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1
Tamási, Lilla, and Veronika Müller. "Symptoms and diagnostics of lung neuroendocrine tumors." Orvosi Hetilap 152, no. 10 (March 2011): 366–70. http://dx.doi.org/10.1556/oh.2011.29041.
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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. Orv. Hetil., 2011, 152, 366–370.
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Miura, Kentaro, Kimihiro Shimizu, Shogo Ide, Shuji Mishima, Shunichiro Matsuoka, Tetsu Takeda, Takashi Eguchi, Kazutoshi Hamanaka, and Takeshi Uehara. "A Novel Strategy for the Diagnosis of Pulmonary High-Grade Neuroendocrine Tumor." Diagnostics 11, no. 11 (October 20, 2021): 1945. http://dx.doi.org/10.3390/diagnostics11111945.
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Correctly diagnosing a histologic type of lung cancer is important for selecting the appropriate treatment because the aggressiveness, chemotherapy regimen, surgical approach, and prognosis vary significantly among histologic types. Pulmonary NETs, which are characterized by neuroendocrine morphologies, represent approximately 20% of all lung cancers. In particular, high-grade neuroendocrine tumors (small cell lung cancer and large cell neuroendocrine tumor) are highly proliferative cancers that have a poorer prognosis than other non-small cell lung cancers. The combination of hematoxylin and eosin staining, Ki-67, and immunostaining of classic neuroendocrine markers, such as chromogranin A, CD56, and synaptophysin, are normally used to diagnose high-grade neuroendocrine tumors; however, they are frequently heterogeneous. This article reviews the diagnostic methods of lung cancer diagnosis focused on immunostaining. In particular, we describe the usefulness of immunostaining by Stathmin-1, which is a cytosolic phosphoprotein and a key regulator of cell division due to its microtubule depolymerization in a phosphorylation-dependent manner, for the diagnosis of high-grade neuroendocrine tumors.
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Kasajima, Atsuko, Yuichi Ishikawa, Ayaka Iwata, Katja Steiger, Naomi Oka, Hirotaka Ishida, Akira Sakurada, et al. "Inflammation and PD-L1 expression in pulmonary neuroendocrine tumors." Endocrine-Related Cancer 25, no. 3 (March 2018): 339–50. http://dx.doi.org/10.1530/erc-17-0427.
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In the light of novel cancer immune therapies, the status of antitumor inflammatory response and its regulation has gained much attention in patients with lung cancer. Ample datasets exist for non-small-cell lung cancer, but those for pulmonary neuroendocrine tumors are scarce and controversial. Here, tumor-associated inflammation, CD8+ cell infiltration and PD-L1 status were evaluated in a cohort of 57 resected carcinoids and 185 resected neuroendocrine carcinomas of the lung (58 large cell carcinomas and 127 small cell carcinomas). Data were correlated with clinicopathological factors and survival. Moderate or high tumor-associated inflammation was detected in 4 carcinoids (7%) and in 37 neuroendocrine carcinomas (20%). PD-L1 immunoreactivity was seen in immune cells of 73 (39%) neuroendocrine carcinomas, while tumor cells were labeled in 21 (11%) cases. Inflammatory cells and tumor cells in carcinoids lacked any PD-L1 expression. In neuroendocrine carcinomas, PD-L1 positivity in immune cells, but not in tumor cells, was associated with intratumoral CD8+ cell infiltration (P < 0.001), as well as with the severity of tumor-associated inflammation (P < 0.001). In neuroendocrine carcinomas, tumor-associated inflammation and PD-L1 positivity in immune cells correlated with prolonged survival and the latter factor was also an independent prognosticator (P < 0.01, hazard ratio 0.4 for overall survival,P < 0.001 hazard ratio 0.4 for disease-free survival). Taken together, in neuroendocrine tumors, antitumor inflammatory response and PD-L1 expression are largely restricted to neuroendocrine carcinomas, and in this tumor entity, PD-L1 expression in inflammatory cells is positively correlated to patient survival.
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Mouna, Bourhafour, Chekrine Tarik, Bouchbika Zineb, Benchakroun Nadia, Jouhadi Hassan, Tawfiq Nezha, Benider Abdellatif, and Sahraoui Souha. "NON SURGICAL TREATMENT OF CARCINOID LUNGS TUMORS." International Journal of Advanced Research 9, no. 12 (December 31, 2021): 647–51. http://dx.doi.org/10.21474/ijar01/13954.
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Typical carcinoid lungs tumors are neuroendocrine bronchopulmonary tumors with a low-grade malignancy, and an atypical carcinoid is an intermediate form of these tumors. Their systemic treatment is greatly influenced by therapeutic evidence derived from the more frequent gastroenteropancreatic neuroendocrine neoplasms. Currently, systemic therapies for lung carcinoids, aiming at controlling tumor growth include long acting somatostatin analogues (SSAs), peptide receptor radionuclide therapy, chemotherapy and molecular-targeted therapy.
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Chytaieva, Halyna, Bohdana Shkurupii, and Liubov Zakhartseva. "Correlation between expression of immunohistochemical markers and morphology in lung neuroendocrine neoplasms." Ukrainian Scientific Medical Youth Journal 128, no. 1 (March 27, 2022): 6–18. http://dx.doi.org/10.32345/usmyj.1(128).2022.6-18.
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lung neuroendocrine neoplasms embrace rather heterogeneous and rare malignancies which are usually characterized by nonspecific, “blurred” clinical signs thus complicating correct diagnosis or seriously delays it. Pulmonary neuroendocrine neoplasms accurate diagnostics and classification need to be improved. Histological examination should be supplemented by immunohistochemical tests to verify the neuroendocrine component, assess proliferative index of tumor cells, and confirm its bronchopulmonary origin. Immunohistochemistry is especially important in case of small or crushed biopsies, which account more than 50% of all specimens in lungs neuroendocrine neoplasms. Modern classification of lung neuroendocrine neoplasms and their grading are based on morphological criteria. Immunohistochemical markers expression is quite variable in different histological subtypes of bronchopulmonary neuroendocrine neoplasms, often data are descriptive, and correlation with morphology is studied insufficiently. The aim of this study was to define any significant correlation between different immunohistochemical markers expression, necrosis, proliferative index (Ki-67 ratio), and tumor grade in broncho-pulmonary neuroendocrine neoplasms. Histological blocks of lung neuroendocrine neoplasms from 113 unique patients (36 resections and 77 biopsies (54.5% of biopsies appeared to be small or crushed) were used in this study. The sample comprised 91 male and 22 female patients; the mean age was 59.2, CI 95% (56.9–61.4) years (from 19 to 77 years). Histological examination (including neuroendocrine morphology, necrosis, and grade) was provided in all cases. Also, immunohistochemistry, using Chr A, Syn, CD56, TTF-1, CK7, and Ki-67 before chemotherapy was performed. All morphological and immunohistochemical data were assessed by two different independent pathologists without the access to patient’s clinical data. All the observations were classified based on 2021 WHO Thoracic Tumors Classification. The sample was censored. We used nonparametric statistics (Spearman’s rank correlation) for this study. In was found that Chr A expression strongly (p<0.05) correlated with immunohistochemical markers of primary lung malignancies (TTF-1 and CK7) that are mainly expressed in highly and moderately differentiated neuroendocrine neoplasms. Also, positive expression for TTF-1 and CK7 correlated with each other (p<0.01). There was a strong negative correlation (p<0.05) between Chr A staining and necrosis presence and it’s severity; between Chr A expression and tumor cells proliferation (Ki-67 ratio) (p<0.01); and between Chr A labeling and tumor grade (p<0.01). The correlation of immunohistochemical markers expression with necrosis, Ki-67 ratio and tumor grade was significant only for Chr A. All other tested options, for other markers were not statistically significant. It was defined that decrease or loss of Chr A expression reliably indicates tumors progression. Chr A expression can be used as an additional tool for grading of lung neuroendocrine neoplasms.
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Slodkowska, J., J. Zych, M. Szturmowicz, U. Demkow, E. Rowinska-Zakrzewska, and K. Roszkowski-Sliz. "Neuroendocrine Phenotype of Non-Small Cell Lung Carcinoma: Immunohistological Evaluation and Biochemical Study." International Journal of Biological Markers 20, no. 4 (October 2005): 217–26. http://dx.doi.org/10.1177/172460080502000404.
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Aims and methods The prevalence and distribution of neuroendocrine differentiation in non-small cell lung cancer (NSCLC) was estimated by assays for synaptophysin (SYN), chromogranin A (CgA), Leu7 and neuron-specific enolase (NSE). Serum NSE and CgA were determined in parallel to find the values of these markers for distinguishing neuroendocrine differentiation in NSCLC. Fifty-eight resected NSCLC specimens and 34 sera of NSCLC patients entered the study. Neuroendocrine differentiation was graded according to the percentage of neuroendocrine tumor cells as NE0 – 0%, NE1–NE4 – 1%->76%. Serum NSE <12.5 ng/mL and serum CgA <46 U/L were taken as cutoff levels. Results 63.8% (37/58) of NSCLC were scored as NE1–NE4 according to the SYN, CgA and Leu7 levels; 34.5% as NE1; 29.3% as NE2–NE4. 56.8% of tumors were positive for SYN, 34.4% for CgA, 22.4% for Leu7, and 79.3% for NSE. A significant relationship was found between tumor SYN and tumor CgA expression, and between tumor SYN expression and tumor stage. Adenocarcinomas showed a significantly higher rate of neuroendocrine differentiation than squamous cell carcinomas. All normal serum CgA levels corresponded to a lack of CgA expression in the tumors. The increased serum NSE levels presented by 26% of NSCLC patients (mainly <16 ng/mL) did not correlate with tumor NSE expression. Conclusions The prevalence of neuroendocrine differentiation in NSCLC varies and depends on the immunohistochemical criteria used; this warrants standardization of the immunohistochemical criteria for neuroendocrine differentiation in NSCLC. NSE expression in the tumor and a mild increase in serum NSE are poor markers for distinguishing neuroendocrine differentiation in NSCLC.
