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The management of patients with an explanted malignancy after lung transplantation is not well understood. We reviewed our institutional experience and outcomes at a single academic medical centre between December 1997 and April 2021 for patients with malignancies of all histologic types identified on explant pathology. Primary lung cancers were reclassified using the 8th Edition TNM staging and the 2021 World Health Organization histologic classification of lung cancers. Of the 733 patients undergoing lung transplantation, 15 (2.05%) were found to have malignancy on the explanted lungs, including 6 (0.82%) primary lung cancers. Four patients were found to have early-stage lung cancers, while 2 patients had advanced-stage IV disease. Survival ranged from 0 to 109 months for the entire cohort with median 23.2 [49.9] months in those with primary lung cancers. There were 2 recurrences following explanted stage I (15 months) and stage IV (53 months) diseases. Other explant pathologies included carcinoid tumourlets in 6 patients, lymphoma in 2 and metastatic leiomyosarcoma in 1. In conclusion, explanted lung malignancies are an infrequent but significant finding on explant pathology. Further data are needed to better characterize and stratify this patient cohort., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Pulmonary neuroendocrine tumors (pNETs) include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). The optimal treatment strategy for each subtype remains elusive, partly due to the lack of comprehensive understanding of their molecular features. We aimed to explore differential genomic signatures in pNET subtypes and identify potential prognostic and therapeutic biomarkers., Methods: We investigated genomic profiles of 57 LCNECs, 49 SCLCs, 18 TCs, and 24 ACs by sequencing tumor tissues with a 520-gene panel and explored the associations between genomic features and prognosis., Results: Both LCNEC and SCLC displayed higher mutation rates for TP53, PRKDC, SPTA1, NOTCH1, NOTCH2, and PTPRD than TC and AC. Small cell lung carcinoma harbored more frequent co-alterations in TP53-RB1, alterations in PIK3CA and SOX2, and mutations in HIF-1, VEGF and Notch pathways. Large cell neuroendocrine carcinoma (12.7 mutations/Mb) and SCLC (11.9 mutations/Mb) showed higher tumor mutational burdens than TC (2.4 mutations/Mb) and AC (7.1 mutations/Mb). 26.3% of LCNECs and 20.8% of ACs harbored alterations in classical non-small cell lung cancer driver genes. The presence of alterations in the homologous recombination pathway predicted longer progression-free survival in advanced LCNEC patients with systemic therapy (P = .005) and longer overall survival (OS) in SCLC patients with resection (P = .011). The presence of alterations in VEGF (P = .048) and estrogen (P = .018) signaling pathways both correlated with better OS in patients with resected SCLC., Conclusion: We performed a comprehensive genomic investigation on 4 pNET subtypes in the Chinese population. Our data revealed distinctive genomic signatures in subtypes and provided new insights into the prognostic and therapeutic stratification of pNETs., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Using data from four tertiary referral centers in the U.S., we assessed real-world treatment patterns and clinical outcomes of patients with advanced lung neuroendocrine tumors (NETs)., Subjects, Materials, and Methods: We performed a retrospective chart review of adult patients with locally advanced/metastatic (typical/atypical) lung NETs treated between July 2011 and December 2014. Index date was histologically confirmed typical/atypical carcinoid tumor diagnosis date. Data included baseline characteristics, treatment patterns, progression, death, and lung NET-related health care resource use from index date through last contact/death. Time to treatment discontinuation and first progression, time from first to second progression, and overall survival (OS) were estimated using Kaplan-Meier analysis., Results: We identified 83 patients; 19 (23%) had functional NET. First-line treatments included somatostatin analogs (SSAs) alone (56%) or in combination with other therapies (6%), cytotoxic chemotherapy (20%), external beam radiation therapy (EBRT) (9%), liver-directed therapy (LDT) (4%), and everolimus/other (5%). Sixty patients had second-line therapy including SSA alone (18%) or in combination (40%), cytotoxic chemotherapy (17%), everolimus (12%), LDT (7%), EBRT (3%), and other treatments (3%). Median time (months) to first-line discontinuation were as follows: SSAs, 43.3; cytotoxic chemotherapy, 3.6. Overall median time (months) to investigator-assessed progression following treatment initiation was 12.4. Median OS (months) following treatment initiation was 66.4 for all patients and 81.5 for patients receiving SSAs., Conclusion: SSAs, alone and in combination, are common treatments for advanced lung NETs. Patients have additional treatment options and relatively long survival compared with patients with other advanced cancers. Treatment pattern assessment following approval of newer treatments is needed., Implications for Practice: Somatostatin analogs (SSAs), cytotoxic chemotherapy, EBRT, liver-directed therapy, and targeted therapies are common treatments for locally advanced/metastatic (typical/atypical) lung neuroendocrine tumors (NETs). SSAs alone or in combination with other treatment modalities were the most common first- and second-line therapy, followed by cytotoxic chemotherapy. Patients continued treatment with SSAs long-term with median treatment duration of 43 months. Median overall survival was 66 months following initiation of first-line therapy for all patients. Treatment pattern assessment beyond the time period of this study is needed given recent U.S. Food and Drug Administration approvals for additional treatments for lung NETs that will likely be incorporated in the treatment landscape., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Context: Cabergoline has been shown to have some effect in the treatment of moderate Cushing's disease, but its effectiveness in Cushing's syndrome of ectopic or occult origin remains to be investigated., Case Series: In this case series, cabergoline was used in combination with steroidogenesis inhibitors in nine patients with severe Cushing's syndrome of ectopic or occult origin. Cabergoline's effectiveness enabled rapid withdrawal of the steroidogenesis inhibitors and long-term control of the hypercortisolism in three of the cases., Review of the Literature: In the literature, we found only 11 cases of ectopic or occult Cushing's syndrome treated with dopamine receptor agonists, alone or in combination. Yet of these 11 cases, 10 responded., Conclusions: Although limited, the existing experience highlights the potential value of cabergoline in the treatment of ectopic or occult Cushing's syndrome.

