Breakthrough Symptoms Remain an Unmet Need in Symptomatic Patients With Neuroendocrine Tumors and Carcinoid Syndrome.

OBJECTIVES: The aims of the study were to assess the effects of breakthrough carcinoid syndrome symptoms on well-being in neuroendocrine tumor (NET) patients insufficiently controlled on long-acting somatostatin analog (SSA) and to assess patient experience with treatment options, physician communication, and disease information sources. METHODS: This study surveyed US NET patients from 2 online communities, experiencing at least one symptom, by utilizing a 64-item questionnaire. RESULTS: One hundred patients participated: 73% female, 75% age 56 to 75 years, and 93% White. Primary tumor distribution was as follows: gastrointestinal NET (n = 55), pancreatic NET (n = 33), lung NET (n = 11), and other NET (n = 13). All patients were actively treated with one long-acting SSA and experiencing breakthrough symptoms: diarrhea, flushing, or other (13% experienced one, 30% two, 57% greater than two). More than one third of treated patients experienced carcinoid-related symptoms daily. Sixty percent of respondents reported not having short-acting "rescue" treatment available, impacting well-being though anxiety or depression (45%), trouble exercising (65%), sleeping (57%), employment (54%), and maintaining friendships (43%). CONCLUSIONS: Breakthrough symptoms remain an unmet need, even in treated patients with NETs. Though still relying on physicians, NET patients are now also using the Internet. Improved awareness of optimal SSA use may improve syndrome control.

PANCREATODUODENECTOMY IN PATIENT WITH VON HIPPEL-LINDAU DISEASE: A LITERATURE REVIEW.

BACKGROUND: The von Hippel-Lindau disease is a highly penetrant autosomal dominant syndrome characterized by tumor predisposition in different organs. AIM: This study aimed to describe a case of a pancreatoduodenectomy for a 30-year-old male patient with von Hippel-Lindau disease. METHODS: We present a case study and the literature review aiming at the state-of-the-art management of a patient with pheochromocytoma, capillary hemangioblastoma in the peripheral retina, and two neuroendocrine tumors in the pancreas. RESULTS: A larger pancreatic lesion was located in the uncinate process, measuring 31 mm. The smaller lesion was located in the proximal pancreas and was detected only on the positron emission tomography-computed tomography scan with DOTATOC-68Ga. Genetic investigation revealed a mutation in the locus NM_000551.3 c.482G>A (p.Arg161Gln) of the Von Hippel-Lindau Human Suppressor gene. The uncinate process tumor was larger than 30 mm and the patient had a mutation on exon 3; therefore, we indicated a pancreatoduodenectomy involving the proximal pancreas to resect both tumors en bloc. During the postoperative period, the patient presented a peripancreatic fluid collection, which was treated as a grade B pancreatic fistula with clinical resolution of the complication. On postoperative day 21, he was discharged home. CONCLUSION: The management of patients with von Hippel-Lindau disease and pancreatic neuroendocrine tumors is complex and must be centered on tertiary institutions with a large volume of pancreatic surgery. Although the current literature assists in decision-making in most situations, each step of the treatment requires analysis and discussion between different medical specialties, including surgeons, clinicians, radiologists, and anesthesiologists.

[Small bowel obstruction caused by lymph nodes of a neuroendocrine tumor. A clinical case report]. / Metástasis ganglionar mesentérica de neoplasia neuroendocrina: una causa infrecuente de obstrucción de intestino delgado.

Small intestine neuroendocrine tumors (NET-SI) are relatively rare neoplasms. If encountered, the most common location is the ileum. Symptoms are usually non-specific, delaying the tumors diagnosis. NET-SI are often small in size and can be challenging to recognize on imaging studies. However, they have a tendency to induce a pronounced fibrotic reaction in the mesentery, often accompanied by large calcified mesenteric adenopathies. In some cases, the fibrotic reaction can produce rare complications, such as intestinal obstruction or vascular congestion with occasional secondary ischemia. This case report presents a 79-year-old male with a partial small bowel obstruction caused by a fibrotic reaction and mesenteric adenopathies of a well-differentiated neuroendocrine tumor of the ileum. The patient also presented multiple peritoneal metastases at diagnosis. Characteristic imaging findings of the tumor, allowed an accurate and early diagnosis. Once the acute episode was resolved, the diagnosis was confirmed with an image guided biopsy.

