High-grade Large Cell Neuroendocrine Research Articles

Gastric Large-Cell Neuroendocrine Carcinoma Presenting as Perforation Peritonitis: a Rare Case Report

Gastric neuroendocrine carcinomas (GNECs) are rare tumors characterized by an aggressive clinical course, rapid progression, metastatic dissemination, and poor prognosis. Due to overlapping radiological features and small pre-operative biopsy specimens, they are frequently misdiagnosed as adenocarcinoma in the pre-operative period. These tumors are generally asymptomatic or present with non-specific symptoms like epigastric pain or discomfort, weight loss, and loss of appetite. However, GNECs presenting as perforation peritonitis are rarely reported in the literature. A 60-year-old man presented to the emergency department with complaints of pain upper abdomen with loss of weight and appetite for four months. He had an endoscopic biopsy report suggestive of antral growth reported as poorly differentiated adenocarcinoma. Radiological investigations were notable for the presence of a malignant lesion in the stomach with perforation. Subtotal gastrectomy with D1 lymph node resection was done. Specimen pathology confirmed poorly differentiated high grade large cell neuroendocrine carcinoma. This article emphasizes the importance of considering GNEC as a differential diagnosis for gastric adenocarcinoma despite overlapping radiological features and challenges with pre-operative diagnosis due to its aggressive nature and to allow for appropriate management.

High-grade large cell neuroendocrine carcinoma of the esophagus: a case report and review of the literature

BackgroundNeuroendocrine carcinomas are extremely rare in the esophagus as they represent less than 0.04% of all neuroendocrine tumors. To date, only 14 cases of poorly differentiated, high-grade esophageal NEC have been described in the literature. The majority of these patients presented with typical dysphagia symptoms. Due to its rarity, no standardized guidelines have been proposed to treat esophageal neuroendocrine carcinoma, although general recommendations suggest surgery with adjuvant chemoradiotherapy as the treatment of choice.Case presentationA 67-year-old previously healthy White male presented with a year-long intermittent nonspecific retrosternal discomfort, with the absence of any other symptoms. Esophagogastroduodenoscopy revealed an ulcerative mass in his lower esophagus, with concern of malignancy. Endoscopic ultrasound-guided biopsy revealed poorly differentiated neuroendocrine carcinoma of the esophagus with metastasis to a diaphragmatic lymph node. He was treated with neoadjuvant chemoradiation followed by surgery, and he has been in remission for over 5 years.ConclusionHere, we review the literature and report a unique case of a patient with a vague presentation of esophageal neuroendocrine carcinoma as he enters his sixth year of survival following neoadjuvant chemoradiotherapy.

ODP361 A Case of Panhypopituitarism in the Setting of Metastatic Large Cell Neuroendocrine Carcinoma

Abstract Introduction Metastasis to the pituitary gland is an uncommon cause of panhypopituitarism. The pituitary gland is an infrequent site overall for metastasis, with breast and lung cancer as most often found primary sites. Large cell neuroendocrine carcinoma is a rare form of lung cancer, and while metastasis to brain is not uncommon is this form of cancer, metastasis to the pituitary gland has rarely been reported. Clinical Case Patient was a 64 year old male with history of homelessness and substance use who had repeated hospitalizations for right sided pneumonia. Eventually bronchoscopy was performed, and tissue obtained via biopsy revealed a high-grade large cell neuroendocrine carcinoma. Initial brain imaging noted extensive brain metastases with numerous enhancing lesions in the cortex, as well as a 13×9×8 mm suprasellar mass abutting the optic chiasm. Thickening of the infundibulum was also noted. Lab testing demonstrated hypopituitarism with free thyroxine 0.52 (reference 0.93-1.7) ng/dL, thyroid-stimulating hormone 0.11 (2.7-4.2) ulU/mL, sodium 139 (135-147) mEq/L, total testosterone <0.1 (2.8-8) ng/ml, follicular-stimulating hormone 0.4 mlU/ml, lutenizing hormone <0.10 mlU/ml, prolactin 25.7 (4-15.2) ng/ml, cortisol <2 (3-12) ug/dL, and adrenocorticotropic hormone <5 (6-50) pg/mL. Diabetes insipidus was not present. Metastatic cancer was treated with dexamethasone and atezolizumab plus carboplatin and etoposide. Panhypopituitarism was treated with levothyroxine, testosterone replacement, and glucocorticoid replacement. One month later, patient represented with shortness of breath and headache. Repeat brain imaging showed an enhancing sellar mass measuring 21×15×11 mm extending superiorly to involve the pituitary stalk and hypothalamus. The extending suprasellar mass was noted to have enhancement and characteristics akin to remainder of brain metastases. The patient passed away from complications of metastatic carcinoma about three months after initial biopsy proven diagnosis. Conclusion This patient developed extensive brain metastases from pulmonary large cell neuroendocrine carcinoma, which included a metastasis in the sella resulting in panhypopituitarism. While pituitary metastases from primary cancer are very rare events (with lung and breast carcinoma the most frequent sources), only a single case report exists describing a pituitary metastasis from a large cell neuroendocrine carcinoma. This case is also an important reminder to consider the pretreatment anatomy of the sella in patients subsequently exposed to immunomodulating chemotherapy, as a mass lesion seen during treatment may represent a preexisting metastasis rather than treatment-induced hypophysitis. Presentation: No date and time listed

