Academic literature on the topic 'Serotonin-producing neuroendocrine carcinoma'

INTRODUCTION Endogenous Cushing's syndrome is a clinical state resulting from prolonged, inappropriate exposure to excessive endogenous secretion of Cortisol and hence excess circulating free cortisol, characterized by loss of the normal feedback mechanisms of the hypothalamo-pituitary-adrenal axis and the normal circadian rhythm of cortisol secretion [2]. The etiology of Cushing's syndrome may be excessive ACTH secretion from the pituitary gland, ectopic ACTH secretion by nonpituitary tumor, or excessive autonomous secretion of cortisol from a hyperfunctioning adrenal adenoma or carcinoma. Other than this broad ACTH-dependent and ACTH-independent categories, the syndrome may be caused by ectopic CRH secretion, PPNAD, MAH, ectopic action of GIP or catecholamines, and other adrenel-dependent processes associated with adrenocortical hyperfunction. CASE REPORT A 31 year-old men with b-month history of hyperpigmentation, weight gain and proximal myopathy was refereed to Institute of Endocrinology for evaluation of hypercortisolism. At admission, patient had classic cushingoid habit with plethoric face, dermal and muscle atrophy, abdominal strie rubrae and centripetal obesity. The standard laboratory data showed hyperglycaemia and hypokaliemia with high potassium excretion level. The circadian rhythm of cortisol secretion was blunted, with moderately elevated ACTH level, and without cortisol suppression after low-dose and high-dose dexamethason suppression test. Urinary 5HIAA was elevated. Abdominal and sellar region magnetic resonance imaging was negative. CRH stimulation resulted in ACTH increase of 87% of basal, but without significant increase of cortisol level, only 7%. Thoracal CT scan revealed 14 mm mass in right apical pulmonary segment. A wedge resection of anterior segment of right upper lobe was performed. Microscopic evaluation showed tumor tissue consisting of solid areas of uniform, oval cells with eosinophilic cytoplasm and centrally located nuclei. Stromal tissue was scanty, and mitotic figures were infrequent. Tumor cells were immunoreactive for synaptophysin, neuron-specific enolase, and ACTH. The postoperative course was uneventful and the patient was discharged on glucocorticoid supplementation. Signs of Cushing's syndrome were in regression, and patient remained normotensive and normoglycaemic without therapy. DISCUSSION A multitude of normal nonpituitary cells from different organs and tissues have been shown to express the POMC gene from which ACTH is derived. The tumors most commonly associated the ectopic ACTH syndrome arise from neuroendocrine tissues, APUD cells. POMC gene expression in non-pituitary cells differs from that in pituitary cells both qualitatively and quantitatively [8], Aggressive tumors, like small cell cancer of the lung (SCCL) preferentially release intact POMC, whereas carcinoids rather overprocess the precursor, releasing ACTH and smaller peptides like CLIP. Some tumors associated with ectopic ACTH syndrome express other markers of neuroendocrine differentiation like two specific prohormone convertases (PCs). Assessment of vasopressin (V3) receptor gene expression in ACTH-producing nonpituitary tumors revealed bronchial carcinoid as a particular subset of tumors where both V3 receptor and POMC gene may be expressed in pattern indistinguishable from that in corticotroph adenoma [9]. In most, but not all, patients with ectopic ACTH syndrome, cortisol is unresponsive to high-dose dexamethason suppression test, what is used as diagnostic tool. It is not clear if the primary resistance resulted from structural abnormality of the native glucocorticoid receptor (GR), a low level of expression, or some intrinsic property of the cell line [9]. It appears that ectopic ACTH syndrome is made of two different entities. When it is because of highly differentiated tumors, with highest level of pituitary-like POMC mRNA, expressing PCs, high level of V3 receptors and GR, like bronchial carcinoids, it might be called ectopic corticotroph syndrome. In contrast, when it is caused by aggressive, poorly differentiated tumors, with much lower expression of V3 receptor, like SCCL, it might be called aberrant ACTH secretion syndrome. Carcinoid tumors have been reported in a wide range of organs but most commonly involve the lungs, bronchi, and gastrointestinal tract. They arise from neuroendocrine cells and are characterized by positive reactions to markers of neuroendocrine tissue, including neuron specific enolase, synaptophysin, and chromogranina [11]. Carcinoid tumors are typically found to contain numerous membrane-bound neurosecretory granules composed of variety of hormones and biogenic amines. One of the best characterized is serotonin, subsequently metabolized to 5-hydrohy-indolacetic acid (5-HIAA), which is excreted in the urine. In addition to serotonin, carcinoid tumors have been found to secrete ACTH, histamine, dopamine, substance P, neurotensin, prostaglandins and kallikrein. The release of serotonin and other vasoactive substances is thought to cause carcinoid syndrome, which manifestations are episodic flushing, weezing, diarrhea, and eventual right-sided valvular heart disease. These tumors have been classified as either well-differentiated or poorly differentiated neuroendocrine carcinomas. The term ?pulmonary tumorlets" describes multiple microscopic nests of neuroendocrine cells in the lungs [12]. Pulmonary carcinoids make up approximately 2 percents of primary lung tumors. The majority of these tumors are perihilar in location, and patients often presents with recurrent pneumonia, cough, hemoptisis, or chest pain. The carcinoid syndrome occurs in less than 5 percent of cases. Ectopic secretion of ACTH from pulmonary carcinoid accounts for 1 percent of all cases of Cushing's syndrome. They are distinct clinical and pathologic entity, generally peripheral in location. Although they are usually typical by standard histologie criteria, they have mush greater metastatic potential than hormonally quiescent typical carcinoids [13]. Surgical treatment therefore should be one proposed for more aggressive malignant tumors. In all cases of ACTH-dependent Cushing's syndrome with regular pituitary MRI and bilateral inferior petrosal sinus sampling, thin-section and spiral CT scanning of the chest should be routine diagnostic procedure [14], We present thirty-one year old patient with typical pulmonary carcinod with ACTH ectopic secretion consequently confirmed by histology.

