Prognostic significance of neutrophil-to-lymphocyte ratio in collecting duct carcinoma

Prognostic significance of neutrophil-to-lymphocyte ratio in collecting duct carcinoma Abstract Collecting (Bellini) duct carcinoma of the kidney is a rare lethal tumor, and its prognostic factors remain unclear. The present study investigated the prognostic significance of neutrophil-to-lymphocyte ratio, which has recently been recognized as a readily available prognostic marker in various malignancies, in patients with collecting duct carcinoma. Of 11 patients who were pathologically diagnosed with collecting duct carcinoma at our institution, nine died of collecting duct carcinoma, one died of a postoperative complication, and one was alive, with a median follow-up period of 6 (range: 0–97) months. Both univariate and multivariate analyses associated neutrophil-to-lymphocyte ratio ≥4 (median) with worse cancer-specific survival. Notably, the sole surviving patient maintained a low neutrophil-to-lymphocyte ratio (<4) both at the initial diagnosis and at the time of distant recurrence. These results suggest that neutrophil-to-lymphocyte ratio might serve as a useful biomarker for collecting duct carcinoma as well as other malignancies. Bellini duct carcinoma, collecting duct carcinoma, neutrophil-to-lymphocyte ratio, prognosis, renal cell carcinoma Collecting duct carcinoma (CDC), also known as Bellini duct carcinoma, is a rare aggressive neoplasm of putative distal nephron origin that accounts for <1% of renal malignancies (1). Because of its extreme rarity, there have been few studies of CDC and its clinicopathological features, and its prognostic factors remain poorly understood (2–8). Recent studies have revealed that the neutrophil-to-lymphocyte ratio (NLR) is a useful prognostic marker in various malignancies (9), including urological cancers (10). The present study aimed to elucidate the prognostic significance of NLR in CDC patients. We retrospectively reviewed 12 patients who were pathologically diagnosed with CDC at our institution between 1996 and 2016. After one patient was excluded for missing data, the remaining 11 patients were assessed for associations between various clinicopathological factors, including NLR and cancer-specific survival. NLR was calculated from blood tests performed immediately before nephrectomy or initial biopsy. Survival distributions were estimated using the Kaplan–Meier method. Univariate and multivariate analyses were carried out using log-rank tests and Cox proportional hazards model, respectively. For the multivariate analysis, a backward stepwise procedure (entry, 0.05; removal, 0.10) was selected, due to the small sample size. All statistical analyses were carried out using JMP Pro version 11.0.0 (SAS Institute, Cary, NC, USA). A value of P < 0.05 was considered significant. Follow-up information was obtained as of December 2017. Patient characteristics are summarized in Table 1. Nine of the 11 patients died of CDC, one died of multiple organ failure 16 days after nephrectomy with inferior vena cavectomy, and one was alive on the last follow-up date. Based on the median NLR (4.08), a cutoff value of 4 was selected for assessment of associations, which is one of the most commonly used cutoffs in previous studies (9). As shown in Fig. 1, a NLR of ≥4 was strongly associated with poorer cancer-specific survival (log-rank test, P = 0.0076). In addition, T stage ≥3, M1 stage, leukocyte count ≥9000 cells/μl (upper limit of normal), neutrophil count ≥5100 cells/μl (median), and lactate dehydrogenase ≥237 IU/l (upper limit of normal) were also associated with poorer outcome by univariate analysis. Multivariate analysis determined that NLR ≥4 and T stage ≥3 were independent predictors of worse cancer-specific survival. However, the hazard ratios did not converge, probably