Non-small Cell to Small Cell Lung Cancer on PD-1 Inhibitors: Two Cases on Potential Histologic Transformation

Introduction: Histologic transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a well-recognized mechanism of resistance in -mutant adenocarcinoma upon treatment with TKIs, but rarely reported with programmed death1 (PD-1) inhibitors. We report two cases of potential transformation during treatment with PD-1 inhibitors.

Case Presentations: Case 1, a 65-year-old man was diagnosed with stage IVa lung adenocarcinoma on pleural fluid cytology. He received six cycles of carboplatin and pemetrexed, then maintained on pemetrexed. He had disease progression after nine cycles of pemetrexed and was switched to nivolumab. He progressed after five cycles of nivolumab. Core biopsy of the lung mass revealed SCLC. Case 2, a 68-year-old man was diagnosed with two primary NSCLCs and underwent resection. He had recurrence after several months and was treated with four cycles of carboplatin, paclitaxel, and pembrolizumab on clinical trial, with partial response. He was continued on pembrolizumab and had disease progression after 30 cycles. Biopsy of the new lesions showed SCLC.

Discussion: Histologic transformation from NSCLC to SCLC can be explained by the presence of a common cell precursor. Proposed molecular mechanisms include loss of , mutations, and amplification. The distinction between transformation and mixed histology tumors is challenging, especially when pathologic material used for the initial diagnosis is limited. The possibility of a second metachronous primary lung cancer cannot be excluded in our cases.

Conclusion: Histologic transformation with PD-1 inhibitors could be under-recognized. Disease progression should prompt re-biopsy to uncover new histology and change in treatment. Future studies are needed to elucidate mechanisms and predictors of transformation.