S3338 An Unusual Case of a Large Cell Neuroendocrine Carcinoma and Acute Liver Failure

Introduction: Large cell neuroendocrine carcinomas (LCNECs) are characterized as large cells with areas of necrosis, neuroendocrine traits (palisading, trabeculae, etc.), ample cytoplasm and high mitotic rates. LCNECs are a rare, aggressive form of neuroendocrine tumor known to have high rates of metastasis. Our case highlights acute liver failure with rapid progression to death due to metastatic spread of LCNEC. Case Description/Methods: 71-year-old male with a history of prostate cancer requiring prostatectomy, hypertension, hyperlipidemia, and tobacco use, presented for shortness of breath and abdominal pain for 3 days. He was a poor historian and was unable to provide much history. Of note, the patient reported that he had imaging performed in spring 2021 to further evaluate his degenerative disc disease and was told there was concern for a cancerous process. Initial laboratory studies showed an elevated AST and ALT (over 300), and thrombocytopenia, but were otherwise unremarkable. Further imaging was performed, given the patient's history of reported malignancy. Initial chest X-ray was negative for acute findings and an abdominal ultrasound revealed a markedly abnormal appearance of the liver, suggestive of possible hepatic metastatic disease. Computed tomography scan of the chest/abdomen/pelvis showed a left hilar mass measuring 5.5 x 6cm with regional lymphadenopathy. The patient underwent a biopsy of the liver, and was later noted to have worsening liver enzymes, platelets, INR, and renal function, along with a lactic acid. He was transferred to the intensive care unit for further monitoring. Bowel ischemia and portal vein thrombosis were ruled out, and the patient became continually more acidotic, and had a pulseless electrical activity (PEA) arrest. He was revived and intubated, and placed on pressor support and continuous renal replacement therapy. His family decided to change his code status to “do not resuscitate” and the patient was made comfortable. Final results of the liver biopsy were obtained 2 days later, and showed findings consistent with high grade large cell neuroendocrine carcinoma. Immunohistochemical staining was positive for CD56, synaptophysin, CK7 and CK5/6. (Figure) Discussion: Liver metastasis has been documented throughout the literature for other carcinomas, however very few in regards to LCNEC. Acute liver failure in such a short span of time, as in our case, highlights the mortality associated with LCNECs, and the difficulty in diagnosing the condition early in the disease course.Figure 1.: CT abdomen/pelvis showing diffuse heterogeneity of the liver.

Neuroendocrine Lung Cancer Mouse Models: An Overview

Simple SummaryNeuroendocrine lung tumors are a heterogeneous group of malignancies that share a common neuroendocrine nature. They range from low- and intermediate-grade typical and atypical carcinoma, to the highly malignant large cell neuroendocrine lung carcinoma and small cell carcinoma, with marked differences in incidences and prognosis. This review delineates the current knowledge of the genetic landscape of the human tumors, its influence in the development of genetically engineered mouse models (GEMMs) and the molecular imaging tools available to detect and monitor these diseases. While small cell lung carcinoma is one of the diseases best represented by GEMMs, there is a worrying lack of animal models for the other members of the group, these being understudied diseases. Regardless of the incidence and material available, they all are in urgent need of effective therapies. 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.