Background: Thymic atypical carcinoid (TAC) is a rare thymic neuroendocrine tumor that originates in the neuroendocrine system and lacks a standardized treatment. The combination of capecitabine (CAP) and temozolomide (TEM) is associated with an extremely high and long-lasting response rate in patients with metastatic pancreatic neuroendocrine tumors. However, there is little evidence showing that the CAPTEM regimen is effective for TAC. For patients with unresectable or metastatic atypical carcinoid of the thymus, few treatment options are available, and the treatment efficacy is not satisfactory. To explore the efficacy and safety of the CAPTEM regimen against TAC, we conducted a retrospective review., Patients and Methods: A total of nine patients with advanced atypical carcinoid of the thymus in the China-Japan Friendship Hospital were treated with capecitabine (750 mg/m 2 twice daily, days 1-14) and temozolomide (200 mg/m 2 once daily, days 10-14) every 28 days between 2014 and 2018. The disease control rate (DCR), progression-free survival (PFS), and adverse effects after treatment were analyzed. The DCR was calculated by RECIST version 1.1. Progression-free survival was calculated by the Kaplan-Meier survival method., Results: A total of nine patients (six male and three female) were included. The median age at CAPTEM initiation was 50 years (range, 26-58). The median number of CAPTEM cycles was 8 (range, 3-23). The DCR was 89% (8/9), with eight patients achieving stable disease. Only one patient (11%) showed progressive disease. The median PFS was 8 months. Because we applied vitamin B6 and ondansetron before administering the drugs, the side effects of this regimen were very small. Adverse reactions were all below grade 3 and included myelosuppression and digestive tract reaction., Conclusion: Our results suggest that the CAPTEM regimen may be effective and well tolerated for the treatment of TAC. More evidence is needed to validate the effectiveness of this regimen., Implications for Practice: Capecitabine and temozolomide regimen is effective and well tolerated in patients with advanced thymic atypical carcinoid., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Context: Pulmonary carcinoids (PCs) belong to neuroendocrine tumors that often overexpress somatostatin receptors (SSTRs). This overexpression provides a molecular basis for tumor imaging and treatment with somatostatin analogs., Objective: To evaluate SSTR1 to SSTR5 distribution in a large set of PC tumors and to investigate whether the expression is associated with clinicopathological and outcome data., Design, Setting, and Patients: This retrospective study was conducted at Helsinki University Hospital and University of Helsinki. It included 178 PC tumors coupled with patients' clinical data retrieved through Finnish biobanks. After histological reclassification, tissue specimens were processed into next-generation tissue microarray format and stained immunohistochemically with monoclonal SSTR1 to SSTR5 antibodies., Main Outcome Measure: SSTR1 to SSTR5 expression in PC tumors., Results: Expression of SSTR1 to SSTR5 was detected in 52%, 75%, 56%, 16%, and 32% of the tumors, respectively. Membrane-bound staining was observed for all receptors. SSTR2 negativity and SSTR4 positivity was associated with lymph node involvement at the time of surgery (P = 0.014 and P = 0.017, respectively) and with distant metastasis (P = 0.027 and P = 0.015, respectively). SSTR3 and SSTR4 expression was associated with increased risk of shorter survival [P = 0.046, hazard ratio (HR) 4.703, 95% CI 1.027 to 21.533; and P = 0.013, HR 6.64, 95% CI 1.48 to 29.64, respectively], whereas expression of SSTR1 and SSTR2 was associated with improved outcome (P = 0.021, HR 0.167, 95% CI 0.037 to 0.765; and P = 0.022, HR 0.08, 95% CI 0.01 to 0.70, respectively)., Conclusion: SSTR1 to SSTR5 expression is observed in PCs. As SSTR expression is associated with the tumor's metastatic potential and patient outcome, these receptors may offer the possibility for individualized prognosis estimation., (Copyright © 2019 Endocrine Society.)

Pulmonary carcinoid tumours are well-differentiated neuroendocrine tumours with indolent behaviour; complete resection offers long-term survival. When centrally located, these tumours can be treated with lung-sparing procedures. We present a case of a centrally located typical carcinoid tumour treated with a minimally invasive, right upper lobe sleeve lobectomy using a single port., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: In 2012, the European Society of Thoracic Surgeons (ESTS) created the Lung Neuroendocrine Tumors Working Group (NETs-WG) with the aim to develop scientific knowledge on clinical management of such rare neoplasms. This paper outlines the outcome and prognostic factors of two aggressive NETs: atypical carcinoids (ACs) and large-cell neuroendocrine carcinomas (LCNCs)., Methods: Using the ESTS NETs-WG database, we retrospectively collected data on 261 patients in seven institutions in Europe, between 1994 and 2011. We used a Cox regression model to evaluate variables affecting patient survival and disease-free survival. Univariate and multivariate analysis were also carried out., Results: Five-year overall survival rates for ACs and LCNCs were 77 vs 28% (P < 0.001), respectively. We found that for ACs, age (P < 0.001), tumour size (P = 0.015) and sub-lobar surgical resection (P = 0.005) were independent negative prognostic factors; for LCNCs, only pTNM stage III tumours (P = 0.016) negatively affected outcome in the multivariate analysis. Local recurrences and distant metastases developed in 93 patients and were statistically more frequent in LCNCs (P = 0.02)., Conclusions: The biological aggressiveness of ACs and LCNCs has been demonstrated with this study. Our aim is to confirm these results with enhanced data collection through the ESTS NETs database., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs., (©AlphaMed Press.)

Thymic carcinoid tumour associated with pulmonary squamous cell carcinoma is very rare. We present a case of synchronous lung cancer and mediastinal tumour treated with simultaneous video-assisted thoracoscopic surgery (VATS) sleeve lobectomy and thymectomy. A 67-year old man presented with cough and bloody sputum. Chest computed tomography showed an anterior mediastinal mass with a right hilar nodule. A right upper sleeve lobectomy and a thymectomy were performed via a VATS approach. Thymic carcinoid tumour associated with pulmonary squamous cell carcinoma was diagnosed, and the patient received adjuvant radiochemotherapy., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Context: Carcinoids have rarely been described in von Hippel-Lindau (VHL) disease., Objective: We describe the first reported case of a patient with VHL who developed a pulmonary carcinoid that subsequently metastasized to a pre-existent cranial hemangioblastoma., Results: Histological and immunohistochemical features of the metastatic lesion were similar to the primary carcinoid. Both lesions demonstrated heterozygous VHL gene deletions with fluorescence in situ hybridization analysis., Conclusions: This case provides direct molecular genetic evidence of an association between VHL and carcinoids.

