Fig. 3.

Drug resistance and transformation of NSCLC to SCLC. The SCLC histological phenotype was observed in five (14%) NSCLC patients who had acquired resistance. Two examples are shown. (A) Patient 23 had an exon 19 deletion in EGFR. (B) Patient 22 carried the L858R mutation in EGFR. The presence of the original activating mutation was confirmed in both pretreatment (pre-Rx) specimens (upper panels) and drug-resistant specimens (lower panels). Hematoxylin and eosin (H&E) (left) and synaptophysin (right) staining are shown for each case. Notably, the pretreatment biopsies (A and B, upper panels) demonstrate adenocarcinoma consisting of cellular growths of atypical glands with (A) or without (B) a cribriform pattern that are negative for synaptophysin. The post-resistance biopsies (A and B, lower panels) demonstrate a SCLC phenotype consisting of nests of small cells with a high nuclear-to-cytoplasmic ratio with (A) or without (B) the classic SCLC-associated finding of “crush artifact,” with positive immunohistochemical staining for synaptophysin. (C) Computed tomography scans of a representative patient (patient 25) with SCLC in the acquired resistance specimen before (above) and after (below) chemotherapy with cisplatin and etoposide (the standard regimen for treating SCLC). Yellow arrows denote right third rib metastases, and white arrows denote left axillary adenopathy.