Prevalence, one-year-incidence and predictors of carcinoid heart disease.

BACKGROUND: Carcinoid heart disease (CHD) caused by neuroendocrine tumours (NET) is associated with an increased morbidity and mortality due to valvular dysfunction and right sided heart failure. The present study aimed to assess the prevalence and one-year-incidence of CHD in NET patients. Tumour characteristics, laboratory measurements, and echocardiographic findings were evaluated to identify predictors of CHD manifestation. METHODS: The study was an investigator-initiated, monocentric, prospective trial. Patients with NET without previously diagnosed CHD were included and underwent comprehensive gastroenterological and oncological diagnostics. Echocardiographic examinations were performed at baseline and after one year. RESULTS: Forty-seven NET patients were enrolled into the study, 64% of them showed clinical features of a carcinoid syndrome (CS). Three patients presented with CHD at baseline and three patients developed cardiac involvement during the follow-up period corresponding to a prevalence of 6% at baseline and an incidence of 6.8% within one year. Hydroxyindoleacetic acid (5-HIAA) was identified to predict the occurrence of CHD (OR, 1.004; 95% CI, 1.001-1.006 for increase of 5-HIAA), while chromogranin A (CgA), and Kiel antigen 67 (Ki 67%) had no predictive value. Six patients with CHD at twelve-month follow-up revealed a tendency for larger right heart diameters and increased values of myocardial performance index (MPEI) at baseline compared to NET patients. CONCLUSION: The prevalence at baseline and one-year-incidence of CHD was 6-7%. 5-HIAA was identified as the only marker which predict the development of CHD.

Skin manifestations of neuroendocrine neoplasms: review of the literature.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumours derived from peptidergic neurons and specialized neuroendocrine cells capable of secreting various peptides or amines. These cells may be present in endocrine tissue or diffused in the tissues of the digestive or respiratory system. The article reviews the characteristic features of NENs, with particular emphasis on skin manifestations, such as necrolytic migratory erythema (NME), tongue inflammation, angular cheilitis, venous thrombosis and alopecia in glucagonoma; "flushing", "lion face", pellagra skin symptoms, "scleroderma-like features without Raynaud's phenomenon" in carcinoid tumours. The paper also presents the clinical picture of the neuroendocrine tumour of the skin - Merkel cell carcinoma. The aim of this study was to draw attention to the need for precise and comprehensive diagnosis of the patients, with particular emphasis on skin lesions as a revelator of neuroendocrine tumours. This management allows for the early implementation of appropriate treatment.

Long-term effect of everolimus in recurrent thymic neuroendocrine neoplasia.

PURPOSE: Neuroendocrine neoplasia (NEN) of the thymus is a very rare entity with a poor prognosis. None of the treatments was proofed by studies. Usually, therapy protocols for bronchopulmonary carcinoids are used. So far no data exist on the effect of mammalian target of rapamycin (mTOR) inhibitors. We describe our long-term experience with everolimus and give a thorough review of the therapeutic strategies used so far. PATIENTS AND METHODS: Four patients (mean age 46 years, range 37-55) with progressing thymic NEN (t-NEN) (two well-differentiated atypical carcinoids and two atypical carcinoids with large cell characteristics) were treated with everolimus 10 mg/day after the failure of at least one previous medical therapy. Everolimus was applied after a mean interval of 32.4 months (range 5-56) after the first diagnosis. The follow-up included clinical examination, imaging and chromogranin A testing in 3 or 6 monthly intervals. RESULTS: We observed stable disease for a mean of 20.8 months. Both patients with large cell characteristics t-NEN (Ki-67 of 20%) had rapid progress after 7 and 10 months and had more previous therapies (three and six) than the patients with well-differentiated t-NEN (Ki-67 5% and 10%, progress after 24 and 42 months, one and two previous therapies). No severe side effects occurred. In three of four patients, everolimus led to stable disease for the longest compared to the other nonsurgical therapies used. CONCLUSION: Comparing the sparse data available everolimus is a promising treatment for t-NEN at least in second-line therapy. A low Ki-67 index was associated with a better outcome.

Evaluating cost-effectiveness in the management of neuroendocrine neoplasms.