Background: Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2., Methods: Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer., Results: A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes., Conclusions: Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies., (© 2014 The American Association for Clinical Chemistry.)

Endobronchial tumours requiring sleeve resection have been usually considered a contraindication for video-assisted thoracoscopic surgery (VATS). However, with new technical advances and the experience gained in VATS, sleeve lobectomy has been performed by thoracoscopy in experienced VATS centres. Right-sided sleeve anastomoses are easier to perform by VATS than left-sided ones because of the presence of the pulmonary artery and aortic arch on the left side. Most surgeons use a 3 to 4 incision VATS technique for sleeve anastomosis but the surgery can be performed by using only one incision. This is the first report of a left-sided sleeve lobectomy by uniportal approach.

Context: MEN1 gene alterations have been implicated in lung carcinoids, but their effect on gene expression and disease outcome is unknown., Objective: Our objective was to analyze MEN1 gene and expression anomalies in lung neuroendocrine neoplasms and their correlations with clinicopathologic data and disease outcome., Design: We examined 74 lung neuroendocrine neoplasms including 58 carcinoids and 16 high-grade neuroendocrine carcinomas (HGNECs) for MEN1 mutations (n = 70) and allelic losses (n = 69), promoter hypermethylation (n = 65), and mRNA (n = 74) expression. Results were correlated with disease outcome., Results: MEN1 mutations were found in 7 of 55 (13%) carcinoids and in 1 HGNEC, mostly associated with loss of the second allele. MEN1 decreased expression levels correlated with the presence of mutations (P = .0060) and was also lower in HGNECs than carcinoids (P = .0024). MEN1 methylation was not associated with mRNA expression levels. Patients with carcinoids harboring MEN1 mutation and loss had shorter overall survival (P = .039 and P = .035, respectively) and low MEN1 mRNA levels correlated with distant metastasis (P = .00010) and shorter survival (P = .0071). In multivariate analysis, stage and MEN1 allelic loss were independent predictors of prognosis., Conclusion: Thirteen percent of pulmonary carcinoids harbor MEN1 mutation associated with reduced mRNA expression and poor prognosis. Also in mutation-negative tumors, low MEN1 gene expression correlates with an adverse disease outcome. Hypermethylation was excluded as the underlying mechanism.

Objectives: Bronchopulmonary carcinoid tumours are relatively uncommon primary lung neoplasms. A small proportion of these lesions are predominantly endobronchial and do not extend beyond the bronchial wall. Endoscopic resection can be performed, but carries around a one in three risk of local recurrence and, therefore, mandates long-term surveillance. An alternative is complete surgical resection via bronchoplastic resection. We present our experience of surgical resection in patients with endobronchial carcinoids., Methods: From 2000 to 2010, 13 patients (age 45±16 years, 10 males) underwent pure bronchoplastic resection, including systematic nodal dissection, for endobronchial carcinoid tumours, without the resection of lung parenchyma., Results: There was no significant operative morbidity or mortality. This is a retrospective review of a consecutive case series. The last follow-up for all patients was obtained in 2011. The mean maximum tumour size was 18±8 mm. No lymph node invasion was observed. The median follow-up was 6.3±3.3 years, with no regional recurrence. In 1 case, a tumourlet was identified at 5 years in the contralateral airway and viewed as a metachronous new lesion., Conclusions: Bronchial sleeve resection is a safe procedure for suitably located endobronchial carcinoid tumours. Endoscopic resection should be reserved for patients who decline, or are unfit, for surgery.

We report the case of a 35-year old woman with a giant thymic carcinoid of the left hemithorax. Enhanced computed tomography showed marked vascularization of the tumour, with an enlarged drainage vein. Endovascular embolization of the major feeding arteries of the tumour was performed preoperatively with good angiographic results. A left thoracotomy was performed the following day. Minimal bleeding was observed due to prior embolization. The patient made a rapid postoperative recovery and was discharged 8 days later.

Objectives: To analyse statistical aspects of mortality, morbidity and survival after bilobectomy (BT), an operation rarely studied in the literature., Methods: One hundred and ten cases were studied, comprising 58 upper-middle bilobectomies and 52 lower-middle bilobectomies performed between 1999 and 2010. Indications were of 9 benign diseases, 12 carcinoid tumours, 5 metastases and 84 non-small cell lung cancers (2 stage 0; 34 stage I; 22 stage II; 25 stage III and 1 stage IV)., Results: Mortality was nil. Twenty-six percent of patients experienced significant morbidity, influenced in multivariate analysis by the presence of three or more comorbidities (P = 0.03) and by a forced expiratory volume in 1 s of <60% (P = 0.01). Lower-middle BT was associated with more postoperative complications than upper-middle BT (P = 0.012). The 5-year survival rate of patients with non-small cell lung carcinoma was 82% in stage I, 59% in stage II and 20% in stage IIIA. Survival was significantly influenced by stage (P = 0.0018) and tobacco weaning (P = 0.0012)., Conclusions: BT can be achieved with low mortality, and survival results that are comparable with those unregistered after standard lobectomy. However, almost one quarter of patients experienced significant postoperative complications. Surgical techniques aiming to reduce residual pleural space should be especially considered after lower-middle BT, due to the highest morbidity being associated with this procedure.

Objective: To study the clinical presentation, diagnostic approach, response to treatment, and the presence of other pathologies in patients with gastric carcinoid type 1 (GC 1) tumors., Design and Methods: Retrospective analysis of 111 patients from four institutions and a mean follow-up of 76 months., Results: The main indications for gastroscopy were upper gastrointestinal tract symptoms. The mean number of lesions, maximum tumoral diameter, and percentage of cells expressing Ki-67 labeling index were 3.6±3.8, 8±12.1 mm and 1.9±2.4% respectively. Serum gastrin and chromogranin A (CgA) levels were elevated in 100/101 and 85/90 patients respectively. Conventional imaging studies demonstrated pathology in 9/111 patients. Scintigraphy with radiolabeled octreotide was positive in 6/60 without revealing any additional lesions. From the 59 patients who had been followed-up without any intervention, five developed tumor progression. Thirty-two patients were treated with long-acting somatostatin analogs (SSAs), leading to a significant reduction of gastrin and CgA levels, number of visible tumors, and CgA immune-reactive tumor cells in 28, 19, 27, and 23 treated patients respectively. Antrectomy and/or gastrectomy were initially performed in 20 patients and a complete response was achieved in 13 patients. The most common comorbidities were vitamin B12 deficiency, thyroiditis, and parathyroid adenomas., Conclusions: Most GCs1 are grade 1 (82.7%) tumors presenting with stage I (73.9%) disease with no mortality after prolonged follow-up. Ocreoscan did not provide further information compared with conventional imaging techniques. Treatment with SSAs proved to be effective for the duration of administration.