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Travis, William D., Anthony A. Gal, Thomas V. Colby, David S. Klimstra, Roni Falk, and Michael N. Koss. "Reproducibility of neuroendocrine lung tumor classification." Human Pathology 29, no. 3 (March 1998): 272–79. http://dx.doi.org/10.1016/s0046-8177(98)90047-8.
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Song, Jie, Mei Li, Maria Tretiakova, Ravi Salgia, Philip T. Cagle, and Aliya N. Husain. "Expression Patterns of PAX5, c-Met, and Paxillin in Neuroendocrine Tumors of the Lung." Archives of Pathology & Laboratory Medicine 134, no. 11 (November 1, 2010): 1702–5. http://dx.doi.org/10.5858/2009-0664-oar1.1.
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Abstract Context.—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. Objective.—To investigate the expression patterns of PAX5, paxillin, c-Met, and phosphorylated c-Met in 4 categories of pulmonary neuroendocrine tumors. Design.—Tissue microarrays of 38 typical carcinoids, 6 atypical carcinoids, 34 SCLCs, and 11 large cell neuroendocrine carcinomas were studied with immunohistochemistry. Results.—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. Conclusions.—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.
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Kumar, Kishore, Rafeeq Ahmed, Chime Chukwunonso, Hassan Tariq, Masooma Niazi, Jasbir Makker, and Ariyo Ihimoyan. "Poorly Differentiated Small-Cell-Type Neuroendocrine Carcinoma of the Prostate: A Case Report and Literature Review." Case Reports in Oncology 11, no. 3 (October 31, 2018): 676–81. http://dx.doi.org/10.1159/000493255.
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Neuroendocrine cells are widespread throughout the body and can give rise of neuroendocrine tumors due to abnormal growth of the chromaffin cells. Neuroendocrine tumors divide into many subtypes based on tumor grade (Ki-67 index and mitotic count) and differentiation. These tumors can be further divided into secretory and nonsecretory types based on the production of peptide hormone by tumor cells. Poorly differentiated small-cell-type neuroendocrine tumors are one of the subtypes of neuroendocrine tumors. These tumors are less common; however, they tend to be locally invasive and aggressive in behavior with poor overall median survival. Treatment of the nonsecretory small-cell type is modeled to small-cell lung cancer with a regimen consisting of platinum-based chemotherapy and etoposide with variable response. Here, we present a case of poorly differentiated small-cell neuroendocrine tumor originating from the prostate.
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Børglum, Tine, Jens F. Rehfeld, Lars B. Drivsholm, and Linda Hilsted. "Processing-Independent Quantitation of Chromogranin A in Plasma from Patients with Neuroendocrine Tumors and Small-Cell Lung Carcinomas." Clinical Chemistry 53, no. 3 (March 1, 2007): 438–46. http://dx.doi.org/10.1373/clinchem.2006.076158.
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Abstract Background: Most neuroendocrine tumors express chromogranin A (CgA). The posttranslational processing of neuroendocrine proteins such as CgA is often specific for the individual tumor. To cope with this variability and improve tumor diagnosis, we developed a processing-independent analysis (PIA) method to measure the total CgA product. Methods: For PIA, samples underwent trypsin treatment followed by measurement of CgA by the “CgA(340→)” assay, in which the antiserum binds an epitope starting at amino acid 340 of CgA and including amino acid residues located in the C-terminal direction. The diagnostic accuracy of the CgA PIA and 3 sequence-specific assays for CgA were evaluated on plasma samples from patients with neuroendocrine tumors and small-cell lung carcinomas. Furthermore, we investigated whether the CgA plasma concentrations correlated with the tumor burden. Results: Size-exclusion chromatography of plasma showed that CgA immunoreactivity mainly consisted of high–molecular-weight forms, indicating that neuroendocrine tumors may secrete large amounts of poorly processed CgA. Accordingly, trypsination of plasma from 54 patients with neuroendocrine tumors or small-cell lung carcinomas increased the CgA(340→) immunoreactivity up to 500-fold. Both the CgA(340→) assay and the PIA measured significantly higher plasma concentrations in patients with very extensive disease than in patients with less widespread disease. The diagnostic sensitivity was 0.91 when using the CgA(340→) assay and 0.82 using the CgA PIA. Conclusion: The CgA(340→) assay and CgA PIA are both useful for diagnosis of neuroendocrine tumors and small-cell lung carcinomas and both assays correlate with tumor burden.
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Grygoruk, O. G., D. A. Tsoi, L. M. Bazulina, and I. V. Vihlyanov. "Small‑cell lung carcinoma. Cytological diagnosis." Malignant tumours 12, no. 1 (April 8, 2022): 36–43. http://dx.doi.org/10.18027/2224-5057-2022-12-1-36-43.
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The purpose of this article is to evaluate the possibilities of cytology for lung neuroendocrine tumors (small‑cell lung carcinoma and carcinoids) diagnostics. Cytology specimens obtained by bronchoscopy (n = 112), biopsy of metastatic lymph nodes (n = 27) or from pleural effusion (n = 8) were collected within over 1 year from 147 patients and studied. Small-cell lung carcinoma was diagnosed in 143 patients, representing 23,9 % of all lung carcinomas. The proportion of carcinoid tumors was 2,7 % of all neuroendocrine tumors. Typical carcinoid was observed in three cases, and atypical carcinoid — in one case. Cytologic features most significant for cytological diagnosis of small‑cell lung carcinoma and carcinoids were identified (n = 11). Discriminant analysis demonstrated that the proportion of accurate cytological diagnosis of small‑cell lung carcinoma and carcinoids was 96,69 %. Cytology is a reliable method for neuroendocrine tumor diagnosis. Immunocytochemistry with neuroendocrine markers along with light microscopy should be used to differentiate small‑cell lung carcinoma metastases from other tumors and non‑malignant pathology in pleural effusion specimens.
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Broaddus, Russell R., Cynthia E. Herzog, and M. John Hicks. "Neuroendocrine Tumors (Carcinoid and Neuroendocrine Carcinoma) Presenting at Extra-appendiceal Sites in Childhood and Adolescence." Archives of Pathology & Laboratory Medicine 127, no. 9 (September 1, 2003): 1200–1203. http://dx.doi.org/10.5858/2003-127-1200-ntcanc.
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Abstract Objective.—Epithelial neuroendocrine neoplasms arising outside the appendix are extremely rare in the pediatric population. We reviewed the clinicopathologic characteristics of 13 carcinoid tumors and neuroendocrine carcinomas presenting at extra-appendiceal sites to better characterize this rare set of neoplasms in childhood. Design.—The pathology archives of M. D. Anderson Cancer Center and Texas Children's Hospital were searched for cases of carcinoid tumor and neuroendocrine carcinoma arising at extra-appendiceal sites in children. Hematoxylin-eosin–stained sections and, when available, immunohistochemistry, electron photomicrographs and gross photographs were reviewed. The tumors were classified as either carcinoid tumor or neuroendocrine carcinoma based upon histopathologic features. Demographic information was obtained from review of the surgical pathology reports, autopsy reports, and clinical charts. Patients.—The study population included 8 males and 5 females, ranging in age from 8 to 18 years. Results.—The majority of the cases were classified as carcinoid tumors (8/13), with the remainder being neuroendocrine carcinomas (5/13). The lung was the initial site of presentation in most children (6/13). The liver was the next most common site (5/13) of tumor presentation with no other primary site identified. Neuroendocrine carcinoma within an inguinal lymph node, with no primary tumor site identified, was present in a single case. The final case was a neuroendocrine carcinoma with widespread involvement of multiple organs with no definitive primary site identified. Conclusion.—Carcinoid tumors and neuroendocrine carcinomas presenting at extra-appendiceal sites in children primarily involve the lungs or liver. These neuroendocrine neoplasms have the ability to metastasize, regardless of histology at initial diagnosis.
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Westerman, B. A., R. H. J. Breuer, A. Poutsma, A. Chhatta, L. A. Noorduyn, M. G. J. Koolen, P. E. Postmus, M. A. Blankenstein, and C. B. M. Oudejans. "Basic Helix-Loop-Helix Transcription Factor Profiling of Lung Tumors Shows Aberrant Expression of the Proneural Gene Atonal Homolog 1 (ATOH1, HATH1, MATH1) in Neuroendocrine Tumors." International Journal of Biological Markers 22, no. 2 (April 2007): 114–23. http://dx.doi.org/10.1177/172460080702200205.