due to small sample size, and these results are therefore for reference purposes only (Table S1). The sole surviving patient had an NLR of 2.00 at the time he underwent nephrectomy for T1aN0M0 tumor. At 68 months after nephrectomy, he developed solitary lung metastasis and underwent video-assisted thoracic surgery; at that time, his NLR was 3.54. The patient is still alive 27 months after video-assisted thoracic surgery and has no evidence of disease. Table 1. Patient characteristics (n = 11) Parameter  Value  Gender, no (%)     Male  8 (73)   Female  3 (27)  Age at nephrectomy/initial biopsy, years, median (range)  58 (44–77)  T stage, no. (%):     T1  3 (27)   T2  1 (9)   T3  3 (27)   T4  4 (36)  N stage, no. (%):     0  2 (18)   1  1 (9)   2  8 (73)  M stage, no. (%):     0  4 (36)   1  7 (64)  Fuhrman grade, no. (%):     G1  0 (0)   G2  0 (0)   G3  5 (45)   G4  6 (55)  Pathological diagnosis, no. (%):     Nephrectomy  5 (45)   Renal biopsy  4 (36)   Lymph node biopsy, followed by autopsy  2 (18)  Additional treatments (including overlaps), no. (%):     Chemotherapy  6 (55)   Radiotherapy  6 (55)   Embolization  2 (18)   Metastasectomy  1 (9)  Laboratory parameters, median (range):     Leukocyte count, cells/μl  7100 (5700–17 800)   Neutrophil count, cells/μl  5096 (3954–14 500)   Lymphocyte count, cells/μl  1300 (900–1973)   Neutrophil-to-lymphocyte ratio (NLR)  4.08 (2.00–11.56)   Hemoglobin, g/dl  11.2 (5.0–14.9)   Albumin, g/dl  3.4 (1.9–4.3)   Lactate dehydrogenase, IU/l  192 (151–1339)   Alkaline phosphatase, IU/l  263 (95–765)   C-reactive protein, mg/dl  2.27 (0.09–22.4)  Median follow-up, months (range)  6 (0–97)  Parameter  Value  Gender, no (%)     Male  8 (73)   Female  3 (27)  Age at nephrectomy/initial biopsy, years, median (range)  58 (44–77)  T stage, no. (%):     T1  3 (27)   T2  1 (9)   T3  3 (27)   T4  4 (36)  N stage, no. (%):     0  2 (18)   1  1 (9)   2  8 (73)  M stage, no. (%):     0  4 (36)   1  7 (64)  Fuhrman grade, no. (%):     G1  0 (0)   G2  0 (0)   G3  5 (45)   G4  6 (55)  Pathological diagnosis, no. (%):     Nephrectomy  5 (45)   Renal biopsy  4 (36)   Lymph node biopsy, followed by autopsy  2 (18)  Additional treatments (including overlaps), no. (%):     Chemotherapy  6 (55)   Radiotherapy  6 (55)   Embolization  2 (18)   Metastasectomy  1 (9)  Laboratory parameters, median (range):     Leukocyte count, cells/μl  7100 (5700–17 800)   Neutrophil count, cells/μl  5096 (3954–14 500)   Lymphocyte count, cells/μl  1300 (900–1973)   Neutrophil-to-lymphocyte ratio (NLR)  4.08 (2.00–11.56)   Hemoglobin, g/dl  11.2 (5.0–14.9)   Albumin, g/dl  3.4 (1.9–4.3)   Lactate dehydrogenase, IU/l  192 (151–1339)   Alkaline phosphatase, IU/l  263 (95–765)   C-reactive protein, mg/dl  2.27 (0.09–22.4)  Median follow-up, months (range)  6 (0–97)  Tumors were re-staged according to the seventh TNM classification of the Union for International Cancer Control and the American Joint Committee on Cancer Guidelines. Table 1. Patient characteristics (n = 11) Parameter  Value  Gender, no (%)     Male  8 (73)   Female  3 (27)  Age at nephrectomy/initial biopsy, years, median (range)  58 (44–77)  T stage, no. (%):     T1  3 (27)   T2  1 (9)   T3  3 (27)   T4  4 (36)  N stage, no. (%):     0  2 (18)   1  1 (9)   2  8 (73)  M stage, no. (%):     0  4 (36)   1  7 (64)  Fuhrman grade, no. (%):     G1  0 (0)   G2  0 (0)   G3  5 (45)   G4  6 (55)  Pathological diagnosis, no. (%):     Nephrectomy  5 (45)   Renal biopsy  4 (36)   Lymph node biopsy, followed by autopsy  2 (18)  Additional treatments (including overlaps), no. (%):     Chemotherapy  6 (55)   Radiotherapy  6 (55)   Embolization  2 (18)   Metastasectomy  1 (9)  Laboratory parameters, median (range):     Leukocyte count, cells/μl  7100 (5700–17 800)   Neutrophil count, cells/μl  5096 (3954–14 500)   Lymphocyte count, cells/μl  