Abstract
Histomorphologic changes are known to be associated the acquired resistance of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) treatment. Rebiopsy is usually used to detect the underlying molecular mechanism of resistance, however meticulous histologic examination is very important to identify the change of cancer phenotype. Here we tried to investigate histomorphologic changes between the initial and rebiopsy specimens. We retrospectively evaluated the initial biopsy and rebiopsy specimens of 60 patients with acquired resistance to EGFR-TKI between 2010 and 2016 in Seoul National University Bundang Hospital, Republic of Korea. EGFR mutation tests were performed in all specimens. Various histologic parameters including spindle cell components, discohesive growth pattern and stromal change, subtype of the tumor and nuclear grade were evaluated. In addition, immunohistochemistry (IHC) for epithelial-mesenchymal transition (EMT) markers (E-cadherin and vimentin) and neuroendocrine markers (CD56 and synaptophysin) was performed. In rebiopsy specimens, 18 cases (30%) showed changes of cellular morphology including spindle cell components and discohesive growth pattern representing EMT features. On IHC, acquisition of vimentin expression in spindle cell components and decreased expression of E-cadherin in adenocarcinoma of rebiopsy specimens were identified. Furthermore, histologic transformation to small cell carcinoma (2 cases, 3.3%) with expression of neuroendocrine markers and squamous differentiation (2 cases, 3.3%) were observed. In this study, histologic transformation to EMT is the most frequent finding in rebiopsy samples of the patients with EGFR-TKI resistance while small cell carcinoma has been known to be the most common in the literatures. Although EMT has been reported to be about 5% of EGFR-TKI resistance, we observed it in approximately 30% of our rebiopsy cases. These findings suggest that detailed and meticulous pathologic evaluation plays an important role to find delicate histomorphologic changes associated with EGFR-TKI resistance.
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