Pulmonary Neuroendocrine Tumors Research Articles

A Rare Case of Synchronous Bilateral Pulmonary Neuroendocrine Tumor Detected by 68Ga-DOTANOC PET/CT

A Rare Case of Synchronous Bilateral Pulmonary Neuroendocrine Tumor Detected by 68Ga-DOTANOC PET/CT

Differential expression of forkhead box M1 and its downstream cyclin‐dependent kinase inhibitors p27kip1 and p21waf1/cip1 in the diagnosis of pulmonary neuroendocrine tumours

Pulmonary neuroendocrine (NE) tumours represent a spectrum of phenotypically distinct entities with different biological behaviours. Difficulties in classifying these tumours are frequently encountered in clinical practice. Forkhead box M1 (FoxM1) is essential for the development of various cancers and is a proliferation-specific transcription factor that regulates transcription of cell cycle genes, including cyclin-dependent kinase inhibitors p27(kip1) and p21(waf1/cip1) . This study was performed to determine the utility of FoxM1, p27(kip1) and p21(waf1/cip1) as immunomarkers for subtyping pulmonary NE tumours. FoxM1, p27(kip1) and p21(waf1/cip1) expression was evaluated by immunohistochemistry in 60 pulmonary NE tumours [19 typical carcinoids (TCs), six atypical carcinoids (ACs), 17 large cell neuroendocrine carcinomas (LCNECs) and 18 small cell lung cancers (SCLCs)]. The frequencies of FoxM1 and p21(waf1/cip1) expression were significantly different between TCs and ACs (each P = 0.009), and those of FoxM1 and p27(kip1) expression were significantly different between LCNECs and SCLCs (P = 0.012 and P = 0.002, respectively). The combined FoxM1((-)) /p21(waf1/cip1(-)) and FoxM1((+)) /p27(kip1(high)) phenotypes had the best diagnostic accuracy for distinguishing TCs from ACs, and SCLCs from LCNECs, respectively. FoxM1, p27(kip1) and p21(waf1/cip1) showed distinct immunoreactivity according to histological subtype, which may be of value as an ancillary test in the differential diagnosis of pulmonary NE tumours.

18F-FDG uptake on PET could be a predictive marker of Excision Repair Cross-Complementation Group 1 (ERCC1) expression in patients with thoracic neoplasms?

The aim of this study is to examine the relationship between the expression level of excision repair cross-complementation group 1 (ERCC1) and of 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) in various thoracic neoplasm.Three hundreds-eight patients [non-small cell lung cancer (NSCLC)(n=56), malignant pleural mesothelioma (MPM)(n=21), pulmonary metastatic tumors (PMT)(n=148), thymic epithelial tumors (n=49) and pulmonary neuroendocrine tumor (n=34)] who underwent 18F-FDG PET before treatment were included in this study. Tumors sections were stained by immunohistochemistry for ERCC1, glucose transporter 1(Glut1), vascular endothelial growth factor (VEGF) and microvessel density (MVD) by determinate by CD34. The expression of ERCC1 in thoracic neoplasms had a positivity of 49% (152/308), and the positive rates of ERCC1 expression in NSCLC, PMT, thymic epithelial tumor, pulmonary neuroendocrine tumor and MPM were 52, 43, 53, 47 and 85%, respectively. The positivity of ERCC1 expression was significantly higher in MPM and SQC than in the other histological types. A statistically significant correlation between ERCC1 expression and 18F-FDG uptake was observed in thymic epithelial tumors, especially thymoma. Moreover, ERCC1 expression was also closely associated with the expression of Glut1, VEGF and MVD.Our results indicated that 18F-FDG uptake may be an alternative biomarker for predicting ERCC1 expression in patients with thymoma.

