Preoperative neutrophil-lymphocyte and lymphocyte-monocyte ratios predict prognosis in patients with penile cancer undergoing partial or total penectomy

doi:10.21203/rs.3.rs-4931505/v1

Purpose

To investigate the prognostic values of preoperative neutrophil–lymphocyte ratio (NLR)and lymphocyte–monocyte ratio (LMR) in patients with penile squamous cell carcinoma (PSCC).

Methods

A total of 47 patients with PSCC who underwent partial or total penectomy from 2000 to 2022 was retrospectively analyzed. The receiver operating characteristic(ROC) curves were used to determine the cutoff values of NLR and LMR for diagnosis of tumor recurrence. Kaplan–Meier method and log-rank test were used in the survival analysis. Cox proportional-hazards regression model was used in the independent risk factor analysis.

Results

The cutoff values of NLR and PLR derived from the ROC curves were 2.3 and 3.9 respectively. Univariate analysis revealed that NLR and LMR were significantly associated with PFS (P < 0.001, P = 0.029). Lymph node metastasis (P < 0.001 and P < 0.001), distant metastases (P = 0.001 and P = 0.001) and pathological stage (P = 0.001 and P < 0.001) correlate significantly with PFS and OS, respectively. Multivariate analysis verified pathological stage, lymph node metastasis, and NLR to be independent prognostic factors for PFS (P = 0.021, P = 0.001 and P = 0.033).

Conclusions

NLR could be an independent predictor of PFS in patients with PSCC.

penile squamous cell carcinoma

neutrophil–lymphocyte ratio

lymphocyte–monocyte ratio

prognosis

Penile squamous cell carcinoma (PSCC) is a rare disease, with an incidence of 1–10 per 100000 men worldwide, but in the developing countries such as Asia and Africa the incidence is higher, varying from 3 to 8.3 cases per 100000men.^1,2 The majority of patients could be diagnosed at a localized stage, and the 5-year cancer-specific survival in patients without lymphovascular invasion could be 90–100%. ¹ However, PSCC can behave aggressively, which is manifested by locallymph node metastasis and distant metastasis. The 5-year cancer-specific survival drops to 30% when the patients suffered bilateral inguinal lymphatic invasion.¹

Some prognostic factors have been verified for patients with PSCC, among which the most important is lymphatic invasion.³ But there are some studies reporting that only 20% of the lymph nodes that could not be touched showed the presence of lymph node metastases.⁴In addition, up to 50% of palpable inguinal lymph nodes were induced by the inflammatory response.⁵ Other prognostic factors such as tumor stage and grade can only be obtained from postoperative data. Therefore, it is urgent to determine some reliable pretreatment prognostic factors.

There is a growing number of evidence supporting the role of systemic inflammation in carcinogenesis and tumor development.^6,7 As the most widely studied systemic inflammatory indicator, neutrophil–lymphocyte ratio (NLR) has been reported as an independent prognostic factor for several solid malignancies.^8–11 In addition, the lymphocyte–monocyte ratio (LMR) has also been proved to have diagnostic values in some solid malignancies.^12–15 Although NLR and LMR had been investigated in lots of studies, there are few studies evaluating their prognostic values in PSCC. In the retrospective study, we evaluated the prognostic values of preoperative NLR and LMR in patients with PSCC simultaneously.

Study subjects

A total of 47 patients, who underwent penile cancer surgery from 2000 to 2022 at the Department of Urology in our hospitals were included in the study. We excluded the patient if he had clinical evidence of infection, or advanced disease. We retrospectively reviewed patient and tumor characteristics, such as age, smoking status, surgery type, tumor–node–metastasis (TNM) staging, and differential grade. The routine blood test was carried out within 3 days prior to surgery. We defined the disease recurrence as local treatment failure or lymph node metastases or distant metastases. The last follow-up date was April 30, 2024. The Institutional Review Board of the clinical center approved the study.

Statistical analysis

The NLR and LMR were calculated using the neutrophil and lymphocyte counts, the lymphocyte and monocyte counts, respectively. The primary endpoint of this study was progression-free survival (PFS). Receiver operating characteristic (ROC) curves were plotted to determine the cutoff values of NLR and LMR. We used Pearson’s χ2 test to compare the relationships between NLR, LMR and other variables. Kaplan–Meier method was used to draw the OS and PFS curves, which was evaluated by the log-rank test. The Cox proportional hazards regression models were used in the univariate and multivariate analyses. For all statistical tests, P < 0.05 was regarded as statistically significant. Statistical analyses were performed using SPSS version 19.0 (IBM Corporation, Somers, NY, USA).