The rapid evolution of novel, costly therapies for neuroendocrine neoplasia (NEN) warrants formal high-quality cost-effectiveness evaluation. Costs of individual investigations and therapies are high; and examples are presented. We aimed to review the last ten years of standalone health economic evaluations in NEN. Comparing to published standards, EMBASE, Cochrane library, Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database and the Health Technology Assessment (HTA) Database were searched for health economic evaluations (HEEs) in NEN published between 2010 and October 2019. Of 12 economic evaluations, 11 considered exclusively pharmacological treatment (3 studies of SSAs, 7 studies of sunitinib, everolimus and/or 177Lu-DOTATATE and 1 study of telotristat ethyl) and 1 compared surgery with intraarterial therapy. 7 studies of pharmacological treatment had placebo or best supportive care as the only comparator. There remains a paucity of economic evaluations in NEN with the majority industry funded. Most HEEs reviewed did not meet published health economic criteria used to assess quality. Lack of cost data collected from patient populations remains a significant factor in HEEs where clinical expert opinion is still often substituted. Further research utilizing high-quality effectiveness data and rigorous applied health economic analysis is needed.

Neuroendocrine tumour of the ampulla of Vater: A rare neoplasm at an atypical site.

The periampullary neuroendocrine tumour is an infrequently occurring tumour. Its prevalence among gastrointestinal neuroendocrine neoplasms is less than 0.3%, and less than 2% out of periampullary tumours. These neoplasms have relatively poor prognosis. Jaundice and pain in the abdomen are the early and most commonly occurring symptoms with weight loss being a late event. The carcinoid syndrome presents infrequently in periampullary neuroendocrine tumour and happens only if hepatic metastasis occurs. In this scenario, histopathology plays a paramount role in the diagnosis. Specific immunohistochemical staining is used for diagnosis while the treatment options are local excision, endoscopic excision and pancreaticoduodenectomy. Here is a case report of a 42-year-old patient who presented with complaint of obstructive jaundice for one month. Periampullary carcinoid tumour was diagnosed on biopsy, and she underwent Pancreaticoduodenectomy as treatment. Literature shows that there is poor precision of preoperative and intraoperative lymph node metastatic involvement regardless of the size of the tumour. Hence, radical resection must be considered the standard approach.

Elevated prevalence of nodal positivity in carcinoid tumours of the appendix smaller than 2 cm has a negative impact on overall survival.

AIM: The current standard of care for clinically node-negative carcinoid tumours of the appendix < 2.0 cm in size is appendectomy alone. The aim of this analysis was to evaluate the prevalence of pathological nodal positivity in clinically node-negative appendiceal tumour specimens < 2.0 cm and quantify the impact of occult pathological nodal positivity on overall survival following resection. METHOD: A retrospective database review of the 2019 US National Cancer Database for appendiceal cancer identified 2007 cases of clinically node-negative appendiceal carcinoid tumours based on SEER histology codes 8240, 8241, 8242, 8243, 8243, 8244, 8245, 8246 and 8249. Kaplan-Meier with log-rank testing and multivariate Cox regression analysis evaluated the impact of occult nodal positivity on overall survival following resection for clinically node-negative appendiceal carcinoma. RESULTS: The prevalence of occult nodal positivity increased from 1.9% for sub-centimetre tumours to 7% for tumours between 1.0 and 1.5 cm, 16.5% for tumours between 1.5 and 2.0 cm and to >29.5% for tumours > 2.0 cm. Rates of metastatic spread were similar for tumours < 2.0 cm but increased for larger tumours. Over two-thirds of patients received a segmental colectomy as definitive surgical therapy. After controlling for differences in cohorts, multivariate analysis showed an increased hazard ratio for mortality of 162% (HR 2.62, CI 1.884-3.541) for patients with pathological node-positive disease. CONCLUSION: Clinically node-negative carcinoid tumours of the appendix bigger than 1.5 cm have an increased rate of occult nodal spread which has a negative impact on overall survival.

Gastrointestinal and pancreatic neuroendocrine tumours and carcinomas; a review of rare tumour type.

Neuroendocrine tumours are a rare tumour type involving neuroectodermal cells. They are also termed carcinoids. Gastroenteropancreatic system is most commonly involved. They are classified as low, intermediate or high grade depending upon mitotic index and Ki-67 index. Their diagnosis involves measurement of chromogranin A levels. Ultrasound is the initial imaging modality for their evaluation. Endoscopic ultrasound allows close evaluation of the tumour. Staging is commonly undertaken by computed tomography scan. These tumours typically show hyper-enhancement on arterial phase. Their metastasis to the liver also shows arterial enhancement. Small bowel carcinoids tend to have hepatic and mesenteric spread. Mesenteric spread of disease gives a characteristic spoke wheel appearance. On magnetic resonance imaging, these tumours typically appear as hypointense on T1 weighted image, hyperintense on T2 weighted image and show avid enhancement on postcontrast scan. Surgical resection is appropriate treatment with follow-up at 6-month intervals during the first year. The current review was planned to cover the aetiology, diagnosis, staging, imaging techniques, imaging features and treatment of these rare tumours that need prompt diagnosis.

