MPM has a highly variable disease course that is to predict at diagnosis. This study investigates the prognostic role of the predominant inflammatory cell type within routinely collected diagnostic samples. Using a prospectively collected cohort it demonstrates that a lymphocyte predominance in pleural fluid and tumour, as well as low blood NLR, infers a better overall survival.
Previous studies have investigated inflammatory markers as prognostic markers in MPM, including NLR, CRP, platelet/lymphocyte ratio, total leucocyte count and total lymphocyte count . Our results for serum neutrophil-lymphocyte ratio validate prior findings. A study by Kao et al with 173 patients receiving chemotherapy found a median survival of 16.7 months for those with NLR < 5 at baseline, compared to 6.6 months for those with an NLR > 5. In our study, we observed similar median survival of 421 days (15.1 months) for NLR < 5 versus 240 days 3(8.6 months) for NLR > 5 (p < 0.01). A study by Hooper et al. found a significant difference in survival with 453 versus 257 days for those with NLR < 4 compared to NLR ⩾ 4.
To our knowledge, this is the first study to investigate the significance of tumoural inflammatory cell infiltration in a cohort of patients not undergoing radical surgery for MPM, and who had not yet received any systemic treatment. We demonstrated a significant difference in survival between patients with a lymphocytic cell infiltration around the tumour cells, suggesting a more chronic inflammatory response. Suzuki and colleagues reported a cohort of 175 patients who had undergone radical surgery for epithelioid MPM . They investigated the role of acute and chronic inflammatory response and level of inflammatory cell infiltration in excised mesothelioma tumour and stroma. They showed that patients with a lymphocyte predominance in the tumour stroma had improved survival (median OS = 19.4 vs. 15.0 months, P = 0.01). Suzuki et al did not show a difference in survival between high and low-grade infiltration by inflammatory cells, and a post-hoc analysis of our data did not either. Other smaller series have identified similar patterns within tumour, with higher levels of CD8(+) tumour-infiltrating lymphocytes associated with better prognosis in post-surgical patients. There are two potentially overlapping hypotheses for this finding. Firstly, that lymphocytes (e.g. CD8 T-cells) are playing a role in the response to the tumour suppressing its growth and angiogenesis. Secondly that an abundance of lymphocytes simply reflects chronicity of naturally more indolent tumour subtypes at the point of biopsy.
Although a number of studies have looked at pleural fluid biochemical parameters for prognostication of malignancy, few have investigated pleural fluid lymphocyte predominance in MPM. A recent study by Popowicz and colleagues found that in malignant effusions of all types (n = 117) a higher ratio of lymphocytes to neutrophils was associated with improved survival, although the study protocol did not specify that the sample needed to be collected at the time of diagnosis. In our study we found that where the pleural fluid predominance was calculable this was an independent prognostic marker. However, given that not all patients present with pleural effusions that can be sampled and that cytological assessment can be limited by the presence of blood or poor cellular quality, this finding was applicable to a minority of patients (45%).
Our study is not without limitations. This is a single centre study conducted in the pre-immunotherapy era, although samples were collected from consecutive patients prior to chemotherapy reducing confounding by treatment. Consequently, the results may not be relevant to people receiving immune checkpoint inhibition. Secondly, only 118 biopsy samples out of our original 184 patient cohort were available for analysis. Finally, biopsy samples were generally small samples, as is typical for diagnostic samples from CT guided biopsy or medical thoracoscopies, compared with some of the other studies using larger surgical samples. Given the heterogeneous nature of MPM tumours, smaller biopsies may not provide an accurate representation of the entire tumour. However, we have shown that even the smaller samples obtained without surgery can provide crucial information that could influence the management of patients with MPM.