Histological analysis remains the primary method of distringuishing between small cell (SCLC) and non-small cell lung cancer (NSCLC). This distinction has significant impact therapeutically because of their relative difference in chemoresponsiveness (J. D. Minna et al., Principles and Practice of Oncology, pp. 396–474, 1981). Yet for at least 10% of lung tumors, pathologists will disagree upon the classification (A. R. Feinstein et al., Am. Rev. Respir. Dis., 101: 671–684, 1970). Furthermore, current neuroendocrine markers lack specificity for SCLC although the presence of these markers may help predict chemosensitivity (S. L. Graziano et al., J. Clin. Oncol., 7: 1375–1376, 1989; S. B. Baylin, J. Clin. Oncol., 7:1375–1376, 1989; C. L. Berger et al., J. Clin. Endocrinol. Metab., 53: 422–429, 1981; A. F. Gazdar et al., Cancer Res., 45: 2924–2930, 1985). In vitro growth characteristics may more accurately reflect biological properties of aggressiveness and susceptibility to chemotherapy. In this study, 3-dimensional gel-histoculture was used to retrospectively distinguish between NSCLC and SCLC. Tumor explants from 78 patients with NSCLC and 13 patients with SCLC were grown in gelsupported histocultures with an overall success rate of 92%. These 2 tumor types were distinguishable by their 3-dimensional in vitro tissue architecture. In addition, proliferation rates were measured by histological autoradiography after 4-day incorporation of [3H]dThd. The percentage of cells labeled in the most proliferatively active regions of the autoradiograms was termed the growth fraction index (A. F. Gazdar et al., Cancer Res., 45: 2924–2930, 1985; R. A. Vescio et al., Proc. Natl. Acad. Sci. U. S. A., 84: 5029–5033, 1987; R. M. Hoffman et al., Proc. Natl. Acad. Sci. U. S. A., 86: 2013–2017, 1989). The mean growth fraction index for pure small cell lung cancer was 79 ± 10%, differing markedly from that of 35 ± 19% for mixed small cell/large cell tumors, adenocarcinoma (38 ± 16%), large cell undifferentiated carcinoma (40 ± 18%), and squamous cell carcinoma (33 ± 15%) (P < 0.001 in each case). We therefore conclude that 3-dimensional gel-histoculture is a useful means of distinguishing pure SCLC from NSCLC, which may improve treatment decision making.


This study was supported by National Cancer Institute Small Business Innovation Research Grant R44 CA44 CA43411, National Cancer Institute Grant R01-CA27564, and American Cancer Society Grant PDT 330.

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