In the WHO version of 1981, the carcinoid and the small-cell carcinoma only were categorized under the term neuroendocrine tumors. In 1985, Carter called for a more precise differentiation of neuroendocrine tumors of the lung ; in an elaborate immunohistochemical analysis of non-small-cell carcinomas, Linnoila identified several neuroendocrine markers, especially in large-cell tumors . In a study based on this, Travis introduced the term large-cell neuroendocrine carcinoma (LCNEC) as a variant of the large-cell carcinoma and suggested this tumor be considered a new tumor entity in addition to the carcinoid as well as the small-cell carcinoma. This was characterized by light-microscopically determined phenotypically large, polygonal cells, a high incidence of mitoses and necroses, as well as the immunohistochemical or electron microscopic determination of neuroendocrine markers . Due to the absence of a consensus as well as the call for reproducibility and clinical significance , in 1999 the WHO along with the IASLC 1999 included the large-cell neuroendocrine bronchial carcinoma as a variant of the large-cell carcinoma into the classification system . Subsequently, on the basis of clearly defined criteria, an increasing number of clinical series were published giving consideration to this new type of tumor [11–14].
Based on our series of 12 patients, we studied the significance of neuroendocrine expression by considering a further difference between large-cell bronchial carcinomas with neuroendocrine morphology only (LCCNM) as well as large-cell bronchial carcinomas showing the expression neuroendocrine markers (LCNEC). These tumor groups differ only in the expression of neuroendocrine markers, the morphology determined using a light microscope, on the other hand, being identical in both tumors. Both groups show growth patterns that are generally typical for neuroendocrine tumors, independent of their site of origin. Thus, tumor cell rosettes and clearly delimited spherical cell clusters are found on a regular basis.
This subtyping is not made in the criteria formulated in 1999 by the WHO and IASLC; using a careful division into these two types of tumor, Zacharias and Iyoda, however, show that this stratification is of importance with respect to prognosis and therapy [6, 7]. In both the uni-as well as in the multivariate analysis, Iyoda was able to demonstrate a worse overall as well as tumor-free survival time in patients showing the expression of neuroendocrine markers . Travis demonstrated a relationship between increased CEA in the serum and shorter survival times . These observations concur with our results on the tumor-free intervals, which were almost four times shorter in patients with LCNEC. In contrast, Harada et al, showed an improved survival time in such tumors in which more than 2 neuroendocrine markers could be identified immunohistochemically . The 1-year survival rate in the LCCNM group was 40%, in the LCNEC group 50%. In the largest series published so far on large-cell neuroendocrine bronchial carcinomas by Takei , the 5-year survival (YS) in stage I was 67%, in stage IV 0%. In our series, only 2 patients survived 5 years in a tumor stage I B and II B, all the other patients died within the first 2 postoperative years. Jiang reports on a stage-dependent 1-YS of 58.8%, which is comparable to our LCNEC 1-YS. The poor prognosis of this tumor becomes clearer when one considers the 1-YS of 86.2% in patients with NSCLC undergoing surgery , although the overall poor median survival cannot solely attributed to the neuroendocrine nature of these tumors but also to the advanced tumor stages of the patients in this series.
The clinically aggressive behavior of the LCNEC was also demonstrated by Iyoda by a significantly enhanced expression of Bcl-2. He could observe also a shorter tumor-free survival times .
The exact preoperative diagnosis using a bronchoscopic or transthoracic biopsy proved unsuccessful in all our cases. The success of a definitive diagnosis of LCNEC preoperatively is also judged to be extremely difficult by other authors as well . Wiatrowska and Kakinuma report on reliable data based on cytological material [18, 19]. Whether a cytological diagnosis is adequate to determine a therapy concept remains uncertain.
In the group of patients with LCNEC, we could demonstrate that one tumor recurrence occurred in the form of a distant metastasis exclusively, whereas in the group of patients with an LCCNM there was a regular occurrence of intrapulmonary metastasis. This observation is not to be found in any of the clinical series published to date; it is possible that neuroendocrine markers have an influence on the metastatic process as well as the site of metastasis. Due to the small number of patients involved, this trend is not subject to any statistical analysis.
With respect to its severity, LCCNM and LCNEC are classified as being between the atypical carcinoid and the small-cell carcinoma, whereby some authors ascribe these types of tumors a greater similarity to the small-cell carcinoma. There are features in common regarding the high incidence of mitosis and necrosis as well as several phenotypic characteristics; small-cell carcinomas can also express a similar spectrum of endocrine markers. Until present, LCNEC were treated in a similar way to NSCLC, incorporating adjuvant chemotherapy in a fixed treatment regimen, however, remaining up until now not being taken into account. In light of the small number of cases in the reported series to date, the advantage of such a form of chemotherapy must be evaluated as still being uncertain. Whereas in a clinical study in patients with non-small cell bronchial carcinoma and neuroendocrine differentiation, an improved survival time as a result of adjuvant chemotherapy was not reported , Iyoda was able to demonstrate an improvement of survival time of about 20% in stage I with adjuvant chemotherapy . Until now there have been no studies on this providing a randomized comparison of the group undergoing surgery with and without adjuvant chemotherapy.
Another adjuvant therapeutic approach already described before was taken up again by Caretta in a study on 44 neuroendocrine carcinomas, in which he points out the importance of the octreotide scan . Filosso was able to demonstrate a significant increase in survival time with adjuvant octreotide therapy in 55% of scintigraphically positive patients .