Neuroendocrine (NE) or carcinoid tumors of the small intestine (SI) frequently metastasize and produce the hormone serotonin, causing significant morbidity and mortality. A member of the ETS oncogene family of transcription factors, Fev, acts with the homeodomain transcription factor Nkx2.2 in the development of serotonin neurons in mice. In this study, we investigated the role of Fev in normal and neoplastic SI. In NE tumors (NETs) of the SI, serotonin stimulates tumor growth and causes debilitating symptoms, such as diarrhea, flushing, wheezing, and right-sided valvular heart disease (i.e. carcinoid syndrome). Compared with those in the matched normal human SI, FEV expression levels were significantly elevated in primary NETs (20-fold, P<0.0001), lymph node metastases (35-fold, P=0.004), and NET liver metastases (22-fold, P<0.0001) resected from patients with serotonin excess. Fev is expressed in the wild type but not in Nkx2.2 (−/−) mouse SI, in which cells producing serotonin are absent. Using recombination-based cell lineage tracing, we found that FEV-positive cells give rise to serotonin-producing cells in the SI. In Fev (−/−) mouse SI, we observed no difference in the number of cells producing serotonin or other hormones. We conclude that FEV expression identifies serotonin-producing cells in normal and neoplastic SI and is a novel target for diagnosis of patients with NETs of the SI.

Abstract Background: We evaluated the discriminating capacity of the indole markers urinary 5-hydroxyindoleacetic acid (5-HIAA), urinary serotonin, and platelet serotonin in the diagnosis of carcinoid tumors. Methods: Indole markers were measured in 688 patients with suspected carcinoid disease. The initial values of indole markers from patients in whom a carcinoid tumor was confirmed during follow-up (n = 98) were used for ROC analysis. Two groups served as reference populations. The first consisted of 45 healthy individuals (“healthy controls”). The second was a random sample of 40 patients, drawn from the 590 (688 minus 98) patients with carcinoid-like symptoms but without a carcinoid tumor (“clinically suspected patients”). Results: ROC curve analysis showed platelet serotonin to have the highest discriminating capacity, especially in foregut carcinoids. Cutoff values for platelet serotonin obtained from ROC analysis with healthy controls as reference group (5.4 nmol/109 platelets) gave a sensitivity of 74%, specificity of 91%, positive predictive value of 63%, and negative predictive value of 95% when applied to the initial 688 patients. Using the cutoff value with the clinically suspected patients as the reference group (9.3 nmol/109 platelets) gave a sensitivity of 63%, specificity of 99%, positive predictive value of 89%, and negative predictive value of 93%. Indole markers were increased in 169 (25%) of 688 patients. In 76 (45%) of these 169 patients, a carcinoid tumor was present. Slight increases of markers were associated with non-carcinoid neuroendocrine tumors, non-neuroendocrine tumors, and disturbed bowel motility. Conclusions: ROC curve analysis shows that platelet serotonin is the most discriminating indole marker for the diagnosis of carcinoid tumors. Platelet serotonin especially improves the diagnosis of carcinoids producing small amounts of serotonin.