The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites

Most Merkel cell carcinomas display pure neuroendocrine differentiation (pure Merkel cell carcinoma), whereas a minority show combined neuroendocrine and nonneuroendocrine elements (combined Merkel cell carcinoma). Recent identification of Merkel cell polyomavirus DNA and Merkel cell polyomavirus large T antigen expression in a proportion of Merkel cell carcinomas has suggested viral-induced oncogenesis. To date, Merkel cell polyomavirus immunohistochemistry has shown an absence of viral large T antigen expression in combined Merkel cell carcinoma as well as select non-Merkel cell carcinoma cutaneous lesions and visceral neuroendocrine tumors. In our series, we aimed to further characterize the frequency and pattern of Merkel cell polyomavirus large T antigen expression by CM2B4 immunohistochemistry in primary and metastatic Merkel cell carcinoma (pure Merkel cell carcinoma and combined Merkel cell carcinoma) and various non-Merkel cell carcinoma lesions from patients with Merkel cell carcinoma, patients without Merkel cell carcinoma, and individuals with altered immune function. Merkel cell polyomavirus large T antigen was detected in 17 (63%) of 27 pure Merkel cell carcinomas and absent in all 15 (0%) combined Merkel cell carcinomas. Furthermore, complete concordance (100%) of Merkel cell polyomavirus large T antigen expression was observed in 10 cases of primary Merkel cell carcinoma and subsequent tumor metastases. We also evaluated 70 non-Merkel cell carcinoma lesions including 15 cases each of pulmonary and gastrointestinal neuroendocrine tumors. All 70 non-Merkel cell carcinoma lesions were negative for Merkel cell polyomavirus by CM2B4 immunohistochemistry, irrespective of any known Merkel cell carcinoma diagnosis and immune status. In summary, our identification of Merkel cell polyomavirus large T antigen expression in a subset of Merkel cell carcinoma and lack of findings in combined Merkel cell carcinomas and non-Merkel cell carcinoma lesions concur with earlier findings and implicate Merkel cell polyomavirus-independent pathogenesis in these cases. Overall, CM2B4 immunohistochemistry appears to be a specific method for Merkel cell polyomavirus detection and has the potential to play an important role in the diagnosis and classification of Merkel cell carcinoma in the future.

Respiratory Disease Registries in Spain: Fundamentals and Organization

This present paper describes the general characteristics, objectives and organizational aspects of the respiratory disease registries in Spain with the aim to report their activities and increase their diffusion. The document compiles information on the following registries: the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency, Spanish Registry of Bronchiectasis, International Registry of Thromboembolic Disease, Spanish Registry of Occupational Diseases, Spanish Registry of Pulmonary Artery Hypertension, Registry of Pleural Mesothelioma, Spanish Registry of Tuberculosis and Spanish Multi-center Study of Neuroendocrine Pulmonary Tumors. Our paper provides information on each of the registries cited. Each registry has compiled specific clinical information providing data in real situations, and completes the results obtained from clinical assays. Said information has been published both in national as well as international publications and has led to the creation of various guidelines. Therefore, the activities of the professionals involved in the registries have spread the knowledge about the diseases studied, promoting the exchange of information among workgroups.

Specific expression of ZO-1 and N-cadherin in rosette structures of various tumors: possible recapitulation of neural tube formation in embryogenesis and utility as a potentially novel immunohistochemical marker of rosette formation in pulmonary neuroendocrine tumors

Neuroendocrine tumors can develop in various organs. All of these tumors are designated on the basis of their morphologic characteristics evident by light microscopy, and by immunohistochemistry for antigens such as synaptophysin, chromogranin-A, and CD56/NCAM. In the present study, we attempted to demonstrate the localization of Zonula occludens-1 (ZO-1) and N-cadherin in rosette structures of neuroendocrine tumors using immunohistochemistry and to clarify their specific distribution in rosettes in human pulmonary neuroendocrine tumors in comparison with various types of adenocarcinoma. Among 40 neuroendocrine tumors of the lung examined, 18 cases (45%) and 22 cases (55%) were positive for ZO-1 and N-cadherin, respectively. In addition, we divided the cases into two types: 16 cases of Flexner-type tumor and 24 cases of Homer-Wright-type tumor. We then determined the Rosette Index (RoI; the percentage fraction of rosette structures positive for ZO-1 or N-cadherin among the total number of rosette structures). The Flexner-type neuroendocrine tumors showed significantly higher levels of RoI in ZO-1 than the Homer-Wright-type neuroendocrine tumors (median; 38.8% vs 0%, p < 0.001). On the other hand, N-cadherin and ZO-1 were hardly detected in tubular adenocarcinomas in various organs, and their immunoreactivities differed significantly between adenocarcinoma and pulmonary neuroendocrine tumor (ZO-1, mean 0.23% vs 18%, p < 0.0001; N-cadherin, mean 0% vs 33%, p < 0.0001). In conclusion, expression of ZO-1 and N-cadherin may reflect the mechanisms leading to rosette formation in neuroendocrine tumors, which possibly recapitulate neural tube formation in embryogenesis and could represent a specific immunohistochemical marker for neuroendocrine carcinoma of the lung.

