This study was conducted to evaluate the relationship between PIV and LIPI score, survival time, and prognosis in patients with LCNECs. In our study, LIPI score, PIV, ECOG performance score, de novo metastasis, albumin level, and lymphocyte and platelet counts are associated with prognosis.
Inflammatory status and immune status play a key role in determining cancer formation, progression, invasion, metastasis, response to treatment, and survival [9]. In peripheral blood, biomarkers formed by the values of neutrophils, lymphocytes, monocytes, and platelets reflecting the circulating inflammatory and immune status have shown prognostically significant results [10].
LCNEC has an aggressive course but is rare and constitutes 2–3% of all lung cancers [1]. Because of its high grade, aggressive behavior, frequent recurrence after surgery, and positive neuroendocrine markers, it is similar to SCLC and has been classified among high-grade neuroendocrine cancers of the lung together with SCLC by the World Health Organization [3–6].
However, they are similar to NSCLC due to features such as being peripherally located, detecting mutations such as EGFR ALK RAF, etc., although rare, and patients benefiting from treatments targeting these mutations and immunotherapies such as nivolumab pembrolizumab in case-level reports [11–15]. The most important prognostic marker in follow-up and treatment is the stage. However, the prognosis of patients with the same stages may be different. Therefore, there is a need for other prognostic markers beside the stage. Due to the rarity of the information with LCNEC, there is no controlled study, and it is obtained from retrospective data, case reports, or LCNEC adaptation of this information due to similarities between both SCLC and NSCLC. Many studies have been showing between many markers reflecting inflammation and immune status and the prognosis of SCLC, NSCLC, and other cancers. Therefore, prognostic markers reflecting inflammation and the immune system in NSCLC and SCLC may be useful in LCNEC patients.
LIPI score is an inflammatory marker that includes the neutrophil-to-lymphocyte ratio (dNLR) and serum lactate dehydrogenase (LDH). Significant results were obtained in studies on prognosis and survival in studies with LIPI scores in SCLC and NSCLC [16–18]. LIPI score can predict prognosis as in SCLC and NSCLC. To our knowledge, there is no study in the literature showing the benefit of the LIPI score in predicting the prognosis of LCNEC.
Peripheral blood neutrophilia and relative lymphopenia before treatment are potential prognostic indicators of the tumor-related inflammatory response [19]. In studies conducted in SCLC and NSCLC, a high neutrophil-lymphocyte ratio was found to be associated with short progression-free survival and short overall survival [20–21]. LDH is a prognostic marker in lung cancer [22]. Normal differentiated cells obtain energy through mitochondrial oxidative phosphorylation, while tumor cells rely on aerobic energy to support cell proliferation. This phenomenon is called the Warburg effect [23]. It promotes the expression and activation of glycolytic enzymes in cancer. LDH is one of them and plays a vital role in the glycolysis pathway process that can convert pyruvate to lactate [24]. High LDH levels are associated with poor prognosis in lung cancer, renal cell carcinoma, breast cancer, and colorectal cancer [25–29]. Therefore, as the LIPI score is calculated using lymphocyte neutrophil and LDH values, it may be useful in predicting the prognosis in LCNEC
In previous studies, a relationship was found between LDH, lymphocytes, neutrophils, LIPI, and many cancers. However, the relationship between LIPI and prognosis in patients with LCNEC has not been investigated until now.. In our study, median OS was associated with LIPI scores. Our study is the first in the literature to demonstrate a relationship between LIPI and LCNEC prognosis.
PIV is an evaluation of inflammation and the immune system in cancer patients and is calculated according to neutrophil, platelet, monocyte, and lymphocyte levels [30]. There are many studies evaluating prognosis, treatment response, and survival in colorectal, skin, lung, breast, kidney, esophagus, and Merkel cell cancers [31–35]. In studies conducted in SCLC and NSCLC, a relationship was found between high PIV values and short survival [32, 36]. There is no study conducted on PIV in patients with LCNEC.
Cancer cells and platelets have important interactions in circulation [37]. It has been found that platelets may play a key role in tumor growth and metastasis [38].To escape the immune system effect, tumor cells form a thrombus with Platelets. In addition, activated platelets form various growth factors that help tumor invasion and development [38]. Monocytes are associated with cancer prognosis, and after affecting circulating macrophages, they affect angiogenesis, invasion, and immunosuppression due to the release of endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-10 [39–40]. Neutrophils are associated with tumor growth by the generation of reactive oxygen species and secretion of pre-tumor IL 1 and IL 6 tumor necrotic factor alpha [41–42]. Lymphocytes are involved in the basic defense against cancer [43]. So PIV may predict a prognosis similar to SCLC and NSCLC.
Earlier studies have established a relationship between PIV and many cancers. However, the relationship between PIV and prognosis in patients with LCNEC has not been examined. In our study, median OS was linked to PIV. Our research is the first in the literature to show a link between PIV and the LCNEC prognosis.
Despite limitations, such as the retrospective and single-center design, and the small sample size, our study is important in that it is the first to show prognostic factors in LCNEC with LIPI score and PIV
In conclusion, due to their rarity, there is no randomized clinical study, standard follow-up, and treatment for LCNECs. In LCNEC patients, LIPI and PIV are simply relevant parameters that demonstrate inflammation and the immune system and can guide treatment selection and patient prognosis. LIPI, PIV, ECOG performance score, de novo metastases, albumin levels, lymphocytes, and platelet counts are related to prognosis. These factors can be used for patient monitoring and treatment as simple and inexpensive biomarkers.