearranged during transfection proto-oncogene; SDH = succinate dehydrogenase; SDHA, -B, -C, -D = succinate dehydrogenase subunits A, B, C, D; SDHAF2 = succinate dehydrogenase complex assembly factor 2; SDHB, C, D = succinate dehydrogenase subunits B, C, D; SDHx = succinate dehydrogenase subunits; SSTRs = somatostatin receptors; VHL = von Hippel-Lindau     

Can Microwave Ablation be an Alternative to Resection for the Treatment of Neuroendocrine Liver Metastases?

Objective: Surgical resection of neuroendocrine tumor liver metastases has been proven to improve survival, but the benefit of microwave ablation as an alternative or adjunct to surgery has yet to be assessed. Our hypothesis is that ablation is equal to surgery in terms of local recurrence and survival.Methods: We conducted a retrospective analysis including all patients treated with microwave ablation and/or surgical resection for neuroendocrine liver metastases in our institution between 2008 and 2017.Results: A total of 47 patients and 68 treatments were analyzed, including 34 liver resections, 20 ablations, and 14 combined procedures. A total of 130 individual metastases were treated with ablation, representing a median of 4 per session (range 1–30). While no major complications occurred after ablation, we observed 11 minor and 3 major complications after open surgical resection (P = .0135). Length of stay was significantly shorter after ablation (P = .0008). The majority of patients (33/47, 70.2%) underwent curative procedures, 14 patients underwent (29.8%) debulking procedures. There was no difference in local recurrence rate between tumors treated with ablation or resection. Liver-only disease progression was detected in 29% of the patients and overall progression was detected in 66% of the patients. The mean survival was not significantly different between patients treated with ablation only versus resection with or without ablation (P = .1570). Overall survival was mean 75.3 months (6 to 374 months).Conclusion: Depending on the extent of the liver metastases, microwave ablation might be a safe alternative or addition to resection for neuroendocrine tumor liver metastases with low morbidity and high local efficiency.Abbreviations: CT = computed tomography; MWA = microwave ablation; NET = neuroendocrine tumor; PET = positron emission tomography; RFA = radiofrequency ablation; RFS = recurrence-free survival; SMWA = stereotactic microwave ablation     

Cushing’s Syndrome Due to a Corticotropin-releasing Hormone- and Adrenocorticotrophic Hormone-producing Neuroendocrine Pancreatic Tumor

Objective: To our knowledge, only 2 cases of pancreatic neuroendocrine tumors have been described as the source of corticotropin-releasing hormone (CRH) in Cushing’s syndrome. Here, we describe a case of ectopic adrenocorticotrophic hormone (ACTH-) and CRH-production caused by a pancreatic neuroendocrine tumor.Methods:We analyzed and summarized the patient’s medical history, physical examination results, laboratory data, imaging studies, and histopathologic results.Results: An endocrinologic workup revealed massive ACTH-dependent hypercortisolism. Pituitary magnetic resonance imaging (MRI) showed no pathologic findings and led to extensive imaging in search of the suspected ectopic lesion. Ketoconazole treatment was initiated. Rapid deterioration of the patient’s clinical condition due to escalating cortisol levels and resulting sepsis required an emergency adrenalectomy to control the hypercortisolism. A positron emission tomography-computed tomography (PET-CT) scan revealed a hepatic lesion, which was biopsied. Histology of the lesion showed a well-differentiated endocrine tumor. Subsequent scintigraphy with octreotide (a somatostatin [SMS] analog) detected a pancreatic tumor, which was endosonographically confirmed. The initiated SMS therapy was followed by a distal splenopancreatectomy and a right hemihepatectomy. Immunostaining of the specimen showed positive expression for CRH and ACTH.Conclusion: We conclude that SMS-scintigraphy did have an additional diagnostic benefit compared to PET-CT. In hypercortisolemic patients, rapid endocrinologic evaluation is crucial to prevent rapid deterioration and a possible fatal outcome. (Endocr Pract. 2014;20:e53-e57)     

Imaging Localization and Surgical Approach in the Management of Ectopic Parathyroid Adenomas