Expression of 4F2hc (CD98) in pulmonary neuroendocrine tumors

4F2hc (CD98) has been associated with tumor growth, and is highly expressed in various tumors. The aim of this study was to evaluate the clinicopathological significance of 4F2hc expression in pulmonary neuroendocrine (NE) tumors. Surgically-resected patient tumors including 16 large cell neuroendocrine carcinoma (LCNEC), 12 small cell lung cancer (SCLC), 1 atypical carcinoid (AC) and 5 typical carcinoid (TC) samples were included in this study. Tumor sections were immunohistochemically stained for 4F2hc (CD98), glucose transporter 1 (Glut1) and 3 (Glut3), hypoxia-inducible factor-1α (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessel density (CD34), epidermal growth factor receptor (EGFR), Akt/mammalian target of rapamycin (mTOR) signaling pathway (p-Akt, p-mTOR and p-S6K) and for a cell cycle regulator (p53). 4F2hc was overexpressed in 0% of the pulmonary carcinoids (TCs and ACs), 62.5% of the LCNECs and 50.0% of the SCLCs. A positive 4F2hc expression was significantly associated with age, histology and Glut1 expression. Moreover, a significant correlation was found between 4F2hc expression, and Glut1, HIF-1α, p-Akt, p-mTOR and p-S6K. The expression of 4F2hc was also significantly associated with poor overall survival. The expression of 4F2hc expression tended to increase from low-grade to high-grade pulmonary NE tumors. Our results suggest that 4F2hc may play a significant role in tumor progression, hypoxic conditions and poor outcome in patients with pulmonary NE tumors.

Evaluation of somatostatin receptors in large cell pulmonary neuroendocrine carcinoma with 99mTc-EDDA/HYNIC-TOC scintigraphy

Large cell pulmonary neuroendocrine carcinoma (LCNEC) is a poorly differentiated and high-grade neoplasm. It is positioned between an atypical carcinoid and small cell neuroendocrine carcinoma of the lung in a distinct family of pulmonary neuroendocrine tumors. The aim of our study was to detect somatostatin receptors in this uncommon malignancy and to evaluate the sensitivity of somatostatin receptor scintigraphy (SRS) in LCNEC staging. We analyzed data of 26 patients (mean age: 61.5±7.9 years) with histologically confirmed diagnosis of LCNEC, including 18 cases not treated surgically and eight patients after the resection of the primary tumor. SRS was carried out with technetium-99m ethylene diamine-diacetic acid/hydrazinonicotinyl-Tyr3-octreotide (Tc-TOC). A visual analysis of scintigraphic images was done with reference to conventional imaging modalities (computed tomography and bone sicintigraphy). SRS sensitivity for the detection of primary lesions, supradiaphragmatic metastases, and infradiaphragmatic metastases was 100, 83.3%, and 0%, respectively. Five out of 13 metastases to the liver appeared on SRS as photopenic foci, visible on the background of physiological hepatic activity. Only one of the nine metastases to the skeletal system was found by SRS with sensitivity as low as 11.1%. The overall SRS sensitivity for the detection of secondary lesions and of all lesions was 54.8 and 62.2%, respectively. Within a rather large series of LCNEC, the primary tumor showed an uptake of Tc-TOC in all cases, whereas some metastases did show Tc-TOC uptake and some others did not.