Carcinoid tumors located in the minor duodenal papilla are extremely rare, with only a few cases reported in the literature. Herein, we report the case of a 71-year-old man with a 12-mm carcinoid tumor at the minor duodenal papilla with lymph node metastases. Multidetector-row computed tomography with contrast enhancement revealed a 12-mm well-enhanced tumor in the duodenum. Upper gastrointestinal endoscopy showed a 12-mm submucosal tumor at the minor papilla of the duodenum. Biopsy specimens revealed a carcinoid tumor, and a subtotal stomach-preserving pancreatoduodenectomy was performed. Carcinoid tumors at the minor duodenal papilla have a high prevalence of nodal disease, even for tumors <2 cm in diameter. Therefore, we believe that radical resection with tumor-free margins (i.e. pancreatoduodenectomy) is the treatment of choice.

Objectives: Positron emission tomography using [(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG-PET) plays an important role in many oncological settings. In this study, we assessed the utility of (18)F-FDG PET-CT for predicting the histologic type and stage of thymic epithelial tumours., Methods: We retrospectively analyzed 58 patients with thymic epithelial tumours who underwent PET-CT before treatment and investigated the relationship between the histologic type based on the World Health Organization classification and the maximum standardized uptake value (SUV(max)) of each tumour. We also analyzed the relationship between the Masaoka tumour stage and the SUV(max)., Results: The study included 31 males and 27 females, ranging in age from 25 to 80 years (median: 62 years). The tumour histology of 44 tumours was thymoma and that of the remaining tumours was thymic carcinoma, including 11 squamous cell carcinomas and 3 carcinoids. The Masaoka tumour stage was as follows: Stage I in 8, Stage II in 24, Stage III in 18 and Stage IV in 8 patients. The patients were divided into three groups according to a simplified histologic classification: low-risk thymomas (types A, AB and B1, n = 23), high-risk thymomas (types B2 and B3, n = 21) and thymic carcinomas (n = 14). The SUV(max) of the thymic carcinoma group was significantly higher than those of the low-risk thymoma and high-risk thymoma groups (P < 0.001, respectively). No significant differences between the low-risk thymoma and high-risk thymoma groups were observed (P = 0.204). The SUV(max) of Stages III and IV thymomas showed a higher trend toward Stages I and II thymomas (P = 0.060)., Conclusions: PET-CT is a useful modality for predicting the histologic type and tumour stage of thymic epithelial tumours.

Objectives: The hypothesis that asbestos exposure may have more specific associations with particular histological types of lung cancer remains controversial. The aim of this study was to analyze the relationships between asbestos exposure and pulmonary carcinoid tumors., Methods: A retrospective case-control study was conducted in 28 cases undergoing surgery for pulmonary carcinoid tumors and aged >40 years and in 56 controls with lung cancer of a different histological type, matched for gender and age, from 1994 to 1999, recruited in two hospitals in the region of Paris. Asbestos exposure was assessed via expertise of a standardized occupational questionnaire and mineralogical analysis of lung tissue, with quantification of asbestos bodies (AB)., Results: Definite asbestos exposure was identified in 25% of cases and 14% of controls (ns). Cumulative asbestos exposure was significantly higher in cases than in controls (P < 0.05), and results of the quantification of AB tended to be higher in cases than in controls (24 and 9% had >1000 AB per gram dry lung tissue, respectively, P = 0.09). Mean cumulative smoking was lower in cases than in controls (P < 0.05)., Conclusions: This study argues in favor of a relationship between asbestos exposure and certain pulmonary carcinoid tumors.

Small bowel neoplasms, including adenocarcinoma, carcinoid tumour, lymphoma and gastrointestinal stromal tumours, represent a small percentage of gastrointestinal cancers, yet are among those with the poorest prognosis compared with other gastrointestinal malignancies. Unclear clinical scenarios and difficult radiological diagnosis often delay treatment with negative effects on patient survival. Recently, multidetector CT (MDCT) and MRI have been introduced as feasible and accurate diagnostic techniques for the identification and staging of small bowel neoplasms. These techniques are gradually replacing conventional barium radiography as the tool of choice. However, the inherent technical and physiological challenges of small bowel imaging require a familiarity with patient preparation and scan protocols. Adequate knowledge of the histopathology and natural evolution of small bowel neoplasms is also important for differential diagnosis. The aim of this article is to review MDCT and MRI protocols for the evaluation of small bowel tumours and to provide a concise yet comprehensive guide to the most relevant imaging features relative to histopathology.

Merkel cell carcinoma (MCC) is an uncommon tumor with indistinct clinical features. The differential diagnosis includes small cell lung carcinoma (SCLC). We characterized the expression of terminal deoxynucleotidyl transferase (TdT) and a panel of immunohistochemical markers in 40 MCC, 30 SCLC, and 6 pulmonary carcinoid tumor (PCT) cases. We used antibodies against TdT, thyroid transcription factor (TTF)-1, cytokeratins (CKs) 7 and 20, chromogranin, and synaptophysin. Immunostaining was recorded semiquantitatively. Of 40 MCC cases, 28 (70%) were positive for TdT, showing, on average, more than 25% of tumor cells reactive with moderate nuclear staining intensity. TTF-1 (1 [3%]), CK7 (2 [5%]), CK20 (35 [88%]), chromogranin (29 [73%]), and synaptophysin (39 [98%]) were expressed in the MCCs. Of the 5 CK20- MCC cases, 4 were positive for TdT. SCLC showed expression of TTF-1 (23/30 [77%]), CK7 (22/30 [73%]), chromogranin (16/30 [53%]), and synaptophysin (22 [73%]) and no CK20 (0%) expression. Of 30 SCLC cases, 2 (7%) were positive for TdT. TdT may be beneficial in rare cases of CK20- MCC and may assist in distinguishing between MCC and SCLC. There is significant immunohistochemical variability and overlap between these 2 tumors.