1300 (900–1973)   Neutrophil-to-lymphocyte ratio (NLR)  4.08 (2.00–11.56)   Hemoglobin, g/dl  11.2 (5.0–14.9)   Albumin, g/dl  3.4 (1.9–4.3)   Lactate dehydrogenase, IU/l  192 (151–1339)   Alkaline phosphatase, IU/l  263 (95–765)   C-reactive protein, mg/dl  2.27 (0.09–22.4)  Median follow-up, months (range)  6 (0–97)  Parameter  Value  Gender, no (%)     Male  8 (73)   Female  3 (27)  Age at nephrectomy/initial biopsy, years, median (range)  58 (44–77)  T stage, no. (%):     T1  3 (27)   T2  1 (9)   T3  3 (27)   T4  4 (36)  N stage, no. (%):     0  2 (18)   1  1 (9)   2  8 (73)  M stage, no. (%):     0  4 (36)   1  7 (64)  Fuhrman grade, no. (%):     G1  0 (0)   G2  0 (0)   G3  5 (45)   G4  6 (55)  Pathological diagnosis, no. (%):     Nephrectomy  5 (45)   Renal biopsy  4 (36)   Lymph node biopsy, followed by autopsy  2 (18)  Additional treatments (including overlaps), no. (%):     Chemotherapy  6 (55)   Radiotherapy  6 (55)   Embolization  2 (18)   Metastasectomy  1 (9)  Laboratory parameters, median (range):     Leukocyte count, cells/μl  7100 (5700–17 800)   Neutrophil count, cells/μl  5096 (3954–14 500)   Lymphocyte count, cells/μl  1300 (900–1973)   Neutrophil-to-lymphocyte ratio (NLR)  4.08 (2.00–11.56)   Hemoglobin, g/dl  11.2 (5.0–14.9)   Albumin, g/dl  3.4 (1.9–4.3)   Lactate dehydrogenase, IU/l  192 (151–1339)   Alkaline phosphatase, IU/l  263 (95–765)   C-reactive protein, mg/dl  2.27 (0.09–22.4)  Median follow-up, months (range)  6 (0–97)  Tumors were re-staged according to the seventh TNM classification of the Union for International Cancer Control and the American Joint Committee on Cancer Guidelines. Figure 1. View largeDownload slide Kaplan–Meier curve depicting cancer-specific survival stratified by NLR (≥4 vs. <4; log-rank test, P = 0.0076). Figure 1. View largeDownload slide Kaplan–Meier curve depicting cancer-specific survival stratified by NLR (≥4 vs. <4; log-rank test, P = 0.0076). The present study is the first assessment of the prognostic significance of NLR in patients with CDC. It demonstrated NLR ≥4 as an independent poor prognostic factor for CDC as well as T stage ≥3. Furthermore, it should be noted that the sole surviving patient maintained a low NLR (<4) both at the initial diagnosis and at the time of distant recurrence. These results suggest that although the majority of CDC patients eventually die of the disease (3), patients with a low NLR (<4) may achieve long-term survival, even after developing metastasis. The link between high NLR and poor outcome of cancer patients has not been fully elucidated, but could be explained in general terms as follows (9–11). As the tumor progresses, neutrophils are produced by granulocyte colony-stimulating factor and mobilized into a circulating pool by interleukin-6. These tumor-associated neutrophils may contribute to the creation of an inflammatory tumor microenvironment (9). Conversely, tumor-infiltrating lymphocytes, which can inhibit tumor growth, may be suppressed by an aggressive tumor due to immune escape mechanisms (11). The NLR may thus reflect the degree of tumor progression in a more sensitive manner than either measure alone, since the ratio can be elevated by both an increased neutrophil-dependent inflammatory reaction and a decreased lymphocyte-mediated anti-tumor immune response (10). Additionally, a meta-analysis of 100 studies that evaluated the prognostic role of NLR in solid tumors demonstrated stronger associations between elevated NLR and worse outcome for metastatic than for non-metastatic disease, possibly reflecting a greater tumor burden or a more prolonged chronic inflammation process (9). Given that CDC generally presents at an advanced stage, the NLR may be a useful prognostic marker for this disease. The limitations of the present study include its retrospective design and small sample