Primary thymus tumors: retrospective case analysis at a reference center in Latin America, 2011-2019.

BACKGROUND: Thymic tumors are unusual neoplasms, representing 0.2 to 1.5% of tumors in humans, but correspond to 20% of mediastinal tumors and 50% of those that occur in the anterior mediastinum. They tend to appear around the fourth and fifth decades of life without gender predilection. Up to 30% of patients are asymptomatic, therefore many are incidentally diagnosed. Radical thymectomy is the treatment of choice with high survival rates when detected in the early stages. METHODS: This was a retrospective descriptive study, including 18 adult patients' diagnosis of thymic neoplasm, who were managed with surgical resection from 2011 to 2019. Information about demographics, clinical characteristics, imaging findings, surgical and medical management, plus histological findings was obtained and reported. RESULTS: 18 patients with thymic tumors were included, of which specific histologic studies reveled thymomas, carcinomas, neuroendocrine tumors, thymolipoma and thymic cyst. Mean age was 52.7 years, with a predominance of male population. The main symptom was dyspnea, followed by cough and chest pain. Paraneoplastic syndromes such as myasthenia gravis, aplastic anemia and Cushing syndrome were reported. 89% of cases were treated by radical thymectomy alone, while only 2 cases required chemotherapy and radiotherapy. There were no surgical complications. Mean hospital stay length was 11. 9 days, with only 1 mortality during hospital admission. 5-year survival rate was 81%. CONCLUSIONS: The treatment of choice is radical thymectomy, which has been shown to positively impact patient mortality. Early detection is key to improve patient outcomes.

Metástasis ganglionar mesentérica de neoplasia neuroendocrina: una causa infrecuente de obstrucción de intestino delgado / Small bowel obstruction caused by lymph nodes of a neuroendocrine tumor: a clinical case report

Small intestine neuroendocrine tumors (NET-SI) are relatively rare neoplasms. If encountered, the most common location is the ileum. Symptoms are usually non-specific, delaying the tumors diagnosis. NET-SI are often small in size and can be challenging to recognize on imaging studies. However, they have a tendency to induce a pronounced fibrotic reaction in the mesentery, often accompanied by large calcified mesenteric adenopathies. In some cases, the fibrotic reaction can produce rare complications, such as intestinal obstruction or vascular congestion with occasional secondary ischemia. This case report presents a 79-year-old male with a partial small bowel obstruction caused by a fibrotic reaction and mesenteric adenopathies of a well-differentiated neuroendocrine tumor of the ileum. The patient also presented multiple peritoneal metastases at diagnosis. Characteristic imaging findings of the tumor, allowed an accurate and early diagnosis. Once the acute episode was resolved, the diagnosis was confirmed with an image guided biopsy.

Pituitary neuroendocrine tumors and differentiated thyroid cancer: do metabolic and inflammatory risk factors play roles?

PURPOSE: It is postulated that patients with different types of pituitary neuroendocrine tumors (PitNETs) may present a higher incidence of cancer. Factors underlying individuals becoming overweight, such as insulin resistance, hyperleptinemia, and low-grade inflammation, may play a role in the risk of differentiated thyroid carcinoma (DTC) in such patients. This study aimed to investigate the frequency of and obesity-related risk factors associated with DTC in patients with PitNETs. METHODS: This cross-sectional study involved 149 patients with nonacromegalic PitNETs (AG group), 71 patients with acromegaly (ACRO group), and 156 controls (CG group). All participants underwent insulin and blood glucose measurements with the determination of the homeostatic model assessment-insulin resistance (HOMA-IR) index, leptin, and high-sensitivity C-reactive protein (hsCRP), and they also underwent thyroid ultrasound. Clinically significant nodules were biopsied for subsequent cytopathological evaluation, and participants were operated on when indicated. RESULTS: Patients in the AG group had high levels of insulin resistance and significantly higher levels of leptin and hsCRP compared with those of patients in the ACRO group. There were no cases of DTC in the AG group; two findings, one incidental, of DTC occurred in the CG group, and three cases of DTC were present in the ACRO group. Acromegaly was associated with DTC after adjusted analysis. CONCLUSIONS: Our findings in patients with nonacromegalic PitNETs do not indicate a high risk for DTC despite the presence of metabolic and inflammatory risk factors for neoplastic events. In contrast, acromegaly promotes a greater risk of DTC.