Abstract A83: Genes of epithelial-mesenchymal transition (EMT) reveal impact on progression and metastasis of neuroendocrine lung carcinomas: A preliminary study

Abstract Background: Metastasis are responsible for the death of 90% of patients with lung cancer, indicating the need to know the multiple signaling pathways involved. Neuroendocrine lung carcinomas (NELC) encompass a wide spectrum of tumors, from the low-grade typical carcinoid (TC) and atypical carcinoid (AC), to the high-grade large cell neuroendocrine carcinoma (LCNEC) and the small-cell lung carcinoma (SCLC). Low-grade NELC are indolent, while high-grade NELC invade and metastasize rapidly. Biomarkers of NELC aggressiveness remain to be determined. Epithelial to mesenchymal transition (EMT) genes profile show promise as indicator of invasion and metastasis. Our aim was to evaluate: (1) EMT gene expression in NELC, (2) its relationship with the histologic subtypes, and (3) its impact on behavior of the tumors. Methods: Patients with SCLC (n = 10), LCNEC (n=5), AC (n=2) and TC (n=7) were included. EMT gene expression was quantified with a quantitative real-time (RT)-PCR carried out on StepOnePlus™ Real-Time PCR System (Applied Biosystems) with RT2 Profiler PCR Array System (Qiagen, Dusseldorf, Germany). Associations of the gene signature and clinicopathologic features, as well as prognostic factors were evaluated. Results: A 13-gene signature (AHNAK, COL3A1, DSP, IL1RN, MSN, PDGFRB, SNAI1, SNAI3, TCF3, TGF-beta 1, TGF-beta 2, TGF-beta 3, and VIM) that was related to EMT was upregulated in tumor-tissue from all NELC patients, mainly in those with high-grade NELC. An increased expression of DSP, TCF3, and TGF-beta 2 genes were shown in high-grade when compared to low-grade NELC and associated with lymph node metastasis with statistical significance respectively for DSP (p<0.05), TGF-beta 3 (p<0.05), and marginal significance for TCF3 (p=0.08). TCF3 was also associated with tobacco history (p=0.04). Conclusion: The EMT analysis identified genes involved in cell proliferation, motility, invasion, and metastasis of NELC. We further inferred DSP, TCF3, and TGF-beta 3 as target against lung cancer metastasis and invasion, thus arising as a promising therapeutic agent. Citation Format: Tabatha Gutierrez Prieto, Vanessa Karen de Sá, Eloisa Helena Ribeiro Olivieri, Eduardo Caetano Albino da Silva, Rui Manuel Reis, Dirce Maria Carraro, Vera Luiza Capelozzi. Genes of epithelial-mesenchymal transition (EMT) reveal impact on progression and metastasis of neuroendocrine lung carcinomas: A preliminary study [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A83.

P1.07-027 13-Gene Signature of EMT Reveals Impact on Invasion and Metastasis of Neuroendocrine Carcinomas of the Lung: A Preliminary Study

Metastasis are responsible for the death of 90% of patients with lung cancer, indicating the need to know the multiple signaling pathways involved. Neuroendocrine lung carcinomas (NELC) encompass a wide spectrum of tumors, from the low-grade typical carcinoid (TC) and atypical carcinoid (AC), to the high-grade large cell neuroendocrine carcinoma (LCNEC) and the small cell lung carcinoma (SCLC). Low-grade NELC are indolent, while high-grade NELC invade and metastasize rapidly. Biomarkers of NELC aggressiveness remain to be determined. Epithelial to mesenchymal transition (EMT) genes profile emerge promise as indicator of invasion and metastasis. Our aim was to evaluate: (1) EMT gene expression in NELC; (2) its relationship with the histologic subtypes and (3) its impact on behavior of the tumors. Patients with SCLC (n = 10), LCNEC (n=5), AC (n=2) and TC (n=7) were included, EMT gene expression was quantified with a quantitative real-time (RT)- PCR carried out on StepOnePlus™ Real-Time PCR System (Applied Biosystems), with RT2 Profiler PCR Array System for EMT (Qiagen, Dusseldorf, Germany). Associations of the gene signature and clinicopathological features, as well as prognostic factors were evaluated. A 13-gene signature (AHNAK, COL3A1, DSP, IL1RN, MSN, PDGFRB, SNAI1, SNAI3, TCF3, TGFβ1, TGFβ2, TGFβ3 and VIM) that was related to EMT was up-regulated in tumor-tissue from all NELC patients, mainly in those with high-grade NELC. An increased expression of DSP, TCF3 and TGFβ3 was found in SCLC compared to AC, TC and LCNEC, and associated with lymph nodes metastasis with statistical significance respectively for DSP (p=0.03 and 0.02), TCF3 (p=0.02) and marginal significance for TCF3 and TGFβ3 (p=0.08 and p=0.08). TCF3 was also associated with tobacco history (p=0.04). A significant correlation was found between enolase and IL1RN (p=0.03), chromogranin and TGFβ2 (p=0.04), synaptophysin and TGFβ1 and TGFβ2 respectively (p=0.04 and p=0.02). The EMT analysis identified genes involved in cell proliferation, motility, invasion and metastasis of NELC. We further inferred DSP, TCF3 and TGFβ3 as target against lung cancer metastasis and invasion, thus arising as promising therapeutic agent.

