Diagnosis and Molecular Profiles of Large Cell Neuroendocrine Carcinoma With Potential Targets for Therapy (original) (raw)
Related papers
Pulmonary large-cell neuroendocrine carcinoma (LCNEC
Objective: The experiences on the treatment of seven consecutive patients with large-cell neuroendocrine carcinoma (LCNEC) were studied, observed over 6 years from 1992. Since LCNEC was recognized as a separate histological entity, only very few series have been reported. Together with the carcinoids (atypical and typical) and the small-cell lung carcinoma (SCLC), it forms the spectrum of neuroendocrine tumors. Methods: Between 1992 and 1997, seven patients who underwent surgical resection were diagnosed as LCNEC postoperatively. Mean age was 65 years (range 54-77 years), five patients were male, all patients were heavy smokers. One patient was staged as IA, four as IB, one as IIIB and one as IV. Results: In five patients, preoperative diagnosis was unknown, in one squamous cell carcinoma and in one adenocarcinoma was suspected. There were four lobectomies, two bilobectomies and one resection of the lingular division with a wedge resection of the upper division of the left upper lobe. Three patients received adjuvant chemotherapy and one, adjuvant radiotherapy. Survival ranged from 7 to 39 months. There are no patients currently alive. Conclusions: LCNEC is a high-grade neuroendocrine tumor with a poor prognosis. In our patients, after surgical resection or multimodality treatment, all have developed widespread metastatic disease with a rapidly fatal course. Due to the rarity of this tumor, the incidence, prognosis and optimal treatment remain to be determined. q
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2012
Pulmonary neuroendocrine tumors (NETs) are traditionally described as comprising a spectrum of neoplasms, ranging from low grade typical carcinoids (TCs) via the intermediate grade atypical carcinoids (ACs) to the highly malignant small cell lung cancers (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). Recent data, however, suggests that two categories can be distinguished on basis of molecular and clinical data, i.e. the high grade neuroendocrine (NE) carcinomas and the carcinoid tumors. Bronchial carcinoids and SCLCs may originate from the same pulmonary NE precursor cells, but a precursor lesion has only been observed in association with carcinoids, termed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. The occurrence of mixed tumors exclusively comprising high grade NE carcinomas also supports a different carcinogenesis for these two groups. Histopathologically, high grade NE lung tumors are characterized by high mitotic and proliferative indices, while carcinoids are defined by maximally 10 mitoses per 2 mm 2 (10 high-power fields) and rarely have Ki67-proliferative indices over 10%. High grade NE carcinomas are chemosensitive tumors, although they usually relapse. Surgery is often not an option due to extensive disease at presentation and early metastasis, especially in SCLC. Conversely, carcinoids are often insensitive to chemoand radiation therapy, but cure can usually be achieved by surgery. A meta-analysis of comparative genomic hybridization studies performed for this review, as well as gene expression profiling data indicates separate clustering of carcinoids and carcinomas. Chromosomal aberrations are much more frequent in carcinomas, except for deletion of 11q, which is involved in the whole spectrum of NE lung tumors. Deletions of chromosome 3p are rare in carcinoids but are a hallmark of the high grade pulmonary NE carcinomas. On the contrary, mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are restricted to carcinoid tumors. Many of the differences between carcinoids and high grade lung NETs can be ascribed to tobacco consumption, which is strongly linked to the occurrence of high grade NE carcinomas. Smoking causes p53 mutations, very frequently present in SCLCs and LCNECs, but rarely in carcinoids. It further results in other early genetic events in SCLCs and LCNECs, such as 3p and 17p deletions. Smoking induces downregulation of E-cadherin and associated epithelial to mesenchymal transition. Also, high grade lung NETs display higher frequencies of aberrations of the Rb pathway, and of the intrinsic and extrinsic apoptotic routes. Carcinoid biology on the other hand is not depending on cigarette smoke intake but rather characterized by aberrations of other specific genetic events, probably including Menin or its targets and interaction partners. This results in a gradual evolution, most likely from proliferating pulmonary NE cells via hyperplasia and tumorlets towards classical carcinoid tumors. We conclude that carcinoids and high grade NE lung carcinomas are separate biological entities and do not comprise one spectrum of pulmonary NETs. This implies the need to reconsider both diagnostic as well as therapeutic approaches for these different groups of malignancies.