Carcinoid syndrome (CS) develops in patients with hormone-producing neuroendocrine neoplasms (NENs) when hormones reach a significant level in the systemic circulation. The classical symptoms of carcinoid syndrome are flushing, diarrhoea, abdominal pain, and wheezing. Neuroendocrine neoplasms can produce multiple hormones: 5-hydroxytryptamine (serotonin) is the most well-known one, but histamine, catecholamines, and brady/tachykinins are also released. Serotonin overproduction can lead to symptoms and also stimulates fibrosis formation which can result in development of carcinoid syndrome-associated complications such as carcinoid heart disease (CaHD) and mesenteric fibrosis. Transforming growth factor beta (TGF-β) is one of the main factors in developing fibrosis, but platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF2), and connective tissue growth factor (CTGF or CCN2) are also related to fibrosis development. Treatment of CS focuses on reducing serotonin levels with somatostatin analogues (SSA’s). Telotristat ethyl and peptide receptor radionuclide therapy (PRRT) have recently become available for patients with symptoms despite being established on SSA’s. Screening for CaHD is advised, and early intervention prolongs survival. Mesenteric fibrosis is often present and associated with poorer survival, but the role for prophylactic surgery of this is unclear. Depression, anxiety, and cognitive impairment are frequently present symptoms in patients with CS but not always part of their care plan. The role of antidepressants, mainly SSRIs, is debatable, but recent retrospective studies show evidence for safe use in patients with CS. Carcinoid crisis is a life-threatening complication of CS which can appear spontaneously but mostly described during surgery, anaesthesia, chemotherapy, PRRT, and radiological procedures and may be prevented by octreotide administration.

A 27-year-old otherwise healthy man of African descent presented to the hospital with initial symptoms of carcinoid syndrome that later evolved into symptoms of hyperinsulinemic hypoglycaemia. Investigations revealed a metastatic neuroendocrine tumour (NET), co-secreting both serotonin and insulin. Management involved a multimodal approach in an attempt to reduce tumour burden and achieve euglycaemia, which proved to be a significant challenge in the face of refractory hypoglycaemia despite the administration of multiple prohyperglycaemic agents in combination. Unfortunately, given the burden of metastatic disease and multiple medical complications that ensued, the patient passed away. This case highlights the clinical history of a NET co-secreting serotonin and insulin, the use of combination therapy in the treatment of refractory hypoglycaemia in a metastatic insulin-producing tumour and emerging therapeutic modalities in the treatment of these rare malignancies.

Abstract Background: Distant metastasis from Squamous Cell Carcinoma (SCC) of the Vulva is very rare and typically associated with poor outcomes. In the literature, there have been no reported cases of vulvar SCC with metastasis to the thyroid, which augments the uniqueness of the case we are presenting. Clinical Case: A 29-year-old female was hospitalized for abdominal pain & altered mental status. Labs showed calcium 21 (RR 8.5-10.5 mg/dL) with iPTH 4.3 (RR 12-88 pg/mL). Imaging revealed an 8.6 x 7.2 cm right thyroid mass (solid with cystic internal components, hyperechoic to isoechoic, wider than tall, lobulated margins, punctate echogenic foci occupying nearly the entire right lobe, minimal vascularity), mildly effacing the trachea. There were also extensive lesions consistent with systemic metastasis involving the left hilar lymph nodes, pre-tracheal lymph nodes, right hepatic lobe, head of pancreas, retroperitoneal lymph nodes, right inferior pubic ramus, proximal right humerus, left humerus, proximal femur & frontal lobe of the brain. Hypercalcemia of malignancy from an unknown cancer was diagnosed. FNA biopsy of the thyroid mass was consistent with atypia of undetermined significance. Liver biopsy showed evidence of high grade carcinoma with non-calcitonin producing neuroendocrine differentiation. Labs showed serum serotonin 11 (RR 56-244 ng/mL), CA 19-9 &lt; 0.8 (RR 0-35 U/mL), alpha-fetoprotein 2.12 (RR 0-9 ng/mL), CEA 20.97 (RR 0-2.9 ng/mL), PTHrP 33 (RR 14-27 pg/mL), 1,25OH Vit D 18 (RR 18-72 pg/mL), chromogranin A 189 (RR 25-140 pg/mL), & calcitonin &lt; 2 (RR &lt; 5 pg/mL). A vaginal lesion was discovered on exam & biopsy showed squamous cells with cytopathic effect of Herpes Simplex Virus (confirmed with immunohistochemical stain). Subsequent biopsy of the brain & core needle biopsy of the thyroid showed morphology similar to a concurrent biopsy of a vulvar lesion also found on exam: poorly differentiated SCC. The patient was diagnosed with vulvar SCC with extensive metastasis. Her hospital course was complicated by atrial fibrillation, acute respiratory failure, & sepsis. She, unfortunately, passed away from her severe morbidities. Discussion: Metastasis to the thyroid is an infrequent occurrence. It is commonly encountered in breast, lung & renal cell carcinomas. It can occur due to direct spread from adjacent tissues or by lymphatic or hematogenous spread. Thyroid gland metastasis is more commonly seen in patients with aggressive or widespread carcinomas, especially by hematogenous route, due to the thyroid’s extensive vascularity. Conclusion: Thyroid gland metastasis, particularly due to vulvar SCC, is a rare entity with a poor prognosis. In patients with extensive poorly differentiated carcinoma such as our patient, it is of utmost importance to identify suspicious thyroid nodules and perform comprehensive diagnostic testing to facilitate timely intervention for improved outcomes.

