Primary Cilia Are Frequently Present in Small Cell Lung Carcinomas but Not in Non-Small Cell Lung Carcinomas or Lung Carcinoids.

Most human malignant neoplasms show loss of primary cilia (PC). However, PC are known to be retained and involved in tumorigenesis in some types of neoplasms. The PC status in lung carcinomas remains largely uninvestigated. In this study, we comprehensively assessed the PC status in lung carcinomas. A total of 492 lung carcinomas, consisting of adenocarcinomas (ACs) (n = 319), squamous cell carcinomas (SCCs) (n = 152), and small cell lung carcinomas (SCLCs) (n = 21), were examined by immunohistochemical analysis using an antibody against ARL13B, a marker of PC. The PC-positive rate was markedly higher in SCLCs (81.0%) than in ACs (1.6%) and SCCs (7.9%). We subsequently performed analyses to characterize the PC-positive lung carcinomas further. PC-positive lung carcinomas were more numerous and had longer PC than normal cells. The presence of PC in these cells was not associated with the phase of the cell cycle. We also found that the PC were retained even in metastases from PC-positive lung carcinomas. Furthermore, the hedgehog signaling pathway was activated in PC-positive lung carcinomas. Because ARL13B immunohistochemistry of lung carcinoids (n = 10) also showed a statistically significantly lower rate (10.0%) of PC positivity than SCLCs, we searched for a gene(s) that might be upregulated in PC-positive SCLCs compared with lung carcinoids, but not in PC-negative carcinomas. This search, and further cell culture experiments, identified HYLS1 as a gene possessing the ability to regulate ciliogenesis in PC-positive lung carcinomas. In conclusion, our findings indicate that PC are frequently present in SCLCs but not in non-SCLCs (ACs and SCCs) or lung carcinoids, and their PC exhibit various specific pathobiological characteristics. This suggests an important link between lung carcinogenesis and PC.

Preliminary analysis of immune-related markers in thymic carcinoid.

The immune-related microenvironment of thymic carcinoid has rarely been reported. We analyzed the expression of PD-L1 and VISTA, and the distribution of CD4+ T cells, CD8+ T cells and CD68+ macrophages in the thymic carcinoid by immunohistochemical staining, and showed the correlation between these markers and clinical survival, indicating the potential therapeutic prospects.

Altered splicing machinery in lung carcinoids unveils NOVA1, PRPF8 and SRSF10 as novel candidates to understand tumor biology and expand biomarker discovery.

BACKGROUND: Lung neuroendocrine neoplasms (LungNENs) comprise a heterogeneous group of tumors ranging from indolent lesions with good prognosis to highly aggressive cancers. Carcinoids are the rarest LungNENs, display low to intermediate malignancy and may be surgically managed, but show resistance to radiotherapy/chemotherapy in case of metastasis. Molecular profiling is providing new information to understand lung carcinoids, but its clinical value is still limited. Altered alternative splicing is emerging as a novel cancer hallmark unveiling a highly informative layer. METHODS: We primarily examined the status of the splicing machinery in lung carcinoids, by assessing the expression profile of the core spliceosome components and selected splicing factors in a cohort of 25 carcinoids using a microfluidic array. Results were validated in an external set of 51 samples. Dysregulation of splicing variants was further explored in silico in a separate set of 18 atypical carcinoids. Selected altered factors were tested by immunohistochemistry, their associations with clinical features were assessed and their putative functional roles were evaluated in vitro in two lung carcinoid-derived cell lines. RESULTS: The expression profile of the splicing machinery was profoundly dysregulated. Clustering and classification analyses highlighted five splicing factors: NOVA1, SRSF1, SRSF10, SRSF9 and PRPF8. Anatomopathological analysis showed protein differences in the presence of NOVA1, PRPF8 and SRSF10 in tumor versus non-tumor tissue. Expression levels of each of these factors were differentially related to distinct number and profiles of splicing events, and were associated to both common and disparate functional pathways. Accordingly, modulating the expression of NOVA1, PRPF8 and SRSF10 in vitro predictably influenced cell proliferation and colony formation, supporting their functional relevance and potential as actionable targets. CONCLUSIONS: These results provide primary evidence for dysregulation of the splicing machinery in lung carcinoids and suggest a plausible functional role and therapeutic targetability of NOVA1, PRPF8 and SRSF10.

The single-cell transcriptional landscape of lung carcinoid tumors.

