Background
Penile squamous cell carcinoma (PSCC) is a rare disease in developed countries, with an incidence of 0.3–1.0 per 100,000 males in Europe and North America and 0.4–0.5 per 100,000 males in Japan [
1,
2]. However, it represents an important public health problem for developing countries in Asia, Africa and South America, where its incidence varies from 3 to 8.3 cases per 100,000 [
3]. The major prognostic factors in PSCC are tumor grade and the presence of perineal and lymphatic invasion [
4]. SCC, a soluble epithelial antigen and a classical molecular marker lacks sensitivity in the detection of small tumor burdens and has little prognostic significance in survival after surgery [
5]. The overexpression of p53 and Ki-67 and the loss of membranous E-cadherin determined immunohistochemically in biopsy or penectomy tissue specimens are also shown to associate with the detection of lymph node metastases, but these markers are not useful in clinical practice [
4,
6].
The neutrophil-to-lymphocyte ratio (NLR) has been suggested as a simple marker of the systemic inflammatory response in critical care patients [
7]. It has also been reported as an independent prognostic factor for several solid malignancies [
8‐
17]. Importantly, the NLR can easily be calculated from routine complete blood counts (CBCs) in peripheral blood samples [
15,
16].
We investigated the utility of the pretreatment NLR as a prognosticator in patients who presented with penile cancer.
Discussion
We have evaluated the pretreatment NLR as a predictor of survival in penile cancer patients. We found that high NLRs were associated with a poorer prognosis of penile cancer.
Several prognostic factors have been established for patients with penile cancer. Nodal metastasis is the most important predictor of a poor clinical outcome [
4]. Tumor grade and perineural or lymphatic invasion are also known prognostic predictors. p53, Ki-67, E-cadherin, and epidermal growth factor receptor (EGFR) are considered to be molecular prognostic markers, but they are not always useful in clinical practice [
4,
6].
It has been suggested that the NLR can be used to estimate the magnitude of systemic inflammation in cancer patients [
8,
18‐
20]. The NLR is easily and inexpensively measured [
21]. An elevated NLR has been reported to be associated with a poorer survival rate in a variety of cancers [
8‐
13,
22].
Pond et al. demonstrated that the NLR was significantly associated with survival in 26 patients with penile cancer [
21]. This has been the only paper to describe the relationship between the NLR and the prognosis of penile cancer; however, the subjects were limited to patients who were undergoing concurrent chemo-radiotherapy.
The AUROC determined the cut-off value of the NLR to be 2.82 in the present study. Several studies in patients with advanced pancreatic cancer have shown NLR cut-off values of approximately five [
8]. In patients with intrahepatic cholangiocarcinoma and those with liver metastasis from colorectal carcinoma [
9], the NLR cut-off value is also set at five. In urological cancers, an NLR cut-off value of approximately five has been used for prostate cancer, while scores of 2 to 5 have been used for renal cell carcinoma [
23]. Our cut-off point for the NLR was thus somewhat lower than the values determined in previous studies, despite the fact that the NLR for penile cancer was high in comparison to other urological diseases. Of note, in most of these studies [ref], the NLR was assessed in advanced cases. On the other hand, in our prevous study [
24], the NLR cut-off point for predicting the prognosis of patients most of who had organ-confined prostate cancer was 2.4.
In recent studies, the preoperative levels of C-reactive protein (CRP) were found to predict survival in patients with penile squamous cell carcinoma [
24,
25]. In various tumors, other markers of the systemic inflammatory response have also been developed to predict patient outcomes, such as the platelet-to-lympocyte ratio (PLR), the lympocyte-to-monocyte ratio (LMR), and the preoperative haemogolobin and albumin levels [
26‐
31]. It is necessary to investigate the relationship between these markers and the prognosis of penile cancer in the future.
The management of the regional lymph nodes in penile cancer patients is highly important for long-term survival. However, there is no non-invasive or minimally invasive staging technique that can be used to determine their lymph node status. Proven molecular markers or accurate minimally invasive tests which can be used to identify nodal metastasis are desired.
The present study is associated with some limitations due to its retrospective nature. Our patients received a variety of therapies, including surgery, chemotherapy, radiation therapy, other treatments, and their combinations. Although the treatment options were heterogeneous, we found that the NLR was associated with patient outcomes. Second is that we did not perform mechanistic experiments to determine the roles of neutrophils and/or lymphocytes in penile cancer progression. Nonetheless, the current results support the findings of previous studies indicating correlations between the NLR/inflammation and the clinical outcome of patients with several types of advanced-stage solid tumors. Third, the sample size was low because of the low incidence of penile cancer and the lack of some information, including the degree of extranodal extension [
32]. Despite this limitation, the population of the present study represents the largest number of penile cancer patients in whom the NLR was investigated. An additional limitation is that the data in the clinical database study was extracted electronically. Thus, the detailed information about the specific diseases was not confirmed, while the technique allowed us to obtain a large number of cases.
Our immunohistochemistry revealed no significant correlations between the number of tumor-infiltrating CD66b- or CD8-positive immune cells and tumor grade or stage. Nonetheless, higher number of CD66b-positive neutrophils was correlated with lower tumor stage. Wang et al. showed that increased tumor-infiltrating neutrophils and neutrophil-to-lymphocyte ratio in esophageal cancer specimens correlated with disease progression [
33]. Although a large number of studies have demonstrated the prognostic value of NLR in various solid tumors, others have failed to show that of tumor-infiltrating neutrophils/lymphocytes in tissue specimens. We indeed performed immunohistochemical staining for CD66b and CD8 in bladder cancer and prostate cancer specimens, but found no significant correlations between the number of immunoreactive immune cells and patient outcomes (unpublished data).
Acknowledgement
We would like to thank Drs. Kazuki Kobayashi (Yokosuka Kyosai Hospital, Yokosuka, Japan), Junichi Ohta (Yokohama Municipal Citizen’s Hospital, Yokohama, Japan), Kazuo Kitami (Fujisawa City Hospital, Fujisawa, Japan), Kotaro Hirai (Sagamihara National Hospital, Sagamihara, Japan), Yoshiki Hara (Odawara Municipal Hospital, Odawara, Japan), Kiyoshi Fujinami (Chigasaki Municipal Hospital, Chigasaki, Japan), Hiroshi Misaki (Yamato Municipal Hospital, Yamato, Japan), Takeshi Watanabe (Kanagawa Prefectural Ashigarakami Hospital, Matsuda, Japan), Yoshiharu Ogo (Yokohama Sakae Kyosai Hospital, Yokohama, Japan), Futoshi Tsuchiya (Yokohama Minato Red Cross Hospital, Yokohama, Japan), Ichiro Ikeda (Yokohama Minami Kyosai Hospital, Yokohama, Japan), Teichiro Ueki (Hadano Red Cross Hospital, Hadano, Japan), Tetsuo Murai (International Goodwill Hospital, Yokohama, JAPAN), Hitomi Kanno (Toshiba Rinkan Hospital, Sagamihara, Japan), Hideki Ouchi (Fujisawa Shonandai Hospital, Fujisawa, Japan), Koichi Udagawa (Hiratsuka Kyosai Hospital, Hiratsuka, Japan), Kimio Chiba (Kawasaki Municipal Ida Hospital, Kawasaki, Japan), Kotaro Suzuki (Saiseikai Yokohama City Southern Hospital, Yokohama, Japan), Yoshitake Kato (Yokohama Hodogaya Central Hospital, Yokohama, Japan) and Takeshi Kishida (Kanagawa Cancer Center, Yokohama, Japan).