Incidentally Detected Small Cell Transformation in a Patient With Resected Oligometastatic EGFR-Mutated Lung Cancer Treated With Osimertinib

Introduction

Adenocarcinoma is the most common NSCLC subtype that recently experienced a rapid expansion of treatment options, mainly with target therapy in patients with mutations. Here, we report about a 46-year-old woman, pediatrician, who was diagnosed as having EGFR-mutant lung adenocarcinoma and submitted to osimertinib and lobectomy, with focal transformation to small cell carcinoma (SCC). The emergence of SCC features while under osimertinib is uncommon, and only a few reports with tissue analysis are available so far.¹

Case Report

On admission in July 2018, clinical staging revealed right lower lobe mass (7.5 cm × 5.0 cm) (Fig. 1), and three small lesions in the central nervous system, which were treated with stereotactic radiosurgery. After a mass biopsy was done confirming adenocarcinoma, next-generation sequencing was performed and revealed a point mutation at exon 21 EGFR (L858R). She was started on osimertinib and had a major response at the primary tumor within 12 months of therapy (Fig. 2). At that time, the brain metastasis was considered controlled, and a lobectomy was proposed. The operation was performed in September 2019; the pathologic report revealed a partial response with extensive tumor cystification and approximately 40% remaining viable neoplastic cells. Remarkably, a well-defined 0.6 cm focus of SCC transformation was incidentally detected within the adenocarcinoma-predominant component (Fig. 3A-D).

Figure 1.

Computed tomography with a 7.5 cm × 5 cm mass in the right lower lobe (July 13, 2018).

Figure 2.

Computed tomography with a partial response after 12 months (August 8, 2019).

Figure 3.

Pathologic findings. (A) Gross specimen revealing extensive tumor cystification (dotted line) with a focal nodular area (arrow) corresponding to the small cell carcinoma transformation; (B) Hematoxylin and eosin (×400) stained section with acinar adenocarcinoma (upper right half of the field) continuous to the focus of transformation for small cell carcinoma (lower left half); (C) Immunohistochemistry disclosing synaptophysin positivity in the small cell carcinoma component; (D) Ki-67 positivity in more than 90% of neuroendocrine neoplastic cells.

Discussion

One of the great improvements in patients with EGFR mutation was the gain of unprecedented overall survival after moving third-generation EGFR tyrosine kinase inhibitor osimertinib to the first-line setting. The AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA) trial revealed 38 months of survival versus 31 months in the first-generation tyrosine kinase inhibitor.² Recent research is focusing on understanding the resistance mechanisms when starting with a third-generation inhibitor, as in this case.

Ramalingam et al.¹ reported several resistance mechanisms after osimertinib exposure as first-line, but only liquid biopsy samples were analyzed, so the transformation of SCC was not verified. The phenomenon of histologic transformation as a resistance mechanism is not yet fully understood. Some reports revealed that tumors harboring inactivated Rb1 and p53 may be transformed into SCC; these instances also probably happened under first-line osimertinib exposure.³ In our patient, we incidentally identified such a transformation because plenty of material was obtained through lobectomy.

The local aggressive therapy in oligometastatic disease, as was done in this patient, was prospectively studied by Gomez et al.⁴ In this phase II trial, local aggressive therapy extended overall survival (41.2 mo × 17.0 mo) compared with maintenance therapy.⁴ One Chinese study found that consolidative treatment to all metastatic sites in patients with EGFR mutation had risen overall survival up to 10 months compared with any ablative treatment (40.9 mo versus 30.8 mo).⁵

At present, the patient is still under treatment with osimertinib and has no evidence of progression after 6 months of lobectomy. A new biopsy will be mandatory at the time of disease progression to identify the histologic pattern, which, in turn, can serve as a guide in choosing the best subsequent treatment.