Erratum

HistopathologyVolume 58, Issue 5 p. 809-809 Free Access Erratum This article corrects the following: The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and non-neuroendocrine cell carcinomas Selim M H Rizvi, Joseph Goodwill, Eric Lim, Yoong K Yap, Athol U Wells, David M Hansell, Peter Davis, Syed Abdel-Ghani, Peter Goldstraw, Andrew G Nicholson, Volume 55Issue 3Histopathology pages: 332-337 First Published online: August 28, 2009 First published: 12 April 2011 https://doi.org/10.1111/j.1365-2559.2011.03850.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat DOI: 10.1111/j.1365-2559.2009.03371.x In Rizvi S M H et al., Dr. Syed Abdel-Ghani’s name should have appeared as: Abdel-Ghani Selim. We apologize for this error. Reference 1 Rizvi SMH, Goodwill J, Lim E et al. The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and non neuroendocrine cell carcinomas. Histopathology 2009; 55; 332– 337. Wiley Online LibraryPubMedWeb of Science®Google Scholar Volume58, Issue5April 2011Pages 809-809 ReferencesRelatedInformation

Non-epithelial ovarian tumours: a review of selected patterns that mimic epithelial tumours and other high-grade malignancies

Non-epithelial ovarian tumours exhibit a diverse array of growth patterns that can mimic epithelial ovarian cancers or other high-grade malignancies. This review highlights selected morphologic features that may assist in the differential diagnosis, as well as recent advances in immunohistochemistry. Steroidogenic factor-1 is a novel marker for sex cord-stromal differentiation and is useful in the diagnosis of granulosa cell tumour. SALL4 is a novel marker of primitive germ cell tumours and is useful in the diagnosis of yolk sac tumour. Distinction of primary versus metastatic origin of carcinoid tumour is important and gross and microscopic features are more accurate to this end than immunohistochemistry, except for the value of TTF-1 in pulmonary or cervical neuroendocrine tumours. Finally, unusual presentations of struma ovarii are also discussed, including proliferative struma, extra-ovarian struma, and carcinoma arising within struma ovarii.

PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma

PAX (paired box) genes encode a family of transcription factors that regulate organogenesis in a variety of organs. Very little is known about the role of PAX8 in endocrine cell development and the expression of PAX8 in neuroendocrine tumors. The purpose of this study was to analyze PAX8 immunohistochemical expression in gastroenteropancreatic and pulmonary well-differentiated neuroendocrine tumors to determine whether PAX8 can reliably distinguish pancreatic neuroendocrine tumors from neuroendocrine tumors of other anatomic sites and other pancreatic non-ductal neoplasms. In total, 221 well-differentiated neuroendocrine tumors were evaluated: 174 primary neuroendocrine tumors (66 pancreatic, 31 ileal, 21 pulmonary, 20 gastric, 17 rectal, 11 appendiceal, and 8 duodenal) and 47 neuroendocrine tumors metastatic to the liver (31 pancreatic, 11 ileal, 2 pulmonary, 2 duodenal, and 1 rectal). Fifteen solid-pseudopapillary neoplasms and six acinar cell carcinomas of the pancreas were also evaluated. PAX8 was positive in 49/66 (74%) primary pancreatic neuroendocrine tumors. PAX8 expression did not correlate with World Health Organization categorization, grade, size, functional status, or the presence of liver or lymph node metastasis. PAX8 expression was identified in 0/31 (0%) ileal, 0/21 (0%) pulmonary, 2/20 (10%) gastric, 5/17 (29%) rectal, 1/11 (9%) appendiceal, and 6/8 (75%) duodenal neuroendocrine tumors. PAX8 was positive in 4/15 (27%) solid-pseudopapillary neoplasms of the pancreas, whereas all acinar cell carcinomas (0/6) lacked immunoreactivity. Among liver metastases, only pancreatic neuroendocrine tumors (20/31, 65%) were PAX8 positive, whereas no cases of ileal (0/11), pulmonary (0/2), duodenal (0/2), and rectal (0/1) neuroendocrine tumor metastases were PAX8 positive. PAX8 is expressed in primary and metastatic pancreatic well-differentiated neuroendocrine tumors, and its expression can reliably distinguish pancreatic from ileal and pulmonary well-differentiated neuroendocrine tumors. Duodenal neuroendocrine tumors and a subset of rectal, gastric, and appendiceal neuroendocrine tumors may also express PAX8. PAX8 expression can distinguish pancreatic neuroendocrine tumors from acinar cell carcinomas, but its utility in distinguishing neuroendocrine tumors from solid-pseudopapillary neoplasms is limited.

