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