Neuroendocrine tumors of the urinary bladder - Report of two cases

Primary paraganglioma and small cell neuroendocrine carcinoma of the urinary bladder are rare tumors, comprising 0.05% of all bladder tumors and <1% of all malignant bladder tumors, respectively. These tumors can be the cause of a diagnostic dilemma or misdiagnosis on morphology. Paraganglioma is often mistaken for urothelial carcinoma and small cell carcinoma for poorly differentiated carcinoma or lymphoma. Herein, we report a case of primary paraganglioma and another of a small cell carcinoma of the urinary bladder and discuss their closest differential diagnoses. The diagnostic pitfalls should be kept in mind so that correct, timely diagnosis of these entities can be made due to implications in the management and prognosis.

Rectal Neuroendocrine Tumor With Inferior Vena Cava Tumor Thrombosis Diagnosed With 68Ga-DOTANOC PET/CT.

A 69-year-old man with a history of back pain, urinary obstruction, and deep vein thrombosis of both lower extremities 4 years earlier was diagnosed with rectal neuroendocrine tumor, grade 2, Ki-67 index 3%. Ga-DOTANOC PET/CT images showed a left pelvic mass extended to the lumen of the inferior vena cava with a high affinity for somatostatin receptor. A tubular focus of radiotracer accumulation after the course of inferior vena cava with filling defect was suggestive of tumor thrombus.

Differential Diagnosis of Diarrhea in Patients With Neuroendocrine Tumors.

Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience diarrhea that can have a debilitating effect on quality of life. Diarrhea also may develop in response to other hormonal syndromes associated with NETs, surgical complications, medical comorbidities, medications, or food sensitivities. Limited guidance on the practical approach to the differential diagnosis of diarrhea in these patients can lead to delays in appropriate treatment. This clinical review and commentary underscore the complexity in identifying the etiology of diarrhea in patients with NETs. Based on our collective experience and expertise, we offer a practical algorithm to guide medical oncologists and other care providers to expedite effective management of diarrhea and related symptoms in patients with NETs.

High Molecular Weight ACTH-Precursor Presence in a Metastatic Pancreatic Neuroendocrine Tumor Causing Severe Ectopic Cushing's Syndrome: A Case Report.

Ectopic ACTH-secretion causing Cushing's syndrome is unusual and its diagnosis is frequently challenging. The presence of high-molecular-weight precursors throughout pro-opiomelanocortin (POMC) translation by these tumors is often not reported. We present the case of a 49-year-old woman with a 3-month history of proximal muscular weakness, skin pigmentation, and weight loss. Upon initial evaluation, she had a full moon face, hirsutism, and a buffalo hump. Laboratory workup showed hyperglycemia, hypokalemia and metabolic alkalosis. ACTH, plasma cortisol, and urinary free cortisol levels were quite elevated. Serum cortisol levels were not suppressed on dexamethasone suppression testing. An octreo-SPECT scan showed enhanced nucleotide uptake in the liver and pancreas. Transendoscopic ultrasound-guided biopsy confirmed the diagnosis of a pancreatic ACTH-secreting neuroendocrine tumor (NET). Surgical excision of both pancreatic and liver lesions was carried out. Western blot analysis of the tumor and metastases revealed the presence of a high-molecular-weight precursor possibly POMC (at 30 kDa) but not ACTH (normally 4.5 kDa). ACTH-precursor secretion is more frequent in ectopic ACTH-secreting tumors compared with other causes of Cushing's syndrome. Hence, the measurement of such ACTH precursors warrants further evaluation, especially in the context of ACTH-dependent hypercortisolism.

Primary Functioning Neuroendocrine Tumor of the Appendix with Hypoglycemia Syndrome: A Case Report and Review of Neuroendocrine Tumors.