Objective: (1) Review the anatomy and epidemiology of ectopic parathyroid adenomas (EPAs), (2) summarize the role of relevant imaging modalities in the localization of EPAs, and (3) characterize surgical approaches for various ectopic locations.Methods: Literature review of published English-language articles from 1995 through August 2017.Results: Summary of the literature indicates that the prevalence of EPA is approximately 20% in unexplored patients with primary hyperparathyroidism, but it is as high as 66% in re-operative patients. EPAs may be located anywhere from the carotid bifurcation to the aorto-pulmonary window. Ultrasound has limited accuracy in identifying EPAs except near the thyroid and thyrothymic ligament and requires expert experience from the user. Among dual-phase ^99mTc sestamibi scintigraphy techniques, hybrid imaging with both single-photon emission computed tomography (SPECT) and computed tomography (CT) (SPECT/CT) is superior to planar scintigraphy or SPECT alone at localizing EPAs. Four-dimensional computed tomography (4DCT) precisely delineates important anatomic relationships and is highly sensitive in localizing EPAs. Although 4DCT requires radiation, intravenous iodinated contrast, and reader experience, it is well-equipped to detect lesions at various ectopic sites and guide the surgical approach. EPAs frequently require alternative surgical approaches. Re-operative parathyroidectomy may be attempted in patients having previously undergone bilateral neck exploration by an experienced surgeon once the lesion is colocalized by 2 repeat imaging modalities. Removal of nonlocalized disease requires a careful and systematic exploration of superior and inferior gland locations.Conclusion: EPAs pose challenges during both localization and surgical removal. High-volume experience and multidisciplinary care are necessary for optimal outcomes.Abbreviations: CT = computed tomography; 4DCT = 4-dimensional CT; EPA = ectopic parathyroid adenoma; EPG = ectopic parathyroid gland; PHPT = primary hyperparathyroidism; RLN = recurrent laryngeal nerve; SPECT = single-photon emission computed tomography; TE = tracheo-esophageal     

Management Of Catecholamine-Secreting Tumors In Pregnancy: A Review

Objective: Catecholamine-secreting tumors (pheochromocytomas and paragangliomas) presenting during pregnancy are extremely rare, but they can be fatal to both mother and fetus. Recent discoveries in the genetic background of these tumors are expected to address an increasing number of at-risk women to prenatal diagnosis.Methods: The literature was reviewed in order to provide clinicians with a practical and updated guide on how to manage this life-threatening condition.Results: The clinical presentation of catecholamine-secreting tumors can be deceptive and mimic common disorders of pregnancy. Silent catecholamine-secreting tumors can become evident during pregnancy, and hypertension cannot be considered a hallmark for this condition: some women may be normotensive or develop orthostatic hypotension. Biochemical screening includes measurement of plasma free metanephrines or urinary fractioned metanephrines. Measurement of catecholamines, dopamine, and methoxytyramine can provide further information on tumor biology, location, and prognosis. Diagnostic imaging is limited, and medical treatment requires a cautious balance between hemodynamic control and effects on the fetoplacental unit. Several genes have been associated with syndromes including catecholamine-secreting tumors, and positive genetic testing can correlate with tumor behavior. Timing and modalities for tumor removal and delivery, including anesthetic management, depend on gestational age, maternal and fetal wellbeing, control of catecholamine excess, suspicion of multiple or malignant disease, and surgical accessibility to the tumor.Conclusion: A timely diagnosis and a multidisciplinary approach are the keys to improve pregnancy outcomes in patients with a catecholamine-secreting tumor; each case should be managed in a tertiary referral center.Abbreviations:CCB = calcium channel blockerCST = catecholamine-secreting tumorMRI = magnetic resonance imagingPG = paragangliomaPHEO = pheochromocytoma     

Chromogranin-A as a serum marker for neuroendocrine tumors: comparison with neuron-specific enolase and correlation with immunohistochemical findings

