Elsevier

Lung Cancer

Volume 75, Issue 3, March 2012, Pages 368-373
Lung Cancer

Clinical features of unresectable high-grade lung neuroendocrine carcinoma diagnosed using biopsy specimens

https://doi.org/10.1016/j.lungcan.2011.08.012Get rights and content

Abstract

Background

The overall clinicopathological features or the optimal therapy for large cell neuroendocrine carcinoma (LCNEC) have yet to be defined, because LCNEC has not been studied in the same depth as had small cell lung carcinoma (SCLC) in both clinical and biological standpoints. The aim of this study was to elucidate the clinical features of high-grade neuroendocrine carcinoma (HGNEC)-probable LCNEC diagnosed by biopsy, and compare therapeutic efficacy with patients with SCLC.

Methods

We retrospectively examined the chart of total of 25 patients who underwent chemotherapy or chemoradiotherapy as initial therapy for a histologic diagnosis of HGNEC-probable LCNEC, using biopsy samples and compared their data with those of 180 patients with SCLC. We analyzed their responses to chemotherapy and/or radiation therapy and survival outcomes.

Results

In 25 patients with HGNEC-probable LCNEC, 18 patients initially received chemotherapy (17 (94%) of whom received platinum-based chemotherapy) with an overall response rate (ORR) of 61%. The remaining 7 patients received chemoradiotherapy with an ORR of 86%, and 12 of the 25 patients who received second-line chemotherapy had an ORR of 17%. A total of 101 patients with SCLC who initially received chemotherapy had an ORR of 63%, and 79 patients who initially received chemoradiotherapy had an ORR of 98%, and 102 of the 180 patients who received second-line chemotherapy had an ORR of 45%. The 1-year overall survival rate for patients with stage IV HGNEC-probable LCNEC (n = 13) and those with ED-SCLC (n = 80) was 34% and 49%, respectively (p = 0.84).

Conclusion

The overall response rate to initial treatment and the survival outcomes of HGNEC-probable LCNEC were comparable to those of SCLC, but the effectiveness of second-line chemotherapy appeared to differ between the 2 groups.

Introduction

Large cell neuroendocrine carcinoma (LCNEC) of the lung and small cell lung carcinoma (SCLC) are both now considered to be high-grade neuroendocrine carcinomas arising in the lung. Travis et al. [1] were the first to propose the term LCNEC in 1991, to describe cancer which exhibits neuroendocrine morphologic features such as rosette formation, organoid nesting, and palisading, large tumor cells (typically 3 times larger in diameter than a small resting lymphocyte) with a low nuclear/cytoplasmic ratio, numerous nucleoli, a high mitotic rate (>10 in 10 high-power fields), a large degree of necrosis, and immunohistochemical positive staining findings for 1 or more neuroendocrine markers [2]. The tumor cells of SCLC are round, oval, or spindle-shaped; usually less than the size of three small resting lymphocytes, and have scant cytoplasm, finely granular chromatin, and absent or inconspicuous nucleoli [2]. The morphologic features of LCNEC differ distinctly from those of SCLC by definition, however, distinguishing LCNEC from SCLC based on the tumor cell size and chromatin morphology may be difficult in some cases.

SCLC has poorer outcome, despite its marked chemosensitivity, enabling temporary remission in most SCLC patients because most tumors relapse after chemotherapy or chemoradiotherapy. The standard therapeutic strategy for SCLC has already been established, and second-line chemotherapy has been recognized to be well-tolerated and effective in patients with chemotherapy-sensitive SCLC [3], [4], [5], [6], [7]. In contrast, the overall clinicopathological features or the standard treatment for LCNEC have yet to be defined, because LCNEC has not been studied in the same depth as had SCLC in both clinical and biological standpoints. Moreover, the incidence of the pre-therapeutic diagnosis of LCNEC in unresectable cases is unknown. Although obtaining a definitive diagnosis of LCNEC using small biopsy specimen is difficult, there is an urgent need to establish the diagnostic criteria for LCNEC. Therefore, instead of diagnosing LCNEC, we usually use the term “high-grade neuroendocrine carcinoma (HGNEC)-probable LCNEC” based on the proposed criteria (Table 1).

The aim of this study was to elucidate the clinical features of unresectable HGNEC-probable LCNEC (HG-pLCNEC) with those of SCLC, and compare their outcomes.

Section snippets

Patient enrollment

From January 2002 through December 2009, we retrospectively examined the charts of total of 25 patients with a histologic diagnosis of HG-pLCNEC, using biopsy specimens. Diagnoses of HG-pLCNEC were all confirmed by pathological examination on biopsy specimens according to the modified criteria for the diagnosis of high-grade non-small cell neuroendocrine carcinoma using biopsy specimens proposed by Igawa et al. [8] (Table 1). All patients had undergone a minimum of 1 course of chemotherapy or

Results

Overall, 25 patients were recognized to have tumors with histological characteristics consistent with HG-pLCNEC based on biopsy specimens. The typical microscopic appearances of the transbronchial biopsy specimens in the current study are shown in Fig. 1. The tumor cells showed a proliferation of polygonal cells, and a low nuclear–cytoplasmic ratio, with no differentiation of acinar or squamoid features (A). Positive immunostaining findings for NCAM antibody were observed (B), but findings for

Discussion

We set out to determine the clinical features of HG-pLCNEC and other related tumors diagnosed by biopsy specimens and compare these with those of SCLC. We also examined the efficacy of chemotherapy or chemoradiotherapy between HG-pLCNEC and that of SCLC. Little is known about the optimal treatment strategy of LCNEC because most publications concerning LCNEC are based on surgical materials, with limited cohort data [11], [12], [13]. From a treatment point of view, it is imperative to establish

Conflict of interest statement

The authors declare no potential conflicts of interest regarding this study.

Grant support

This study was supported in part by a Grant-in-Aid for Cancer Research (19-10) from the Ministry of Health, Labour, and Welfare of Japan and a Grant-in-Aid for the Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour, and Welfare of Japan.

Acknowledgements

The authors thank Roderick J. Turner and Professor J. Patrick Barron of the Department of International Medical Communications of Tokyo Medical University for reviewing the English manuscript.

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    All work included in the manuscript was performed at the National Cancer Center Hospital East, Kashiwa, Chiba, Japan. The research was approved by the Institutional Review Board. No patient consent was required as the research was a retrospective chart review and no personally identifiable information is included in the manuscript.

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