Lung carcinoid tumors, also referred to as pulmonary neuroendocrine tumors or lung carcinoids, are rare neoplasms of the lung with a more favorable prognosis than other subtypes of lung cancer. Still, some patients suffer from relapsed disease and metastatic spread. Several recent single-cell studies have provided detailed insights into the cellular heterogeneity of more common lung cancers, such as adeno- and squamous cell carcinoma. However, the characteristics of lung carcinoids on the single-cell level are yet completely unknown. To study the cellular composition and single-cell gene expression profiles in lung carcinoids, we applied single-cell RNA sequencing to three lung carcinoid tumor samples and normal lung tissue. The single-cell transcriptomes of carcinoid tumor cells reflected intertumoral heterogeneity associated with clinicopathological features, such as tumor necrosis and proliferation index. The immune microenvironment was specifically enriched in noninflammatory monocyte-derived myeloid cells. Tumor-associated endothelial cells were characterized by distinct gene expression profiles. A spectrum of vascular smooth muscle cells and pericytes predominated the stromal microenvironment. We found a small proportion of myofibroblasts exhibiting features reminiscent of cancer-associated fibroblasts. Stromal and immune cells exhibited potential paracrine interactions which may shape the microenvironment via NOTCH, VEGF, TGFß and JAK/STAT signaling. Moreover, single-cell gene signatures of pericytes and myofibroblasts demonstrated prognostic value in bulk gene expression data. Here, we provide first comprehensive insights into the cellular composition and single-cell gene expression profiles in lung carcinoids, demonstrating the noninflammatory and vessel-rich nature of their tumor microenvironment, and outlining relevant intercellular interactions which could serve as future therapeutic targets.

Differential Orthopedia Homeobox expression in pulmonary carcinoids is associated with changes in DNA methylation.

Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. We analyzed publicly available multi-omics data (whole-exome-, whole-genome-, RNA sequencing and Epic 850K-methylation array) of 58 typical carcinoids, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K-methylation analysis was cross-validated using targeted pyrosequencing on 35 carcinoids. We report bimodality of OTP expression in carcinoids (OTPhigh vs OTPlow group, likelihood-ratio test P = 1.5 × 10-2 ), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (FDR < 0.05 and ß-value effect size > .2). OTPlow carcinoids harbor high DNA methylation levels as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (log-rank test P = .0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, that is, sustaining proliferative signaling, evading growth suppressor and genome instability and mutation. Together our data suggest that high OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis and that in poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels.

Proposal of a Panel of Genes Identified by miRNA Profiling as Candidate Prognostic Biomarkers in Lung Carcinoids.

AIM: To validate the prognostic role of a panel of genes previously uncovered by our group to be specific targets of miRNAs differentially expressed in lung carcinoids with aggressive pathological features. METHODS: Four genes, namely, cyclic AMP response element binding protein-1 (CREBP1), activin A receptor type 2B (ACVR2B), LIM homeobox 2 (LHX2), and Krüppel-like factor 12 (KLF12), were identified in a previous study by our group using in silico analysis to be regulated by 3 miRNAs (miR-409-3p, miR-409-5p, and miR-431-5p) that were shown to be downregulated in aggressive lung carcinoids. These genes were analyzed using real-time PCR in a cohort of 102 lung carcinoids. Fifty high-grade lung carcinomas served as control group. Their expression was correlated with the expression of miR-409-3p, miR-409-5p, and miR-431-5p and with clinical pathological parameters and disease-free survival. RESULTS: The expression of all but CREBP1 gene was significantly different between lung carcinoids and high-grade neuroendocrine carcinomas. ACVR2B and LHX2 were significantly inversely correlated with miR-409-3p and miR-409-5p. High levels of ACVR2B and LHX2 were significantly associated with atypical histotype, high tumor grade, and higher proliferation Ki-67 index (all p < 0.05). Low levels of KLF12 were significantly associated with the presence of necrosis and positive nodal status (all p < 0.05). Finally, low KLF12 expression was associated with shorter disease-free survival in lung carcinoids as a whole and in atypical carcinoids, only (all p < 0.001). CONCLUSIONS: ACVR2B, LHX2, and KFL12 are novel potential biomarkers associated with aggressive features in lung carcinoids.

Transcriptomic data helps refining classification of pulmonary carcinoid tumors with increased mitotic counts.

