There is still a role for cytology in the ‘liquid biopsy’ era. A lesson from a TKI-treated patient showing adenocarcinoma to squamous cell carcinoma transition during disease progression

Abstract

Non-small cell lung carcinoma harbouring epidermal growth factor receptor () mutation, usually progress after an initial response to tyrosine-kinase inhibitors (TKI). Liquid biopsy enables with a simple blood draw the accurate detection of p.T790M mutation, the most common resistance mechanism, avoiding the more invasive tissue re-biopsy. However, in a subset of cases, resistance mechanisms are more complex featuring both genetic and morphological changes. Here we report the case of a 67 years-old woman, affected by an mutated lung adenocarcinoma and treated by TKI. At disease progression, the patient developed a morphological transition to squamous cell carcinoma in association to the arising of a p.E542K mutant subclone. This case illustrates that, even in the "liquid biopsy" era, cytology can have still a role by providing an overall assessment of both morphology and genetic TKI resistance mechanisms.

Liquid biopsy in breast cancer: A comprehensive review

“…Acquired polyclonal resistance in tumors and the development of new resistant tumor cell clones are consequential for treatment. It has previously been shown that liquid biopsy has the potential to further enhance our ability in longitudinal monitoring of dynamic clonal evolution of tumor cells during drug therapy . Tumor resistant mutations, specifically in breast cancer, can be divided into two subgroups.…”

“…It has previously been shown that liquid biopsy has the potential to further enhance our ability in longitudinal monitoring of dynamic clonal evolution of tumor cells during drug therapy. 197,198 Tumor resistant mutations, specifically in breast cancer, can be divided into two subgroups. One of these is the first-generation mutations developed during tumorigenesis, while the other is acquired mutations that could result in development of resistance.…”

Transformation of lung adenocarcinoma to small cell lung carcinoma in the setting of tyrosine kinase inhibitor therapy: Cytological approach of a clinically challenging phenomenon

“…23 In addition, MET and HER2 amplification and over-expression (which create resistance by bypassing the EGFR signaling pathway) were seen in 15% to 20% of cases of resistance in one series, 9,12 another series reported resistance due to MET amplification in 3% of the cases, and due to HER2 amplification in 13% of the cases. [26][27][28][29][30][31][32][33] These cases were observed to retain their original EGFR mutation, three cases developed an addition mutation in Thr790Met of EGFR Exon 20, 30,31 whereas two cases harbored an addition PIK3CA mutation. Immunocytochemistry stains for Synaptophysin (d) and CD56 (e) were positive, supporting the diagnosis of small cell carcinoma [Color figure can be viewed at wileyonlinelibrary.com] carcinoma transformation, 5,12,13,[16][17][18] or squamous cell transformation.…”

“…Molecular testing of the case discussed in this review and of the core biopsy cases reported in literature, performed at the time of TKI resistance acquisition, revealed retention of the same type of EGFR mutation detected in the initial diagnostic biopsies. [26][27][28][29][30][31][32][33] EMT manifests on the ultrastructural level by acquiring mesenchymal markers such as Vimentin and Fibronectin, and downregulating the expression of cellular junction proteins, such as Ecadherin and Gamma Catenin. 12 One year after TKI resistance acquisition, a third FNA was performed to monitor patient's disease progression.…”

“…5 Histological transformation of the tumor as part of the resisting mechanisms has been reported in mostly three forms, either through an epithelial mesenchymal transition, 12,24,25 or through a small cell F I G U R E 3 A third FNA of the lung lesion, a year after the second biopsy, revealed full blow small cell carcinoma on Diff-Quick-stained smears, Papanicolau-staineds mears (a, b) and cell block (c). 32,33 The commonly accepted view of separating small cell lung carcinoma and primary lung adenocarcinoma into two biologically different entities is challenged by the fact that some cases of NSCLCs with a certain EGFR mutation transform into SCLC after developing resistance to EGFR TKI, while preserving the same EGFR mutation. [26][27][28][29][30][31][32][33] EMT manifests on the ultrastructural level by acquiring mesenchymal markers such as Vimentin and Fibronectin, and downregulating the expression of cellular junction proteins, such as Ecadherin and Gamma Catenin.…”