High-Grade Large Cell Neuroendocrine Carcinoma Arising from Low- and High-Grade Dysplasia of the Gallbladder: Case Report and Review of the Literature

High-Grade Large Cell Neuroendocrine Carcinoma Arising from Low- and High-Grade Dysplasia of the Gallbladder: Case Report and Review of the Literature

Systemic therapy for pulmonary carcinoids.

Between 25 and 33% of neuroendocrine tumours arise in the lung as low-grade typical pulmonary carcinoids (TPC), intermediate-grade atypical pulmonary carcinoids (APC), and high-grade large cell neuroendocrine or small cell carcinomas. The relatively uncommon incidence and prevalence of PCs are progressively increasing. However, data regarding systemic treatment for PCs are limited, controversial and based on old reports with few randomized or placebo-controlled trials, small sample sizes, or including tumours with very different behaviours. Moreover, conclusions are generally extrapolated from the outcome of extra-pulmonary carcinoids, treatment arms are not well defined or mix different therapies, and the indolent nature of some PCs is not adequately considered in designing control arms. Here, we reviewed and discuss current recommendations regarding systemic treatments for PCs.

Large cell neuroendocrine carcinoma of the colon: A rare and aggressive tumor.

A 74-year old female presented to the emergency room with right lower quadrant abdominal pain, nausea and vomiting for 3 days. Due to a contrast dye allergy, a non-contrast CT scan of the abdomen and pelvis was performed which showed a lesion in the right colon with a dilated cecum and small bowel (Figure 1). Plain X-ray of the chest showed no obvious pathology. An exploratory laparotomy revealed a large obstructing mass at the right colon proximal to the hepatic flexure, with massive lymphadenopathy and abdominal adhesions. Intra-operative palpation and inspection of the liver was unremarkable without evidence of a suspicious mass. The patient underwent right hemicolectomy with anastomosis. Figure 1 Serial non-contrast CT scans of abdomen. (A) CT performed at the time of initial evaluation at admission showed no visible liver lesions. (B) Subsequent CT taken 10 days later showed multiple large liver lesions. The surgical tissue was reviewed by pathology, and on gross specimen, while the ileocecal valve mucosa contained discontinuous deposits of tumor associated with lymphatic tumor emboli, there was no evidence of distant metastasis. On microscopic evaluation the tumor cells had diffuse architecture with necrosis, ample cytoplasm, and numerous mitotic figures (10-20 mitoses per single high power field). Immunohistochemistry showed diffuse cytoplasmic staining for synaptophysin, as well as positive staining for CD-56, CK-7, Ki-67 (in nearly 90% of the cells) and negative staining for CK-20 consistent with large cell neuroendocrine carcinoma (Figure 2). Of the total lymph nodes present in the surgical specimen 17 out of 24 showed metastatic disease. Thus the final pathology was felt to be most compatible with an aggressive high-grade large cell neuroendocrine carcinoma of the colon. Figure 2 Pathologic examination with H&E staining and immunohistochemical analysis. (A) H&E stain showing tumor ulcerating though normal surface epithelium. (B) H&E stain at high magnification showing cytological malignant features such ... On post-operative day number 10, the patient developed bilious drainage from the lower portion of the surgical incision. A non-contrast CT of the abdomen and pelvis showed interval development of approximately 5 hypodense lesions within the liver measuring 4-6 cm in size. Comparison of the post-operative scan to the pre-operative CT indicated that the hepatic lesions were new (Figure 1). Given the rapid development of these lesions and concern for potential liver abscesses the decision was made for a drainage procedure. An attempt at interventional radiology guided drainage was unsuccessful and subsequently the patient underwent a surgical exploration. Intra-operative findings were notable for multiple palpable hepatic masses through out both lobes of the liver. By gross inspection the hepatic lesions measured 4-6 cm in size, with complete replacement of the left hepatic lobe and a large firm mass at the surface of the right hepatic lobe. A wedge biopsy of one of the liver masses was performed and frozen section showed morphologic features similar to the previously resected tumor consistent with metastatic large cell neuroendocrine carcinoma. An additional intra-operative finding was a small bowel enterocutaneous fistula 10 cm proximal to the previous anastomotic site, which was resected and reanastomized. Two weeks later, the patients condition deteriorated with development of a second enterocutaneous small bowel fistula. At that time the family withdrew care and the patient subsequently expired.