Pulmonary neuroendocrine neoplasms are classified by WHO as either typical or atypical carcinoids, large cell (LCNEC) or small cell (SCLC) neuroendocrine carcinoma based on mitotic count, morphology, and necrosis assessment. LCNEC with low mitotic count and sharing morphologic features with carcinoids are in a gray zone for classification and their rare prevalence and the paucity of studies precludes proper validation of the current grading system. In this study, we aim to investigate their clinicopathological and transcriptomic profiles. Lung resection specimens obtained from 18 patients diagnosed with carcinoids or LCNEC were selected. Four of them were characterized as borderline tumors based on a mitotic rate ranging between 10 and 30 mitoses per 2 mm2. Comprehensive morphological and immunohistochemical (IHC) evaluation was performed and tumor-based transcriptomic profiles were analyzed through unsupervised clustering. Clustering analysis revealed two distinct molecular groups characterized by low (C1) and high (C2) proliferation. C1 was comprised of seven carcinoids and three borderline tumors, while C2 was comprised of seven LCNEC and one borderline tumor. Furthermore, patients in cluster C1 had a better recurrence-free survival compared with patients in cluster C2 (20% vs 75%). Histological features, IHC profile, and molecular analysis showed that three out of four borderline tumors showed features consistent with carcinoids. Therefore, our findings convey that the current diagnostic guidelines are suboptimal for classification of pulmonary neuroendocrine tumors with increased proliferative index and carcinoid-like morphology. These results support the emerging concept that neuroendocrine tumors with carcinoid-like features and mitotic count of <20 mitoses per 2 mm2 should be regarded as pulmonary carcinoids instead of LCNEC.

Multiple Assays to Determine Methylguanine-Methyltransferase Status in Lung Carcinoids and Correlation with Clinical and Pathological Features.

BACKGROUND: O6-methylguanine-methyltransferase (MGMT) is a key enzyme for the DNA repair machinery strongly associated with response to alkylating agents in different tumors. Data on its expression and related clinical impact in neuroendocrine tumors are limited to the gastro-entero-pancreatic system, with controversial results in terms of prognostic or predictive value. In lung carcinoids, although clinical efficacy of alkylating agents has been shown in small studies, very few data to date are available on MGMT status. OBJECTIVE: To assess MGMT status in lung carcinoids using multiple assays and to compare data with major clinical and pathological features. METHODS: A retrospective series of 95 lung carcinoids and 51 control cases of high-grade neuroendocrine lung carcinomas was analyzed for MGMT promoter methylation, MGMT gene expression, and MGMT protein expression using pyrosequencing, quantitative real-time PCR, and immunohistochemistry, respectively. RESULTS: MGMT protein expression was inversely correlated with MGMT promoter methylation and positively with MGMT gene expression. MGMT promoter methylation progressively increased from carcinoids to high-grade carcinomas. In the carcinoid group, decreased MGMT gene expression was significantly associated with aggressive features (atypical histotype, grade G2, larger tumor size, higher T stage, and positive nodal status) but not with survival. MGMT promoter methylation was associated with lower stage and negative nodal status. CONCLUSIONS: Our study investigated MGMT status in a large series of lung carcinoids in the attempt to move forward a rational use of alkylating agents in these tumors. Interestingly, low MGMT gene expression defines a subgroup of lung carcinoids with aggressive features.

Complete remission of Cdx-2 positive primary testicular carcinoid tumor: 10-years follow-up and literature review.

BACKGROUND: The neuroendocrine cells can cause a variety of malignancies throughout the human body known as the neuroendocrine tumors (NETs) or carcinoid tumors. The primary testicular carcinoid tumor (PTCT) accounts for less than 1% of the testicular neoplasms and for only 0.2% of all carcinoid tumors representing already a very rare neoplastic entity. Here, we present a patient with a history of an exceptionally rare primary testicular carcinoid tumor, staining positive for Cdx-2 along with a literature review. CASE PRESENTATION: A 44-year old patient without significant past medical history was diagnosed in September 2009 with primary testicular carcinoid tumor, which was surprisingly staining positively for Cdx-2, too. At the time of the initial diagnosis the tumor was already showing histopathological infiltration of veins. DOTA-TATE-PET/CT imaging and endoscopy studies did not show any signs of distant metastases and in particular no gastrointestinal manifestation following no further medical indication for systemic chemotherapy. The continuous and close follow-up of the patient has reached a total of over 10 years at the time of publication remaining in complete remission. CONCLUSION: The diagnosis of primary testicular carcinoid is based on histopathology. The detailed histopathologic assessment of biomarkers based on immunohistochemistry is very important for the classification and the prognosis of the primary testicular carcinoid tumor. Primary testicular carcinoid tumor with Cdx-2 positive stain outlines an exceptionally rare neoplastic entity without a consensus about general follow-up guidelines, requiring close clinical and imaging aftercare and consideration in Cdx-2 positive metastatic tumor of unknown origin.

