DOI: https://doi.org/10.21203/rs.3.rs-2363112/v1
Large cell neuroendocrine carcinomas (LCNEC) are rare tumors of the lung. Due to their rarity, there is no standard follow-up and treatment. Inflammation and immune systems play an important role in the pathogenesis, development, and progression of lung and other cancers. Lung Immune Prognostic Index (LIPI) and Pan-immune-inflammation value (PIV) are markers of inflammation and immune marker, and there is no study with LCNEC. Therefore, in our study to evaluate the relationship between these markers and LCNEC prognosis; We retrospectively analyzed 109 patients diagnosed with metastatic LCNEC in our center between 2009 and 2022 by calculating the LIPI and PIV values at the time of diagnosis. Median OS was 7.8 (95% Confidence interval (CI), 6.20-9.39) months. Respectively median OS times were 9.6 (95% CI, 7.28-11.91) months versus 4.5 (95% CI, 2.87-6.13) months in low and high LIPI scores. Median OS times were 10.25 months (95 CI, 9.12-11.32) compared to 3.95 months (95 CI, 2.5-6.36) in low and high PIV, respectively. In multivariate analysis ECOG performance score ( p=0.005), metastasis time (de novo vs recurrent) (p=0.008), platelet (p=0.04), albumin (p=0.026), lymphocyte count (p =0.037), LIPI (p =0.002) score and PIV (p =0.001) were related with survival time. In conclusion LIPI, PIV, ECOG performance score, de novo metastases, albumin levels, lymphocyte and platelet counts are associated with prognosis. These factors can be used in patient monitoring and treatment as simple and inexpensive biomarkers.
Neuroendocrine tumors constitute 20% of lung cancers [1]. LCNEC is extremely rare and constitutes 2–3% of all lung cancers [1]. They were first defined by Travis et al [2]. They have a high grade, aggressive course, and poor prognosis. Considering the 5-year survival of the patients in all stages, it varies between 15–57% [3–5]. In 2015, the World Health Organization classified small cell lung cancer (NSCLC) and LCNEC together as separate groups of high-grade lung neuroendocrine tumors [6]. However, they show clinical, biological, and pathological features similar to SCLC and non-small cell lung cancer (NSCLC). Since LCNEC is rarely seen and therefore randomized clinical trials cannot be performed, there is no standard approach for its follow-up and treatment. Information on follow-up and treatment of patients is based on retrospective data, and case reports, and is often derived from LCNEC adaptation of results from SCLC and NSCLC.
In recent years, numerous studies have been reported on blood parameters showing inflammation, the immune system, and the prognosis of SCLC, NSCLC, and many other cancers[7–8]. By using blood parameters, new markers, scoring and nomograms were developed to obtain information about cancer prognosis. LIPI and PIV are among these scorings and be associated with prognosis in many cancers. However, there are no studies on the prognostic and surveillance of LIPI and PIV with LCNEC. In our study, we aimed to examine the relationship between LIPI and PIV results at the time of metastasis, prognosis, and surveillance in LCNEC patients.
Patients, who were followed up with a diagnosis of LCNEC in the Medical Oncology Department of Manisa City Hospital between 2009 and 2022, were retrospectively analyzed. The demographic characteristics of the patients, such as age and sex, sites of metastasis, metastasis time( de novo vs recurrent) Eastern Cooperative Oncology Group (ECOG) performance score, smoking habit, smoking pack year ((packs of cigarettes smoked per day) multiply (year)), albumin, hemoglobin, lactate dehydrogenase( LDH), uric acid levels, white blood cell count, lymphocyte and platelet counts. LIPI, PIV, and overall survival (OS) time were recorded, and the correlation between OS and other parameters was retrospectively analyzed. OS time referred to the time from the date of diagnosis to the death of the patient. The PIV was calculated using the following formula: neutrophil (103/mm3) x monocyte (103/mm3) x platelet (103/mm3)/lymphocyte (103/mm3). LIPI is a marker combining the derived neutrophil-to-lymphocyte ratio (dNLR, calculated as neutrophil count/white blood cell- neutrophil count) and serum lactate dehydrogenase (LDH). dNLR ≥ 3 and LDH higher than the upper limit of normal (ULN) are defined as “Poor (LIPI 2)”, patients with dNLR ≥ 3 and LDH lower than ULN or dNLR < 3 and LDH higher than ULN are defined as “Intermediate (LIPI 1)”, and patients with dNLR < 3 and LDH lower than ULN are defined as “Good (LIPI 0). LIPI values were defined as LIPI 0–1 low LIPI and LIPI 2 Hıgh LIPI. The median PIV value of the patients was 600 (103/mm3). PIV values were defined as 600 > low PIV and 600 ≤ high PIV. Patients according to ECOG score (3 > or 3≤), Metastasis time (de novo or recurrent), PIV(Low or High), and LIPI ( Low or High) divided into groups.