size. Nevertheless, our series (n = 11) is one of the largest cohorts of CDC from a single institution thus far reported (8), while nationwide studies conducted in Japan (2) and the United States (5,6) comprised 81, 160 and 227 patients, respectively (the latter two studies used the Surveillance, Epidemiology and End Results [SEER] database). Furthermore, as reported in previous studies, it is generally difficult to make an accurate diagnosis of CDC (2), especially on biopsies or limited sections (1), and misclassification may occur without centralized pathology review (5). Since our series included some cases who were diagnosed as CDC by biopsy or autopsy, not by nephrectomy, all specimens were reviewed by a genitourinary pathologist and confirmed as CDC. Although studies with larger populations are warranted to confirm our results, our data suggest that NLR might serve as a readily accessible predictive and prognostic biomarker for CDC in real-world clinical practice. Supplementary data Supplementary data are available at Japanese Journal of Clinical Oncology online. Acknowledgements We thank Anne M. O’Rourke, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. Conflict of interest statement The authors declare that they have no competing interests. Abbreviations CDC collecting duct carcinoma NLR neutrophil-to-lymphocyte ratio References 1 Gupta R, Billis A, Shah RB, et al.  . Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship. Am J Surg Pathol  2012; 36: 1265– 78. Google Scholar CrossRef Search ADS PubMed  2 Tokuda N, Naito S, Matsuzaki O, Nagashima Y, Ozono S, Igarashi T. Japanese Society of Renal Cancer. Collecting duct (Bellini duct) renal cell carcinoma: a nationwide survey in Japan. J Urol  2006; 176: 40– 3; discussion 43. Google Scholar CrossRef Search ADS PubMed  3 Karakiewicz PI, Trinh QD, Rioux-Leclercq N, et al.  . Collecting duct renal cell carcinoma: a matched analysis of 41 cases. Eur Urol  2007; 52: 1140– 5. Google Scholar CrossRef Search ADS PubMed  4 Oudard S, Banu E, Vieillefond A, et al.  . GETUG (Groupe d’Etudes des Tumeurs Uro-Génitales). Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs Uro-Génitales) study. J Urol  2007; 177: 1698– 702. Google Scholar CrossRef Search ADS PubMed  5 Wright JL, Risk MC, Hotaling J, Lin DW. Effect of collecting duct histology on renal cell cancer outcome. J Urol  2009; 182: 2595– 9. Google Scholar CrossRef Search ADS PubMed  6 Abern MR, Tsivian M, Polascik TJ, Coogan CL. Characteristics and outcomes of tumors arising from the distal nephron. Urology  2012; 80: 140– 6. Google Scholar CrossRef Search ADS PubMed  7 May M, Ficarra V, Shariat SF, et al.  . CORONA and SATURN projects; Young Academic Urologists Renal Cancer Group. Impact of clinical and histopathological parameters on disease specific survival in patients with collecting duct renal cell carcinoma: development of a disease specific risk model. J Urol  2013; 190: 458– 63. Google Scholar CrossRef Search ADS PubMed  8 Ciszewski S, Jakimów A, Smolska-Ciszewska B. Collecting (Bellini) duct carcinoma: a clinical study of a rare tumour and review of the literature. Can Urol Assoc J  2015; 9: E589– 93. Google Scholar CrossRef Search ADS PubMed  9 Templeton AJ, McNamara MG, Šeruga B, et al.  . Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst  2014; 106: dju124. Google Scholar CrossRef Search ADS PubMed  10 Taguchi S, Nakagawa T, Matsumoto A, et al.  . Pretreatment neutrophil-to-lymphocyte ratio as an independent predictor of survival in patients with metastatic urothelial carcinoma: a multi-institutional study. Int J Urol  2015; 22: 638– 43. Google Scholar CrossRef Search ADS PubMed  11 Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology  2007; 121: 1– 14. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Prognostic significance of neutrophil-to-lymphocyte ratio in collecting duct carcinoma