Appendix Tumor Microenvironment.

The pathological features of the appendix tumors fundamentally recall those of the more frequent colorectal neoplasms, although with a higher relative incidence of carcinoids, due to the abundant presence of enteroendocrine cells in the appendix wall. Moreover, different types of lymphomas, Hodgkin and non-Hodgkin, arising from the extra-nodal mucosal-associated lymphatic tissue, can be encountered. The appendix tumor microenvironment (TME) consists of a cellular component and of a noncellular component: the former includes the immunocompetent cells, while the latter represents the support stroma. Particularly in carcinoids, the immune cell reaction can be explicated by tumor-infiltrating lymphocytes, which, in some circumstances, may arrange around and inside the tumor in a brisk fashion influencing favorably the prognosis. This active reaction has to be distinguished from any preexisting inflammatory condition of the appendix and from superimposed tumor complications, such as infection or ischemia. In practice, we consider the appendix TME a complex framework with immunological, mechanic, and metabolic functions, all supported by a marked neo-lymphoangiogenesis.

Primary renal well-differentiated neuroendocrine tumour (carcinoid): next-generation sequencing study of 11 cases.

AIMS: Primary renal well-differentiated neuroendocrine tumour (NET) (hereafter referred to as renal NET) is rare, with ~100 cases having been reported in the literature. There are also limited data on the molecular-genetic background of primary renal NETs. METHODS AND RESULTS: We analysed 11 renal NETs by using next-generation sequencing (NGS) to identify characteristic genetic aberrations. All tumours were positive for synaptophysin, and also expressed insulinoma-associated protein 1 (10/11), chromogranin-A (8/11), and CD56 (3/11). Cytoplasmic positivity of CD99 was present in eight of 11 cases, and strong nuclear expression of α-thalassaemia/mental retardation syndrome X-linked (ATRX) was retained in all 11 cases. Molecular-genetic analysis of aberration of VHL gave negative results in all cases. Loss of heterozygosity on chromosome 3p21 was found in three of nine analysable cases. NGS was successful in nine cases, showing a total of 56 variants being left after the updated filtering process, representing an average of five variants per sample. All analysable cases were negative for ATRX and DAXX (death-domain associated protein X) mutations. The most frequently mutated genes were CDH1 and TET2, with three mutations in two cases. Mutations in AKT3, ROS1, PIK3R2, BCR and MYC were found in two cases. The remaining 41 genes were found to be mutated only in individual cases. In four cases, the mutations affected a subset of genes related to angiogenesis. CONCLUSIONS: Overall, the mutation profile of primary renal NETs is variable, and none of the studied genes or affected pathways seems to be specific for renal NET.

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane.

BACKGROUND: Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. METHODS: Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. RESULTS: Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. CONCLUSIONS: Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.

Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20.

The clinicopathological features of lung neuroendocrine neoplasms (NEN) with a high proliferative index at the border area between atypical carcinoid and neuroendocrine carcinoma have not been investigated so far. The aim of this study was, therefore, to search for lung NENs which are well differentiated but show Ki67 values that overlap with those of poorly differentiated (PD)-NENs. Resected lung NENs from 244 Japanese patients were reviewed, and Ki67 indices were assessed in all tumors. The data were then correlated to clinicopathological parameters and patient outcome. Among 59 (24%) well-differentiated (WD)-NENs and 185 (76%) lung PD-NENs, 7 were defined as WD-NENs with Ki67 indices > 20%. The Ki67 indices of these tumors (mean 29%, range 24-36) were significantly lower than those of PD-NENs (mean 74%, range 34-99). All WD-NENs with Ki67 > 20% lacked abnormal p53 and loss of retinoblastoma 1 (Rb1) expression. In contrast, many PD-NENs expressed p53 (48%) and showed loss of Rb1 (86%). The 2- and 5-year disease-free survival rates in WD-NEN patients with Ki67 > 20% were lower than those of WD-NEN patients with Ki67 ≤20% (p < 0.01 for disease-free and overall survival). No statistical differences were detected between outcome of WD-NEN patients with Ki67 > 20% and those of PD-NEN. It is concluded that WD-NEN patients with Ki67 > 20% share the morphological and immunohistochemical features of WD-NEN patients with Ki67 ≤20%, but they have a worse prognosis, suggesting that this tumor group requires particular attention in future classifications and probably new therapeutic regimes.

