All-in-One: The Dream and Reality of Molecular
Cytopathology Testing on Routine Lung Cancer Smears
Giancarlo Troncone, MD, PhD
Personalized/precision medicine requires the rapid, cost-effective, and reliable tissue-based assessment of clini-
cally validated predictive biomarkers.
In particular, modern thoracic oncology has deeply transformed the way
in which we practice lung cytopathology. The initial perception that cytological samples were merely sufficient
for a generic microscopic diagnosis of non-small cell lung cancer (NSCLC) whereas molecular analysis could
only be applied to formalin-fixed paraffin-embedded material now has been completely overcome.
microscopy with biomarker characterization, cytology can guide targeted therapy for NSCLC. In individuals
with locally advanced or metastatic disease, when patients are not surgical candidates, fine-needle aspiration
biopsy is an ideal minimally invasive approach to inform targeted lung cancer therapy decisions.
The study by Guseva et al, published in this issue of Cancer Cytopathology, represents a step ahead to maxi-
mize the informativeness of cytological smears.
Indeed, treatment paradigms for patients with advanced lung
cancer are well established.
If the epidermal growth factor receptor (EGFR) gene demonstrates an activating
(sensitizing) mutation, the first-generation tyrosine kinase inhibitors (TKIs) gefitinib (Iressa; AstraZeneca,
Cambridge, United Kingdom) and erlotinib (Tarceva; Hoffmann-La Roche, Basel, Switzerland) or the second-
generation TKI afatinib (Giotrif; Boehringer Ingelheim, Ingelheim, Germany) should be given as first-line ther-
apy. Similarly, the TKI crizotinib (Xalkori, Pfizer, New York, New York) has been approved by the US Food
and Drug Administration in the first-line treatment setting of patients harboring abnormal fusion of the ana-
plastic lymphoma kinase (ALK) gene or of the ROS proto-oncogene 1, tyrosine kinase (ROS1). Conversely, in
the absence of an actionable oncogenic driver mutation, lung cancer can be targeted by immunotherapy, and
the 2017 National Comprehensive Cancer Network guidelines recommend testing for programmed death-
ligand 1 (PD-L1) expression on tumor cells at the time of diagnosis of advanced NSCLC.
To this end, the
Food and Drug Administration approved a reliable and reproducible immunohistochemical (IHC) companion
diagnostic test for identifying patients who respond to checkpoint inhibitors.
A tumor PD-L1 score of at least
50% allows for first-line treatment with pembrolizumab (Keytruda; Merck, Kenilworth, New Jersey), whereas
in patients with any PD-L1 immunocytochemistry (ICC) staining (1%), second-line immunotherapy could
However, the clinical implication of a PD-L1 expression value that is near the cutoff may be debat-
able because patients who score just below a threshold may not have the prospect of a response that is far more
diverse compared with that of those who score just above the threshold. In addition, several clones raised against
Corresponding author: Giancarlo Troncone, MD, PhD, Department of Public Health, University of Naples Federico II, via Sergio Pansini 5, I-80131,
Naples, Italy; email@example.com
Department of Public Health, University of Naples Federico II, Naples, Italy.
See referenced original article on pages 158-69, this issue.
Received: November 9, 2017; Revised: December 5, 2017; Accepted: December 8, 2017
Published online January 24, 2018 in Wiley Online Library (wileyonlinelibrary.com)
DOI: 10.1002/cncy.21962, wileyonlinelibrary.com