Sleeve resection for bronchial carcinoid tumour in two children under six years old.

BACKGROUND: Paediatric tracheobronchial tumours are very rare, and pneumonectomy and lobectomy procedures are rarely indicated due to their surgical difficulties and high sequelae. Bronchoplastic techniques preserving lung parenchyma allow the resection and reconstruction of the main bronchi and carina. CASE PRESENTATION: Here, we present a 6-year-old boy suffering from a carcinoid tumour of the right main bronchus which was successfully managed with a right upper sleeve lobectomy and a 4-year-old girl with an endobronchial carcinoid tumour narrowing the left main bronchus that received a sleeve resection of that bronchus. CONCLUSION: Bronchoplastic techniques are widely used in adults, can be very successful in paediatric patients where the preservation of the lung parenchyma is more important.

Clinicopathological study of ovarian carcinoid tumours.

OBJECTIVE: To describe the clinical features, treatment, clinical course and survival rates of women diagnosed with ovarian carcinoid tumours. METHODS: A retrospective chart review was performed of all patients diagnosed with primary ovarian carcinoid tumours who were managed by the Queensland Centre for Gynaecological Cancer from 1982 to 2015. RESULTS: Eighteen patients were identified with ovarian carcinoid tumours over the 32 years of the study period. Of the 18 patients, 14 were diagnosed with stage 1 disease, two were diagnosed with stage 3 disease and two were diagnosed with stage 4 disease. Carcinoid syndrome was present in two patients. All patients underwent surgical management. Follow-up strategies varied for early stage disease, but no patient with early stage disease received any adjuvant treatment and no patient developed recurrent disease. Patients with advanced stage disease were treated with cytoreductive surgery and chemotherapy. The five year survival was 100% for stage 1 disease, and 25% for stages 3 and 4 disease. CONCLUSIONS: The vast majority of carcinoid tumours are diagnosed as an incidental finding. Prognosis for early stage disease is excellent, whether conservative or more extensive surgery with staging was performed, and intensive follow up did not influence survival. Optimal treatment for advanced disease remains unknown and requires further study.

'Neuroendocrine' middle ear adenomas: consistent expression of the transcription factor ISL1 further supports their neuroendocrine derivation.

AIMS: Neuroendocrine middle ear adenoma (MEA) is a rare epithelial neoplasm of uncertain histogenesis that frequently shows neuroendocrine features. To date, <120 cases have been reported. The aims of the current study were to describe our experience with neuroendocrine MEA, to assess the frequency of specific neuroendocrine differentiation, and to test these lesions for transcription factors known to be expressed in a variety of other neuroendocrine tumours. METHODS AND RESULTS: We investigated six cases of neuroendocrine MEA, and stained them, for the first time, for the transcription factors CDX2, TTF1, PAX8, and ISL1 (islet-1). The patients were four men and two women (mean age, 39 years; range, 27-53 years). Two of four patients with extended follow-up (4.5-22 years) experienced recurrence at 92 months, and at 9 and 22 years, respectively. One case extending into the external ear coexisted with cholesteatoma. Histological examination showed trabecular, solid, acinar, glandular, cribriform, organoid, nested, diffuse non-cohesive plasmacytoid and pseudoalveolar patterns in varying combinations. Immunohistochemistry showed consistent expression of vimentin (4/4), pancytokeratin (6/6), synaptophysin (6/6), CD56 (4/4), and ISL1 (6/6). A CK7 antibody stained scattered cells in two of five cases. The myoepithelial markers and transcription factors TTF1, CDX2 or PAX8 were not expressed in any of the cases. CONCLUSIONS: Middle ear adenoma is an indolent, locally recurring, but generally non-metastasizing neoplasm with uniform expression of synaptophysin and ISL1, indicating true neuroendocrine differentiation. Because of its highly varied cellular and architectural appearance, MEA should be distinguished from tympanic paraganglioma and a variety of rare benign and malignant lesions at this site.

Huge carcinoid tumour causing complete obstruction of the left main bronchus and destruction of left lung.