INTRODUCTION: Primary neuroendocrine tumors (NETs) of the appendix are uncommon, but when present are usually not hyperfunctioning. This case represents an extraordinarily rare primary hyperfunctioning NET of the appendix with a clinical presentation of symptomatic hypoglycemia in an otherwise healthy man. CASE PRESENTATION: A previously healthy 34-year-old man was found to be symptomatically hypoglycemic in early 2018. After the workup, the apparent explanation was a tumor in his midappendix, for which he was referred to our surgical oncology service for resection. The patient's clinical course is described in detail, including imaging, as well as surgical and pathologic descriptions of the appendiceal NET. DISCUSSION: A literature review demonstrates no other case series or reports of a primary hyperfunctioning NET of the appendix presenting with hypoglycemic crisis. The symptoms of tumor-induced hypoglycemia more typically arise with islet cell tumors, such as pancreatic NETs or insulinomas. We believe this case represents a nonislet cell tumor-induced hypoglycemia. This patient's elevated serum proinsulin level preoperatively implies secretion of proinsulin by the tumor. However, tumor-induced hypoglycemia caused by proinsulin has been described previously only in pancreatic tumors. This unique case adds knowledge to the possible glycemic endocrine effects of nonpancreatic NETs, specifically those that arise primarily in the appendix.

Neuroendocrine tumor associate with inflammatory bowel disease: two cases report.

INTRODUCTION: Patients with inflammatory bowel disease (IBD) have a higher risk of developing gastrointestinal tumors, the adenocarcinoma is the most frequently associated, and neuroendocrine tumor (NET) the most rare. CLINICAL CASES: We present two patients, one with Crohn's disease and the other with ulcerative colitis, who present nonspecific symptoms, and after resection of an intestinal lesion, a gastrointestinal NET (GINET) is diagnosed. DISCUSSION AND CONCLUSION: The GINET have an insidious clinic and these can be confused with those of the IBD. There could be an association between both pathologies; an important role of the chronic intestinal inflammatory process is suggested. The best treatment for GINET is the resection.

INTRODUCCIÓN: Los pacientes con enfermedad inflamatoria intestinal (EII) tienen mayor riesgo de desarrollar neoplasias gastrointestinales y el adenocarcinoma es el relacionado con más frecuencia y el tumor neuroendocrino (TNE) el más raro. CASO CLÍNICO: Se presentan los casos de dos pacientes, uno con enfermedad de Crohn y otro con colitis ulcerosa, que cursan con clínica inespecífica, y tras resección de la lesión intestinal se diagnostica un TNE gastrointestinal (TNEGI). DISCUSIÓN Y CONCLUSIONES: Los TNEGI tienen una clínica insidiosa y pueden confundirse con los de la EII. Es posible un nexo entre ambas entidades, lo que sugiere un papel importante del proceso inflamatorio crónico intestinal. El tratamiento de elección de los TNEGI es la resección.

Use of cinacalcet and sunitinib to treat hypercalcaemia due to a pancreatic neuroendocrine tumor.

Neuroendocrine tumors (NETs) can secrete hormones, including ectopic secretions, but they have been rarely associated with malignant hypercalcemia. A 52-year-old man with a history of diabetes mellitus was diagnosed with a pancreatic tumor. A pancreatic biopsy confirmed a well-differentiated pancreatic NET (pNET). The patient subsequently developed liver metastasis and hypercalcemia with high 1,25 OH vitamin D and suppressed parathyroid hormone (PTH) levels. Hypercalcemia was refractory to chemotherapy, intravenous saline fluids, diuretics, calcitonin and zoledronate. Cinacalcet administration (120 mg/day) resulted in a significant calcium reduction. Hypocalcemia was observed when sunitinib was added three months later and cinacalcet was stopped. Subsequently, the calcium and PTH levels normalized. After six months, we observed 20% shrinkage of the pancreatic tumor and necrosis of a liver metastasis. Cinacalcet is an allosteric activator of the calcium receptor agonist, and it is used for severe hypercalcemia in patients with primary (benign and malignant) hyperparathyroidism. In this patient, cinacalcet demonstrated a calcium lowering effect, normalized hypophosphatemia, and improved the clinical condition of the patient. The mechanism through which cinacalcet improved PTH-rp mediated hypercalcemia is still unclear, but studies have suggested that a potential mechanism is the activation of calcitonin secretion. Sunitinib is an oral multi-targeted tyrosine kinase inhibitor used to treat advanced pNETs. The hypocalcemic effects of sunitinib have not been previously described in a patient with pNET. Here, we report for the first time the successful combination of cinacalcet and sunitinib in the treatment of a pNET patient presenting with malignant hypercalcemia.