Objective: Primary major airway tumors are rare. A retrospective analysis of referral centers experience could be helpful for their management., Methods: Fifty-one patients, including 44 (86%) malignant and seven (14%) benign with primary tumors of subglottis, trachea, carina, and main stem bronchi, were managed in a 14-year period. Based on computed tomography (CT) scan and rigid bronchoscopy findings, those who evaluated as resectable underwent airway resection and reconstruction. The others were managed by one or a combination of these methods: core out, laser, chemotherapy, radiotherapy, and tracheostomy. Follow-up was completed in 88.2%, mean (35.2 ± 33.2 months)., Results: Extraluminal extension of the tumor found in CT scan was significantly associated with unresectability (p = 0.006). Thirty-two patients underwent resection with three complications (9%) and one mortality (3%). Nineteen were managed by non-resectional methods; of these, 15 were found unresectable, because of tumor length, extensive local invasion or diffuse distant metastases, and four due to risk-benefit ratio or patient preference. Among 18 patients with adenoid cystic carcinoma 13 (72%) were resected (seven with negative margins). Overall 1-, 2-, 5-, and 8-year survival was 90.9%, 90.9%, 77.9%, and 19.5%, respectively. In unresectable tumors with adenoid cystic carcinoma, overall 1- and 2-year survival was 60% and 40%, respectively. Data analysis found significant association of long-term survival with resection (p = 0.005) but not with negative margins in adenoid cystic carcinoma. Among 15 patients with carcinoid tumors, all were alive at the end of follow-up, except one who died after surgery., Conclusions: Airway resection, if feasible, may extend survival and may even be curative, with low morbidity and mortality, in most patients with major airway tumors., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: Few published reports have examined the incidence and outcomes for patients with carcinoid lung tumors. The aim of the current study was to explore incidence, type of surgical treatment given, and outcome for patients with typical (TC) and atypical (AC) lung carcinoids in a national cohort (Norway)., Methods: All lung-cancer patients diagnosed in the period 1993-2005 and who were reported to the Cancer Registry of Norway were identified. Biopsies or resection specimens were reviewed and reclassified according to the World Health Organization (WHO) 2004 classification. Surgically treated patients were staged according to the seventh edition of the pathological tumor-node-metastasis (pTNM) staging system., Results: Of 26665 lung cancers registered during the period, 265 (1%) had carcinoid tumors, of which 11 were diagnosed coincidentally at autopsy. In the remaining 254 patients, TCs were found in 188 cases, and ACs were found in 59 cases; seven cases had unclassifiable carcinoids. Of the 217 resected tumors, 173 (80%) were TCs. General surgeons performed 94 resections, including 11 of 17 pneumonectomies. All six bronchial resections were performed by thoracic surgeons. Of the 33 operated patients who died during follow-up, 18 had metastatic carcinoid tumors, of which 10 (56%) were ACs. In 37 non-resected patients (15 with AC and seven with unclassifiable histology), metastatic or locally advanced disease (N=21, 12 of which were ACs) was the main cause of inoperability and death. Five-year survival for all patients was 92% for TC and 66% for AC; for resected patients, the survival rates were 96% and 79%, respectively., Conclusions: Carcinoids are rare malignant tumors and are, in most cases, resectable; the TC subgroup had better prognosis than the AC in univariate analyses. The main cause of death was metastasis/locally advanced tumor at presentation or recurrent disease following resection; both situations were three times more common in patients with AC., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: Pulmonary carcinoid tumors are rare low-grade malignant neoplasms and constitute 2-5% of all lung tumors. In this study, we aimed to determine the clinical presentations, types of surgery, long-term treatment outcomes and survival rates of patients diagnosed with carcinoid tumor treated surgically in our clinic., Methods: Patients operated in our clinic between 1992 and 2008 with confirmed or suspected diagnoses of carcinoid tumors were included in our study. Patients' hospital records were retrospectively analyzed., Results: A total of 104 patients (age 19-71 years, mean 44±13 years, 2 SD) with pathologically confirmed carcinoid tumor were analyzed. A total of 84 patients (81%) were diagnosed as typical and the remaining 20 (19%) being atypical carcinoid tumor. As many as 24 patients (23%) were asymptomatic. The most frequent symptom was recurrent respiratory infection (35%). The most used surgical procedures were lobectomy (47%) and bilobectomy (16%). Mean postoperative follow-up period was 72 months (6-190 months). No surgery related mortality was noticed. As many as 15 (14%) patients died during the follow-up period. Overall 5- and 10-year survival rates were 89% and 72%, respectively. For typical carcinoid tumors, the 5- and 10-year survival rates were 92% and 83%, and for atypical carcinoids 73% and 46%, respectively (p<0.001)., Conclusions: In our study, we noticed histological subtype, stage of the disease and the type of surgery performed to be prognostic factors of carcinoid tumors. Atypical carcinoid tumors tend to be more metastatic and had worse prognosis when compared with typical carcinoid tumors. We conclude that surgery is the best treatment of choice for carcinoid tumors, especially parenchyma-sparing procedures, because of their good mid- and long-term survival rates., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

We report a case of combined typical carcinoid and acinic cell tumor of the lung in a 55-year-old female. A chest radiograph revealed an abnormal shadow. Computed tomography (CT) showed a tumor in the S3 segment of the right lung. The transbronchial biopsy yielded a diagnosis of non-small-cell lung cancer. Radical surgery was performed. The pathological diagnosis was combined typical carcinoid and acinic cell tumor of the right lung. This is third case of this tumor which has been reported.

We present the case of a 73-year-old woman who presented with clinical features of Cushing's syndrome, confirmed biochemically with elevated levels of cortisol and adrenocorticotrophic hormone (ACTH). Petrosal venous sampling showed no ACTH gradient and MRI of pituitary was normal, suggesting ectopic ACTH production. In the course of further investigations, a thoracic CT was carried out to look for evidence of bronchial neoplasm. Although there was no discrete tumour identified, CT revealed widespread fine nodularity in the right middle and lower lobe. Subsequent trans-bronchial and video-assisted thorascopic biopsy showed pulmonary tumourlets and two typical carcinoid tumours on a background of diffuse idiopathic pulmonary neuroendocrine cell neoplasia (DIPNECH). We describe the clinical, radiological and histological features of this rare condition.