Pulmonary neuroendocrine tumors: treatment need and new treatment options

Pulmonary neuroendocrine tumors: treatment need and new treatment options

Symptoms and diagnostics of lung neuroendocrine tumors

Pulmonary neuroendocrine tumors comprise 20% of all lung cancers. They are separated into 4 subgroups: typical carcinoid tumor, atypical carcinoid tumor, large-cell neuroendocrine carcinoma, and small-cell lung carcinoma. The major symptoms present in 60% of patients are cough, hemoptysis, and obstructive pneumonia. They may also exhibit hormonally related symptoms e.g. carcinoid syndrome. Small cell lung cancer is the most common subgroup, with rapid progression, aggressive metastatic potential and the worst prognosis. Large cell neuroendocrine carcinoma is rare but also has a poor prognosis. Typical carcinoid may be accompanied with hormone related symptoms and has the best prognosis; atypical one on the contrary may cause lymph node and distant metastases in half of the cases. Elevated plasma levels of chromogranin-A are present in majority of pulmonary neuroendocrine tumors and act as tumor marker. The mainstay of treatment is radical surgery if possible. In locally advanced or metastatic disease combination chemotherapy and somatostatin-analogues may have beneficial effect. This review focuses on the general features, and current diagnostic options of pulmonary neuroendocrine tumors.

PAX8 is expressed in pancreatic well‐differentiated neuroendocrine tumors and in extrapancreatic poorly differentiated neuroendocrine carcinomas in fine‐needle aspiration biopsy specimens

PAX (paired box) genes encode a family of transcription factors important for organogenesis. Recently, PAX8 has been recognized as a potential immunohistochemical marker of pancreatic neuroendocrine tumors. The authors evaluated PAX8 expression in fine-needle aspiration biopsies of neuroendocrine tumors to establish whether PAX8 immunohistochemistry can be used as an ancillary marker of pancreatic origin for neuroendocrine tumors. Fine-needle aspiration biopsies from 72 neuroendocrine tumors were evaluated for PAX8 expression: 32 primary and 23 metastatic well-differentiated neuroendocrine tumors (25 pancreatic, 13 pulmonary, 3 ileal, 2 duodenal, 1 rectal, 1 ovarian, and 10 primary site unknown) and 17 poorly differentiated neuroendocrine carcinomas (11 pulmonary, 1 pancreas, 1 breast, 1 thymus, and 3 primary site unknown). Among well-differentiated neuroendocrine tumors, only tumors from the pancreas were PAX8 positive (14 of 25, 56%) whereas no cases of pulmonary (0 of 13), ileal (0 of 3), duodenal (0 of 2), rectal (0 of 1), or ovarian (0 of 1) well-differentiated neuroendocrine tumors were positive for PAX8. One of 10 (10%) well-differentiated neuroendocrine tumors of unknown primary origin was PAX8 positive. Among poorly differentiated neuroendocrine carcinomas, PAX8 expression was identified in 1 of 1 (100%) pancreatic, 1 of 1 (100%) thymic, 4 of 11 (36%) pulmonary, and 0 of 1 (0%) breast carcinomas. One of 3 (33%) poorly differentiated neuroendocrine carcinomas of unknown primary origin was PAX8 positive. Pancreatic well-differentiated neuroendocrine tumors frequently express PAX8, which can help distinguish pancreatic primary tumors from tumors of other anatomic sites. In contrast, PAX8 expression in poorly differentiated neuroendocrine carcinomas is not specific for pancreatic origin and can be seen in extrapancreatic poorly differentiated neuroendocrine carcinomas.

TTF-1 positive small cell cancers: Don’t think they’re always primary pulmonary!