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Abstract

Abstract Collecting (Bellini) duct carcinoma of the kidney is a rare lethal tumor, and its prognostic factors remain unclear. The present study investigated the prognostic significance of neutrophil-to-lymphocyte ratio, which has recently been recognized as a readily available prognostic marker in various malignancies, in patients with collecting duct carcinoma. Of 11 patients who were pathologically diagnosed with collecting duct carcinoma at our institution, nine died of collecting duct carcinoma, one died of a postoperative complication, and one was alive, with a median follow-up period of 6 (range: 0–97) months. Both univariate and multivariate analyses associated neutrophil-to-lymphocyte ratio ≥4 (median) with worse cancer-specific survival. Notably, the sole surviving patient maintained a low neutrophil-to-lymphocyte ratio (<4) both at the initial diagnosis and at the time of distant recurrence. These results suggest that neutrophil-to-lymphocyte ratio might serve as a useful biomarker for collecting duct carcinoma as well as other malignancies. Bellini duct carcinoma, collecting duct carcinoma, neutrophil-to-lymphocyte ratio, prognosis, renal cell carcinoma Collecting duct carcinoma (CDC), also known as Bellini duct carcinoma, is a rare aggressive neoplasm of putative distal nephron origin that accounts for <1% of renal malignancies (1). Because of its extreme rarity, there have been few studies of CDC and its clinicopathological features, and its prognostic factors remain poorly understood (2–8). Recent studies have revealed that the neutrophil-to-lymphocyte ratio (NLR) is a useful prognostic marker in various malignancies (9), including urological cancers (10). The present study aimed to elucidate the prognostic significance of NLR in CDC patients. We retrospectively reviewed 12 patients who were pathologically diagnosed with CDC at our institution between 1996 and 2016. After one patient was excluded for missing data, the remaining 11 patients were assessed for associations between various clinicopathological factors, including NLR and cancer-specific survival. NLR was calculated from blood tests performed immediately before nephrectomy or initial biopsy. Survival distributions were estimated using the Kaplan–Meier method. Univariate and multivariate analyses were carried out using log-rank tests and Cox proportional hazards model, respectively. For the multivariate analysis, a backward stepwise procedure (entry, 0.05; removal, 0.10) was selected, due to the small sample size. All statistical analyses were carried out using JMP Pro version 11.0.0 (SAS Institute, Cary, NC, USA). A value of P < 0.05 was considered significant. Follow-up information was obtained as of December 2017. Patient characteristics are summarized in Table 1. Nine of the 11 patients died of CDC, one died of multiple organ failure 16 days after nephrectomy with inferior vena cavectomy, and one was alive on the last follow-up date. Based on the median NLR (4.08), a cutoff value of 4 was selected for assessment of associations, which is one of the most commonly used cutoffs in previous studies (9). As shown in Fig. 1, a NLR of ≥4 was strongly associated with poorer cancer-specific survival (log-rank test, P = 0.0076). In addition, T stage ≥3, M1 stage, leukocyte count ≥9000 cells/μl (upper limit of normal), neutrophil count ≥5100 cells/μl (median), and lactate dehydrogenase ≥237 IU/l (upper limit of normal) were also associated with poorer outcome by univariate analysis. Multivariate analysis determined that NLR ≥4 and T stage ≥3 were independent predictors of worse cancer-specific survival. However, the hazard ratios did not converge, probably due to small sample size, and these results are therefore for reference purposes