Ectopic ACTH syndrome (EAS) accounts for 10-15% of cases of Cushing's syndrome and is mostly caused by small cell lung cancers or thymic carcinoids. EAS is characterized by tumoral cortisol resistance, whose underlying mechanism remains unknown. In this study, we reported that silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), a major nuclear corepressor, was aberrantly expressed in ACTH-secreting thymic carcinoids. Overexpression and knockdown of SMRT in the ACTH-secreting AtT-20 cell line demonstrated that SMRT participated in the negative feedback of dexamethasone-mediated suppression of proopiomelanocortin. Posttranslational modification by the small ubiquitin-like modifiers (SUMO), i.e. SUMOylation plays an important role in fine-tuning transcriptional activities. SUMOylation of SMRT was observed in dexamethasone-resistant cell lines. Moreover, overexpression of the deSUMOylation enzyme enhanced the suppression of proopiomelanocortin by dexamethasone in AtT-20 cells. An evolutionarily conserved consensus SUMOylation site was identified close to the histone deacetylase 3 recruiting domain of SMRT, which might interfere with the recruiting process. These results suggested that aberrant expression and modification of SMRT might be involved in the pathogenesis of tumoral cortisol resistance. A therapeutic approach targeting SMRT SUMOylation might be developed for EAS patients.

Activation of tyrosine kinase receptors (TKRs) and their related pathways has been associated with development of endocrine tumors. Compounds that target and inactivate the kinase function of these receptors, tyrosine kinase inhibitors (TKIs), are now being applied to the treatment of endocrine tumors. Recent clinical trials of TKIs in patients with advanced thyroid cancer, islet cell carcinoma, and carcinoid have shown promising preliminary results. Significant reductions in tumor size have been described in medullary and papillary thyroid carcinoma, although no complete responses have been reported. Case reports have described significant tumor volume reductions of malignant pheochromocytomas and paragangliomas. In addition, these compounds showed an initial tumoricidal or apoptotic response followed by long-term static effects on tumor growth. Despite the promising preliminary results, this class of therapeutic agents has a broad spectrum of adverse effects, mediated by inhibition of kinase activities in normal tissues. These adverse effects will have to be balanced with their benefit in clinical use. New strategies will have to be applied in clinical research to achieve optimal benefits. In this review, we will address the genetic alterations of TKRs, the rationale for utilizing TKIs for endocrine tumors, and current information on tumor and patient responses to specific TKIs. We will also discuss the adverse effects related to TKI treatment and the mechanisms involved. Finally, we will summarize the challenges associated with use of this class of compounds and potential solutions.

Well-differentiated endocrine tumors (WDETs) of the appendix show characteristic morphologic features, including proliferation of cells with finely granulated eosinophilic cytoplasm. However, clear cell WDETs, which can present a diagnostic challenge, have been occasionally described, but it is unknown whether they represent a morphologic variant with distinct clinicopathologic features. Moreover, the clear cell appearance of the cytoplasm has never been explained. We studied 13 appendiceal WDETs composed of clear cells, which showed an immunophenotype identical to that of conventional appendiceal WDETs. Ultrastructural examination demonstrated abundant lipid accumulation. Patient survival was excellent and equal to that of conventional appendiceal WDETs. These neoplasms, which represent a lipid-rich variant of appendiceal WDETs, do not have different relevant clinical implications compared with conventional WDETs, but it is important to know of their existence for the differential diagnosis with more aggressive neoplasms, including goblet cell carcinoids and appendiceal metastases from clear cell carcinomas.

Background: We sought to evaluate factors influencing long-term survival in 19 patients with primary neuroendocrine tumours of the thymus., Methods: From January 1990 to December 2004, 19 patients (14 males, 5 females; mean age 48.6 years) were surgically treated for a primary neuroendocrine tumour of the thymus., Results: All patients underwent radical R0 thymomectomy and were followed up for a total of 1,459 months (median: 69 months; range: 8-180). Nine patients had associated paraneoplastic syndrome. No operative mortality occurred. Two patients underwent re-do surgery because of local recurrence, respectively, 25 and 35 months after surgery. Five patients died of disease, respectively, 51, 70, 95, 131 and 153 months after surgery. One patient died of myocardial infarction with no evidence of disease. Thirteen patients are alive, of which 10 are free from disease and three with disease. The overall 5-year and 10-year actuarial survival rates were 91.6% and 69.8%, respectively (median survival: 153 months). The 10-year survival was evaluated according to histology (typical carcinoid 100%; atypical carcinoid: 66.6%; large cell neuroendocrine tumours: 0%), Masaoka staging (stage I: 100%; stage II: 50%; stage III: 66.6%; stage IV: 0%), presence of paraneoplastic syndrome (no: 87.5%; yes: 0%) and postoperative radiotherapy (yes: 40%; no: 83.3%)., Conclusions: The prognosis of primary neuroendocrine tumours of the thymus is related to the grading of the neoplasm, the presence of a paraneoplastic syndrome and to the Masaoka staging but not to the postoperative radiotherapy., (Copyright (c) 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: To present evidence supporting the hypothesis that the coexistence of gastric carcinoids (GCs) and hyperparathyroidism may represent a distinct clinical entity, not related to multiple endocrine neoplasia type 1 (MEN1)., Methods: We studied a cohort of five young siblings (age range 26-42 years), one of whom had been found to have GC and hyperparathyroidism. All siblings underwent serial gastroscopies for the assessment of gastric neuroendocrine cell proliferations over a mean follow-up period of 31.2 months. Imaging, biochemical and hormonal as well as molecular genetic investigations were performed in the direction of MEN1 syndrome. The literature was searched for cases with coexistence of GCs and hyperparathyroidism not associated with MEN1., Results: Four of the siblings, all male, were found to have GCs in a background of Helicobacter pylori-associated chronic atrophic gastritis and pernicious anaemia, with no serological evidence of gastric autoimmunity. In two of them, asymptomatic hyperparathyroidism was also present. Screening for MEN1 gene mutations or large deletions was negative, and hormone and imaging investigations did not support a diagnosis of familial MEN1 syndrome. A literature search revealed sporadic reports of cases with GC and hyperparathyroidism not attributable to MEN1., Conclusions: The association of GCs and hyperparathyroidism appears to constitute a distinct syndrome that can be encountered in genetically predisposed individuals, and should not be regarded as 'atypical' or 'incomplete' expression of MEN1. Its prevalence and aetiology should be the subject of future studies. Screening for hyperparathyroidism seems to be justified in patients with GC of any type.