Pediatric Bronchial Carcinoid Tumors: A Case Series and Review of the Literature.

Bronchial carcinoid tumor, while rare, remains the most common primary malignant lung tumor in children. We present a retrospective analysis of 7 patients with typical bronchial carcinoid tumors diagnosed at 2 pediatric tertiary care referral centers between 1990 and 2014. The most common presenting symptom was pneumonia, followed by respiratory distress. Somatostatin scans were performed in selected patients. All patients had negative resection margin following surgery and were alive without disease at last follow-up. Typical carcinoid tumors have a good prognosis following definitive surgical resection. A review of published literature on pediatric bronchial carcinoid tumors is provided.

Challenges in diagnosis of disease reported 100 years back: Cushing syndrome; recent advances.

Treatment of Cushing syndrome depends on diagnosis of etiology responsible for hypercortisolism in the body, which sometimes presents with a challenge. Inferior petrosal sinus sampling for ACTH levels, followed by peripheral venous sampling is a proven tool to be a gold standard for differentiating between peripheral and central cause of ACTH dependent Cushing syndrome. This case report is of an elderly female who presented as an outpatient in the endocrinology clinic of Aga Khan university hospital on 22/6/2017 with clinical features of hypercortisolism. After workup she was found to have cushing syndrome secondary to ACTH secreting bronchial carcinoid tumour.

Appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid are genetically distinct from primary colorectal-type adenocarcinoma of the appendix.

The appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. We therefore performed a next-generation sequencing analysis of 25 appendiceal carcinomas including 11 goblet cell carcinoids, 7 adenocarcinomas ex-goblet cell carcinoid, and 7 primary colorectal-type adenocarcinomas, using a modified Colorectal Cancer specific Panel comprising 32 genes linked to colorectal and neuroendocrine tumorigenesis. The mutational profiles of these neoplasms were compared with those of conventional adenocarcinomas, mixed adenoneuroendocrine carcinomas, and neuroendocrine carcinomas of the colorectum. In addition, a large-scale pan-cancer sequencing panel covering 409 genes was applied to selected cases of goblet cell carcinoid/adenocarcinoma ex-goblet cell carcinoid (n=2, respectively). Mutations in colorectal cancer-related genes (eg, TP53, KRAS, APC) were rare to absent in both, goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid, but frequent in primary colorectal-type adenocarcinomas of the appendix. Additional large-scale sequencing of selected goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid revealed mutations in Wnt-signaling-associated genes (USP9X, NOTCH1, CTNNA1, CTNNB1, TRRAP). These data suggest that appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid constitute a morphomolecular entity, histologically and genetically distinct from appendiceal colorectal-type adenocarcinomas and its colorectal counterparts. Altered Wnt-signaling associated genes, apart from APC, may act as potential drivers of these neoplasms. The absence of KRAS/NRAS mutations might render some of these tumors eligible for anti-EGFR directed therapy regimens.

Lung Carcinoids: Long-Term Surgical Results and the Lack of Prognostic Value of Somatostatin Receptors and Other Novel Immunohistochemical Markers.

BACKGROUND/AIMS: Lung carcinoids (LCs) are often diagnosed at an early stage and surgical intervention becomes the next phase of treatment. To date, there is lack of long-term follow-up data after surgery and prognostication based on WHO classification criteria and evolving prognostic markers, particularly the expression of somatostatin receptors (SSR). METHODS: We included 102 consecutive patients (72 women; age at baseline 51 ± 16 years [mean ± SD]) with LCs, who underwent thoracic surgery (n = 99) and/or laser treatment (n = 8). Hospital charts were reviewed for clinico-pathological parameters. Immunohistochemical (IHC) expression of SSR1-5 and other novel markers were studied with regard to their prognostic value. RESULTS: Five- and 10-year overall survival (OS) was 96 and 83% respectively; relative survival (RS) was 101 and 93% respectively; and event-free survival (EFS) was 80 and 67% respectively. Independent prognostic factors for OS, RS and/or EFS were age at diagnosis, histopathological type and the presence of ipsilateral mediastinal subcarinal lymph node metastases. Macro-radicality of resective surgery and its extent were associated with increased OS and EFS. The IHC expression of SSR1-5 and other novel markers was not associated with OS or EFS. CONCLUSION: The long-term outcome of surgically treated patients with LCs is favourable. Age, histopathological type and ipsilateral mediastinal subcarinal lymph node status at baseline were independent prognostic factors for survival and disease recurrence or progression. The extent of surgery and operative macro-radicality also had an impact on prognosis. None of the IHC markers tested appeared to be associated with disease prognosis.

