Large cell neuroendocrine carcinoma of the lung: pathological study and clinical outcome of 18 resected cases
Introduction
Large cell neuroendocrine carcinomas of the lung (LCNEC) share morphological characteristics with classic large cell carcinomas (LC) and immunohistochemical features with the wide spectrum of neuroendocrine (NE) tumours. Significant controversy exists over the classification of these carcinomas [1], [2]. Recently, Travis et al. affirmed the usefulness of a three-grade, four-type scheme for classification of NE tumours of the lung with typical carcinoid (TC) representing a low grade tumour, atypical carcinoid (AC) representing an intermediate grade tumour, and LCNEC and small cell lung carcinoma (SCLC) representing high grade tumours [3]. The same grading is proposed in the 1999 World Health Organization (WHO) classification with rigorous criteria for each subtype even if LCNEC is still considered as a variant of LC [4].
LCNEC represents about 1–2% of lung malignancies and is known for having a very poor prognosis [3], [5]. At the present time, it is not clear how these patients should be treated. Surgery is considered as the primary therapeutic option for TC and chemotherapy for SCLC, but the appropriate treatment remains very unclear for AC and LCNEC [6].
We reported 18 consecutive patients that underwent surgery in our institution between 1996 and 2000 for LCNEC. In order to obtain a homogenous series, we applied rigorously the WHO criteria and all the slides were submitted to a double reading. Until now, LCNEC was considered in our institution as non-small lung carcinoma (NSCLC), and all patients were treated by surgery without any adjuvant treatment except post-operative radiotherapy for N2 or T3 disease with chest involvement. Chemotherapy was only proposed in a palliative purpose when a metastatic disease was diagnosed. We reported the pathological findings and the clinical outcome of these 18 patients in order to better specify the morphological and molecular characteristics of this distinct subset of tumour and to evaluate the result of applying to LCNEC the NSCLC standard treatment.
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Patients and methods
Registries of the Department of Thoracic Surgery and of the Department of Pathology from our institution were reviewed to cull all cases of LCNEC resected between 1996 and 2000. During this period, 1118 patients underwent surgery for primary lung cancer in our institution including 46 (4%) NE tumours (6 SCLC, 9 TC, 5 AC and 26 LCNEC). The 46 NE tumours were reviewed by two pathologists. Hematoxylin–eosin stained slides, alcian blue sections and immunohistochemical stains for chromogranin A and
Pathological characteristics (Table 1)
By definition, all selected tumours had a NE appearance with organoid, trabecular or rosette-like patterns. The frequency of rosette-structures was variable (from less than 1 to 5 for 10 HPF). The mitotic index was high from 35 to 71 and a median of 52. In all patients, histologic NE differentiation was confirmed by the presence of positive immunohistochemical staining for chromogranine A (18 cases) or synaptophysin (15 cases). NCAM was expressed in 11 cases. Bcl-2 was positive in nine cases
Discussion
Multiplication of several classifications and of alternative terms has led to considerable confusion in the diagnosis and treatment of NE tumours. LCNEC must be strictly separated from other NE tumours such as SCLC and AC and also from NSCLC with NE differentiation. The distinction between AC and LCNEC is based on Travis's works [3] that had identified a better correlation with the clinical prognosis by considering the threshold mitotic rate at 10 per 2 mm2. In fact, LCNEC and SCLC have very
Acknowledgements
The authors thank Bill Mazières and Maité Turmon for their help in reviewing the manuscript.
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