only (Table S1). The sole surviving patient had an NLR of 2.00 at the time he underwent nephrectomy for T1aN0M0 tumor. At 68 months after nephrectomy, he developed solitary lung metastasis and underwent video-assisted thoracic surgery; at that time, his NLR was 3.54. The patient is still alive 27 months after video-assisted thoracic surgery and has no evidence of disease. Table 1. Patient characteristics (n = 11) Parameter  Value  Gender, no (%)     Male  8 (73)   Female  3 (27)  Age at nephrectomy/initial biopsy, years, median (range)  58 (44–77)  T stage, no. (%):     T1  3 (27)   T2  1 (9)   T3  3 (27)   T4  4 (36)  N stage, no. (%):     0  2 (18)   1  1 (9)   2  8 (73)  M stage, no. (%):     0  4 (36)   1  7 (64)  Fuhrman grade, no. (%):     G1  0 (0)   G2  0 (0)   G3  5 (45)   G4  6 (55)  Pathological diagnosis, no. (%):     Nephrectomy  5 (45)   Renal biopsy  4 (36)   Lymph node biopsy, followed by autopsy  2 (18)  Additional treatments (including overlaps), no. (%):     Chemotherapy  6 (55)   Radiotherapy  6 (55)   Embolization  2 (18)   Metastasectomy  1 (9)  Laboratory parameters, median (range):     Leukocyte count, cells/μl  7100 (5700–17 800)   Neutrophil count, cells/μl  5096 (3954–14 500)   Lymphocyte count, cells/μl  1300 (900–1973)   Neutrophil-to-lymphocyte ratio (NLR)  4.08 (2.00–11.56)   Hemoglobin, g/dl  11.2 (5.0–14.9)   Albumin, g/dl  3.4 (1.9–4.3)   Lactate dehydrogenase, IU/l  192 (151–1339)   Alkaline phosphatase, IU/l  263 (95–765)   C-reactive protein, mg/dl  2.27 (0.09–22.4)  Median follow-up, months (range)  6 (0–97)  Parameter  Value  Gender, no (%)     Male  8 (73)   Female  3 (27)  Age at nephrectomy/initial biopsy, years, median (range)  58 (44–77)  T stage, no. (%):     T1  3 (27)   T2  1 (9)   T3  3 (27)   T4  4 (36)  N stage, no. (%):     0  2 (18)   1  1 (9)   2  8 (73)  M stage, no. (%):     0  4 (36)   1  7 (64)  Fuhrman grade, no. (%):     G1  0 (0)   G2  0 (0)   G3  5 (45)   G4  6 (55)  Pathological diagnosis, no. (%):     Nephrectomy  5 (45)   Renal biopsy  4 (36)   Lymph node biopsy, followed by autopsy  2 (18)  Additional treatments (including overlaps), no. (%):     Chemotherapy  6 (55)   Radiotherapy  6 (55)   Embolization  2 (18)   Metastasectomy  1 (9)  Laboratory parameters, median (range):     Leukocyte count, cells/μl  7100 (5700–17 800)   Neutrophil count, cells/μl  5096 (3954–14 500)   Lymphocyte count, cells/μl  1300 (900–1973)   Neutrophil-to-lymphocyte ratio (NLR)  4.08 (2.00–11.56)   Hemoglobin, g/dl  11.2 (5.0–14.9)   Albumin, g/dl  3.4 (1.9–4.3)   Lactate dehydrogenase, IU/l  192 (151–1339)   Alkaline phosphatase, IU/l  263 (95–765)   C-reactive protein, mg/dl  2.27 (0.09–22.4)  Median follow-up, months (range)  6 (0–97)  Tumors were re-staged according to the seventh TNM classification of the Union for International Cancer Control and the American Joint Committee on Cancer Guidelines. Table 1. Patient characteristics (n = 11) Parameter  Value  Gender, no (%)     Male  8 (73)   Female  3 (27)  Age at nephrectomy/initial biopsy, years, median (range)  58 (44–77)  T stage, no. (%):     T1  3 (27)   T2  1 (9)   T3  3 (27)   T4  4 (36)  N stage, no. (%):     0  2 (18)   1  1 (9)   2  8 (73)  M stage, no. (%):     0  4 (36)   1  7 (64)  Fuhrman grade, no. (%):     G1  0 (0)   G2  0 (0)   G3  5 (45)   G4  6 (55)  Pathological diagnosis, no. (%):     Nephrectomy  5 (45)   Renal biopsy  4 (36)   Lymph node biopsy, followed by autopsy  2 (18)  Additional treatments (including overlaps), no. (%):     Chemotherapy  6 (55)   Radiotherapy  6 (55)   Embolization  2 (18)   Metastasectomy  1 (9)  Laboratory parameters, median (range):     Leukocyte count, cells/μl  7100 (5700–17 800)   Neutrophil count, cells/μl  5096 (3954–14 500)   Lymphocyte count, cells/μl  1300 (900–1973)   Neutrophil-to-lymphocyte ratio (NLR)  4.08 (2.00–11.56)   