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Microarray-based expression profiling studies of lung adenocarcinomas have defined neuroendocrine subclasses with poor prognosis. As neuroendocrine development is regulated by members of the achaetescute and atonal classes of basic helix-loop-helix (bHLH) transcription factors, we analyzed lung tumors for expression of these factors. Out of 13 bHLH genes tested, 4 genes, i.e., achaetescute complex-like 1 (ASCL1, HASH1, Mash1), atonal homolog 1 (ATOH1, HATH1, MATH1), NEUROD4 (ATH-3, Atoh3, MATH-3) and neurogenic differentiation factor 1 (NEUROD1, NEUROD, BE-TA2), showed differential expression among lung tumors and absent or low expression in normal lung. As expected, tumors that have high levels of ASCL1 also express neuroendocrine markers, and we found that this is accompanied by increased levels of NEUROD1. In addition, we found ATOH1 expression in 9 (16%) out of 56 analyzed adenocarcinomas and these tumors showed neuroendocrine features as shown by dopa decarboxylase mRNA expression and immunostaining for neuroendocrine markers. ATOH1 expression as well as NEUROD4 was observed in small cell lung carcinoma (SCLC), a known neuroendocrine tumor. Since ATOH1 is not known to be involved in normal lung development, our results suggest that aberrant activation of ATOH1 leads to a neuroendocrine phenotype similar to what is observed for ASCL1 activation during normal neuroendocrine development and in lung malignancies. Our preliminary data indicate that patients with ATOH1-expressing adenocarcinomas might have a worse prognosis.
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Christopher S, Hong, Adam J. Kundishora, Aladine A. Elsamadicy, Andrew B. Koo, Jason M. Beckta, Declan McGuone, E. Zeynep Erson-Omay, and Sacit Bulent Omay. "Genetic characterization of a case of sellar metastasis from bronchial carcinoid neuroendocrine tumor." Surgical Neurology International 11 (September 25, 2020): 303. http://dx.doi.org/10.25259/sni_265_2020.
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Background: Metastasis to the pituitary gland from neuroendocrine tumors is a rare occurrence that may originate from primary tumors the lung, gastrointestinal tract, thyroid, and pancreas, among others. Patients may present with signs of endocrine dysfunction secondary to pituitary involvement, as well as mass effect-related symptoms including headaches and visual deficits. Despite a small but accumulating body of literature describing the clinical and histopathological correlates for pituitary metastases from neuroendocrine tumors, the genetic basis underlying this presentation remains poorly characterized. Case Description: We report the case of a 68-year-old with a history of lung carcinoid tumor who developed a suprasellar lesion, causing mild visual deficits but otherwise without clinical or biochemical endocrine abnormalities. She underwent endoscopic endonasal resection of her tumor with final pathology confirming metastasis from her original neuroendocrine tumor. Whole-exome sequencing was performed on the resected sellar tumor and matching blood, revealing increased genomic instability and key mutations in PTCH1 and BCOR that have been previously implicated in both systemic neuroendocrine and primary pituitary tumors with potentially actionable therapeutic targets. Conclusion: This is the first genomic characterization of a metastatic tumor to the sella and reports potential genetic insight, implicating PTCH1 and BCOR mutations, into the pathophysiology of sellar metastasis from primary systemic tumors.
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Ibrahim, Mohd Elmugtaba, Kerolos Abadeer, Qihui (Jim) Zhai, and Aziza Nassar. "Primary Hepatic Neuroendocrine Tumor with Unusual Thyroid Follicular-Like Morphologic Characteristics." Case Reports in Pathology 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/7931975.
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We describe a primary hepatic neuroendocrine tumor of a 57-year-old Thai woman who presented in 2004 with a suspicious mass in the left hepatic lobe. She underwent left hepatectomy for the 10.5-cm mass, calledintermediate grade neuroendocrine carcinoma of unknown origin,likely metastatic. The tumor recurred in 2007, then calledrecurrent primary hepatic neuroendocrine tumor(PHNET), and the patient underwent liver transplant. Because of similarity between the neuroendocrine tumor and a thyroid tumor—specifically, follicular-like characteristics—immunohistochemical stains for thyroglobulin, TTF1, and calcitonin were performed. However, all were negative. All imaging studies revealed no evidence of a primary lesion other than the liver mass. In 2008, the patient’s liver transplant failed because of ischemic cholangiopathy, and she underwent a second liver transplant. Seven years later, in 2015, she presented with metastatic neuroendocrine tumor of intermediate grade to the lung, consistent with metastatic PHNET. She underwent left upper-lobe wedge resection to remove the tumor. The patient is alive with no evidence of disease at 13 years after initial diagnosis. This rare variant of PHNET had thyroid-like morphologic characteristics but there is no evidence of primary thyroid tumor or thyroid markers in the primary and recurrent hepatic tumors and lung metastasis.
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HONG, SEUNG-KEUN, JIN-HWAN KIM, DMYTRO STARENKI, and JONG-IN PARK. "Autophagy sensitivity of neuroendocrine lung tumor cells." International Journal of Oncology 43, no. 6 (October 11, 2013): 2031–38. http://dx.doi.org/10.3892/ijo.2013.2136.
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Lorz, Corina, Marta Oteo, and Mirentxu Santos. "Neuroendocrine Lung Cancer Mouse Models: An Overview." Cancers 13, no. 1 (December 22, 2020): 14. http://dx.doi.org/10.3390/cancers13010014.
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Neuroendocrine lung tumors comprise a range of malignancies that extend from benign tumorlets to the most prevalent and aggressive Small Cell Lung Carcinoma (SCLC). They also include low-grade Typical Carcinoids (TC), intermediate-grade Atypical Carcinoids (AC) and high-grade Large Cell Neuroendocrine Carcinoma (LCNEC). Optimal treatment options have not been adequately established: surgical resection when possible is the choice for AC and TC, and for SCLC chemotherapy and very recently, immune checkpoint inhibitors. Some mouse models have been generated based on the molecular alterations identified in genomic analyses of human tumors. With the exception of SCLC, there is a limited availability of (preclinical) models making their development an unmet need for the understanding of the molecular mechanisms underlying these diseases. For SCLC, these models are crucial for translational research and novel drug testing, given the paucity of human material from surgery. The lack of early detection systems for lung cancer point them out as suitable frameworks for the identification of biomarkers at the initial stages of tumor development and for testing molecular imaging methods based on somatostatin receptors. Here, we review the relevant models reported to date, their impact on the understanding of the biology of the tumor subtypes and their relationships, as well as the effect of the analyses of the genetic landscape of the human tumors and molecular imaging tools in their development.
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Pelosi, Giuseppe, Mauro Papotti, Guido Rindi, and Aldo Scarpa. "Unraveling Tumor Grading and Genomic Landscape in Lung Neuroendocrine Tumors." Endocrine Pathology 25, no. 2 (April 26, 2014): 151–64. http://dx.doi.org/10.1007/s12022-014-9320-0.
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Rekhtman, Natasha. "Lung neuroendocrine neoplasms: recent progress and persistent challenges." Modern Pathology 35, S1 (October 18, 2021): 36–50. http://dx.doi.org/10.1038/s41379-021-00943-2.
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AbstractThis review summarizes key recent developments relevant to the pathologic diagnosis of lung neuroendocrine neoplasms, including carcinoids, small cell lung carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC). Covered are recent insights into the biological subtypes within each main tumor type, progress in pathological diagnosis and immunohistochemical markers, and persistent challenging areas. Highlighted topics include highly proliferative carcinoids and their distinction from small cell and large cell neuroendocrine carcinomas (NECs), the evolving role of Ki67, the update on the differential diagnosis of NEC to include thoracic SMARCA4-deficient undifferentiated tumors, the recent data on SCLC transcriptional subtypes with the emergence of POU2F3 as a novel marker for the diagnosis of SCLC with low/negative expression of standard neuroendocrine markers, and the update on the diagnosis of LCNEC, particularly in biopsies. There has been remarkable recent progress in the understanding of the genetic and expression-based profiles within each type of lung neuroendocrine neoplasm, and it is hoped that these insights will enable the development of novel diagnostic, prognostic, and predictive biomarkers to aid in the pathologic assessment of these tumors in the future.
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Cui, Min, Zhenjian Cai, Amad Awadallah, and Wei Xin. "Uniform and Robust Nuclear Expression of HES1 in Neuroendocrine Neoplasms." International Journal of Surgical Pathology 27, no. 8 (June 24, 2019): 844–51. http://dx.doi.org/10.1177/1066896919854166.
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Introduction. Neuroendocrine neoplasms (NENs) are neoplasms that most commonly arise from gastrointestinal tract, pancreas, and lung. HES1 is a downstream target of Notch signaling pathway. The current literature about HES1 expression in NENs is sparse and inconsistent. Methods. In this study, we evaluated HES1 expression by immunohistochemistry in a total of 32 cases of NENs, including 13 well-differentiated neuroendocrine tumors from gastrointestinal tract, 10 cases of well-differentiated neuroendocrine tumors of pancreas, 9 cases from lung, including 4 cases of typical carcinoid, 1 case of atypical carcinoid, and 4 cases of neuroendocrine carcinoma. The intensity of the stain was scored from − to +++, and the distribution of the staining of HES1 was evaluated. Results. HES1 demonstrates uniform robust (+++) nuclear staining pattern in the tumor cells of all the NENs (32/32), regardless of the origin of the system and the grade of the tumor. Conclusions. HES1 is uniformly expressed in NENs with robust nuclear expression pattern. Our finding suggests that NOTCH1 or HES1 inhibitor is a potential therapeutic choice for neuroendocrine neoplasms.