Carcinoid tumors are rare, slow-growing neuroendocrine tumors arising from the enterochromaffin cells disseminated throughout the gastrointestinal and bronchopulmonary systems. Though they have been traditionally classified based on embryologic site of origin, morphologic pattern, and silver affinity, newer classification systems have been developed to emphasize the considerable clinical and histopathologic variability of carcinoid tumors found within each embryologic site of origin. These neoplasms pose a diagnostic challenge because they are often innocuous at the time of presentation, emphasizing the need for a multidisciplinary diagnostic approach using biochemical analysis, standard cross-sectional imaging, and newer advances in nuclear medicine. Similarly, treatment of both primary and disseminated carcinoid disease reflects the need for a multidisciplinary approach, with surgery remaining the only curative modality. The prognosis for patients with these tumors is generally favorable; however, it can be quite variable and is related to the location of the primary tumor, extent of metastatic disease at initial presentation, and time of diagnosis.

Background: Gastric carcinoid tumours type 1 (GCA1) originate from hyperplastic enterochromaffin-like (ECL) cells secondary to hypergastrinaemia. Treatment with somatostatin analogues (SSA) might impede ECL-cell hyperplasia by suppressing gastrin secretion and/or by a direct anti-proliferative effect on ECL cells. We conducted a multicentre prospective study to assess the effects of long-acting SSA on hypergastrinaemia and ECL-cell proliferation in patients with GCA1., Methods: We studied 15 patients with GCA1 treated with monthly long-acting release octreotide (LAR) (20-30 mg; n=14) or Lanreotide 90 mg (n=1) for at least 6 months. Patients had serum gastrin and chromogranin A measurements performed and biopsies taken from both tumours and surrounding mucosa before, and every 6-12 months following treatment. Sections were immunostained for neuroendocrine markers. The cell proliferation index Ki-67, intensity of staining before and after treatment and the degree of gastric wall invasion were also assessed., Results: All patients tolerated treatment well (mean follow-up of 18 months). In 11 patients (73%), a complete disappearance of the tumours at 1 year of treatment was observed on endoscopy, while in three patients (20%), the tumours decreased significantly in number and size. Gastrin levels normalized in 25% of patients, and were reduced by more than 80% in the remaining 75%., Conclusions: Treatment with SSAs in GCA1 leads to a substantial tumour load reduction, with a concomitant decrease of serum gastrin levels. Our data indicate an important anti-proliferative effect of SSA on ECL cells, providing clinical benefit and obviating, at least temporarily, the need for invasive therapies for GCA1.

Context: Establishing the cause of Cushing's syndrome (CS) can be a considerable challenge, in particular in ectopic adrenocorticotropic hormone (ACTH) syndrome, and often requires a combination of biochemical tests and imaging procedures., Subject: A 27-year-old man presented with signs of CS. P-ACTH levels were three times above the upper limit of normal (ULN) and free urinary cortisol around 2000 nmol/24 h. The work-up showed remarkable results., Results: A 2-day low-dose dexamethasone suppression test demonstrated paradoxical increases in cortisol. Sampling from the bilateral inferior petrosal sinus sampling (BIPSS) showed a central to peripheral ACTH ratio of 4.7 after corticotrophin-releasing hormone (CRH) stimulation, i.e. indicated pituitary disease, but magnetic resonance imaging of the pituitary was normal. Computed tomography (CT) scan of the lungs showed two oval-shaped masses, 1.3 x 1.8 and 1.3 x 2 cm, in the middle lobe. Both were positive at somatostatin receptor scintigraphy, compatible with tumors or inflammatory lesions. Subsequently, (11)C-5-hydroxytryptophan-PET showed distinct uptake in the tumors but not elsewhere. Two carcinoids situated 3 cm apart, both staining for ACTH, were removed at surgery., Conclusion: This unique case with dual bronchial carcinoids inducing hypercortisolism illustrates the problems with identifying the source of ACTH in CS. Possibly, an abnormal regulation of ACTH production in response to dexamethasone, or steroid-induced tumor necrosis, explains the paradoxical outcome at dexamethasone suppression, and the false positive result at BIPSS reflects an unusual sensitivity of the pituitary corticotrophs to CRH in this patient. The work-up illustrates the great value of (11)C-5-hydroxytryptophan-PET as a diagnostic procedure when other investigations have produced ambiguous results.

Objective: Mainstem bronchus obstruction results in lung function exclusion. The aim of this study was to revisit lung function restoration obtained by different types of bronchial sleeve resections in selected patients with endobronchial tumors., Methods: Eleven patients (9 women and 2 men, mean age 47 years) presented with endobronchial tumors and ipsilateral lung function exclusion. Mainstem bronchial sleeve resection was performed in 7 patients, right bilobar and mainstem bronchial sleeve resection in 2, and left upper sleeve lobectomy in 2. Tumors consisted in 8 bronchial carcinoids, 2 adenoid cystic carcinomas, and one inflammatory myofibroblastic tumor. Fiberoptic bronchoscopy and quantitative ventilation-perfusion lung scan were performed in all patients at work-up to assess lung function exclusion and during the first year following bronchoplastic procedure to study recovery. Long-term follow-up consisted of physical examination, thoracic computed tomographic scan and bronchoscopy every year., Results: There was no postoperative death. The long-term follow-up was complete and ranged from 12 to 192 months (median: 102.7 months). The lung function was completely restored in all patients. The ventilation function was immediate, but the perfusion was restored in a mean interval of 8.2 months (ranging from 3 to 12 months). All patients are currently alive, and no local tumor recurrence was observed., Conclusions: Some obstructing tumors may be removed by various types of bronchial sleeve resections that permit lung function restoration and long-term local control of the disease. However, at least one year is required for lung perfusion to completely recover, despite immediate ventilation restoration.

