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. 2021 Sep 6;13(17):4488.
doi: 10.3390/cancers13174488.

Subpopulations of Circulating Cells with Morphological Features of Malignancy Are Preoperatively Detected and Have Differential Prognostic Significance in Non-Small Cell Lung Cancer

Emanuela Fina  1 , Davide Federico  2   3 , Pierluigi Novellis  4 , Elisa Dieci  4 , Simona Monterisi  1 , Federica Cioffi  4 , Giuseppe Mangiameli  3   4 , Giovanna Finocchiaro  5 , Marco Alloisio  3   4 , Giulia Veronesi  4
Affiliations

Subpopulations of Circulating Cells with Morphological Features of Malignancy Are Preoperatively Detected and Have Differential Prognostic Significance in Non-Small Cell Lung Cancer

Emanuela Fina et al. Cancers (Basel). .

Abstract

Background: Non-small cell lung cancer (NSCLC) frequently presents when surgical intervention is no longer feasible. Despite local treatment with curative intent, patients might experience disease recurrence. In this context, accurate non-invasive biomarkers are urgently needed. We report the results of a pilot study on the diagnostic and prognostic role of circulating tumor cells (CTCs) in operable NSCLC.

Methods: Blood samples collected from healthy volunteers (n = 10), nodule-negative high-risk individuals enrolled in a screening program (n = 7), and NSCLC patients (n = 74) before surgery were analyzed (4 mL) for the presence of cells with morphological features of malignancy enriched through the ISET® technology.

Results: CTC detection was 60% in patients, while no target cells were found in lung cancer-free donors. We identified single CTCs (sCTC, 46%) and clusters of CTCs and leukocytes (heterotypic clusters, hetCLU, 31%). The prevalence of sCTC (sCTC/4 mL ≥ 2) or the presence of hetCLU predicted the risk of disease recurrence within the cohort of early-stage (I-II, n = 52) or advanced stage cases (III-IVA, n = 22), respectively, while other tumor-related factors did not inform prognosis.

Conclusions: Cancer cell hematogenous dissemination occurs frequently in patients with NSCLC without clinical evidence of distant metastases, laying the foundation for the application of cell-based tests in screening programs. CTC subpopulations are fine prognostic classifiers whose clinical validity should be further investigated in larger studies.

Keywords: cancer biomarkers; circulating tumor cells; early diagnosis; lung cancer.

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Conflict of interest statement

The study funders had no role in the design of the study, the collection, analysis, and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication. The authors declare no competing non-financial interests but the following competing financial interest: G.V. received honoraria from Ab Medica SpA (Milan, Italy). All the other Authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Subpopulations of atypical circulating cells differentiate patients with operable non-small cell lung cancer from lung cancer-free individuals. Images depict (a–c) single cells with morphological features of malignancy and (d–f) heterotypic clusters of cells with features of malignancy physically interacting with normal cells, such as (d) neutrophil granulocytes, (e) monocytes or (f) other indeterminate leukocytes, detected in patients, (g–i) atypical macrophage-like cells, (g) oblong or (h) tadpole-like, both detected in patients, and irregularly shaped (i), detected in healthy donors, and (j–l) clusters of epithelial-like cells, detected in patients, on porous membranes stained with May–Grünwald and Giemsa. Objective magnification 40×.
Figure 2
Figure 2
The number of single CTCs (sCTC) and heterotypic CTC clusters (hetCLU) is not associated with the clinicopathological features of stage I–IVA non-small cell lung cancers. Dot plots represent the distribution of (a) sCTC or (b) hetCLU count (median number, line) in 4 mL of peripheral blood according to the tumor stage, the histological subtype (LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma), the visceral pleura invasion and the lymph-node involvement. Differences were not significant (p-value > 0.05) by Kruskal–Wallis (tumor stage) or Mann–Whitney test.
Figure 3
Figure 3
The prevalence of single circulating tumor cells (sCTC) correlates with reduced recurrence-free survival in stages I and II non-small cell lung cancers. Kaplan–Meier plots showing the time-to-event probability of disease recurrence according to (a) the presence of CTCs irrespective of the cell subset, (b,c) the prevalence of sCTC or (d) the presence of heterotypic circulating tumor cell clusters (hetCLU).
Figure 4
Figure 4
The presence of heterotypic circulating tumor cell clusters (hetCLU) correlates with reduced recurrence-free survival in stages III and IVA non-small cell lung cancers. Kaplan–Meier plots showing the time-to-event probability of disease recurrence according to (a) the presence of CTCs irrespective of the cell subset, (b,c) the prevalence of single CTCs (sCTC) or (d) the presence of hetCLU.
See this image and copyright information in PMC

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