Descriptive statistics were presented as mean, standard deviation, median, minimum and maximum values for numerical variables, and as numbers and percentages for categorical variables. The comparison of numerical variables between two independent groups was performed using Student’s t-test in case of normal distribution and the Mann-Whitney U test otherwise. Rates were compared between the groups using the chi-square analysis and Fisher’s exact test. Survival analyses were undertaken with the Kaplan-Meier method. Determinative factors were examined using the Cox regression analysis. P < 0.05 was considered significant in all statistical analyses.
A total of 109 patients, 55 (50.46%) male, and 54 (49.54%) female, with a mean age of 61.86 ± 9.97 years, were retrospectively analyzed. All patients had a habit of smoking. The median packs of cigarettes smoked per year was 50 (10–150). 77 (70.64%) patients were metastatic at the time of diagnosis and metastasis was developed in 32 patients during follow-up (Table 1). Median OS was 7.8 (95% CI, 6.20–9.39) months. Respectively median OS was 9.6 (95% CI, 7.28–11.91) months vs 4.5 (95% CI, 2.87–6.13) months in low and high LIPI scores and 10.25 (95% CI, 9.12–11.32) months vs 3.95 (95% CI, 2.5–6.36) months in low and high PIV. ECOG performance score, smoking habit (smoking pack year), metastasis time ( de novo vs recurrent), liver, bone, adrenal metastasis, LDH, uric acid, albumin level, lymphocyte, platelet, LIPI score, and PIV values were associated with median OS. And In multivariate analysis ECOG performance score( p = 0.005), metastasis time (de novo vs recurrent)(p = 0.008), platelet(p = 0.04), albumin(p = 0.026), lymphocyte count(p = 0.037), LIPI(p = 0.002) score and PIV(p = 0.001) were related with survival time. ( Table 2) (Fig. 1).
| All n(%) = 109(100%) mean ± SD median( min-max) | LIPI(High) n(%) = 55(100%) mean ± SD median( min-max) | LIPI(Low) n(%) = 54(100%) mean ± SD median( min-max) | p value | PIV (High) n(%) = 55(100%) mean ± SD median( min-max) | PIV (Low) n(%) = 54(100%) mean ± SD median( min-max) | P value | ||
|---|---|---|---|---|---|---|---|---|
| Age | 61.86 ± 9.97 | 62.13 ± 9.82 | 60.87 ± 10.69 | 0.593 | 59.59 ± 9.10 | 62.89 ± 1023 | 0.109 | |
| Sex | Male | 55 (50.46%) | 28 (50.90%) | 27 (49.1%) | 0.92 | 24 (43.4%) | 31 (56.6%) | 0.15 |
| Female | 54 (49.54%) | 27 (50%) | 27 (50%) | 31 (57.4%) | 23 (42.6%) | |||
| ECOG | ≥ 3 | 53 (48.62%) | 23 (43.4%) | 30 (56.6%) | 0.58 | 20 (37.74%) | 33 (62.26%) | 0.096 |
| < 3 | 56 (51.38%) | 22 (39.29%) | 34 (60.71%) | 35 (53.03%) | 31 (46.97%) | |||
| Metastasis | Recurrent | 32 (29.36%) | 17 (53.13%) | 15 (46.87%) | 0.72 | 20 (62.5%) | 12 (37.5%) | 0.11 |
| De novo | 77 (70.64%) | 38 (49.35%) | 39 (50.64%) | 35 (45.45%) | 65 (54.55%) | |||
| Smoking | 50 (10–150) | 50 (10–150) | 60 (30–120) | 0.03 | 45 (30–150) | 60 (10–120) | 0.011 | |
| Metastassite | Liver | 31 (28.4%) | 6 (19.4%) | 25 (80.6%) | 0.118 | 7 (22.6%) | 24 (77.4%) | 0.12 |
| Bone | 53 (48.6%) | 10 (18.9%) | 43 (81.1%) | 0.012 | 11 (20.75%) | 42 (79.25%) | 0.22 | |
| Adrenal | 40 (29%) | 6 (15%) | 34 (85%) | 0.008 | 11 (27.5%) | 29 (72.5%) | 0.52 | |
| Brain | 48 (44%) | 13 (27.1%) | 35 (72.9%) | 0.52 | 12 (25%) | 36 (75%) | 0.216 | |
| Lung | 39 (35.8%) | 10 (25.6%) | 29 (74.4%) | 0.43 | 11 (28.20%) | 28 (71.80%) | 0.61 | |
| LN | 51 (46.8%) | 13 (25.5%) | 38 (74.5%) | 0.308 | 16 (31.4%) | 35 (68.6%) | 0.97 | |
| Laboratory | Hb (g/dL) | 12 ± 1.64 | 13.09 ± 1.56 | 12.73 ± 1.928 | 0.64 | 13.64 ± 1.57 | 12.64 ± 1.58 | 0.003 |