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Rosen, Lauren Elizabeth, and Paolo Gattuso. "Neuroendocrine Tumors of the Breast." Archives of Pathology & Laboratory Medicine 141, no. 11 (November 1, 2017): 1577–81. http://dx.doi.org/10.5858/arpa.2016-0364-rs.
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Primary neuroendocrine tumors of the breast are a rare and underrecognized subtype of mammary carcinoma. Neuroendocrine tumors of the breast occur predominately in postmenopausal women. The tumors are subclassified into well-differentiated and poorly differentiated neuroendocrine tumors, and invasive breast carcinoma with neuroendocrine features. Well-differentiated tumors show architectural similarity to carcinoids of other sites but lack characteristic neuroendocrine nuclei. Poorly differentiated neuroendocrine tumors are morphologically identical to small cell carcinoma of the lung. Neuroendocrine differentiation, seen in up to 30% of invasive breast carcinomas, is most commonly associated with mucinous and solid papillary carcinomas. The diagnosis of neuroendocrine differentiation requires expression of the neuroendocrine markers synaptophysin or chromogranin. The main differential diagnosis is a metastatic neuroendocrine tumor from an extramammary site. Neuroendocrine tumors of the breast are treated similarly to other invasive breast carcinomas. Although no consensus has been reached on the prognosis, most studies suggest a poor outcome.
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Szabó, Attila, Péter Igaz, Róbert Kiss, Gergely Lakatos, Ibolya Varga, and Károly Rácz. "Ectopic ACTH-secreting neuroendocrine tumor." Orvosi Hetilap 152, no. 10 (March 2011): 403–6. http://dx.doi.org/10.1556/oh.2011.29053.
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The authors report a case of an ectopic ACTH-syndrome that resulted in severe hypercortisolism, hypokalemia, diabetes mellitus and osteoporosis. The ACTH-secreting tumor tissue was localized in the lung. The tumor was removed by segmentectomy and histological evaluation revealed an ACTH-secreting neuroendocrine tumor. After surgery, however, plasma cortisol and ACTH levels failed to decrease significantly due to subtotal tumor removal. Long-acting somatostatin analogue therapy resulted in a normalization of both plasma cortisol and ACTH levels and the clinical symptoms improved significantly. Residual tumor was removed by repeat surgery and the patient was permanently cured. Orv. Hetil., 2011, 152, 403–406.
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Katsetos, Christos D., George Kontogeorgos, Jennian F. Geddes, Mary M. Herman, Hera Tsimara-Papastamatiou, Yunxia Yu, Lazaros I. Sakkas, et al. "Differential Distribution of the Neuron-Associated Class III β-Tubulin in Neuroendocrine Lung Tumors." Archives of Pathology & Laboratory Medicine 124, no. 4 (April 1, 2000): 535–44. http://dx.doi.org/10.5858/2000-124-0535-ddotna.
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AbstractObjective.—To study the immunoreactivity profile of the neuron-associated class III β-tubulin isotype (β III) in epithelial lung tumors.Design.—One hundred four formalin-fixed, paraffin-embedded primary and metastatic lung cancer specimens were immunostained with an anti–β III mouse monoclonal antibody (TuJ1) and an anti–β III affinity-purified rabbit antiserum. Paraffin sections from fetal, infantile, and adult nonneoplastic lung tissues were also examined.Results.—In the fetal airway epithelium, β III staining is detected transiently in rare Kulchitsky-like cells from lung tissues corresponding to the pseudoglandular and canalicular but not the saccular or alveolar stages of development. β III is absent in healthy, hyperplastic, metaplastic, and dysplastic airway epithelium of the adult lung. In contrast, β III is highly expressed in small cell lung cancer, large cell neuroendocrine carcinoma, and in some non–small cell lung cancers, particularly adenocarcinomas. There is no correlation between expression of β III and generic neuroendocrine markers, such as chromogranin A and/or synaptophysin, in pulmonary adenocarcinomas. Also, focal β III staining is present in primary and metastatic adenocarcinomas (to the lung) originating in the colon, prostate, and ovary. β III is expressed to a much lesser extent in atypical carcinoids and is rarely detectable in typical carcinoids and squamous cell carcinomas of the lung. The distribution of β III in small cell lung cancer and adenocarcinoma metastases to regional lymph nodes and brain approaches 100% of tumor cells, which is substantially greater than in the primary tumors.Conclusions.—In the context of neuroendocrine lung tumors, β III immunoreactivity is a molecular signature of high-grade malignant neoplasms (small cell lung cancer and large cell neuroendocrine carcinoma) although its importance in atypical carcinoids must be evaluated further. In addition, β III may be a useful diagnostic marker in distinguishing between small cell lung cancers and certain non–small cell lung cancers (poorly differentiated squamous cell carcinomas), especially in small biopsy specimens. To our knowledge, β III is the only tumor biomarker that exhibits a substantially more widespread distribution in poorly differentiated than in better differentiated pulmonary neuroendocrine tumors. However, the significance of β III phenotypes in non–small cell lung cancer, particularly adenocarcinoma, with respect to neuroendocrine differentiation and prognostic value, requires further evaluation.
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Barbareschi, Mattia, Cesare Mariscotti, Massimo Barberis, Barbara Frigo, and Leonardo Mosca. "Large Cell Neuroendocrine Carcinoma of the Lung." Tumori Journal 75, no. 6 (December 1989): 583–88. http://dx.doi.org/10.1177/030089168907500614.
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Large cell neuroendocrine (LCNE) carcinomas of the lung are a newly recognized, highly aggressive and frequently misdiagnosed entity. We report a case of stage I LCNE lung carcinoma initially misdiagnosed as large cell undifferentiated carcinoma or poorly differentiated adenocarcinoma. The tumor was very extensively necrotic and its neuroendocrine differentiation was only demonstrable with immunohistochemical staining with PHE-5 monoclonal antibody and with antisera against synaptophysin and calcitonin. ACTH, somatostatin and neurofilaments were not demonstrable. The clinical course was ominous and the patient died within 17 months. The reason for this rapid fatal outcome could be ascribed either to the neuroendocrine phenotype of the tumor, or to the extensive necrosis, or both.
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Delektorskaya, Vera, Andrey Komelkov, Irina Zborovskaya, Yelena Chevkina, A. Yenikeev, and V. Safronova. "NUCLEAR LOCALIZATION OF CRABP1 IN NEUROENDOCRINE LUNG TUMORS IS ASSOCIATED WITH THE DEGREE OF TUMOR MALIGNANCY." Problems in oncology 63, no. 6 (June 1, 2017): 886–93. http://dx.doi.org/10.37469/0507-3758-2017-63-6-886-893.
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Bronchopulmonary neuroendocrine tumors (NETs) refer to malignant epithelial neoplasms of neuroendocrine origin, which form highly heterogeneous group with respect to biological behavior and clinical manifestations. Three main categories of different grades of malignancy are distinguished in the diagnosis of lung NETs: typical carcinoids (TK), atypical carcinoids (AK) and the most aggressive low-differentiated tumors including small-cell and large-cell neuroendocrine lung carcinomas. These groups differ in terms of disease prognosis and therapeutic approaches, but the criteria currently used do not always allow clear boundaries between different histological variants. The search for additional diagnostic parameters and individual prognosis markers is currently actual for the grading and optimal classification of NETs. For the first time we studied the expression of Retinoic Acid Binding Protein-1 (CRABP1) in different variants of lung NETs. IHC analysis of 43 samples of lung NETs with various degrees of differentiation and grades revealed the statistically significant correlation between nuclear localization of CRABP1 and proliferation index «Ki-67» and tumor grade. The results pointed on the involvement of CRABP1 in the pathogenesis of lung NETs and indicated the need for further investigation of the relationship of the nuclear CRABP1 with clinical parameters and patient survival to determine whether this protein can be used as a marker for differential diagnosis and/or disease prognosis.
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Karpina, N. L., L. N. Lepekha, R. B. Amansakhedov, O. M. Gordeeva, A. V. Dudchenko, and A. E. Ergeshov. "A COMPLEX CASE OF DIFFERENTIAL DIAGNOSIS OF PULMONARY TUBERCULOSIS AND A NEUROENDOCRINE TUMOR." Journal of radiology and nuclear medicine 99, no. 5 (December 1, 2018): 259–63. http://dx.doi.org/10.20862/0042-4676-2018-99-5-259-263.
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Pathomorphosis of tuberculosis and other lung diseases that have a similar clinical radiological and morphological picture leads to considerable difficulties and mistakes in the differential diagnosis of pulmonary processes. In particular, there are difficulties in the differential diagnosis of neuroendocrine lung tumors (NET) and pulmonary tuberculosis.A clinical case of timely diagnosis of a neuroendocrine tumor in a young female patient without clinical symptoms typical for NETs has been described. The main manifestations revealed by chest CT scanning were single focal consolidations. The diagnosis was confirmed by histological studies of surgery samples.
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Starr, Jason Scott, Kabir Mody, Ali Roberts, and Pashtoon Murtaza Kasi. "Circulating tumor DNA analysis of neuroendocrine tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15698-e15698. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15698.