Hemoglobin, g/dl  11.2 (5.0–14.9)   Albumin, g/dl  3.4 (1.9–4.3)   Lactate dehydrogenase, IU/l  192 (151–1339)   Alkaline phosphatase, IU/l  263 (95–765)   C-reactive protein, mg/dl  2.27 (0.09–22.4)  Median follow-up, months (range)  6 (0–97)  Parameter  Value  Gender, no (%)     Male  8 (73)   Female  3 (27)  Age at nephrectomy/initial biopsy, years, median (range)  58 (44–77)  T stage, no. (%):     T1  3 (27)   T2  1 (9)   T3  3 (27)   T4  4 (36)  N stage, no. (%):     0  2 (18)   1  1 (9)   2  8 (73)  M stage, no. (%):     0  4 (36)   1  7 (64)  Fuhrman grade, no. (%):     G1  0 (0)   G2  0 (0)   G3  5 (45)   G4  6 (55)  Pathological diagnosis, no. (%):     Nephrectomy  5 (45)   Renal biopsy  4 (36)   Lymph node biopsy, followed by autopsy  2 (18)  Additional treatments (including overlaps), no. (%):     Chemotherapy  6 (55)   Radiotherapy  6 (55)   Embolization  2 (18)   Metastasectomy  1 (9)  Laboratory parameters, median (range):     Leukocyte count, cells/μl  7100 (5700–17 800)   Neutrophil count, cells/μl  5096 (3954–14 500)   Lymphocyte count, cells/μl  1300 (900–1973)   Neutrophil-to-lymphocyte ratio (NLR)  4.08 (2.00–11.56)   Hemoglobin, g/dl  11.2 (5.0–14.9)   Albumin, g/dl  3.4 (1.9–4.3)   Lactate dehydrogenase, IU/l  192 (151–1339)   Alkaline phosphatase, IU/l  263 (95–765)   C-reactive protein, mg/dl  2.27 (0.09–22.4)  Median follow-up, months (range)  6 (0–97)  Tumors were re-staged according to the seventh TNM classification of the Union for International Cancer Control and the American Joint Committee on Cancer Guidelines. Figure 1. View largeDownload slide Kaplan–Meier curve depicting cancer-specific survival stratified by NLR (≥4 vs. <4; log-rank test, P = 0.0076). Figure 1. View largeDownload slide Kaplan–Meier curve depicting cancer-specific survival stratified by NLR (≥4 vs. <4; log-rank test, P = 0.0076). The present study is the first assessment of the prognostic significance of NLR in patients with CDC. It demonstrated NLR ≥4 as an independent poor prognostic factor for CDC as well as T stage ≥3. Furthermore, it should be noted that the sole surviving patient maintained a low NLR (<4) both at the initial diagnosis and at the time of distant recurrence. These results suggest that although the majority of CDC patients eventually die of the disease (3), patients with a low NLR (<4) may achieve long-term survival, even after developing metastasis. The link between high NLR and poor outcome of cancer patients has not been fully elucidated, but could be explained in general terms as follows (9–11). As the tumor progresses, neutrophils are produced by granulocyte colony-stimulating factor and mobilized into a circulating pool by interleukin-6. These tumor-associated neutrophils may contribute to the creation of an inflammatory tumor microenvironment (9). Conversely, tumor-infiltrating lymphocytes, which can inhibit tumor growth, may be suppressed by an aggressive tumor due to immune escape mechanisms (11). The NLR may thus reflect the degree of tumor progression in a more sensitive manner than either measure alone, since the ratio can be elevated by both an increased neutrophil-dependent inflammatory reaction and a decreased lymphocyte-mediated anti-tumor immune response (10). Additionally, a meta-analysis of 100 studies that evaluated the prognostic role of NLR in solid tumors demonstrated stronger associations between elevated NLR and worse outcome for metastatic than for non-metastatic disease, possibly reflecting a greater tumor burden or a more prolonged chronic inflammation process (9). Given that CDC generally presents at an advanced stage, the NLR may be a useful prognostic marker for this disease. The limitations of the present study include its retrospective design and small sample size. Nevertheless, our series (n = 11) is one of the largest cohorts of CDC from a