Neuroendocrine and biologic features of primary tumors and tissue in pulmonary large cell carcinomas
The Annals of Thoracic Surgery, 2004
Background. Because biological behavior in lung tumors with neuroendocrine differentiation is highly dependent on cell death (apoptosis) and angiogenesis, p21 waf1/cip1 and microvessel density have been targeted as potentially useful tumor markers. We sought to validate the importance of p21 waf1/cip1 and microvessel density and study their interrelationship, analyzing clinical factors, subclassifications, and tumor and stromal markers.
Novel antigens characteristic of neuroendocrine malignancies
Cancer, 1991
The authors describe the immunochemical detection, biochemical characterization, and tissue distribution of neuroendocrine antigens recognized by three newly developed monoclonal antibodies (MoAb) obtained after immunization of mice with the variant small cell lung cancer (SCLC) cell line NCI-H82. RNL-1 was reactive with neuroendocrine tissues similar to the SCLC cluster-1 MoAb, known to recognize N-CAM. Antibodies RNL-2 and RNL-3 are directed against different epitopes on the same proteinaceous complex. Both MoAb recognize an intracellularly located, water-soluble antigen which has a subunit composition with a protein triplet ranging in molecular weight between 44 and 45 kilodaltons (kD) next to a component of approximately 30 kD. The antibodies RNL-2 and RNL-3 reacted with a subset of neuroendocrine tissues and neuroendocrine neoplasms. In lung cancer both antibodies reacted only with some SCLC and carcinoids and not with nonneuroendocrine lung carcinomas. The potential diagnostic applicability of antibodies RNL-1, RNL-2, and RNL-3 is discussed. Cancer 67:619-633, 1991. ESPITE GREAT EFFORTS in the battle against lung D cancer during the last decades this type of malignancy remains the number one cancer killer among men in Western countries. Although the incidence of lung cancer among the male population seems to stabilize, the incidence of lung cancer among women is rapidly rising.',' Results of treatment protocols remain disappointingly low, with a 5-year survival of about 10% of all cases3 The subdivision of lung cancer into the main subtypes, i.e., small cell lung cancer (SCLC), adenocarcinoma, squamous cell carcinoma (SQC), and large cell carcinoma, commonly referred to as non-SCLC, is considerably hampered by the large heterogeneity within these tumors.
Clinical and Experimental Medicine, 2023
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive malignancy, which was recently found to comprise three major genomic subsets: small cell carcinoma-like, non-small cell carcinoma (predominantly adenocarcinoma)-like, and carcinoid-like. To further characterize adenocarcinoma-like subset, here we analyzed the expression of exocrine marker napsin A, along with TTF-1, in a large series of LCNECs (n = 112), and performed detailed clinicopathologic and genomic analysis of napsin A-positive cases. For comparison, we analyzed napsin A expression in other lung neuroendocrine neoplasms (177 carcinoids, 37 small cell carcinomas) and 60 lung adenocarcinomas. We found that napsin A was expressed in 15% of LCNEC (17/112), whereas all carcinoids and small cell carcinomas were consistently negative. Napsin A reactivity in LCNEC was focal in 12/17 cases, and weak or moderate in intensity in all cases, which was significantly lower in the extent and intensity than seen in adenocarcinomas (Po 0.0001). The combination of TTF-1-diffuse/napsin A-negative or focal was typical of LCNEC but was rare in adenocarcinoma, and could thus serve as a helpful diagnostic clue. The diagnosis of napsin A-positive LCNECs was confirmed by classic morphology, diffuse labeling for at least one neuroendocrine marker, most consistently synaptophysin, and the lack of distinct adenocarcinoma component. Genomic analysis of 14 napsin A-positive LCNECs revealed the presence of mutations typical of lung adenocarcinoma (KRAS and/or STK11) in 11 cases. In conclusion, LCNECs are unique among lung neuroendocrine neoplasms in that some of these tumors exhibit low-level expression of exocrine marker napsin A, and harbor genomic alterations typical of adenocarcinoma. Despite the apparent close biological relationship, designation of adeno-like LCNEC as a separate entity from adenocarcinoma is supported by their distinctive morphology, typically diffuse expression of neuroendocrine marker(s) and aggressive behavior. Further studies are warranted to assess the clinical utility and optimal method of identifying adenocarcinoma-like and other subsets of LCNEC in routine practice.