Pulmonary Carcinoids and Low-Grade Gastrointestinal Neuroendocrine Tumors Show Common MicroRNA Expression Profiles, Different from Adenocarcinomas and Small Cell Carcinomas.

BACKGROUND: It is still uncertain whether small cell lung carcinomas (SCLCs), pulmonary carcinoids, and the gastrointestinal neuroendocrine tumors (GI-NETs) have a common origin. MicroRNA (miRNA) expression may clarify their genetic relationships and origin. METHODS: First, we compared the miRNA expression signature of formalin-fixed paraffin-embedded (FFPE) samples with frozen samples to verify the applicability of microarray analysis. Second, we compared the comprehensive miRNA expression patterns of pulmonary carcinoids and GI-NETs as well as other types of tumors and normal tissues from each organ using FFPE samples. These data were analyzed by hierarchical clustering and consensus clustering with nonnegative matrix factorization. RESULTS: We confirmed that FFPE samples retained the miRNA signatures. In the first hierarchical clustering comparing carcinoids/NETs with adenocarcinomas and normal tissues, most of the carcinoids (48/50) formed 1 major cluster with loose subpartitioning into each organ type, while all the adenocarcinomas (9/9) and normal tissues (15/15) formed another major cluster. The nonnegative matrix factorization approach largely matched the classification of the hierarchical clustering. In the additional cluster analysis comparing carcinoids/NETs with SCLCs, most carcinoids/NETs (17/22) formed a major cluster, while SCLCs (9/9) grouped together with pulmonary adenocarcinomas (3/3) and normal tissues (6/6) in another major cluster. Furthermore, a subset of miRNAs was successfully identified that exhibited significant expression in carcinoids/NETs. CONCLUSION: Carcinoids/NETs had a characteristic pattern of miRNA expression, suggesting a common origin for pulmonary carcinoids and GI-NETs. The expression profiles of pulmonary carcinoids and SCLCs were quite different, indicating the distinct histogenesis of these neuroendocrine neoplasms.

Diffusely Metastasized Adenocarcinoma Arising in a Mucinous Carcinoid of the Ovary: A Case Report.

Mucinous (goblet cell) carcinoids are a rare type of ovarian carcinoid tumors. Only a limited number of primary mucinous carcinoids of the ovary have been reported in the literature. We describe the case of a 55-year-old woman with a diffusely metastasized adenocarcinoma arising in a primary ovarian mucinous carcinoid. The differential diagnosis with a metastatic goblet cell carcinoid from the appendix or elsewhere can be very challenging. In our case, especially the immunohistochemical profile of the tumor with diffuse positivity for cytokeratin 7 and PAX8, and no expression of cytokeratin 20 and CDX2, directed us toward a primary ovarian origin. Expression of PAX8 in ovarian mucinous carcinoid has never been reported before.

Hemolytic Anemia and Gastric Carcinoid in a Russian Seafarer: Highlighting the Role of Diagnostic Technologies in Modern Clinical Practice.

Vitamin B-12 deficiency, most commonly due to pernicious anemia, can cause intramedullary hemolysis. The pathogenesis is thought to be due to increased membrane rigidity and reduced red blood cell elasticity, which predisposes the patient to hemolysis and microangiopathic hemolytic anemia. In this article, we discuss a Russian engineer who worked aboard a petroleum tanker that presented from his ship with profound B-12 deficiency, microangiopathic anemia, elevated lactate dehydrogenase levels, low haptoglobin, and reticulocyte count in the setting of normal renal and neurologic function. The patient traveled around the world seven months of the year for work and had occupational exposure to fluorinated hydrocarbons. Extensive diagnostic work-up, including endoscopic biopsy, and a radio-labeled octreotide scan was performed. The patient was found to have autoimmune gastritis and a gastric carcinoid tumor. With assistance from his global health insurance provider and a local hospital near his hometown in Russia, care was coordinated to be transitioned there with a plan for repeat endoscopy and mapping biopsies to determine the extent of his tumor burden. This study adds to the now growing base of literature describing this atypical presentation of pernicious anemia with normal neurologic function and underscores the importance of screening for B-12 deficiency in these patients. It also highlights the increased risk of gastric carcinoids in patients with autoimmune gastritis. With the collaboration of different medical specialists, the full gamut of medical technology was utilized in the care of the patient. This included in vitro diagnostics, advanced endoscopic tools, pathology, and radio-isotope based imaging studies.