Use of cinacalcet and sunitinib to treat hypercalcaemia due to a pancreatic neuroendocrine tumor

SUMMARY Neuroendocrine tumors (NETs) can secrete hormones, including ectopic secretions, but they have been rarely associated with malignant hypercalcemia. A 52-year-old man with a history of diabetes mellitus was diagnosed with a pancreatic tumor. A pancreatic biopsy confirmed a well-differentiated pancreatic NET (pNET). The patient subsequently developed liver metastasis and hypercalcemia with high 1,25 OH vitamin D and suppressed parathyroid hormone (PTH) levels. Hypercalcemia was refractory to chemotherapy, intravenous saline fluids, diuretics, calcitonin and zoledronate. Cinacalcet administration (120 mg/day) resulted in a significant calcium reduction. Hypocalcemia was observed when sunitinib was added three months later and cinacalcet was stopped. Subsequently, the calcium and PTH levels normalized. After six months, we observed 20% shrinkage of the pancreatic tumor and necrosis of a liver metastasis. Cinacalcet is an allosteric activator of the calcium receptor agonist, and it is used for severe hypercalcemia in patients with primary (benign and malignant) hyperparathyroidism. In this patient, cinacalcet demonstrated a calcium lowering effect, normalized hypophosphatemia, and improved the clinical condition of the patient. The mechanism through which cinacalcet improved PTH-rp mediated hypercalcemia is still unclear, but studies have suggested that a potential mechanism is the activation of calcitonin secretion. Sunitinib is an oral multi-targeted tyrosine kinase inhibitor used to treat advanced pNETs. The hypocalcemic effects of sunitinib have not been previously described in a patient with pNET. Here, we report for the first time the successful combination of cinacalcet and sunitinib in the treatment of a pNET patient presenting with malignant hypercalcemia.

[ACTH's ectopic secretion in a patient with precedents of Cushing's disease]. / Secreción ectópica de ACTH en un paciente con antecedentes de enfermedad de Cushing.

A 54-year-old man, with a history of Cushing's disease diagnosed 32 years earlier, presented with edema, asthenia and general malaise. Abnormal laboratory studies depicted hypokalemia and metabolic alkalosis. A CT scan of the chest revealed a 3×3 cm tumor in the anterior mediastinum. The pathology was consistent with a thymic carcinoid. These findings led to a diagnosis of biochemical Cushing's syndrome secondary to ectopic secretion of ACTH. Thus, this patient suffered twice of Cushing's syndrome. The first instance was the consequence of an ACTH--secreting pituitary adenoma and the second of an ectopic secretion of ACTH. To the best of our knowledge this is the first such case reported in the medical literature.

Secreción ectópica de ACTH en un paciente con antecedentes de enfermedad de Cushing / ACTH's ectopic secretion in a patient with precedents of Cushing's disease

Hombre de 54 años con antecedentes de enfermedad de Cushing 32 años antes de la consulta. Ingresó por edemas asociados a astenia y adinamia. En el laboratorio se constató hipopotasemia y alcalosis metabólica. Se realizó diagnóstico humoral de síndrome de Cushing secundario a secreción ectópica de hormona adrenocorticotropa (ACTH). En la tomografía de tórax se halló un tumor de 3 × 3 cm en el mediastino anterior. La anatomía patológica de la pieza quirúrgica fue compatible con un carcinoide tímico. Este paciente sufrió en dos oportunidades un síndrome de Cushing, la primera por enfermedad (adenoma hipofisiario) y la segunda vez por secreción ectópica de ACTH (SEA) una asociación no descripta, en nuestro conocimiento, en la literatura médica.

