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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Joseph B. Shrager Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shrager, J. B. Search for Related Content PubMed Articles by Shrager, J. B. Related Collections Lung - other

Ann Thorac Surg 2004;77:1895
© 2004 The Society of Thoracic Surgeons

Invited commentary

Department of Surgery University of Pennsylvania Health System 4th Floor Silverstein 3400 Spruce St Philadelphia, PA 19104-4283, USA

e-mail: jshrag{at}mail.med.upenn.edu

This paper by Iyoda et al sheds further light on a subtype of bronchogenic carcinoma that has been poorly understood by surgeons and pathologists alike. Large cell neuroendocrine carcinoma (LCNEC) makes up approximately 2–3% of non-small cell lung cancers (NSCLC). However, until the World Health Organization (WHO) formally reclassified pulmonary tumors with neuroendocrine morphology in its 1999 Histological Typing of Lung and Pleural Tumors, the use of widely variable terminologies and criteria for diagnosing LCNEC hindered progress in understanding this tumor.

As defined by the WHO, LCNEC lies with small cell carcinoma (SCLC) at the high-grade end of the spectrum of tumors with neuroendocrine morphology—a spectrum that also includes typical and atypical carcinoids. The diagnosis of LCNEC requires not only the presence of neuroendocrine histological features on light microscopy but also the confirmation of neuroendocrine differentiation by immunohistochemistry or electron microscopy. Although both SCLC and LCNEC share very high mitotic rates, more extensive necrosis than even atypical carcinoids, and frequent p53 mutations, the larger cell size of LCNEC vs. SCLC and a variety of other histological criteria that differ between these two tumors led the WHO to continue to classify LCNEC as a subtype of large cell carcinoma. Despite this, a number of recent investigations have suggested that LCNEC may behave biologically and clinically more like SCLC than NSCLC.

There are a number of issues surrounding LCNEC that are of clinical importance and have come to light in recent publications. First, as should be clear from the above pathological discussion, LCNEC may be easily confused with both SCLC and poorly differentiated NSCLC by cytology (and sometimes even after complete resection), so one must be aware of the possibility of this diagnosis when a needle biopsy of small cell carcinoma is made. Even more importantly, the bulk, if not all, of the evidence suggests that these tumors have a worse prognosis following surgical resection than stage-matched, standard NSCLC. Although there is no clear evidence to date that LCNEC is responsive to chemotherapy in a manner similar to SCLC, the aggressiveness of this tumor and its biological similarity to SCLC has led many to suggest that it may be the most appropriate target among NSCLCs for adjuvant chemotherapy.

This paper by Iyoda et al builds upon previous work by these authors in this area. They have previously reported that the presence of neuroendocrine features in a large cell carcinoma (LCC) confers a worse prognosis and that their patients with stage I LCC with neuroendocrine features had significantly higher survival if they underwent adjuvant chemotherapy than if they did not. They subsequently showed that the prognosis of patients following resection of LCC with neuroendocrine features was so poor as to approach that of patients with SCLC. In the current publication, they zero in specifically on stage I LCNEC and find that the disease-free survival is worse than in stage I classic LCC, and further that mitotic rate, Ki-67 labelling index, and Bcl-2 expression are all higher in stage I LCNEC than stage I classic LCC. This work thus begins to identify histological and molecular correlates that underlie the increased clinical aggressiveness of LCNEC reported by these and other authors.

This work could be criticized for presenting disease-free rather than overall survival. The former is certainly more prone to being biased by failure to recognize recurrences in a timely fashion. Further, the conclusion of the last sentence of the manuscript that "...patients with LCNEC should receive adjuvant chemotherapy following surgical resection even in stage 1 disease" is not supported by the data presented within this work alone. Nevertheless, taking all the recent work in this field into account, there appears to be little doubt that LCNEC is a more aggressive tumor than most other NSCLCs, and that adjuvant therapies should be given very strong consideration in patients who have had these tumors resected.

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Joseph B. Shrager Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Shrager, J. B. Search for Related Content PubMed Articles by Shrager, J. B. Related Collections Lung - other