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e15698 Background: Neuroendocrine tumors (NETs) and carcinomas (NECs) are a diverse group of tumors with an equally diverse biology and clinical behavior. Data on tissue-based genomic profiling of NETs exists, however, there is limited data using circulating tumor DNA (ctDNA) technology. We sought out to characterize NETs via ctDNA to identify genomic alterations. Methods: 27 patients with metastatic NET/NEC with 32 total plasma samples were analyzed using Guardant360 ctDNA assay. Breakdown of NET/NEC by location: 14 pancreatic NET (pNET), 11 NEC, 1 small bowel NET, 1 lung NET. The ctDNA test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: Of the 27 patients, 19 (70%) had a detectable genomic alteration. The detectable (non-synonymous) alterations are as follows: TP53 (n = 14, 70%), NF1 (n = 8, 40%), EGFR (n = 5, 25%), BRCA2 (n = 4, 20%), KRAS (n = 4, 20%), ARID1A (n = 3, 15%), CDK6 (n = 3, 15%), ALK (n = 3, 15%), MET (n = 2, 10%), PTEN (n = 2, 10%), BRAF (n = 2, 10%), MTOR (n = 2, 10%) AKT1 (n = 1), BRCA1 (n = 1), CCND2 (n = 1), CCNE1 (n = 1), CTNNB1 (n = 1), ESR1 (n = 1), FGFR2 (n = 1), HRAS (n = 1), IDH1 (n = 1), KIT (n = 1), MYC (n = 1), NOTCH1 (n = 1), NRAS (n = 1), PDGFRA (n = 1), RAF1 (n = 1), RB1 (n = 1), SMAD4 (n = 1), STK11 (n = 1), TSC1 (n = 1), ERBB2 (n = 1), PIK3CA (n = 1). Conclusions: This experience highlights the feasibility of ctDNA to help identify genomic alterations in this patient population. Further studies incorporating ctDNA testing in this patient population are warranted.
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Segelov, E., E. Bergsland, C. Card, T. Hope, P. Kunz, D. Laidley, B. Lawrence, et al. "The commonwealth neuroendocrine tumour collaboration (CommNETs) and North American neuroendocrine tumor society (NANETS) endorsement and update of European neuroendocrine tumor society (ENETS) best practice consensus for lung neuroendocrine tumors (LNET)." Annals of Oncology 29 (October 2018): viii473. http://dx.doi.org/10.1093/annonc/mdy293.015.
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Adams, Christopher Peter, and Wasif M. Saif. "Targeted radiopeptide therapy Re188-P2045 to treat neuroendocrine lung cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20016-e20016. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20016.
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e20016 Background: : Despite the recent success of checkpoint inhibitors, there continues to be a significant medical need for lung cancer therapies that can be directed to the patients most likely to respond. Somatostatin receptor subtype 2 (SSTR2) is the most widely up-regulated subtype in both small and non-small cell lung cancers and is also expressed in tumoral (but not mature) blood vessels. Peptide targeted radiotherapy has advantages over traditional targeted therapies in that targeted tumor cells as well as surrounding cancer cells and supporting stroma are selectively killed. This study was conducted to determine the ability of Rhenium Re 188 P2045, a radiolabeled somatostatin analog specific for SSTR2 to both image (to select the most appropriate patients) and treat lung cancer patients who over-express somatostatin receptors. Methods: In an open label, single arm study, refractory lung cancer patients to standard of care therapy were identified by image analysis using Rhenium Re 188 P2045, a radiolabeled somatostatin analog. 25 Patients received the imaging dose of 10uCi of Re188 and 265ng of peptide by intravenous injection. Three patients were selected based on high SSTR expression levels to receive 30uCi of Re188 P2045 as a therapeutic dose 14 days after imaging. Patients were followed for 8 weeks post treatment. Results: The imaging study revealed a high density of expression of the somatostatin receptor in the lungs of patients. Patients in the imaging and therapeutic treatment groups reported no adverse advents or signs of toxicity. The image analysis using Re188 P2045 was compared to CT images and demonstrated accurate detection of lung tumor lesions. The images obtained using Re188 P2045 were of sufficiently high quality to enable identification of receptor expression at the tumor site as shown in Figures 1&2. Conclusions: Rhenium Re 188 P2045, a radiolabeled somatostatin analog, may be used to both identify and treat lung cancer tumors. The ability to image and dose patients with the same targeted molecule enables a personalized medicine approach and this highly targeted patient therapy may significantly improve treatment of tumors that over express somatostatin receptor.
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Tashiro, Takahiro, Kosuke Imamura, Yusuke Tomita, Daisuke Tamanoi, Akira Takaki, Kazuaki Sugahara, Ryo Sato, et al. "Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma." International Journal of Molecular Sciences 21, no. 24 (December 19, 2020): 9705. http://dx.doi.org/10.3390/ijms21249705.
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Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.
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Hong, Christopher, Declan McGuone, E. Zeynep Erson-Omay, and Sacit Bulent Omay. "26. GENETIC CHARACTERIZATION OF SELLAR METASTASIS FROM PRIMARY BRONCHIAL CARCINOID TUMOR OF NEUROENDOCRINE PATHOLOGY." Neuro-Oncology Advances 2, Supplement_2 (August 2020): ii4—ii5. http://dx.doi.org/10.1093/noajnl/vdaa073.016.
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Abstract Metastasis to the pituitary gland and surrounding sellar region from systemic tumors is a rare occurrence. Patients may present with signs of endocrine dysfunction secondary to pituitary involvement, as well as mass effect-related symptoms including headaches and visual deficits. Despite a small but accumulating body of literature describing the clinical and histopathological correlates for sellar metastases from systemic tumors, the genetic alterations underlying sellar spread have not been previously described. We describe a 68 year-old female with history of a resected lung carcinoid tumor, followed by chemoradiation, who was diagnosed with a sellar lesion on surveillance PET-CT and subsequent brain MRI. Her tumor was resected via an endoscopic endonasal approach, and final pathology was consistent with neuroendocrine origin, including positive immunohistochemistry for synpatophysin, CK7, TTF-1, and CAM5.2 with a Ki-67 index of 8–12%. Whole-exome sequencing of the sellar specimen demonstrated large-scale deletions of chromosomes 3, 6, and 9 and focal deletions on chromosomes 1,2, 11, 15, and 16. Mutational signature analysis was enriched for COSMIC Signature 4, seen in multiple primary lung cancers. Among 91 total somatic alterations, 7 had been previously associated with oncogenesis (MYO18A, PTCH1, BCOR, CLIC6, TLL2, COL1A1, PTPRK). Notably, mutations in BCOR and PTCH1 have been previously implicated in both systemic neuroendocrine tumors as well as primary tumors of the pituitary gland, while MYO18A, FGF4, and PTPRK mutations had not been reported in systemic neuroendocrine tumors but have been implicated in tumor migration and pituitary adenoma progression. In summary, these data demonstrated an expected mutational pattern indicating a systemic lung neuroendocrine origin but also revealed new mutations previously implicated in primary pituitary pathologies that may have evolutionarily drove divergence from the primary tumor. Further genome studies of these rare lesions may yield further insight into the genetic alterations underlying metastasis to the sellar region.
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Berendsen, H. H., L. de Leij, S. Poppema, P. E. Postmus, A. Boes, H. J. Sluiter, and H. The. "Clinical characterization of non-small-cell lung cancer tumors showing neuroendocrine differentiation features." Journal of Clinical Oncology 7, no. 11 (November 1989): 1614–20. http://dx.doi.org/10.1200/jco.1989.7.11.1614.
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In most cases of small-cell lung carcinomas (SCLC) phenotypic features compatible with a neuroendocrine differentiation status can be identified by monoclonal (MOC) antibody-based immunohistological procedures. Similar features can be recognized only in a minority of non-SCLC tumors. During a period of 30 months, all diagnostic non-SCLC biopsies (141 cases) were prospectively analysed for the presence of markers indicative for neuroendocrine differentiation. In 31% of all cases, such a presence could be noticed. Neuroendocrine differentiation (50% to 100% positive-staining tumor cells) was recognized more frequently in adenocarcinoma when compared to large-cell and squamous-cell carcinoma (chi 2 = 9.31, 2 degrees of freedom, P less than 0.01). To investigate whether the clinical behavior of these "neuroendocrine" non-SCLC cases mimics SCLC, a multivariate analysis for prognostic factors was performed. Among other prognostic factors, biopsies containing more than 50% positive-staining tumor cells with the MOC antibody-1 (MOC-1) were recognized as negative prognostic factors.
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Baloch, Zubair W., and Virginia A. LiVolsi. "Tumor-to-Tumor Metastasis to Follicular Variant of Papillary Carcinoma of Thyroid." Archives of Pathology & Laboratory Medicine 123, no. 8 (August 1, 1999): 703–6. http://dx.doi.org/10.5858/1999-123-0703-tttmtf.