Carcinoid tumours arise from the neuroendocrine cells of the bronchial epithelium known as Kulchitsky cells and comprise 4% of all lung malignancies. We report a case of a 16- year-old male who presented with a 1-month history of fever, cough, left-side chest pain and shortness of breath. Chest X -ray showed loss of lung volume on the left side with cystic spaces and air fluid levels. Computed tomography scan chest demonstrated a homogenous mass extending into the left main bronchus causing its complete obstruction along with extensive bronchiectatic changes in the left lung. Bronchoscopy and bronchial biopsy confirmed the diagnosis of typical carcinoid tumour. A pneumonectomy was performed. This case is unusual due to the large size of the tumour, its location and associated destruction of the entire left lung.

Ampullary carcinoid tumour presenting with extrahepatic biliary obstruction.

Carcinoid tumours are slow growing tumours, derived from enterochromaffin cells located in the crypts of Lieberkühn, which is part of neuroendocrine system. A 36-year-old female patient presented in surgical clinic with complaints of progressively increasing yellowish discolouration of her eyes and pruritis for 6 months. She was deeply jaundiced with a soft and non-tender abdomen. Diagnostic work-up revealed obstructive jaundice secondary to ampullary growth, while computed tomography revealed a small intraluminal lower common bile duct mass. Endoscopic ultrasound showed thickened duodenum at ampulla of Vater. Pancreaticoduodenectomy (Whipple's procedure) with pancreaticojejunostomy, hepaticojejunostomy and gastrojejunostomy was done. Pathological examination of the resected specimen revealed carcinoid tumour. Postoperative course of patient was unremarkable and she is doing well after surgery.

Spindle cell thymomas with neuroendocrine morphology: a clinicopathological and immunohistochemical study of 18 cases.

AIMS: To present 18 cases of spindle cell thymoma (WHO type A) with prominent neuroendocrine morphology. METHODS AND RESULTS: The patients were nine men and nine women aged 36-76 years (average: 56 years). Clinically, the patients presented with non-specific symptoms such as chest pain, or were entirely asymptomatic. None of the patients had a history of autoimmune syndrome. Surgical resection was performed in all patients. The tumour size ranged from 30 to 110 mm. Macroscopically, the tumours were described as light brown or tan masses with a homogeneous and solid appearance. Microscopically, all tumours showed areas that closely resembled the typical growth pattern of neuroendocrine tumours, i.e. rosette-like structures or a trabecular, insular or ribbon-like arrangement of tumour cells. Areas of more conventional spindle cell thymoma were present in all cases. Seven cases were encapsulated, and 10 cases were invasive tumours. Immunohistochemically, the tumours were positive for pancytokeratin but negative for synaptophysin and chromogranin A. Follow-up information for 10 patients showed that all patients were alive after a period ranging from 1 month to 6 years. CONCLUSIONS: Familiarity with this particular pattern of thymoma is important in order to separate this tumour from true neuroendocrine carcinoma and prevent unnecessary adjuvant treatment.

A carcinoid tumour arising within a tailgut cyst: a diagnostic challenge.

A 49-year-old man was referred with constipation that had lasted for a few months. On colonoscopy, a subepithelial tumour more than 4 cm in size was seen in the rectum. He underwent endoscopic ultrasound and pelvic magnetic resonance imaging. He was preoperatively diagnosed with a rectal duplication cyst based on imaging studies. However, the final histopathologic diagnosis after transanal excision of the rectal mass was rectal carcinoid tumour with tailgut cyst. Tailgut cysts are very rare congenital lesions in the presacral area and are most often discovered incidentally in middle-aged women. It is difficult to distinguish the imaging appearance of tailgut cysts from that of many other retrorectal cysts. Malignant transformation of tailgut cysts has been estimated to occur in 2 to 13% of cases. We report the diagnostic difficulties encountered in a case of carcinoid tumour arising from a tailgut cyst in a male patient.

Postoperative Surprises: A Carcinoid Tumor Within a Perforated Meckel's Diverticulum.

Meckel's diverticulum, a true diverticulum originating from the incomplete closure of the vitelline duct during embryologic development, rarely presents with carcinoid tumors. The coexistence of a Meckel's diverticulum and carcinoid tumor following laparoscopic sigmoid colectomy for diverticulitis is an uncommon phenomenon, with limited documented cases in the literature. We present a case of a 74-year-old male with a past medical history of hypertension and diverticulitis who underwent a laparoscopic sigmoid colectomy for dysplastic and cancerous changes of a polyp revealed during a screening colonoscopy. Initially, the patient's postoperative journey was uneventful with the resumption of regular bowel movements and favorable diet progression. However, he later presented to the emergency department for worsening abdominal pain and distension. Imaging prompted surgical intervention due to perforation and obstruction, resulting in the identification of a carcinoid tumor within a perforated Meckel's diverticulum. This case highlights the intricate challenges of postoperative complications, particularly the unexpected emergence of Meckel's diverticulum pathology following a colectomy. The atypical presentation, featuring a carcinoid tumor within a perforated Meckel's diverticulum, underscores the importance of evaluating abdominal symptoms postoperatively.