single institution thus far reported (8), while nationwide studies conducted in Japan (2) and the United States (5,6) comprised 81, 160 and 227 patients, respectively (the latter two studies used the Surveillance, Epidemiology and End Results [SEER] database). Furthermore, as reported in previous studies, it is generally difficult to make an accurate diagnosis of CDC (2), especially on biopsies or limited sections (1), and misclassification may occur without centralized pathology review (5). Since our series included some cases who were diagnosed as CDC by biopsy or autopsy, not by nephrectomy, all specimens were reviewed by a genitourinary pathologist and confirmed as CDC. Although studies with larger populations are warranted to confirm our results, our data suggest that NLR might serve as a readily accessible predictive and prognostic biomarker for CDC in real-world clinical practice. Supplementary data Supplementary data are available at Japanese Journal of Clinical Oncology online. Acknowledgements We thank Anne M. O’Rourke, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. Conflict of interest statement The authors declare that they have no competing interests. Abbreviations CDC collecting duct carcinoma NLR neutrophil-to-lymphocyte ratio References 1 Gupta R, Billis A, Shah RB, et al.  . Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship. Am J Surg Pathol  2012; 36: 1265– 78. Google Scholar CrossRef Search ADS PubMed  2 Tokuda N, Naito S, Matsuzaki O, Nagashima Y, Ozono S, Igarashi T. Japanese Society of Renal Cancer. Collecting duct (Bellini duct) renal cell carcinoma: a nationwide survey in Japan. J Urol  2006; 176: 40– 3; discussion 43. Google Scholar CrossRef Search ADS PubMed  3 Karakiewicz PI, Trinh QD, Rioux-Leclercq N, et al.  . Collecting duct renal cell carcinoma: a matched analysis of 41 cases. Eur Urol  2007; 52: 1140– 5. Google Scholar CrossRef Search ADS PubMed  4 Oudard S, Banu E, Vieillefond A, et al.  . GETUG (Groupe d’Etudes des Tumeurs Uro-Génitales). Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs Uro-Génitales) study. J Urol  2007; 177: 1698– 702. Google Scholar CrossRef Search ADS PubMed  5 Wright JL, Risk MC, Hotaling J, Lin DW. Effect of collecting duct histology on renal cell cancer outcome. J Urol  2009; 182: 2595– 9. Google Scholar CrossRef Search ADS PubMed  6 Abern MR, Tsivian M, Polascik TJ, Coogan CL. Characteristics and outcomes of tumors arising from the distal nephron. Urology  2012; 80: 140– 6. Google Scholar CrossRef Search ADS PubMed  7 May M, Ficarra V, Shariat SF, et al.  . CORONA and SATURN projects; Young Academic Urologists Renal Cancer Group. Impact of clinical and histopathological parameters on disease specific survival in patients with collecting duct renal cell carcinoma: development of a disease specific risk model. J Urol  2013; 190: 458– 63. Google Scholar CrossRef Search ADS PubMed  8 Ciszewski S, Jakimów A, Smolska-Ciszewska B. Collecting (Bellini) duct carcinoma: a clinical study of a rare tumour and review of the literature. Can Urol Assoc J  2015; 9: E589– 93. Google Scholar CrossRef Search ADS PubMed  9 Templeton AJ, McNamara MG, Šeruga B, et al.  . Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst  2014; 106: dju124. Google Scholar CrossRef Search ADS PubMed  10 Taguchi S, Nakagawa T, Matsumoto A, et al.  . Pretreatment neutrophil-to-lymphocyte ratio as an independent predictor of survival in patients with metastatic urothelial carcinoma: a multi-institutional study. Int J Urol  2015; 22: 638– 43. Google Scholar CrossRef Search ADS PubMed  11 Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology  2007; 121: 1– 14. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Japanese Journal of Clinical OncologyOxford University Press

Published: May 29, 2018

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