We enrolled 47 PSCC patients (median age 62 years; range 33–74 years) in the present study. For the 47 patients with PSCC, an NLR of 2.3 was determined by ROC curve, showing the best sensitivity and specificity (Fig. 1A). According to the cutoff value, 18 patients (38%) had an elevated preoperative NLR. The area under the curve (AUC) for NLR was 0.750 (95% confidence interval [CI] 0.584–0.916, P = 0.01). The cutoff of LMR was 3.9, with an AUC of0.701 (95% CI 0.548–0.855, P = 0.039) (Fig. 1B). Nineteen patients (40%) had an elevated preoperative LMR.

We used the cutoffs of NLR and LMR to divide the patients into high- and low-NLR and-LMR groups. The high- and low-LMR groups were not significantly different from the clinicopathological features. However, preoperative NLR was significantly higher in pT 3/4 stage cancer and lymph node metastasis (P = 0.018, P = 0.006) (Table 1).

Table 1 The relationships between clinicopathological parameters and NLR or LMR

Variable	NLR≥2.3	NLR＜2.3	P value	LMR≥3.9	LMR＜3.9	P value
Variable	n	n	P value	n	n	P value
Age （years)			0.194			0.866
＜60 ≥60	9	9		7	11
＜60 ≥60	9	20		12	17
Smoking status			0.252^a			0.833^a
Yes	13	26		15	24
No	5	3		4	4
Surgery type			0.317^a			0.833^a
Partial penectomy Total penectomy	14	25		15	24
Partial penectomy Total penectomy	5	3		4	4
Lymph node metastasis			0.006^a			0.562^a
Yes No	7	1		2	6
Yes No	11	28		17	22
Distant metastases			0.275^a			1.000^a
Yes No	2	0		1	1
Yes No	16	29		18	27
Tumor grade			0.733			0.785
1/2 3	15	23		15	23
1/2 3	3	6		4	5
Pathologic T stage			0.018^a			0.783^a
1/2 3/4	12	28		17	23
1/2 3/4	6	1		2	5

a.continuity correction χ²test

The median survival time was 75 months (range: 16–108 months). Eight patients died from cancer-related causes, and one from heart disease. Twelve patients had tumor recurrence or metastasis. The 5-year PFS rate in the high-NLR (≥ 2.3) group was significantly lower than in the low-NLR (< 2.3) group (58 vs 92.7%; Fig. 2A). The 5-year PFS rate in the low-LMR (< 3.9) group was significantly lower than in the high-LMR (≥ 3.9) group (63 vs 91.3%; Fig. 2B). However, there is no significant difference for the 5-year OS rate(P = 0.368; Fig. 2b).

Univariate analysis revealed that lymph node metastasis (P < 0.001 and P < 0.001), distant metastases (P = 0.001 and P = 0.001) and pathological stage (P = 0.001 and P < 0.001) were significantly associated with PFS and OS, respectively. NLR and LMR correlate significantly with PFS (P < 0.001, P = 0.029) (Table 2). Multivariate analysis verified pathological stage, lymph node metastasis, and NLR to be independent prognostic factors for PFS (P = 0.021, P = 0.001 and P = 0.033) (Table 3). In addition, the multivariate analysis did not reveal any significant independent factors for OS.

Table 2

Univariate analysis of PFS and OS in 47 patients with PSCC
Variable		n	PFS		OS
			χ²	P value	χ²	P value
Age (years)	<60	18	.328	.567	.649	.420
	≥ 60	29
Smoking status	Yes	39	2.300	.129	.395	.529
	No	8
Surgery type	Partial penectomy	39	.315	.574	.295	.587
	Total penectomy	8
Lymph node metastasis	Yes	8	55.206	.000	42.359	.000
	No	39
Distant metastases	Yes	2	10.304	.001	10.876	.001
	No	45
Tumor grade	1/2	38	.341	.559	2.412	.120
	3/4	9
Pathologic T stage	1/2	40	11.076	.001	21.252	.000
	3/4	7
NLR	≥ 2.3	18	14.325	.000	2.511	.113
	<2.3	29
LMR	≥ 3.9	19	4.754	.029	.811	.368
	<3.9	28

Table 3

Multivariate analysis of PFS in 47 patients with PSCC
Variable	PFS
Variable	P value	HR	95% CI
Age	.192	3.200	.557	18.387
Smoking status	.135	4.390	.630	30.580
Surgery type	.804	.750	.078	7.254
Lymph nodemetastasis	.001	144.115	8.544	2430.947
Distant metastases	.980	1.046	.032	34.423
Tumor grade	.786	1.226	.282	5.335
Pathologic T stage	.021	6.797	.790	58.468
NLR	.033	.092	.010	.830
LMR	.866	.796	.056	11.346