Summary Neuroendocrine tumours (NETs) represent a broad spectrum of tumours, of which the serotonin-producing carcinoid is the most common and has been shown to cause right ventricular heart failure. However, an association between heart failure and NETs other than carcinoid has not been established so far. In this case report, we describe a 51-year-old patient with a glucagon-producing NET of the pancreas who developed acute heart failure and even cardiogenic shock despite therapy. Heart failure eventually regressed after initialising i.v. treatment with the somatostatin analogue octreotide. Chromogranin A as a tumour marker was shown to be significantly elevated, and it decreased with clinical improvement of the patient. The effects of long-time stimulation of glucagon on the myocardium have not been studied yet; however, sarcoplasmic reticulum calcium leak can be discussed as a possible mechanism for glucagon-induced heart failure. Learning points Glucagonoma can be a cause for heart failure. i.v. infusion of octreotide can be successfully used to treat glucagonoma-induced acute heart failure. We suggest that cardiac function should be monitored in all NET patients.

Abstract Intro: Carcinoid tumors are rare, slow growing, indolent neuroendocrine tumors typically originating from enterochromaffin in the gastrointestinal tract and bronchopulmonary tree1. While often found to be secreting serotonin, many different secretory products have been described2. We present the case of a patient with refractory hypercalcemia due to a carcinoid tumor producing parathyroid hormone related peptide (PTHrP). Case: A 65-year-old male was found to have hypercalcemia of 14.7 mg/dL after presenting for nausea and vomiting. He was treated with Zolendronic acid and intravenous (IV) fluids as initial work-up revealed an appropriately suppressed parathyroid hormone level, no monoclonal spike, and a PTHrP that was dramatically elevated. He refused further work-up initially but was admitted two months later for persistent severe hypercalcemia. Computed tomography imaging showed innumerable liver lesions. Histologic analysis of the largest liver lesion was consistent with carcinoid tumor. For the next two years, he was managed outpatient with Pamidronate, Denosumab, and Sandostatin, along with two liver embolizations. Control of serum calcium levels became more difficult and he had multiple hospitalizations for symptomatic hypercalcemia until chemotherapy, Sunitinib, was initiated. Calcium levels normalized for one year after starting Sunitinib prior to onset of suspected medication-induced pancreatitis. He was switched to Everolimus but did not respond to that and was readmitted mere weeks later for symptomatic hypercalcemia and a combination of Folinic acid, Fluorouracil, and Oxaliplatin (Folfox) was started. He continued to get frequent bisphosphonates and IV fluids along with Folfox but several months later he stopped responding to all medical options. His calcium level climbed to 19.9mg/dL and he underwent a technically complicated surgical procedure in which significant tumor burden was removed from his liver. Since surgery, the patient has remained normocalcemic without additional medical therapy. Discussion: Carcinoid tumors are uncommon with reported incidence of 40 per one million people2. PTHrP is most commonly produced by squamous cell lung cancer, renal cell cancer, gynecologic cancers, and lymphoma3. Carcinoid tumors producing PTHrP with resultant hypercalcemia is rare with a few cases reported in literature4. Our patient had a complex treatment course including IV fluids, anti-resorptive agents, somatostatin analogs, liver embolization, chemotherapeutic agents, and eventual surgical debulking. Surgical intervention is not commonly required for carcinoid tumors5. This patient had a rare tumor, producing an uncommon hormone, and required extensive treatment. This case shows the importance of a multidisciplinary approach in patients with hypercalcemia secondary to carcinoid tumors but refractory to traditional therapy.