Misdiagnosed case of bronchial carcinoid presenting with refractory dyspnoea and wheeze: a rare case report and review of literature.

A 59-year-old male smoker presented with persistent wheezing and occasional coughing that had been ongoing for two years and had been unsuccessfully treated with an inhalational ß2 agonist, an anticholinergic and an inhalational steroid in the last year. On clinical examination, a left-sided wheeze was detected. The initial chest X-ray was normal. A computed tomography (CT) scan of thorax demonstrated a mass lesion in the left main bronchus. On subsequent bronchoscopy, an endobronchial polypoid mass was detected in the left main bronchus, completely occluding the bronchial lumen. A biopsy taken from the mass revealed features of bronchial carcinoid. Bronchial carcinoid can present uncommonly with wheezes, resulting in misdiagnosis as bronchial asthma or chronic obstructive pulmonary disease (COPD). If an asthma or COPD patient does not respond to conventional therapy, a CT scan and subsequent bronchoscopy is warranted.

Middle Ear Carcinoid Tumour a Diagnostic Dilemma.

Carcinoid tumours are neuroendocrine tumours associated with gastrointestinal tract, lungs and rarely seen in middle ear. A 29 year old male presented with nonspecific symptoms of blocking sensation, reduced hearing and tinnitus in the right ear. Otoscopy showed congestion of right tympanic membrane with bulge in anterior quadrant with no blanching on siegalization. Audiometry showing conductive hearing loss. CT scan showing mildly enhancing mass in the right middle ear cavity. Complete excision was done and Histopathological studied showed features favouring adenoma and immunohistochemistry showed positive staining of Pan Cytokeratin, Synaptophysis and Chromogranin A, with Ki-67 01% suggestive of carcinoid tumour. Patient underwent PET Scaning post operatively to rule out carcinoid tumour elsewhere in the body. Patient is on follow-up every month to look for any recurrence.

Management Strategies and Outcomes for Small Intestinal Neuroendocrine Tumours with Involvement of the Superior Mesenteric Vessels: A Systematic Review.

Small intestinal neuroendocrine tumours (SI-NETs) are the most common small intestinal tumours. A particularly challenging subset of these tumours is those that involve the superior mesenteric artery or vein for which the role and feasibility of surgery are often questioned. This systematic review aimed to identify and evaluate the management strategies used for these complex SI-NETs. The identified studies showed positive outcomes with surgery and multimodality therapy.

A Case of Gastric Glomus Tumor Misdiagnosed as Carcinoid Tumor.

Glomus tumor is a rare mesenchymal tumor commonly located in the periphery of glomus bodies, such as the subungual regions (e.g., fingernails and toenails). Other locations include the forearm, wrist, or trunk. Even rare is when these tumors are found in the submucosa. In the stomach, it is commonly found at the gastric antrum. Gastric glomus tumors (GGTs) are often found incidentally after a presumption of other gastric tumors is diagnosed, such as gastrointestinal stromal tumors (GISTs) or carcinoid tumors. The variable clinical presentation of GGT and the fact that histology is the only way to confirm the diagnosis is what makes GGT such an elusive tumor. Our case is a patient that presented with weight loss and reflux. Esophagogastroduodenoscopy (EGD) and colonoscopy were done, and the diagnosis of carcinoid tumor was presumed. Preliminary pathology was suggestive of a diagnosis of carcinoid tumor. The patient eventually had a subtotal gastrectomy, and a biopsy with immunohistochemical staining of the specimen was received, finally confirming the diagnosis of a GGT.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) Progressing to Carcinoid Tumor: A Case of Chronic Cough.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a rare disease previously overlooked, is gradually being recognized as an important precursor state to pulmonary neuroendocrine tumors. The very insidious onset of symptom presentation makes early diagnosis of DIPNECH almost impossible in clinical settings. In this report, we present a case of persistent and worsening cough for over five years with waxing and waning lung nodules of varying sizes which were eventually diagnosed as DIPNECH on biopsy. However, due to the location and the multiplicity of these nodules, surgical resection was not an option in this case. The diagnostic workup including imaging and biopsy, management options, and possible prognosis of DIPNECH are discussed in detail. This report highlights the growing recognition of DIPNECH as a clinical entity to be aware of during the formulation of a differential diagnosis for patients presenting with chronic unrelenting cough and associated lung nodules.