Lung tumours with neuroendocrine differentiation

Neuroendocrine (NE) tumours of the lung include the low grade typical carcinoid (TC), intermediate grade atypical carcinoid (AC) and the high grade large cell NE carcinoma (LCNEC) and small cell carcinoma (SCLC) (Table 1). NE tumours of the lung comprise approximately 20–25% of all invasive lung malignancies. The most common NE lung tumour is SCLC, which accounts for 15–20% [ 1 Travis WD Travis LB Devesa SS Lung cancer. Cancer. 1995; 75 (Erratum:): 191-202Cancer. 1995; 75 (Erratum:): 2979 Crossref PubMed Google Scholar ], followed by LCNEC, which is about 3% in surgical series, and carcinoid, which accounts for 1–2% of lung cancers. The rarest NE lung tumour is atypical carcinoid which comprises approximately 10% of all lung carcinoids, accounting for approximately 0.1–0.2% of invasive lung cancers [ 2 Chen LC Travis WD Krug LM Pulmonary neuroendocrine tumors: What (little) do we know?. J Natl Compr Cancer Netw. 2006; 4: 623-630 Crossref PubMed Google Scholar ]. These tumours have certain morphologic, ultrastructural, immunohistochemical and molecular characteristics in common [ 3 Gosney JR Pulmonary endocrine pathology. Butterworth-Heinemann, Oxford; Boston1992 Google Scholar , 4 Thunnissen FB Van Eijk J Baak JP et al. Bronchopulmonary carcinoids and regional lymph node metastases. A quantitative pathologic investigation. Am J Pathol. 1988; 132: 119-122 PubMed Google Scholar , 5 Jones DJ Hasleton PS Moore M DNA ploidy in bronchopulmonary carcinoid tumours. Thorax. 1988; 43: 195-199 Crossref PubMed Google Scholar , 6 Rusch VW Klimstra DS Venkatraman ES Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg. 1996; 62: 798-809 Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar , 7 Brambilla E Negoescu A Gazzeri S et al. Apoptosis-related factors p53, Bcl2, and Bax in neuroendocrine lung tumors. Am J Pathol. 1996; 149: 1941-1952 PubMed Google Scholar ], but there are important differences in incidence, clinical, epidemiologic, histological, survival, and molecular characteristics [ 8 Travis WD Brambilla E Müller-Hermelink HK Harris CC Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. IARC, Lyon2004 Google Scholar ]. Diffuse idiopathic NE cell hyperplasia (DIPNECH) is a pre-invasive lesion for carcinoid tumors, but it is very rare. Table 1The spectrum of neuroendocrine (NE) proliferations and neoplasms † Modified from reference [8]. (I)NE cell hyperplasia and tumourlets (A)NE cell hyperplasia 1.NE cell hyperplasia associated with fibrosis and/or inflammation 2.NE cell hyperplasia adjacent to carcinoid tumours 3.Diffuse idiopathic NE cell hyperplasia with or without airway fibrosis/obstruction (B)Tumourlets (less than 0.5 cm) (II)Tumours with NE Morphology (A)Typical carcinoid (0.5 cm or larger) (B)Atypical carcinoid (C)Large cell NE carcinoma Combined large cell NE carcinoma ‡ The histological type of the other component of non-small cell carcinoma should be specified. (D)Small cell carcinoma Combined small cell carcinoma ‡ The histological type of the other component of non-small cell carcinoma should be specified. (II)Non-small cell carcinomas with NE differentiation (NED) (IV)Other tumours with NE properties (A)Pulmonary blastoma (B)Primitive neuroectodermal tumour (C)Desmoplastic round cell tumour (D)Carcinomas with rhabdoid phenotype (E)Paraganglioma † Modified from reference [ 8 Travis WD Brambilla E Müller-Hermelink HK Harris CC Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. IARC, Lyon2004 Google Scholar ]. ‡ The histological type of the other component of non-small cell carcinoma should be specified. Open table in a new tab

