In this study, we analyzed the prognostic value of NLR in a group of 79 patients with surgically-treated thymomas. Factors as gender, presence of MG, total WBC count, neo- and adjuvant therapies, WHO classification and Masaoka-Koga staging did not correlate with NLR.
It is noteworthy that a lower proportion of patients with locally-advanced disease (TNM stages IIIA/B) showed a NLR higher than the cut-off value than those in stages I and II (6% vs 21%, p = 0.028). At first glance, this result appears in contrast with the data of the literature, since previous reports show that NLR values usually increase along with the invasiveness of the tumor . However, we found that while mean neutrophil count was homogeneously distributed among different stages of the disease, TNM stages IIIA/B patients exhibited a higher mean lymphocyte count (p = 0.036), a point which could explain a mean lower NLR in stage III tumors. In detail, since NLR is the quotient between the peripheral neutrophil and lymphocyte counts, a lower NLR value in locally advanced disease could be due to a relative increase of lymphocyte count rather than by a reduction of the neutrophil count.
In fact, thymomas generate autoreactive T-lymphocytes that are responsible for the development of associated paraneoplastic autoimmune diseases [1, 2]. Most of these cells undergo apoptosis before relapse in the systemic blood flow, thus patients affected by thymoma usually show normal peripheral lymphocyte count when compared to healthy controls . However, some authors [14,15,16,17,18,19,20] described sporadic patients affected by aggressive thymic malignancies showing absolute peripheral polyclonal lymphocytosis. The distinctive feature of these tumors was an invasive pattern, with local extracapsular infiltration of mediastinal fat, pleura, and pericardium, with distant pleural or pulmonary metastasis, but also to bone and liver.
The prognostic role of NLR in patients with thymic epithelial tumors has been investigated only in an extremely limited number of studies and has still to be completely assessed.
Yuan et al.  evaluated the value of NLR in 79 patients who underwent resection of thymic carcinoma over an 11-year period. According to the aggressive nature of the disease, a cut-off value of 4.1 was identified. High NLR resulted associated to tumor dimensions, Masaoka-Koga stage, worse DFS and OS. However, the marker did not result to be an independent prognostic factor of death or recurrence at multivariate analysis.
In 2017, Yanagiya et al.  analyzed preoperative NLR in 159 patients completely resected for thymoma between 1976 and 2015. Patients with NLR ≥1.96 had significantly shorter OS, recurrence-free survival, disease-specific survival, disease-related survival, and showed higher cumulative incidence of recurrence. Moreover, NLR resulted independently prognostic for recurrence in early-stage disease.
Recently, Janik et al.  reported about the prognostic value of NLR and other inflammatory markers in 122 patients affected by thymic epithelial tumors (75% thymoma, 25% thymic carcinoma). Higher preoperative values of NLR resulted predictive of lower freedom from recurrence at survival analysis, but not at multivariate analysis. Interestingly, this study included a longitudinal analysis of NLR variation on repeated measurements acquired during the follow-up, and association to the incidence of recurrence.
In our study, univariate survival analysis showed that, when the patients were stratified according to TNM stage, DFS was significantly lower in the group with higher NLR values. NLR could therefore be a useful tool to identify patients with surgically-treated thymoma at higher risk of relapse among the different stages of the disease. Nevertheless, with regard to locally-advanced disease, it is important to notice that such result may be conditioned by the small sample size of patients with TNM stage IIIA/B tumors.
A point which has to be taken into due consideration when selecting patients for adjuvant treatments is the fact that in the new TNM classification system for thymic malignancies  the percentage of patients with stage I disease is considerably higher (approximating to 80%) than that of other stages . Local invasion of the mediastinal pleura is indeed considered to have negligible influence on prognosis , a point which causes downstaging of almost all previously Masaoka-Koga stage II as well as a significant number of stage III tumors, as confirmed by our study. However, further stratification of patients with early-stage disease seems advisable to select those patients who may benefit from adjuvant treatments in order to reduce the risk of recurrence .
Beyond the radiological assessment [25, 26], a number of markers, such as C-reactive protein, have been suggested as possible tools to improve the accuracy of follow-up . If our results will be confirmed by larger studies, preoperative NLR could be used to identify patients with early stage thymoma at higher risk of relapse. Moreover, a few studies are currently in progress focusing on different steps of neutrophils-mediated cancer progression . The introduction of new specific drugs may cover in the future a key role in targeted post-operative therapy of thymoma patients according to their NLR status.
The current indications to adjuvant therapy in early-stage thymoma are still a matter of debate. ESMO  and NCCN  guidelines recommend to consider post-operative radiotherapy in case of tumoral extension beyond the capsule, and state a clear indication in case of more invasive disease. Wu et al.  suggest irradiation following surgery for all Masaoka-Koga stages II and III, but advocate randomized clinical trials to assess its utility in stage I disease. The administration of fractioned radiotherapy with a total dose of 45 to 50 Gy is widely accepted, as it is able to reduce significantly the risk of recurrence. Moreover, the use of advanced techniques, such as intensity-modulated radiotherapy, is advocated to minimize the toxicity over the irradiated field .
Chemotherapy has seldom been adopted alone as adjuvant treatment in thymoma patients. Platinum-based regimens concomitant with radiotherapy are usually administered as first-line treatment . Recently, Carillo et al.  demonstrated that adjuvant chemo-radiotherapy is able to improve survival in Masaoka-Koga stage II disease in case of WHO type B thymomas.
New parameters to identify early-stage tumors at higher risk of recurrence, such as NLR, could therefore be useful in the development of future strategies for adjuvant treatments.
The major limitations of this study are the retrospective design, the relatively small size of the cohort and the relatively short follow-up considering the indolent nature of the disease, which may present recurrences up to 10 years after surgery . At multivariate analysis, NLR did not result an independent prognostic factor of relapse. In fact, other factors, such as the higher proportion of younger patients in the low-NLR-Group, may be responsible for their favorable DFS. Moreover, the limited number of TNM stage IIIA/B patients does not allow to establish significant conclusions about the prognostic role of NLR in locally-advanced thymoma. Further research with a multicenter prospective study is therefore needed to validate the use of this easily accessible and inexpensive tool in the selection process of candidates to adjuvant therapies and follow-up.