Squamous Cell Carcinoma Transformation as a Possible Resistant Mechanism Against Pembrolizumab Plus Chemotherapy
Authors: Yuka Kozuma, Gouji Toyokawa, Fumihiro Shoji, Koji Yamazaki, Shigeto Kawauchi, Seiya Momosaki, Sadanori Takeo
Journal: Journal of Thoracic Oncology (2019)

A 67-year-old male with no smoking history presented with common cold symptoms. Computed tomography revealed infiltrative shadow, measuring 70 mm in size, in the lower lobe of the right lung (Fig. 1A). No metastasis in the lymph nodes and distant organs were identified. Although transbronchial biopsy failed to reach the diagnosis of carcinoma, the patient was suspected to have lung cancer (cT4N0M0, cStage IIIA), and a right lower lobectomy was performed. Tumor size was 72 mm in its diameter (Fig. 1B). Microscopic findings diagnosed the tumor as invasive adenocarcinoma (acinar predominant) (Fig. 1C). Immunohistochemically, carcinoma cells were positive for thyroid transcription factor-1 (TTF1) and negative for interleukin 9 (p40) (Figs. 1D and E). Neither mutations nor alterations in the EGFR, ALK receptor tyrosine kinase (ALK), and ROS1 genes were detected. Expression of programmed death ligand 1 was not detected. The pathologic diagnosis was pT4N0M0, pStage IIIA. Adjuvant chemotherapy with four cycles of cisplatin plus vinorelbine was administered. Five months after the operation, lung metastasis, which was cytologically confirmed, was identified in left lower lobe (Figs. 2A and B). Then, pembrolizumab plus carboplatin plus pemetrexed were administered. During the first cycle, the patient had a high fever and computed tomography scans showed the rapid enlargement of the tumor (Fig. 3A). Bronchoscopic re-biopsy of the tumor revealed the tumor to be morphologically squamous cell carcinoma (SCC), not adenocarcinoma (Fig. 3B). Immunohistochemically, carcinoma cells were negative for TTF1 and neuroendocrine makers, and positive for p40, suggesting poorly differentiated SCC (Figs. 3C and D). Thereafter, docetaxel was administered and the disease remained stable after two cycles.Figure 3(A) Computed tomography image showing the rapid enlargement of the lung metastasis after first line treatment. (B) Histologic image of the re-biopsied tumor showing squamous cell carcinoma features. (C and D) Immunonegativity of carcinoma cells for thyroid transcription factor-1 and immunopositivity for p40.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Histologic transformation from adenocarcinoma to SCLC was first introduced in 2006 and several reports showed that such transformation conferred resistance against EGFR tyrosine kinase inhibitors.1Norkowski E. Ghigna M.R. Lacroix L. et al.Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology.J Thorac Oncol. 2013; 8: 1265-1271Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Furthermore, Izumi et al.2Izumi H. Yamasaki A. Ueda Y. et al.Squamous cell carcinoma transformation from egfr-mutated lung adenocarcinoma: a case report and literature review.Clin Lung Cancer. 2018; 19: e63-e66Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar showed 11 cases which transformed to SCC in EGFR-mutated lung adenocarcinoma acquiring resistance to EGFR tyrosine kinase inhibitors.2Izumi H. Yamasaki A. Ueda Y. et al.Squamous cell carcinoma transformation from egfr-mutated lung adenocarcinoma: a case report and literature review.Clin Lung Cancer. 2018; 19: e63-e66Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar There are only few published cases showing histologic transformation upon treatment with programmed death 1 inhibitors.3Hsu C.L. Chen K.Y. Kuo S.W. Chang Y.L. Histologic transformation in a patient with lung cancer treated with chemotherapy and pembrolizumab.J Thorac Oncol. 2017; 12: e75-e76Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 4Nagasaka M. Pansare R.S. Abdulfatah E. Guan H. Tranchida P. Gadgeel S.M. Histologic transformation in nsclc with pd-1 therapy.J Thorac Oncol. 2017; 12: e133-e134Abstract Full Text Full Text PDF Scopus (7) Google Scholar Among five cases reported, four exhibited transformation to SCLC, whereas only one exhibited transformation to SCC. All cases showed histologic transformation after programmed death 1 inhibitor monotherapy, whereas the current case showed SCC transformation after the combination therapy of pembrolizumab with chemotherapy. The molecular mechanism of transformation conferring resistance to anticancer agents has not been fully elucidated. Recently, some studies have shown convincing evidence supporting adenocarcinoma-to-SCC transition. Deficiency of serine-threonine kinase 11 (STK11), which can activate multiple downstream serine-threonine kinases through phosphorylation of a conserved threonine in the T-loop of the kinase domain, can promote the transformation from adenocarcinoma to SCC.5Hou S. Zhou S. Qin Z. et al.Evidence, mechanism, and clinical relevance of the transdifferentiation from lung adenocarcinoma to squamous cell carcinoma.Am J Pathol. 2017; 187: 954-962Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Another possible mechanism for transformation is intratumoral heterogeneity. In the present case, adenocarcinoma was diagnosed by surgically resected lung, and no component of SCC was identified. It is possible that the amount of the biopsied specimen after tumor relapse was insufficient to identify mixed histology. In conclusion, the possibility of the SCC transformation should be considered after the relapse on pembrolizumab and chemotherapy and repeated biopsies may provide useful information to optimally determine the subsequent treatment.