BACKGROUND: Chromogranin-A (Cg-A) is a 439-amino-acid protein contained in secretory granules of neuroendocrine cells, in addition to specific hormone peptides or neuropeptides. Since Cg-A is co-released with peptide hormones its serum concentration can be used as a marker of neuroendocrine tumors. AIM: Evaluation of the analytical performance of a new IRMA method for Cg-A assay and of the clinical value of serum Cg-A and neuron-specific enolase (NSE) in neuroendocrine tumors. In addition, we compared the diagnostic usefulness of both Cg-A and NSE serum levels and their relationship to tissue expression. PATIENTS AND METHODS: Initially we evaluated the analytical performance (intra- and interassay imprecision, dilution test and detection limit) of the Cg-A RIACT method (CIS Bio-International, Gif-sur-Yvette, France). We selected 50 patients affected by various histologically confirmed neuroendocrine tumors (NETs): 111In-pentetreotide scan and helical computed tomography were employed to assess tumor extent. Cg-A and NSE were measured before surgery in serum samples of patients and 50 age-matched controls by IRMA methods. After surgery immunohistochemical stains for Cg-A and NSE were performed on surgical specimens of tumor tissue. RESULTS: Cg-A levels were significantly higher (p < 0.0001) in patients with NETs than in healthy controls and we found a positive correlation between serum and tissue expression (p < 0.05). Serum levels of Cg-A were also related to tumor extent (p < 0.05) but in some cases we observed significant elevation of serum Cg-A in small, intensely immunoreactive NETs. ROC curve analysis showed better accuracy for serum Cg-A compared to NSE in the diagnosis of NETs, while no significant relationship was found between serum expression and immunostaining for NSE. DISCUSSION: Our results confirmed the biological and clinical significance of circulating Cg-A as an expression of granular content in neuroendocrine tissues and supported the complementary usefulness of serum Cg-A in the diagnosis and evaluation of NETs together with imaging modalities.     

The Mount Sinai Clinical Pathway for the Management of Pheochromocytoma

Objective: Pheochromocytomas are complex tumors that require a comprehensive and systematic management plan orchestrated by a multidisciplinary team.Methods: To achieve these ends, The Mount Sinai Adrenal Center hosted an interdisciplinary retreat where experts in adrenal disorders assembled with the aim of developing a clinical pathway for the management of pheochromocytomas.Results: The result was a consensus for the diagnosis, perioperative management, and postoperative management of pheochromocytomas, with specific recommendations from our team of adrenal experts, as well as a review of the current literature.Conclusion: Our clinical pathway can be applied by other institutions directly or may serve as a guide for institution-specific management.Abbreviations: CCB = calcium-channel blocker CT = computed tomography MEN = multiple endocrine neoplasia MIBG = ¹²³I-metaiodobenzylguanidine MRI = magnetic resonance imaging NF1 = neurofibromatosis type 1 PET = positron emission tomography SPECT = single-photon emission computed tomography VHL = von Hippel-Lindau     

Clinical Heterogeneity of Ectopic ACTH Syndrome: A Long-Term Follow-Up Study

Objective: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a heterogeneous condition caused by neuroendocrine neoplasms (NENs) located in the lungs, thymus, or pancreas. Our purpose was to evaluate the long-term outcome of these patients.Methods: Retrospective study at a referral center. The charts of 164 patients with Cushing syndrome, followed at our center from 1993 to 2019, were analyzed.Results: EAS was found in 16 patients (9.75%, 9 women, mean age 36.01 years) who had been followed for a median of 72 months. The source of EAS was a NEN in 10 patients (8 bronchial and 2 thymic carcinoid tumors) and a mixed corticomedullary tumor, consisting of a pheochromocytoma and an adrenocortical carcinoma in 1 patient. In 2 of the 6 patients initially considered to have occult EAS, the source of the ACTH excess became apparent after adrenalectomy, whereas in the remaining 4 (25%) patients, it has remained occult. Of the 11 patients in whom resection of the NEN was attempted, 10 patients achieved an early remission (91%), but 4 (25%) of these patients had a recurrence during follow-up (biochemically and clinically silent in 2 patients). Three patients died (18.75%): the young woman with the mixed corticomedullary tumor, a man with a thymic NEN that evolved into a neuroendocrine (NE) carcinoma after 11 years of follow-up, and a woman with a bronchial NEN.Conclusion:The course of EAS varies according to tumor type and grade. Some patients have a protracted course, whereas others may evolve into neuroendocrine carcinomas.Abbreviations: ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; CV = coefficient of variation; EAS = ectopic ACTH syndrome; IQR = interquartile range; NEN = neuroendocrine neoplasm; SCCL = small cell carcinoma of the lung; TSS = transsphenoidal surgery; UFC = urinary free cortisol     

Metabolic and Receptor Imaging in Patients with Neuroendocrine Tumors: Comparison of Fludeoxyglucose-Positron Emission Tomography and Computed Tomography with Indium in 111 Pentetreotide