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Abstract Objective.—To describe and document tumor-to-tumor metastases in the thyroid gland. Methods and Results.—In this series we describe 3 cases of tumor-to-tumor metastasis in which the recipient tumor was a follicular variant of papillary thyroid carcinoma. The donor tumors and sites were small cell carcinoma of the lung, neuroendocrine carcinoma probably of pancreatic origin with initial presentation as liver metastasis, and clear cell carcinoma of the kidney with metastasis to liver and pancreas. The donor tumor cells infiltrated the substance of the follicular variant of papillary thyroid carcinoma, the nontumorous thyroid parenchyma, and the lymphovascular spaces. Small cell carcinoma and neuroendocrine carcinoma showed positive reactivity for neuroendocrine markers and were negative for thyroglobulin and calcitonin. The follicular variant of papillary thyroid carcinoma showed positivity with thyroglobulin and cytokeratin 19. Conclusions.—Although tumor-to-tumor metastases in thyroid gland are exceedingly rare, one should be aware of this phenomenon as the metastatic lesion may simulate a thyroid primary. History of a previous tumor and immunohistochemical stains can be helpful in distinguishing between primary and metastatic thyroid neoplasms.
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Pikunov, Michail Y., Alexey A. Pechetov, Yury S. Esakov, and Alexey N. Lednev. "Surgical treatment for the patient with the neuroendocrine lung tumor associated with ectopic ACTH-secretion syndrome: case report." Endocrine Surgery 12, no. 2 (August 24, 2018): 96–101. http://dx.doi.org/10.14341/serg9766.
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Among primary neoplasms of the lungs, the proportion of neuroendocrine tumors is up to 20–25%. According to the Surveillance Epidemiology and Results (SEER) database, since 1970 there has been a significant increase in primary carcinoid tumors of various organs with the highest incidence of morbidity in the broncho-pulmonary localization group. Carcinoid tumors of the lung level are approximately 2% of all primary lung tumors, but only 5% of these formations are associated with ACTH production.
Despite the severity of clinical manifestations and the acceleration of hypercorticoid processes, the topical diagnosis of ACTH-ectopic syndrome often causes certain difficulties. The difficulty in diagnosing ectopic tumors is due to the fact that most of these formations are so small that they can be missed by standard methods of examination (X-ray, ultrasound, MSCT or MRI). After the diagnosis of ACTH-ectopic syndrome is completely optimal method of pathogenetic therapy is a radical removal of the tumor, which leads to the normalization of the functions of the adrenal cortex and the elimination of hypercorticoidism. However, the achievement of this goal in many cases is difficult due to late topical diagnosis, the prevalence of the tumor process and extensive metastasis.
There is a clinical observation of a patient with a diagnosis of a neuroendocrine lung tumor with ACTH-ectopic syndrome. The importance of the multidisciplinary approach, the methods of differential diagnosis, the features of the perioperative period and the long-term results of treatment are described.
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Mazumder, Suparna, and Alexandru Almasan. "Is Caspase-8 a Neuroendocrine Lung Tumor Suppressor?" Cancer Biology & Therapy 1, no. 1 (January 2002): 70–71. http://dx.doi.org/10.4161/cbt.1.1.46.
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Kozuma, Yuka, Gouji Toyokawa, Yuichi Yamada, Fumihiro Shoji, Koji Yamazaki, Yoshinao Oda, and Sadanori Takeo. "Spread through air spaces in lung neuroendocrine tumor." Translational Lung Cancer Research 8, S4 (December 2019): S439—S442. http://dx.doi.org/10.21037/tlcr.2019.10.20.
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Iihara, Kuniko, Kazuyoshi Yamaguchi, Yasunori Fujioka, and Sumiko Uno. "Pigmented neuroendocrine tumor of the lung, showing neuromelanin." Pathology International 52, no. 11 (November 2002): 734–39. http://dx.doi.org/10.1046/j.1440-1827.2002.01415.x.
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Song, In Hye, Youn Soo Lee, Dong-Il Sun, Yong-Kil Hong, and Kyo-Young Lee. "Metachronous double primary neuroendocrine tumors in larynx and lung: a case report." Journal of International Medical Research 48, no. 11 (November 2020): 030006052096292. http://dx.doi.org/10.1177/0300060520962928.
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When a patient harbors two or more neuroendocrine tumors (NETs), it can be difficult to determine whether they are double primary tumors or metastases. A 60-year-old man complained of voice change lasting 1 month. On physical examination and imaging, a 1.8-cm mass was observed in his epiglottis, and a laser epiglottectomy was performed. Upon microscopic examination, the tumor consisted of medium-sized ovoid or short spindle cells. Immunohistochemical staining of the tumor cells was positive for synaptophysin, chromogranin, and calcitonin but negative for CD56; the Ki-67 proliferation index was approximately 5%. The patient was diagnosed with atypical carcinoid tumor. In 2015, a hypermetabolic endobronchial tumor was identified in the left lower lobe by positron emission tomography-computed tomography. Bronchoscopic biopsy revealed palisading large tumor cells with high nuclear-cytoplasmic ratio, frequent mitoses, and necrosis. The tumor cells were positive for CD56 and negative for cytokeratin-7, thyroid transcription factor-1, P40, synaptophysin, chromogranin, and calcitonin; the Ki-67 proliferation index was approximately 90%. Overall histologic findings were consistent with large cell neuroendocrine carcinoma rather than metastatic atypical carcinoid tumor. Detailed clinical and pathological review are essential to differentiate between metastatic NET and double primary NETs and, therefore, to provide the best management of the patient.
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Abrantes, Carlos, Rui Caetano Oliveira, Joana Saraiva, João Bernardo, and Lina Carvalho. "Pulmonary Peripheral Carcinoids after Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Tumorlets: Report of 3 Cases." Case Reports in Pulmonology 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/851046.
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Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and tumorlets are neuroendocrine cells proliferations smaller than 5 mm. The former confines to bronchial/bronchiolar wall, while the latter broke through epithelial basement membrane. The authors present 3 cases of DIPNECH and tumorlets associated with a typical peripheral carcinoid tumor without underlying lung disease. The patients presented with nonspecific pulmonary symptoms: 3 females, 60, 72, and 84 years old, whose CT-scans showed well-defined pulmonary nodules, 2.2, 1.6, and 1.4 cm, respectively; first patient was submitted to lobectomy and the others underwent surgical biopsy. Whitish/brownish lobulated tumors corresponded to typical carcinoids (less than 2 mitoses/2 mm2and without necrosis); polygonal/elongated cells under lobular pattern expressed CD56, chromogranin A, synaptophysin, and CK7; Ki-67 positivity was between 1 and 3%. Bronchial/bronchiolar wall neuroendocrine cell hyperplasia and several neuroendocrine nodules under 5 mm, with identical morphologic and immunoexpression, were observed, without lung disease. Typical carcinoid associated with DIPNECH and tumorlets without other pulmonary diseases is rare. Sporadic cases may recall embryonal neuroendocrine differentiation potentiality to develop peripheral hyperplasia, most commonly in underoxygenated parenchyma. The described cases are elucidative of peripheral spectrum of neuroendocrine cell tumour evolution, reinforcing higher female incidence as in central carcinoids, still without a clear preneoplastic lesion.
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Lima, Cibelle F., Pedro S. Rocha, Junya Fujimoto, Allison Stewart, Robert Cardnell, Wei Lu, Khaja Khan, et al. "Abstract 5305: Delta-like ligand 3 immunohistochemical expression landscape in high-grade lung neuroendocrine tumors." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5305. http://dx.doi.org/10.1158/1538-7445.am2022-5305.
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Abstract Background: High-grade lung neuroendocrine tumors are a heterogeneous group of cancers with aggressive common features and a lack of effective therapeutic options. Recently, efforts have been made to identify new targets and drugs to improve clinical outcomes in these patients. Because of its high expression in neuroendocrine tumors compared to normal tissue, delta-like ligand 3 (DLL3) has emerged as a new therapeutic target in this setting.1,2 Targeting DLL3 with the half-life extended bispecific T cell engager (HLE BiTE®) immune therapy, tarlatamab, in a phase 1 clinical trial has demonstrated promising anti-tumor activity in small cell lung cancer (SCLC) patients.3 In order to more precisely guide patient selection and clinical trial design, a better understanding and quantification of DLL3 expression is required. Thus, we investigated DLL3 immunohistochemical expression across SCLC, large cell neuroendocrine carcinoma (LCNEC), and neuroendocrine carcinoma with combined histology (CNEC), and its associations with clinicopathological characteristics. Design: Formalin-fixed and paraffin-embedded surgically resected lung neuroendocrine carcinomas (SCLC, n=17; LCNEC, n=20; CNEC, n=8) were selected based on tissue availability at MD Anderson Cancer Center and stained with a commercially available immunohistochemistry assay for DLL3 (clone SP347, Ventana). Total percentage and intensity of DLL3 expression of neuroendocrine carcinoma cells were scored and the results were presented as H-Score (0-300) and percentage (%) of DLL3 positive tumor cells. We correlated DLL3 expression with clinicopathological characteristics. Results: DLL3 expression was observed in 37/45 (82%) of all cases (SCLC: %, median=65%, 0-100%; H-score, median=95, 0-175; LCNEC: %, median=65%, 0-100%; H-score, median=100, 0-180; CNEC: %, median=55%, 0-95%; H-score, median=90, 0-175). In patients with LCNEC, DLL3 % was higher in male patients (p=0.0500) and former smokers (p=0.0298) compared to females and current smokers, respectively. No other clinicopathological associations were found with age, Tumor-Node-Metastasis (TNM) staging system, recurrence, neoadjuvant therapy or overall survival. Conclusion:Our work confirms that most high-grade neuroendocrine tumors express DLL3 across histology types and TNM stage. Our results suggest that a large subset of patients with high-grade lung neuroendocrine tumors may be a target population of interest for DLL3-targeted therapies. References 1. Saunders LR, et al. Sci Transl Med. 2015;7(302):302ra136. 2. Alì G, et al. Front Oncol. 2021;11:729765. 3. Owonikoko TK, et al. Abstract 8510. Presented at: ASCO Annual Meeting, June 4-8, 2021; Virtual. Citation Format: Cibelle F. Lima, Pedro S. Rocha, Junya Fujimoto, Allison Stewart, Robert Cardnell, Wei Lu, Khaja Khan, Beate Sable, Aaron R. Ellison, Ignacio I. Wistuba, Carl M. Gay, Neda Kalhor, Lauren A. Byers, Luisa M. Solis-Soto. Delta-like ligand 3 immunohistochemical expression landscape in high-grade lung neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5305.