| LDH(U/L) | 336 (135–9800) | 276 (135–1091) | 698 (157–9800) | < 0.001 | 221(135–608) | 365 (145–9800) | < 0.0001 | |
| Uric acid(mg/dL) | 4.8 (2.5-9) | 4.8 (2.5-9) | 5.8 (2.9–7.7) | 0.001 | 4.4 (2.8-9) | 5 (2.5–7.7) | 0.084 | |
| Albumin(g/dL) | 3.7 (2.6-5.0) | 3.8 (2.6–4.7) | 3.4 (2.6-5) | 0.003 | 4 (3-4.7) | 3.6 (2.6-5) | < 0.0001 | |
| WBC(103/µL) | 9.3 (4.3–20.3) | 9.3 (4.3–20.3) | 9.2 (5.8–14.5) | 0.65 | 9.35 (4.7–20.3) | 9.2 (4.3–16.2) | 0.638 | |
| Neutrophil (103/µL) | 7.0 (2.5–18.00) | 6.8 (2.5–18.0) | 7.8 (4.5–12.5) | 0.61 | 6.85 (3.2–18.0) | 7 (2.5–14) | 0.132 | |
| Lymphocyte(103/µL) | 1.5 (0.7–3.8) | 1.6 (1.0-3.8) | 1.2 (0.7–2.6) | < 0.0001 | 1.8 (1-3.8) | 1.4 (0.7–2.7) | 0.015 | |
| Platelet(103/µL) | 300 (134–614) | 282 (134–557) | 334 (109–614) | 0.004 | 282 (134–557) | 324 (109–614) | 0.005 | |
| SD: standart deviasion min: minumum, max(maximum), LIPI; Lung immun prognostic index, PIV; pan-immune-inflamation value, ECOG; Eastern Cooperative Oncology Groub, LN;Lymph node, Hb; Hemoglobin, LDH: lactate dehydrogenase, WBC; White Blood Cell, | ||||||||
| Univariate analysis (HR, 95% CI) | p value | Multivariate analysis (HR, 95% CI) | p value | |
|---|---|---|---|---|
| Age | 1.006(0.985–1.027) | 0.571 | ||
| Sex | 1.051(0.653–1.692) | 0.836 | ||
| ECOG(< 3 vs 3≤) | 2.178(1.438–3.293) | < 0.0001 | 1.937(1.165–3.219) | 0.005 |
| Smoking | 1.012(1.005–1.020) | 0.001 | 1.008(0.997–1.019) | 0.174 |
| Metastasis (de novo vs recurrent) | 2.885(1.913–4.361) | < 0.0001 | 1.797(1.094–2.952) | 0.008 |
| Liver metastas | 1.856(1.200-2.872) | 0.008 | 1.449(0.853–2.463) | 0.170 |
| Bone metastas | 1.873(1.257–2.790) | 0.002 | 1.352(0.840–2.177) | 0.215 |
| Adrenal metastas | 2.178(1.438–3.299) | 0.001 | 1.622(0.949–2.771) | 0.77 |
| Brain metastas | 1.301(0.936–2.066) | 0.102 | ||
| Lung metastas | 1.354(0895-2.047) | 0.151 | ||
| LN metastas | 1.046(0.703–1.558) | 0.825 | ||
| Hb | -0.933(0.821–1.060) | 0.286 | ||
| LDH | 1.000(1.00-1.001 | 0.001 | 1.000(1.000–1.000) | 0.959 |
| Uric acid | 1.284(1.100-1.499) | 0.002 | 1.000(0.870–1.365) | 0.455 |
| Albumin | -0.348(0.218–0.557) | < 0.0001 | -0.607(0.379–0.970) | 0.026 |
| WBC | 1.000(0.997–1.004) | 0.607 | ||
| Neutrophil | 1.010(0.985–1.020) | 0.259 | ||
| Lymphocyte | -1.000 (1.000-1.010) | 0.033 | -1.000(0.999-1.000) | 0.037 |
| Platelet | 1.004(1.001–1.006) | 0.02 | 1.004(1.001–1.005) | 0.04 |
| LIPI | 1.873(1.257–2.793) | < 0.0001 | 2.393(1.499–3.820) | 0.002 |
| PIV | 2.662(1.731–4.095) | < 0.0001 | 2.143(1.332–3.452) | 0.001 |
| HR: hazard ratio, CI: confidence interval, ECOG; Eastern Cooperative Oncology Groub, LN;Lymph node, Hb; Hemoglobin, LDH: lactate dehydrogenase, WBC; White Blood Cell, LIPI; Lung immun prognostic index, PIV; pan-immune-inflamation value | ||||
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.
Author contributions
All authors contributed to the study's conception and design. Concept: S.M., Design: S.M , Supervision: S.M, Resources: S.M. and E.K., Materials S.M and E.K., Data Collection and/or Processing: S.M and E.K., Analysis and/or Interpretation: E.K Literature Searc: S.M and E.K. The first draft of the manuscript was written by S.M. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that they did not receive any funding for this study.
Competing interests
The authors declare no competing interests.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval
The study was conducted by the principles of the Declaration of Helsinki and reviewed and approved by the Health Sciences Ethics Committee of Manisa Celal Bayar University (decision number: 10.478.486, date: 05/02/2020).