Thyroid transcription factor 1 (TTF-1) plays a key role in morphogenesis of the lungs and is expressed in up to 90% of pulmonary small cell carcinomas. This explains why this marker is frequently used in the search for the primary origin of metastatic endocrine tumours. Here we report on a TTF-1 expressing mixed endocrine-exocrine carcinoma of the common bile duct in a patient with pulmonary nodules that did not appear to be neoplastic. TTF-1 positivity in pulmonary and extrapulmonary neuroendocrine tumours is reviewed, and we conclude that TTF-1 expression in neuroendocrine tumours of the small-cell type are not uncommon at extrapulmonary locations. Therefore, immunohistochemistry for TTF-1 in such tumours should be interpreted with caution.

Abstract B22: Is there a role of estrogen and progesterone receptors in differentiating primary neuroendocrinal lung tumors from metastatic adenocarcinoma?

Abstract Background: The distinction between primary lung carcinoma and metastatic tumors is essential for patient management and treatment. However for metastatic tumors, a wedge resection is often the procedure of choice, whereas for primary pulmonary neoplasms the standard treatment is to perform at least a lobectomy with mediastinal lymph node sampling. Computed tomography scans, histology and immunohistochemical stains still have some limitations in differentiating primary neuroendocrinal lung tumors and metastatic adenocarcinoma. Estrogen and progesterone receptors, although more frequently immunoreactive in breast carcinomas and gynecologic tumors than in primary lung tumors, can be positive in metastatic pulmonary adenocarcinoma. Objective: To assess estrogen and progesterone receptor expression in primary pulmonary neuroendocrine tumors. Design: Fifty seven neuroendocrine lung neoplasms including small cell carcinomas (25), carcinoids (19), large cell neuroendocrine carcinomas (6), and combined small cell carcinomas (7) were evaluated in this cross-sectional study for estrogen and progesterone receptors. Lung metastasis from gynecologic tumors (27) and non-small cell lung carcinomas (30) were also stained for comparison. Settings: Chest and gynecology departments of Assuit and Woman's Health University hospitals. Results: Neuroendocrine primary lung neoplasm demonstrated focal to diffuse estrogen and progesterone expression. There was no correlation with the size of the tumor, the sex or the age of the patients. In comparison with neuroendocrine lung carcinomas, lung metastasis from gynecologic adenocarcinomas (20 endocervical cancer, 7 endometrial cancer) expressed estrogen and progesterone receptors more frequently (p&amp;lt;0.7). Non-small cell carcinomas had less immunoreactivity for estrogen and progesterone than primary neuroendocrinal lung tumors and gynelogic lung metastasis (p&amp;lt;0.4). Conclusions: Although estrogen and progesterone receptor staining is frequently associated with gynecologic tumors, it can also be observed in “nontarget” organs. Therefore, presence of estrogen and progesterone expression in lung metastasis from gynecologic adenocarcinomas should not exclude a primary pulmonary neoplasm. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B22.

Expression patterns of PAX5, c-Met, and paxillin in neuroendocrine tumors of the lung.

c-Met is important in the pathogenesis, invasion, and spread of several forms of lung cancer, and multiple c-Met inhibitors are undergoing clinical trials. PAX5 has been shown to upregulate c-Met in small cell lung carcinoma (SCLC), and coinhibiting PAX5 and c-Met had a synergic effect in killing tumor cells. Paxillin is a downstream target of activated c-Met, and its activation leads to enhanced cell motility and tumor spread. The expression patterns of these functionally related proteins have not, to our knowledge, been systemically studied in neuroendocrine tumors of the lung. To investigate the expression patterns of PAX5, paxillin, c-Met, and phosphorylated c-Met in 4 categories of pulmonary neuroendocrine tumors. Tissue microarrays of 38 typical carcinoids, 6 atypical carcinoids, 34 SCLCs, and 11 large cell neuroendocrine carcinomas were studied with immunohistochemistry. Most of the 4 tumor types expressed c-Met, phosphorylated c-Met, and paxillin. PAX5 was frequently expressed in atypical carcinoids, SCLCs, and large cell neuroendocrine carcinomas but tended to be negative in typical carcinoids. Coexpression of PAX5 with c-Met or phosphorylated c-Met was present in most of the atypical carcinoids, SCLCs, and large cell neuroendocrine carcinomas. Significant correlation between PAX5 and paxillin was detected in SCLCs and large cell neuroendocrine carcinomas but not in carcinoid tumors. The frequent coexpression of PAX5 with c-Met or phosphorylated c-Met in intermediate-grade and high-grade neuroendocrine tumors supports the therapeutic strategy of coinhibiting these proteins. The discrepancy between high-grade and low-grade neuroendocrine tumors in PAX5/paxillin expression correlation may be due to the different underlying molecular genetics of these tumors.

