The Oncogenic Landscape of the Idiopathic Pulmonary Fibrosis: A Narrative Review

Giulia Maria Stella; Vito D'Agnano; Davide Piloni; Laura Saracino; Sara Lettieri; Francesca Mariani; Andrea Lancia; Chandra Bortolotto; Pietro Rinaldi; Francesco Falanga; Cristiano Primiceri; Angelo Guido Corsico; Andrea Bianco


Transl Lung Cancer Res. 2022;11(3):472-496. 

In This Article

Non-invasive Diagnostic and Monitoring Tools

Is There a Role for Liquid Biopsy in IPF Setting?

Liquid biopsy is a minimally invasive procedure that has been developed in molecular oncology. It allows the identification of circulating tumor-derived DNA (ct-DNA) that is shed from tumor cell in body fluids. Serial analysis of circulating tumor DNA (ctDNA) during treatment will provide a dynamic picture of molecular disease changes and could be used to monitor the emergence of secondary resistance and to identify heterogeneous subclonal populations developing during targeted treatments.[192] This non-invasive sampling issue is overall simple to collect, although should present quantity and quality problems and representation bias. There is a strong rationale for application of this technique in early diagnosis and monitoring of IPF patients, although some key differences should be underlined. IPF landscape is enriched in neoplastic potential expressed in a context of complex genomic polyclonality and cellular heterogeneity. Smoking is strongly associated with IPF[193] and is a strong negative predictor for the occurrence of EGFR activating mutations in lung cancer according to previous reports.[194] However, no somatic changes in coding sequences of driver known oncogenes. The latter observation, in therapeutic perspective, results in the absence of oncogenic addiction phenomenon. Thus, the oncogenic shock phenomenon cannot be exploited for therapeutic purposes in IPF. In cancer setting, the application of liquid biopsy: (I) ctDNA; (II) circulating tumor cells (CTC) for genetic analysis; (III) CTC. Interestingly, the level of circulating cell-free double-stranded DNA fragments (ccf-dsDNA) is increased in those IPF patients featuring rapid progression of the diseases if compared to stable IPF and health subjects. Moreover, the high expression of ccf-dsDNA is associated with that of amino acid, energy, and lipid metabolism pathways.[195] Very recently, Pallante and colleagues[196] demonstrated the concordance between ccfDNA and genomic DNA by analyzing and detecting the rs35705950 polymorphism of MUC5B gene promoter, known to be involved in IPF onset.[197] Overall, IPF is associated to increased tumor mutational burden (TMB) which, in turn, significantly contributes to the development of lung adenocarcinoma.[198] However, data from TMB analysis from IPF-associated lung cancer are still controversial, being significantly higher than in lung adenocarcinoma alone.[86,198] However, data from TMB analysis on lung cancer and concomitant ILDs are more controversial since some results reported that squamous cell carcinoma and adenocarcinoma with ILD do not have high TMB values.[199] Due to the implication for therapy with IC inhibitors, since based on these data patients should not be addressed to immunotherapy,[200] these preliminary observations deserve further validation data. Circulating cells have been studied to evaluate their possible role as predictive and prognostic markers. Elevated number of circulating fibrocytes, sorted by flow cytometry, is reported to be associated to higher mortality,[201] rather than as validated marker of disease progression.[202] Levels of circulating endothelial cells and endothelial progenitor cells have been found to be reduced in patients with IPF and treatment with nintedanib and pirfenidone further reduced their levels.[203] Further validations are required regarding the role of circulating monocytes in prediction of disease progression.[204]


The diagnostic algorithm for suspected lung tumor in the IPF setting is still unclear. The most recent ATS/ERS/JRS/ALAT guidelines, updated in 2015, do not address this issue.[205] Also, more "radiologically-oriented" guidelines such as those from the Fleischner society do not specifically include management suggestions tailored for IPF patients. Since those patients can be considered at high-risk of developing a lung tumor the suggested management will therefore rely mostly on surgical lung biopsy and resection. These approaches can be way too aggressive for an IPF patients. For these reasons a recent editorial suggests the following approach: high resolution computed tomography (HRCT) once a year in all patients with IPF. For patients with nodules less than 8 mm in diameter an HRCT every 3–6 months can be performed. If HRCT shows progression of the nodule, a PET-CT scan is recommended. For nodules with diameter of at least 8 mm, PET-CT scan is highly recommended. If PET indicates that a significant uptake is present, minimally invasive diagnostic procedures such as transthoracic needle biopsy or endoscopic approach are mandatory. If the patient is not suitable for biopsy, a multidisciplinary discussion is suggested.[2] Even if nowadays early diagnosis of lung cancer mostly relies on HRCT and PET scans, which represent the cornerstone for timely therapeutic interventions, some new options may be available in the future. Magnetic Resonance (MR) and, especially, diffusion weighted imaging (DWI) has already shown that active lung inflammatory tissue in the IPF setting could be assessed effectively.[206] It also has shown a capability of distinguishing between malignant and benign pathologies thanks to apparent diffusion coefficient (ADC) values.[207] A promising tool may be IVIM (Intravoxel Incoherent Motion)-DWI which can also give information about perfusion. This may lead in the future to put aside data from PET-CT with those from MR. Another possible tool to optimize the management of IPF patients with a suspected lung cancer can be Radiomics. Radiomics is a quantitative approach to medical imaging, which aims, through mathematical extraction of the spatial distribution of signal intensities and pixel interrelationships, to quantify textural information by using analysis methods from the field of artificial intelligence. Radiomics has progressively gained attention for nodule characterization and, since no data are available in the IPF setting, more time is needed to distinguish the hope from the hype.[208]