The Unmet Diagnostic and Treatment Needs in Large Cell Neuroendocrine Carcinoma of the Lung
Currently, large cell neuroendocrine carcinoma of the lung (LCNEC) is classified as a rare lung cancer subtype, but given the high incidence of lung cancer, the overall number of cases is considerable. The pathologic diagnosis is based on the microscopic appearance of the tumor cells, the amount of intra-tumoral necrosis, the mitotic rate, and the presence of positive neuroendocrine markers identified by immunohistochemistry. Recently, a subdivision into two main categories was proposed based on mutation signatures involving the RB1, TP53, KRAS, and STK11/LKB1 genes, into SCLC-like (small cell lung cancer-like) and NSCLC-like (non-small cell lung cancer-like) LCNEC. In terms of treatment, surgery remains the best option for resectable, stage I–IIIA cases. Chemotherapy and radiotherapy have conflicting evidence. Etoposide/platinum remains the standard chemotherapy regimen. However, based on the newly proposed LCNEC subtypes, some retrospective series report better outcomes using a pa...
Pancreas, 2017
Background: Optimal therapy for GEP-NEC is not clear. Traditionally treated like SCLC, overall prognosis is poor and new therapies are needed. We examined genomic alterations (GA) in GEP-NEC of different sites compared to SCLC. Methods: Sequential GEP-NEC cases from a database [Foundation Medicine] of tumors submitted for genomic profiling analyzed after digital pathology images reviewed by two different pathologists. Group 1: 274 cases with "some" component of morphologically apparent NEC −123 pancreas (P), 92 colorectal (CR), and 59 "other GI" sites; Group 2: 159 cases passing an independent, stricter pathology review (>50% NEC with small or large cell histology)-91 P, 51 CR, and 17 "other GI". Hybridization-captured libraries of up to 315 cancer-related genes, plus select introns were sequenced (FoundationOne). All classes of GA identified in 192 cancer-related genes shared across 2 different assay versions. "Actionable" alterations were assessed. 593 SCLC cases used for comparison. Results: There were 9 genes with alterations in >15% of tumors in any group (Group 1). Only TP53 crossed the 15% threshold in every group: MEN1 and DAXX >15% specific to P, APC and KRAS specific to CR, and CCNE1 > 15% specific to "other GI". Every GEP-NEC group had a lower rate of alteration for TP53 and RB1 than SCLC. Analysis of Group 2 GEP-NEC showed similar findings ("Other GI" excluded due to small N). Pooled P and CR NEC with small cell histology (N = 142) showed significantly different GA compared to SCLC. 37% of Group 2 GEP-NEC harbored potentially "actionable" GA. Conclusion: Findings indicate underlying drivers of GEP-NEC may depend on site of origin and distinguish GEP-NEC from SCLC. Presence of potentially actionable GA in GEP-NEC suggest additional therapeutic targets. Lack of access to medical record/original tissue precludes correlation of GA with outcome or proliferation index; additional samples required to more fully explore large v small cell subtypes.