Expression Patterns of PAX5, c-Met, and Paxillin in Neuroendocrine Tumors of the Lung

c-Met is important in the pathogenesis, invasion, and spread of several forms of lung cancer, and multiple c-Met inhibitors are undergoing clinical trials. PAX5 has been shown to upregulate c-Met in small cell lung carcinoma (SCLC), and coinhibiting PAX5 and c-Met had a synergic effect in killing tumor cells. Paxillin is a downstream target of activated c-Met, and its activation leads to enhanced cell motility and tumor spread. The expression patterns of these functionally related proteins have not, to our knowledge, been systemically studied in neuroendocrine tumors of the lung. To investigate the expression patterns of PAX5, paxillin, c-Met, and phosphorylated c-Met in 4 categories of pulmonary neuroendocrine tumors. Tissue microarrays of 38 typical carcinoids, 6 atypical carcinoids, 34 SCLCs, and 11 large cell neuroendocrine carcinomas were studied with immunohistochemistry. Most of the 4 tumor types expressed c-Met, phosphorylated c-Met, and paxillin. PAX5 was frequently expressed in atypical carcinoids, SCLCs, and large cell neuroendocrine carcinomas but tended to be negative in typical carcinoids. Coexpression of PAX5 with c-Met or phosphorylated c-Met was present in most of the atypical carcinoids, SCLCs, and large cell neuroendocrine carcinomas. Significant correlation between PAX5 and paxillin was detected in SCLCs and large cell neuroendocrine carcinomas but not in carcinoid tumors. The frequent coexpression of PAX5 with c-Met or phosphorylated c-Met in intermediate-grade and high-grade neuroendocrine tumors supports the therapeutic strategy of coinhibiting these proteins. The discrepancy between high-grade and low-grade neuroendocrine tumors in PAX5/paxillin expression correlation may be due to the different underlying molecular genetics of these tumors.

A Comparison of the Clinical Presentation and Survival of Patients With Resected Primary Pulmonary Atypical Carcinoid Tumors to Typical Carcinoid and Other Pulmonary Neuroendocrine Tumors

A Comparison of the Clinical Presentation and Survival of Patients With Resected Primary Pulmonary Atypical Carcinoid Tumors to Typical Carcinoid and Other Pulmonary Neuroendocrine Tumors

Advances in neuroendocrine lung tumors

Pulmonary neuroendocrine (NE) tumors include a spectrum of tumors from the low-grade typical carcinoid (TC) and intermediate-grade atypical carcinoid (AC) to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC). Nodular NE proliferations ≥ 0.5 cm are classified as carcinoid tumors and smaller ones are called tumorlets. When NE cell hyperplasia and tumorlets are extensive they represent the rare preinvasive lesion for carcinoids known as diffuse idiopathic pulmonary NE cell hyperplasia. Carcinoid tumors have significant clinical, epidemiologic and genetic differences from the high-grade SCLC and LCNEC. Multiple endocrine neoplasia type I can be found in TC and AC patients but not those with LCNEC and SCLC. Also both LCNEC and SCLC can demonstrate histologic heterogeneity with other major histologic types of lung carcinoma such as adenocarcinoma or squamous cell carcinoma, but is not characteristic of TC or AC. Genetic changes are very high in SCLC and LCNEC, but usually low for TC, intermediate for AC. The diagnosis of SCLC, TC and AC can be made by light microscopy without the need for special tests in most cases, but for LCNEC it is required to demonstrate NE differentiation by immunohistochemistry or electron microscopy.