Abstract
Small cell neuroendocrine carcinomas (SCNC) are composed of round to spindle-shaped cells with features of both neuroendocrine and epithelial neoplasms. SCNC can be found in basically all epitheloid organs; however, the vast majority arises in the lung, while extrapulmonary (EP) localization is rare. Small cell lung cancer (SCLC) and EP SCNC are considered one histological entity and are treated similarly. Despite the high initial response to chemo- and radiotherapy, most patients relapse after short remission, and overall prognosis is dismal. Clinical trials employing high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (auto-SCT) neither demonstrated a clear benefit nor clarified its significance in SCLC. The role of intensified treatment in EP SCNC has not been specifically addressed in detail. Conversely to SCLC, some subgroup analyses indicated that patients with EP SCNC might benefit from intensive treatment. We analyzed a total of 22 patients: 8 with EP SCNC (group A; m:f 3:5; median age 36 years (y) [range 22–56]) and 14 patients with SCLC (group B; m:f 10:4; median age 55 y [40–63]), all undergoing HDCT with auto-SCT at our single center from 07/90–01/05. A control group C consisted of 30 patients with EP SCNC (m:f 21:9, median age 66 years [32–81], who received different standard treatments without auto-SCT. All group A patients had stage IV disease (liver n=5, lymph nodes n=4, pancreas n=1, orbita n=1, bone n=1, kidney n=1). Two of these patients received additional local radiotherapy. In group B, 7 patients had limited and 7 patients extensive disease, (stage I (n=1), II (n=2), III (n=10), IV (n=1). HDCT with VIC (etoposide, ifosfamide, carboplatin; n=21), or CCT (carboplatin, cyclophosphamide, thiotepa; n=1) was followed by infusion of a median 3.2x10^6 CD34+ cells. Prophylactic radiotherapy was performed in 12 patients (mediastinum n=11; brain n=10). With a median follow-up (FU) of 48 months (7–152) for group A and 85 months (0–170) for group B, 5/8 (63%) of patients with EP SCNC (group A) are alive and in complete remission (CR), compared to 5/14 (36%) SCLC patients (group B). Best response ever achieved after HDCT was a CR in 5/8 (63%), a partial remission (PR) in 2/8 (25%) and stable disease (SD) in 1/8 (12%) in group A. In group B, a CR was attained in 11/14 (79%), a PR and a SD in 1/14 (7%) patients, respectively. In the conventionally treated control group C, a transient PR was achieved in 5/30 (16%), and after a median FU of 9.7 months, only 2/30 (6.7%) EP SCNC patients are alive. Our analysis suggests that selected SCNC patients may benefit from HDCT, particularly when integrated into multimodal treatment concepts. The remarkably favorable outcome in patients with EP primary site, even when HDCT was implemented as salvage treatment warrants further studies on the role of HDCT in SCNC. Careful attention will have to be paid to prognostic clinical features, such as primary site and/or histological parameters including neuroendocrine marker profiles and mitotic indices. These may help to predict which patients will benefit from intensified treatment. In addition, further histological studies should address the identification of markers specific for lung- vs. extrapulmonary primary localization. For this purpose all available tumor tissue from our study is currently under histological re-analysis, assessing the expression of the novel tumor testis antigens.
Transcriptome Sequencing Reveals Gene Expression Differences in the Response of Malignant Melanomas Cells to Hypoxia