ObjectiveTo determine whether positron emission tomography/computed tomography (PET/CT) and indium In 111 pentetreotide, individually or collectively, predict the outcome of patients with neuroendocrine tumors (NETs).MethodsBetween July 31, 2002, and May 4, 2007, 29 patients with previously diagnosed NETs underwent both PET/CT and indium In 111 pentetreotide imaging at our institution. The images were evaluated for the presence of abnormalities. Clinical outcomes were classified as survival without major morbidities, survival with severe complications of disease, or death. Time to outcome was measured in months from the imaging date to outcome. Kaplan-Meier survival curves were calculated in which patient outcome was compared with results on PET/CT and indium In 111 pentetreotide imaging.ResultsOf the 29 patients, 9 had abnormalities on both PET/CT and indium In 111 pentetreotide imaging. Two patients had abnormal findings on PET/CT but normal findings on pentetreotide imaging. In 5 patients, findings were normal on PET/CT but abnormal on pentetreotide imaging. In 13 patients, normal findings were noted on both PET/CT and pentetreotide imaging. Kaplan-Meier analysis demonstrated a significant survival advantage for patients who had normal findings on PET/CT in comparison with abnormal PET/CT findings (P = .01). Patients with normal findings on indium In 111 pentetreotide imaging had a higher but insignificant survival advantage over those with abnormal results on pentetreotide imaging (P = .08).ConclusionFor evaluation of NETs, PET/CT and indium In 111 pentetreotide are complementary. Increased metabolic activity in tumor cells is reflected by abnormalities on PET/CT. Patients who had abnormal PET/CT findings had a generally poorer prognosis and a more rapid clinical deterioration than those with normal PET/CT findings. (Endocr Pract. 2009;15:521-527)     

Oncogene Panel Sequencing Analysis Identifies Candidate Actionable Genes in Advanced Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors

Objective: To report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastro-enteropancreatic (GEP) neuroendocrine tumors (NET) and of other genetic alterations that may be associated with tumorigenesis.Methods: A phase II mutation targeted therapy trial was conducted in patients with advanced well-differentiated G1/G2 GEP-NET. Mutations found in the mTOR pathway-associated genes led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor deoxyribonucleic acid (DNA) from GEP-NET were sequenced and compared with germline DNA, using the OncoVAR-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called and copy-number (CN) variant analysis was performed.Results: Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NET, and 5 of other primary sites) harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n = 26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chromosome (Chr) 18 (P<.05), CN gain of Chr 5, and loss of Chr 13. CN losses in Chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesions sequenced.Conclusion: Genome-wide DNA sequencing may identify candidate actionable genes and lead to the identification of novel target genes for advanced well-differentiated GEP-NET.Abbreviations: Chr = chromosome; CN = copy number; DNA = deoxyribonucleic acid; FDA = Food and Drug Administration; GEP = gastro-enteropancreatic; MEN-1 = multiple endocrine neoplasia syndrome type 1; mTOR = mammalian target of rapamycin; NET = neuroendocrine tumor; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumors; SINET = small-intestine neuroendocrine tumor     

Pathogenesis of Cushing Disease: An Update on the Genetics of Corticotropinomas

Objective: Cushing disease is a rare severe condition caused by pituitary tumors that secrete adrenocorticotropic hormone (ACTH), leading to excessive endogenous glucocorticoid production. Tumors causing Cushing disease, also called corticotropinomas, are typically monoclonal neoplasms that mainly occur sporadically.Methods: Literature review.Results: Cushing disease is very rarely encountered in genetic familial syndromes. Oncogenes and tumor suppressor genes commonly associated with other tumor types are only rarely mutated in this tumor type. The advent of next-generation sequencing led to the identification of a single mutational hotspot in the ubiquitin-specific protease 8 (USP8) gene in almost half of Cushing disease tumors.Conclusion: The new discoveries showcase a novel mechanism responsible for corticotroph tumorigenesis and ACTH hypersecretion and highlight USP8 and its downstream signaling pathways as potential promising pharmacologic targets for the management of Cushing disease.Abbreviations: ACTH = adrenocorticotropic hormone; BRG1 = Brahma-related gene 1; CABLES1 = CDK5 and ABL1 enzyme substrate 1; CD = Cushing disease; CNC = Carney complex; DICER1 = cytoplasmic endoribonuclease III; EGFR = epidermal growth factor receptor; GR = glucocorticoid receptor; IL = interleukin; MEN = multiple endocrine neoplasia; miRNA = microRNA; POMC = proopiomelanocortin; SSTR = somatostatin receptor; USP8 = ubiquitin-specific protease 8     

VHL-Related Neuroendocrine Neoplasms And Beyond: An Israeli Specialized Center Real-Life Report

Objective: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN).Methods: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed.Results: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed.Conclusion: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.