Clinical Paradoxes

Perusal of Tables 10–1 through 10–3 and examination of the details of the observations summarized therein raise several questions about the nature of small cell lung cancer. How does one reconcile these relatively favorable outcomes of surgical treatment with the results of the Medical Research Council randomized trial, in which 51% of the patients were unresectable, no patients were

cured by surgery, and the 5-year survival was 1%? Is chemotherapy responsible for the improved outcomes in patients treated with preoperative chemotherapy? If so,

how can the findings in Table 10–2 be explained, where chemotherapy was not used? How can the resection rates in Tables 10–1 through 10–3 be reconciled with that of the Medical Research Council trial? What is the explanation for the finding of non–small cell cancer in a significant number of small cell patients resected after preoperative chemotherapy?

There are several possible explanations for these questions. Certainly stage migration, or the so-called “Will Rogers effect, ” can partially explain some of the discrepancies. As newer imaging technology has improved the sensitivity of staging, patients with previously undetectable occult metastases are transferred from low-stage to advanced-stage categories and the survival of all stages improves without any change in the effectiveness of treatment. More sensitive preoperative staging can eliminate patients with occult metastases from surgical candidacy. Thus, results such as those in Table 10–3 might be attainable even without chemotherapy.

Another factor that emerged in the 1980s was the role that fine-needle aspiration cytology began to play in cancer diagnosis. Small cell lung cancers that previously required thoracotomy for diagnosis could now be diagnosed by transthoracic needle aspiration and be treated with chemotherapy. If such patients were then resected, one might be persuaded that the chemotherapy treatment effect permitted the resection. Some of the results in Table 10–1 could be explained in this manner.

Immunohistochemical staining techniques developed in parallel with fine-needle aspiration cytology. Examination of diagnostic material by these new methods began to reveal mixtures of histologic features in cancers that had previously been classified as pure cell types. As diagnoses are made based on scantier and scantier samples, the question of sampling error arises. The correlation between bronchial biopsy specimens and tumors removed at thoracotomy has been studied, and the correlation coefficient for small cell concordance is only 0.6.The finding of non–small cell histology in resection specimens of small cell lung cancer patients calls into question the initial small cell diagnosis. This type of quandary is not new. There are two autopsy series from the 1970s that show the presence of non–small cell cancer in patients who died after being diagnosed and treated for small cell lung cancer. One of these found that 24% of the patients had squamous cell carcinoma in addition to small cell at autopsy, and the other showed the presence of combinations of all cell types in 27.5% of the small cell patients. The current thinking among lung cancer pathologists is that lung cancer can be a histologically heterogeneous entity, and the newer techniques have allowed this to be appreciated. At any rate, if small cell lung cancer is not a resectable cell type, perhaps some of the cases in Tables 10–2 and 10–3, as well as those documented in Table 10–1, were actually non–small cell cancers that had been erroneously classified because of the nuances of lung cancer pathology that were unrecognized at the time. Finally, the difficulties in distinguishing carcinoid from small cell carcinoma have caused some experts to question the very existence of stage I small cell carcinoma. Its rarity can be seen by examining Table 10–2 and considering the denominators in these series. In addition, in the Lung Cancer Study Group’s (LCSG) limited resection versus lobectomy trial, a total of 771 peripheral nodules were screened, and only 14 (1.8%) were small cell cancers (unpublished data). Perhaps, some of the lesions resected in Tables 10–1 through 10–3 were carcinoids rather than true small cell carcinomas.