Pulmonary neuroendocrine tumours and proliferations: a review and update

Pulmonary neuroendocrine tumours include the low-grade typical carcinoid, the intermediate-grade atypical carcinoid, and the high-grade large cell neuroendocrine and small cell carcinomas. This group of tumours continues to be the subject of much investigation. Continuing issues include the examination of the relationship of these tumours to each other from a molecular standpoint, the appropriate criteria for classification, choice of nomenclature and whether or not the two high-grade carcinomas warrant separate classification. Additionally, diffuse idiopathic neuroendocrine cell hyperplasia and carcinoid tumourlets are being recognized with greater frequency.

Squamous Differentiation in High Grade Large Cell Neuroendocrine Carcinoma of Ampulla of Vater

Squamous Differentiation in High Grade Large Cell Neuroendocrine Carcinoma of Ampulla of Vater

Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors

Association of X chromosome allelic losses with tumor malignancy has been identified in foregut but not in midgut endocrine neoplasms. The aim of this study was to investigate the association of deletions on X chromosome with malignancy in lung neuroendocrine tumors, another family of foregut neoplasms comprising four categories with increased malignancy: typical and atypical carcinoids, large cell neuroendocrine and small cell lung carcinomas. To evaluate loss of heterozygosity, DNA extracted from nine typical carcinoids, 17 atypical carcinoids, six large cell neuroendocrine carcinomas and five small cell lung carcinomas was PCR-amplified for 18 microsatellite markers spanning the whole X chromosome. All tissue samples were formalin-fixed and paraffin-embedded. X chromosome losses were absent in typical carcinoids, whereas they were found in nine out of 17 atypical carcinoids and in five out of six large cell neuroendocrine carcinomas (involving 28 and 70% of informative loci, respectively). On the contrary, deletions on X chromosome were an extremely rare event in small cell lung carcinomas. In atypical carcinoids, the presence of losses was associated with larger tumor size, higher pT status and advanced stage. No death occurred in atypical carcinoid patients without deletions on X chromosome, whereas all atypical carcinoid patients who had died from disease showed allelic losses. In conclusion, X chromosome allelic losses, absent in benign ‘typical' carcinoids, progressively increased in frequency from intermediate-grade ‘atypical' carcinoids to high-grade large cell neuroendocrine carcinomas. These results extend the association of deletions on X chromosome with malignancy, already demonstrated in other foregut endocrine neoplasms, to lung neuroendocrine tumors. The absence of X chromosome allelic losses in small cell lung carcinomas underlines a striking difference from large cell neuroendocrine carcinomas, possibly linked to different pathogenetic mechanisms of these two highly aggressive neuroendocrine lung tumors.

Genetic changes in the spectrum of neuroendocrine lung tumors.

Recent classifications identify four categories of neuroendocrine (NE) tumors of the lung: low grade typical carcinoid (TC), intermediate grade atypical carcinoid (AC), and high grade large cell neuroendocrine carcinoma (LC-NEC) and small cell lung carcinoma (SCLC). The authors studied the molecular changes present in 59 archival NE tumors (10TCs, 11 ACs, 18 LNECs, and 20 SCLCs). Utilizing microdissection and polymerase chain reaction-based assays, the authors examined loss of heterozygosity (LOH) at ten chromosomal regions frequently deleted in lung tumors (3p, 5q, 11q, 13q, and 17p) and for mutations at the p53 and ras genes. With the exception of ras gene mutations, the majority of these changes frequently were present in carcinomas and were present at lower frequencies in carcinoids. LOH at one or more 3p regions was the most frequent change found in the carcinoids. A relatively high incidence of LOH at the MEN1 gene was common in all NE lung tumors. The incidence of LOH and p53 gene abnormalities progressively increased with increasing severity of tumor type. The patterns of p53 gene mutations were different between AC and high grade NE tumors. LOH at 5q21 was correlated with poor survival in the carcinoid group. Although NE lung tumors have varied etiologies, the results of the current study support the clinicopathologic concept that they represent a spectrum ranging from low grade TC to the highly malignant NE carcinomas.