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Novkovic, Dobrivoje, Vesna Skuletic, Jelena Vukovic, Snezana Cerovic, Ilija Tomic, Vukojica Karlicic, and Marko Stojisavljevic. "Disseminated typical bronchial carcinoid tumor." Vojnosanitetski pregled 70, no. 5 (2013): 516–21. http://dx.doi.org/10.2298/vsp1305516n.
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Introduction. Bronchial carcinoids belong to a rare type of lung tumors. If they do not expose outstanding neuroendocrine activity, they develop without clearly visible symptoms. They are often detected during a routine examination. According to their clinical pathological features, they are divided into typical and atypical tumors. Typical bronchial carcinoids metastasize to distant organs very rarely. Localized forms are effectively treated by surgery. The methods of conservative treatment should be applied in other cases. Case report. We presented a 65-year-old patient with carcinoid lung tumor detected by a routine examination. Additional analysis (chest X-ray, computed tomography of the chest, ultrasound of the abdomen, skeletal scintigraphy, bronhoscopy, histopathological analysis of the bioptate of bronchial tumor, as well as bronchial brushing cytology and immunohistochemical staining performed with markers specific for neuroendocrine tumor) proved a morphologically typical lung carcinoid with dissemination to the liver and skeletal system, which is very rarely found in typical carcinoids. Conclusion. The presented case with carcinoid used to be showed morphological and pathohistological characteristics of typical bronchial carcinoid. With its metastasis to the liver and skeletal system it demonstrated unusual clinical course that used to be considered as rare phenomenon. Due to its frequent asymptomatic course and varied manifestation, bronchial carcinoid could be considered as a diagnostic challenge requiring a multidisciplinary approach.
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Salvo, Gloria, Antonio Gonzalez Martin, Naomi R. Gonzales, and Michael Frumovitz. "Updates and management algorithm for neuroendocrine tumors of the uterine cervix." International Journal of Gynecologic Cancer 29, no. 6 (July 2019): 986–95. http://dx.doi.org/10.1136/ijgc-2019-000504.
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Neuroendocrine carcinomas of the cervix account for less than 2% of all invasive cervical cancers and are classified as low-grade (carcinoid, atypical carcinoid tumor) or high-grade (known as small- and large-cell) neuroendocrine carcinomas. There are increasing data showing that cervical neuroendocrine carcinomas may be associated with the human papillomavirus (HPV), especially HPV18, and most will stain positive for p16. Immunohistochemistry markers such as synaptophysin and CD56 are the most sensitive markers. Although there are no commonly associated mutations,PIK3CA,KRAS, andTP53are the most frequently found mutations in neuroendocrine tumors. Neuroendocrine cervical carcinomas are exceedingly aggressive tumors with a high tendency for nodal involvement and distant metastases. Age, lymph node metastases, smoking, pure small-cell histology, and tumor size are independent prognostic factors. Overall, the 5-year survival rate is 36% and the median overall survival ranges between 22 and 25 months. Treatment options are often extrapolated from small-cell lung cancer and limited retrospective studies. The preferred treatment is a multimodal approach of surgery, chemoradiation, and systemic chemotherapy. The most common chemotherapy regimen used as initial therapy is a combination of cisplatin and etoposide. In the setting of recurrent disease, a combination of topotecan, paclitaxel, and bevacizumab has demonstrated favorable outcomes. Multicenter tumor registries, such as the Neuroendocrine Cervical Tumor Registry (NeCTuR), are an opportunity to evaluate patterns of disease treatment and oncologic outcomes.
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Xinli, Wang, Wang Lixiao, Ding Baoqi, Huang Hu, and Zhang Qiang. "Expression and Clinicopathological Significance of SOX11 in Small-Cell Lung Cancer." BioMed Research International 2022 (March 30, 2022): 1–6. http://dx.doi.org/10.1155/2022/1707914.
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Objective. This study aims to investigate the expression of neuronal transcription factor SOX11 in small-cell lung cancer (SCLC) and compare it with the expression of CD56 (nerve cell adhesion molecule), synaptophysin (Syn), chromogranin A (CgA), and thyroid transcription factor-1 (TTF-1) to explore the application value of SOX11 in the pathological diagnosis of SCLC. Methods. Immunohistochemical methods were used to detect the expression of SOX11, TTF-1, CD56, Syn, and CgA in 120 lung tumor tissues, and experimental results were analyzed using SPSS23.0 statistical software. Results. Immunohistochemical results showed that in the 120 lung tumor samples, SOX11 was highly expressed in SCLC and localized to the nucleus, with low or no expression in control carcinoid/lung neuroendocrine tumors, lung adenocarcinomas, and lung squamous cell carcinomas. Statistical analysis results revealed the following points. First, the expression of SOX11 was closely related to the tumor histological type. The expression of SOX11 in SCLC (positive rate of 63.33%) was significantly higher than that in carcinoid/neuroendocrine tumors (positive rate of 12.50%), lung adenocarcinoma (positive rate of 0%), and lung squamous cell carcinoma (positive rate of 0%). Second, immunohistochemical investigation of 60 SCLC cases revealed that the highest positive rates of CD56, TTF-1, and Syn, respectively, were 93.33 percent, 95 percent, and 86.67 percent. SOX11 also exhibited high sensitivity (0.633) and specificity (0.875) in SCLC. The positive rates of SOX11 and CgA were 63.33% and 50.00%, respectively. Statistical results revealed that the positive rate of CgA had no significant difference ( P > 0.05 ). Lastly, the combined use of antibodies SOX11, CgA, CD56, Syn, and TTF-1 was more beneficial to improving the diagnosis rate of SCLC than the single use of one or two antibodies. Conclusion. The expression of SOX11 in different histological types of lung tumors differs considerably. SOX11 is highly expressed in SCLC. SOX11 can be used as a beneficial supplement to the combination of classical neuroendocrine markers and in combination with CgA, CD56, Syn, and TTF-1 to assist in the diagnosis of SCLC.
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Sivanandhan, Dhanalakshmi, Sridharan Rajagopal, Chandru Gajendran, Naveen Sadhu, Mohd Zainuddin, Ramachandraiah Gosu, and Luca Rastelli. "Abstract B029: LSD1-HDAC6 dual inhibitor JBI-802 is an epigenetic modulating agent with a novel mechanism of action that target MYC amplification in multiple neuroendocrine tumor types." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): B029. http://dx.doi.org/10.1158/1538-7445.cancepi22-b029.
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Abstract MYC is considered a master regulator of human cancers by modulating the transcription of numerous cancer-related genes. MYC amplification is reported in about 15% of all human cancers and is generally associated with poor prognosis and resistance to treatments. Focal amplification of MYC together with mutation in RB1 and p53 is an important event in the metastatic process of neuroendocrine tumor development. While limited options are available for direct targeting, transcriptional modulation via epigenetic modulating agent could be an attractive and viable option to target neuroendocrine cancers. JBI-802 inhibits the transcriptional regulator coREST via its component LSD1/HDAC6 therefore blocking neuroendocrine transdifferentiation and inducing cell death resulting in activity against neuroendocrine tumors. At the same time, this molecule has shown a good safety profile in toxicological studies. We have now identified a novel aspect of JBI-802 mechanism of action, the ability to induce downregulation of MYC RNA and degradation of MYC protein both in vitro and in animal models of two neuroendocrine tumors, small cell lung cancer and neuroendocrine prostate cancer JBI-802 showed significant anti-proliferative activity (0.2 to 1 µM) against several cancer cell lines as shown by Alamar blue or CTG assays. Sensitive ones included small cell lung cancer (SCLC), gastric cancer, breast cancer cell lines with RB1 mutation. Interestingly, dual inhibitor JBI-802 was also active in cell lines with MYC over-expression, while LSD1 selective inhibitors have been reported to be inactive in these cell lines. JBI-802 also inhibited MYC at RNA as well as protein level in hematological and solid tumors as assessed by RT-qPCR at RNA level and by Western blotting at protein level, while single agent LSD1 and HDAC6 inhibitors did not show significant modulation. JBI-802 also showed strong tumor growth inhibition of these tumors in mouse xenograft models. MYC levels showed a dose dependent inhibition in these tumors when tested at the end of the study. Only dual inhibition of both LSD1/HDAC6 with JBI-802 as opposed to single target inhibition is able to effectively downregulate MYC level and achieve efficacy in MYC amplified models in vivo and in vitro. This novel mechanism increases the potential population of neuroendocrine patients that could be sensitive to this compound, going beyond the proof of principle already established preclinically and clinically by single target LSD1 inhibitors. Therefore, by targeting 2 major pathways in neuroendocrine tumor development, JBI-802 novel mechanism of action is uniquely suited for the treatment of high unmet neuroendocrine tumors like small cell lung cancer, neuroendocrine prostate cancer and advanced, MYC amplified tumors. Based on this rationale, JBI-802 is being tested in phase 1/2 clinical trial focus on this type of tumors. Citation Format: Dhanalakshmi Sivanandhan, Sridharan Rajagopal, Chandru Gajendran, Naveen Sadhu, Mohd Zainuddin, Ramachandraiah Gosu, Luca Rastelli. LSD1-HDAC6 dual inhibitor JBI-802 is an epigenetic modulating agent with a novel mechanism of action that target MYC amplification in multiple neuroendocrine tumor types. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B029.