Objective: Bronchial typical carcinoid tumors are low-grade malignancies. However, metastases are diagnosed in some patients. Predicting the individual risk of these metastases to determine patients eligible for a radical lymphadenectomy and patients to be followed-up because of distant metastasis risk is relevant. Our objective was to screen for predictive criteria of bronchial typical carcinoid tumor aggressiveness based on a logistic regression model using clinical, pathological and biomolecular data., Methods: A multicenter retrospective cohort study, including 330 consecutive patients operated on for bronchial typical carcinoid tumors and followed-up during a period more than 10 years in two university hospitals was performed. Selected data to predict the individual risk for both nodal and distant metastasis were: age, gender, TNM staging, tumor diameter and location (central/peripheral), tumor immunostaining index of p53 and Ki67, Bcl2 and the extracellular density of neoformed microvessels and of collagen/elastic extracellular fibers., Results: Nodal and distant metastasis incidence was 11% and 5%, respectively. Univariate analysis identified all the studied biomarkers as related to nodal metastasis. Multivariate analysis identified a predictive variable for nodal metastasis: neo angiogenesis, quantified by the neoformed pathological microvessels density. Distant metastasis was related to male gender., Discussion: Predictive models based on clinical and biomolecular data could be used to predict individual risk for metastasis. Patients under a high individual risk for lymph node metastasis should be considered as candidates to mediastinal lymphadenectomy. Those under a high risk of distant metastasis should be followed-up as having an aggressive disease., Conclusion: Individual risk prediction of bronchial typical carcinoid tumor metastasis for patients operated on can be calculated in function of biomolecular data. Prediction models can detect high-risk patients and help surgeons to identify patients requiring radical lymphadenectomy and help oncologists to identify those as having an aggressive disease requiring prolonged follow-up.

Context and Objectives: We were referred a patient with metastatic well-differentiated endocrine tumor of the small intestine (midgut carcinoid) in whom asymptomatic sc gluteal nodules had been identified on routine abdominal computed tomography and labeled as metastases. This prompted us to assess the prevalence and cause of these nodules., Design and Setting: This was a retrospective, cross-sectional study at a university teaching hospital., Methods: Routine abdominal computed tomography scans of 56 patients with metastatic midgut carcinoid were analyzed by two independent radiologists, blinded to treatment status (depot somatostatin analogs)., Main Outcome Measures: Number of patients with nodules, number of injections, and duration and total cumulative dose per patient were assessed., Results: No nodules were detected in 13 patients not on depot somatostatin therapy. Nodules were found in 29 of 43 patients (67%) on somatostatin analog therapy: 16 of 22 patients on lanreotide Autogel, five of 12 patients on octreotide LAR only, and eight of nine patients who had been treated with both somatostatin analogs. There was no difference in the clinical state of those with or without nodules. Per patient, the average number was seven, and average size was 1 cm. Presence of nodules was significantly associated with total number of injections (P = 0.024), duration on treatment (P = 0.022), and cumulative dose of lanreotide Autogel (P < 0.001). Nodules underwent involution on follow-up imaging., Conclusion: Patients with metastatic midgut carcinoid tumors have large numbers of asymptomatic sc nodules in the gluteal area when on either depot somatostatin analog, but these resolve over time. This clear observation gives reassurance to patients and those managing them that such nodules are unlikely to represent metastases.

Pulmonary carcinoids are rare malignant neoplasms, accounting for 2-5% of all lung tumors, with an approximate annual incidence of 2.3-2.8 cases per million of the population. We relate our experience of 54 patients (21 male, 33 female, mean age 53+/-15 years) treated between July 1986 and April 2006. All the patients underwent preoperative fibrobronchoscopy: preoperative diagnosis was made in 28 patients (52%). Surgical treatment consisted of: 31 standard lobectomies, 6 pneumonectomies, 5 bilobectomies, 2 sleeve lobectomies, 2 anatomic segmentectomies, 6 wedge resections; two patients were managed with sleeve bronchial procedure of the left main bronchus without lung resection. Fifty-four patients were followed with a mean time of observation of 67 months: 6 (11%) deaths occurred, at a mean period of 49 months after surgery; there were no postoperative deaths. Overall, 5-year survival was 91%, 10 years 83%: 5-year survival was 91% for typical carcoinoids (TC) vs. 88% for atypical (AC), 10 years 91% for TC and 44% for AC (significant value, P=0.0487). Carcinoid tumors are a distinct group of neuroendocrine tumors with a good prognosis in most cases. Surgery currently represents the best treatment with good results at mid- and long-term survival, according to an acceptable risk.

Context: Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients., Objectives: Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines., Setting and Patients: Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers., Interventions and Outcome Measures: Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features., Results: ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid., Conclusions: Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies.

The World Health Organization classification of lung tumors recognizes 4 histologic subtypes of pulmonary neuroendocrine carcinomas (NECs), which include typical carcinoids (TCs), atypical carcinoids (ACs), small cell carcinomas (SCCs), and large cell NECs (LCNECs). These tumors can be misclassified owing to morphologic parallels, indicating the necessity for adjunctive tests for correct classification. We evaluated immunohistochemical expression of PAX-5 in histologic and fine-needle aspiration (FNA) specimens of pulmonary NECs. Staining was stratified by intensity (0 to 3+) and percentage of cells stained as focal (<10%) or diffuse (=10%). PAX-5 expression was present in 29/37 (78%) of high-grade NECs (22/26 SCCs, 1/2 LCNECs, and 6/9 combined tumors) and none of 51 TCs and ACs; FNA specimens showed concordant staining. This study confirmed that PAX-5 is a useful marker in FNA and surgical specimens for the discrimination of low- to intermediate-grade NECs from high-grade NECs with 100% specificity and 79% sensitivity in surgical specimens.

To our knowledge, this is the first report in the British literature documenting the co-occurrence of melanoma and pulmonary carcinoid. The only other report is from America and documents pulmonary carcinoid in association with a parathyroid hormone-producing melanoma. We report two patients with melanoma who presented with nodules on chest X-ray. Both underwent resection of assumed lung metastasis which unexpectedly revealed primary pulmonary carcinoid. Evidence of an association between these two tumours which show striking biological and pathological similarities is discussed. The incidence of pulmonary carcinoid is increasing and with the improved power of radiological assessment we may see additional accounts of such an association in the near future.