A 54-year-old man, with a history of Cushing’s disease diagnosed 32 years earlier, presented with edema, asthenia and general malaise. Abnormal laboratory studies depicted hypokalemia and metabolic alkalosis. A CT scan of the chest revealed a 3 × 3 cm tumor in the anterior mediastinum. The pathology was consistent with a thymic carcinoid. These findings led to a diagnosis of biochemical Cushing’s syndrome secondary to ectopic secretion of ACTH. Thus, this patient suffered twice of Cushing’s syndrome. The first instance was the consequence of an ACTH - secreting pituitary adenoma and the second of an ectopic secretion of ACTH. To the best of our knowledge this is the first such case reported in the medical literature.

Síndrome de Cushing secundario a secreción ectópica: un desafío diagnóstico / Cushing syndrome secondary to ectopic: diagnostic challenge

The diagnosis of Cushing Syndrome secondary to Ectopic ACTH secretion constitutes a challenge to the endocrinologist. The goal is to make a differential diagnosis of Cushing’s disease and localize the ACTH-secreting tumor, to achieve quick and effective management of a disease that can be fatal. The mainly diffuculties are the limited data due to their low prevalence and the wide variety of the origin tumors. Therefore, a comprehensive and multidisciplinary study is needed, analyzing each particular case. This article reviews the diagnostic alternatives, their strengths and weaknesses, proposing an algorithm that contributes to our clinical practice...

[Clinicopathologic characteristics of 127 cases of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) studied in an oncology hospital]. / Características clínico-patológicas de 127 casos de neoplasias neuroendocrinas del aparato gastrointestinal y páncreas (NNE-GEP) estudiadas en un hospital de oncología.

BACKGROUND: Neuroendocrine tumors (NETs) present all along the length of the gastrointestinal (GI) tract, from the esophagus to the anus, and they also present in the pancreas. AIMS: To classify NETs according to the WHO 2010 criteria and to evaluate their anatomic distribution and clinicopathologic characteristics. MATERIAL AND METHODS: A search was carried out in the hospital pathology archives of all the cases diagnosed with carcinoid tumor and neuroendocrine carcinoma of the GI tract and pancreas studied over a period of 11 years (1999-2010). The cases were reclassified according to the WHO 2010 criteria. The clinical case records of each patient were reviewed. RESULTS: The study group was made up of 127 cases (68 men; 59 women). Age ranged from 24 to 85 years with a median of 52 years. A total of 113 (89.00%) tumors occurred in the GI tract and 14 (11.00%) in the pancreas. Tumor size varied from 0.4cm to 9cm (median: 2.5cm). GI tumor histologic grades were: 54.00% grade 1; 31.00% grade 2; and 15.00% grade 3. Pancreatic tumor histologic grades were: 43.00% grade 1; 36.00% grade 2; and 21.00% grade 3. Ki-67 overexpression was correlated with tumor grade (22.00% grade 3 vs 2.50% grade 1). CONCLUSIONS: Histologic grade of the gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is one of the most important prognostic factors. The term carcinoid should be eliminated because it does not reflect the biological behavior of these tumors.

Dilatación quística del conducto de wirsung por carcinoma neuroendocrino no funcionante de páncreas / Quística expansion of the conduit of wirsung by nonfuncionante neuroendocrino carcinoma of páncreas

Antecedentes: La dilatación quística del Wirsung frecuentemente se asocia con neoplasia intraductual papilomucinosa tipo 1. Pero este tipo de dilatación también puede asociarse a tumores neuroendocrinos. Objetivos: Presentar una nuevaa forma de dilatación quística del conducto de Wirsung observada en pacientes con tumoes neuroendocrinos no funcionantes de páncreas. Lugar de aplicación: Centro Terciario de Referencia. Diseño: Retrospectivo. Población: Pacientes con tumores neuroendocrinos nu funcionantes de páncreas. Método: Mediante un análsis retrospectivo de una base de datos se estudió la incidencia de la dilatación quística del Wirsung en los tumores neuroendocrinos. Resultados: De 35 pacientes con resecciones pancreáticas por tumores neuroendocrinos no funcionantes, tres presentaron dilatación quística del conducto de Wirsung. Fue observado en los estudios por imágen y corroborado en la cirugía. Conclusiones: La dilatación quística del Wirsung por tumor neuroendocrino es una forma de presentación poco frecuente en estos timores pero que debe ser tenida en cuenta para un tratamiento quirúrgico correcto.