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Boutsikou, Efimia, Konstantinos Porpodis, Vasiliki Chatzipavlidou, Georgia Hardavella, George Gerasimou, Kalliopi Domvri, Nikitas Papadopoulos, et al. "Predictive Value of 99MTC-hynic-toc Scintigraphy in Lung Neuroendocrine Tumor Diagnosis." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381984258. http://dx.doi.org/10.1177/1533033819842586.
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Background: Νeuroendocrine tumors of the lungs are rare arising in the thymus and gastro-entero-pancreatic tract and belonging to foregut of neuroendocrine tumors. The aim of the present prospective study was to estimate the potential impact of single-photon emission computed tomography somatostatin receptor scintigraphy using 99mTc-Tektrotyd on diagnosis, treatment response, and prognosis in patients with neuroendocrine tumors of the lungs. Methods: Thirty-six patients with neuroendocrine tumors of the lungs were evaluated by using 99mTc-HYNIC-TOC scintigraphy. The scintigraphic results were compared to liver tissue uptake (Krenning score). Likewise, the functional imaging results were compared with biochemical indices including chromogranin A, neuroendocrine-specific enolase, and insulin-like growth factor 1 at the time of diagnosis (baseline) and disease progression. Results: The number of somatostatin receptors, expressed with Krenning score, did not show any correlation with the survival of patients both at baseline ( P = .08) and at disease progression ( P = .24), and scintigraphy results did not relate significantly to progression-free survival. Comparing the results of 99mTc-HYNIC-TOC scintigraphy according to the response of patients in the initial treatment, a statistically significant negative correlation was observed both in the first and in the second scintigraphy with patients’ response ( P = .001 and P < .001, respectively). The concentrations of biochemical markers were in accordance with scintigraphy results in the diagnosis. Conclusion: This study indicates that 99mTc-HYNIC-TOC scintigraphy appears to be a reliable, noninvasive technique for detection of primary neuroendocrine tumors and their locoregional or distant metastases, although it cannot be used as a neuroendocrine tumors of the lungs predictive technique.
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Arbajian, Elsa, Mattias Aine, Anna Karlsson, Johan Vallon-Christersson, Hans Brunnström, Josef Davidsson, Sofie Mohlin, Maria Planck, and Johan Staaf. "Methylation Patterns and Chromatin Accessibility in Neuroendocrine Lung Cancer." Cancers 12, no. 8 (July 22, 2020): 2003. http://dx.doi.org/10.3390/cancers12082003.
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Lung cancer is the worldwide leading cause of death from cancer. Epigenetic modifications such as methylation and changes in chromatin accessibility are major gene regulatory mechanisms involved in tumorigenesis and cellular lineage commitment. We aimed to characterize these processes in the context of neuroendocrine (NE) lung cancer. Illumina 450K DNA methylation data were collected for 1407 lung cancers including 27 NE tumors. NE differentially methylated regions (NE-DMRs) were identified and correlated with gene expression data for 151 lung cancers and 31 human tissue entities from the Genotype-Tissue Expression (GTEx) consortium. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed on eight lung cancer cell lines, including three NE cell lines, to identify neuroendocrine specific gene regulatory elements. We identified DMRs with methylation patterns associated with differential gene expression and an NE tumor phenotype. DMR-associated genes could further be split into six functional modules, including one highly specific gene module for NE lung cancer showing high expression in both normal and malignant brain tissue. The regulatory potential of NE-DMRs was further validated in vitro using paired ATAC- and RNA-seq and revealed both proximal and distal regulatory elements of canonical NE-marker genes such as CHGA, NCAM1, INSM1, as well as a number of novel candidate markers of NE lung cancer. Using multilevel genomic analyses of both tumor bulk tissue and lung cancer cell lines, we identified a large catalogue of gene regulatory elements related to the NE phenotype of lung cancer.
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Raso, Maria Gabriela, Neus Bota-Rabassedas, and Ignacio I. Wistuba. "Pathology and Classification of SCLC." Cancers 13, no. 4 (February 16, 2021): 820. http://dx.doi.org/10.3390/cancers13040820.
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Lung cancer is consistently the leading cause of cancer-related death worldwide, and it ranks as the second most frequent type of new cancer cases diagnosed in the United States, both in males and females. One subtype of lung cancer, small cell lung carcinoma (SCLC), is an aggressive, poorly differentiated, and high-grade neuroendocrine carcinoma that accounts for 13% of all lung carcinomas. SCLC is the most frequent neuroendocrine lung tumor, and it is commonly presented as an advanced stage disease in heavy smokers. Due to its clinical presentation, it is typically diagnosed in small biopsies or cytology specimens, with routine immunostaining only. However, immunohistochemistry markers are extremely valuable in demonstrating neuroendocrine features of SCLC and supporting its differential diagnosis. The 2015 WHO classification grouped all pulmonary neuroendocrine carcinomas in one category and maintained the SCLC combined variant that was previously recognized. In this review, we explore multiple aspects of the pathologic features of this entity, as well as clinically relevant immunohistochemistry markers expression and its molecular characteristics. In addition, we will focus on characteristics of the tumor microenvironment, and the latest pathogenesis findings to better understand the new therapeutic options in the current era of personalized therapy.
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Li, Tian, John Diks, Snow Trinh Nguyen, Jianying Zeng, Neil Chen, and Shivakumar Vignesh. "Next-generation sequencing proves clonal relationship between two distinguished lung and liver carcinomas by standard histopathology approach." Journal of Case Reports and Images in Pathology 8, no. 2 (December 22, 2022): 6–11. http://dx.doi.org/10.5348/100064z11el2022cr.
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Introduction: Two tumors having different histopathologies at anatomically distinct sites giving the picture of dual primary malignancies. Here we presented a case of two possible primary tumors and one secondary mass. Case Report: A 74-year-old female, active smoker, without personal or family cancer history presented with early satiety and weakness for two months. Systems review was positive for a “raw” feeling in stomach, alleviated with antacids. Vital signs were stable with a negative abdominal exam. Lab showed leukocytosis 24.8 K/uL (3.5–10.8 K/uL) with left shift, microcytic anemia with hemoglobin 6.1 g/dL (12.0–16.0 g/dL), and reactive thrombocytosis 477 K/uL (130–400 K/uL). Contrast-enhanced computed tomography (CT) showed right upper lobe necrotizing cavitating lesion with reactive mediastinal and right hilar lymphadenopathy, two irregular hypodense lesions in pancreatic head and tail without ductal dilation with two irregular hypodense liver lesions. Immunohistochemistry of lung and pancreatic lesions were biopsied through endoscopic ultrasound (EUS), consistent with poorly differentiated squamous cell carcinoma (SCC) with extensive necrosis, which indicates pancreatic masses are likely metastases from the lung. Liver lesion biopsy exhibited high-grade neuroendocrine tumor (NET) with focal necrosis. Next gene sequencing was pursued. Given poor functional status, palliative immunotherapy was offered; however, the patient succumbed to respiratory failure. Conclusion: Given the morphology and immunoprofile, differential diagnosis includes dual primary cancers with one metastasis, or primary SCC with metastasis with neuroendocrine differentiation. Despite having different histopathology and immunophenotype, both lung and liver tumors harbor the same molecular profile even at the variants of unknown significance that show identical mutations. As a result, they are directly related. TP53, RB1, MYCL1, and MEK1 mutations are more prevalent in SCC than NET. Tumor mutation burden values may vary as the tumor clonal structure varies between primary and metastatic sites, with higher rates of monoclonal structure recorded in metastases due to clonal selection, leading to a reduction in overall genetic diversity (“bottlenecking”). This raises the suspicion that the liver tumor is a SCC with neuroendocrine differentiation. The paucity of the specimen and rapid clinical course limited further investigation. Germline testing would have been useful to determine whether these findings are somatic or germline.
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Dzeranova, L. K., E. A. Pigarova, L. S. Selivanova, E. A. Tarabrin, K. Yu Slashchuk, and E. E. Bibik. "Ectopic ACTH-syndrome caused by neuroendocrine tumor of lung." Khirurgiya. Zhurnal im. N.I. Pirogova, no. 9 (2018): 46. http://dx.doi.org/10.17116/hirurgia2018090146.
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Dinis Silva, João, Pedro Pinto Marques, Maria José Brito, Jose Cortés, Rogério Senhorinho, Vasco Herédia, and Ana Nunes. "Large-cell neuroendocrine lung tumor presenting as acute pancreatitis." Gastrointestinal Endoscopy 78, no. 5 (November 2013): 782–83. http://dx.doi.org/10.1016/j.gie.2013.06.020.
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