Table 1.

Comparison of small histopathological and cytology specimens versus liquid biopsy.

Type of Specimen	ADVANTAGES	DISADVANTAGES	Examples of Molecular Markers	Ref.
Small Histopathological Specimens *,** Cytology Specimens *,**	small biopsies and cytology samples are the basic diagnostic specimens due to the small minority of lung cancer cases that can be surgically removed (70% of lung cancers are unresectable) recent guidelines opt for the minimization of cytology use and replacing it with biopsies, which should be the gold standard in lung cancer sampling (more appropriate material for differential and molecular diagnostics)	tumor biopsies are often insufficient for molecular study or impossible to obtain small biopsy and/or cytology samples may not be representative of the total tumor because of histologic heterogeneity in the case of biopsies, multiple sampling is the requirement—minimum of 4 biopsies the rebiopsy is rarely performed, and in the view of intratumor heterogeneity a single-biosy-based analysis for personalized medicine may be a great limitation limited amount of cells in the study by Wang et al. (2015) [30], lung resection specimens had a significantly higher overall mutation rate compared to small biopsy and cytology specimens	FISH tests for ALK and ROS1 can be applied to different biological specimens—biopsies or cytological samples determination of EGFR T790M in tumor tissue and in cfDNA are both valid alternatives; if EGFR T790M testing in plasma is negative, a new biopsy is recommended whenever possible; EGFR can be detected in plasma with a high prevalence, reflecting the landscape and heterogeneity of primary tumors and metastases	[24,30,31,32,33,34]
Liquid biopsy	minimally invasive tool liquid biopsy permits frequent sample collection, timely assessment of the patient′s disease status liquid biopsy offers different possible applications—response monitoring, tumor recurrence detection, determination of residual disease after full tumor resection, early detection of lung cancer, and immuno-oncology liquid biopsy enables testing for genetic and epigenetic abnormalities specific to the tumor, and provides abilities to identify mutations in both primary and metastatic lesions—liquid biopsy represents the whole genomic picture of the tumor a new source for cancer biomarkers	validation and clinical usefulness are not sufficiently determined as yet lack of standardization detection techniques require a high sensitivity in order to detect the DNA from tumor cells negative results require testing with conventional techniques, such as tumor biopsy hemolysis may influence the results	microRNAs are most commonly assessed in patient′s serum or plasma; an example is a panel of circulating microRNAs in the study by Sromek et al. (2017) [35]—the combination of miR-9, miR-16, miR-205, and miR-486 can serve as potential NSCLC biomarkers with 80% sensitivity and 95% specificity	[24,35,36]

* direct comparisons between small histopathological specimens and cytology samples are limited, and both of these specimens appear to perform similarly, with the high feasibility of molecular testing; ** whenever possible, cytology should be interpreted in conjunction with the histology of small biopsies, as the 2 modalities are complementary, in order to achieve the most specific and concordant diagnosis; ALK - anaplastic lymphoma kinase; cfDNA - cell-free circulating DNA; EGFR - epidermal growth factor receptor; FISH - fluorescence in situ hybridization; NSCLC - non-small cell lung carcinoma; ROS1 - c-ros oncogene 1.