In recent years, there are lots of studies extensively investigating the interaction between inflammation and tumor growth, and a growing number of evidence shows that inflammation is closely related tocarcinogenesis and could promote tumor development by multiple mechanisms.^16–18

Being critical components of host immunity, peripheral leukocytes have a great effect on carcinogenesis. Neutrophils could be activated by cytokines such as interleukin(IL)-1, IL-6 and tumor necrosis factor, and produce circulating vascular endothelial cell growth factor which can stimulate cell proliferation and angiogenesis.^19,20 Monocytes can produce high levels of reactive oxygen to initiate tumorigenesis, and can release a great deal of cytokines such as tumor necrosis factor-α,IL-1, and IL-6 to promote tumor development and metastasis.^21,22 Conversely, lymphocytes could induce apoptosis, inhibit tumor proliferation, and mediatie antibody-dependent cell-mediated cytotoxicity.^20,23 The low level of lymphocyte in cancer-adjacent tissues can reduce anti-tumor immunity, which could affect the prognosis of tumor patients.²⁴

It has been proved that the inflammatory indicators such as NLR and LMR are associated with the survival rate in a variety of cancers, and NLR and LMR could be used to predict prognosis in patients with various solid cancers.^25–27 However, the prognostic values of NLR and LMR have been rarely identified in PSCC. To the best of our knowledge, there are only three studies who had examined the prognostic values of NLR in patients with PSCC. Pond et al. conducted two studies: one investigated the PSCC patients receiving concurrent chemo-radiotherapy, and they found that high NLR was significantly associated only with poor OS and showed a trend for association with poor PFS; the other investigated the advanced PSCC patients receiving first-line systemic therapy, and they found that NLR was associated with OS, with the significance only in univariate but not multivariate analysis.^28,29 Kasuga et al. demonstrated that patients with high NLRs showed a significant poorer cancer-specific survival. In addition, patients with high NLRs tended to correlate with poorer overall survival. But in the multivariate analysis, no significant independent factors were proved to predict the prognosis.³⁰

We evaluated NLR and LMR to predict prognosis in patients with penile cancer simultaneously in the study. And to our knowledge, this is the first paper to describe the relationship between the LMR and the prognosis of penile cancer. We found that both NLR and LMR were significantly associated with PFS, which is similar to the findings of Kasuga's study. But it differed from Pond's findings, which revealed that NLR was significantly associated with OS. This was partly because of the study design difference and racial diversity. Pond et al. investigated the patients receiving concurrent chemo-radiotherapy or advanced PSCC patients receiving first-line systemic therapy, who were different from our patients. In addition, tumor characteristics of the Chinese patients in our study were different from those of foreign patients. We also found that preoperative NLR was significantly higher in pT 3/4 stage cancer and lymph node metastasis. As we all know, tumor stage and lymphatic invasion are closely connected with prognosis of PSCC. Good association with pathological T stage and lymph node metastasis indicated that NLR may correlate with prognosis of PSCC. In the multivariate analysis, we verified NLR to be an independent prognostic factor for PFS, but we didn't find any significant independent factors for OS.

It is important that which suitable cutoff value should be selected. Some studies investigating the prognostic values of NLR and LMR determined the cutoff values empirically. In Pond's two studies, he selected the median NLRs of 3.7 and 4.4 to divide the patients.^28,29 Kasuga selected the cut-off value of the NLR using the ROC curve, and he determined the cut-off value of the NLR to be 2.82.³⁰ In our study, we also used the ROC curve to determine the ideal cutoff values of NLR and LMR. The cut-off value of the NLR in our study was 2.3, which is lower than Pond's selected values but similar to the value in Kasuga's study. In addition, we found that NLR was superior to LMR to be a predictive factor, with the AUC of 0.750, superior to 0.701 of LMR.

Our study has some limitations. First, it was hard to ensure the consistency of the clinicopathological data because of its retrospective nature. Second, some other important prognostic factors such as growth pattern and anatomic site were not included in our study. Third, we could not exclude all the interference factors, although we had tried to excluded the effects of inflammation and others. Additionally, the confounding variables had not been adjusted in the study, such as the association between clinical factors (age or stage) and NLR or LMR, which may result in the less accurate results of our survival analysis. Last, the sample number in our study was relatively small.

In conclusion, it is believed that this is the first study to evaluate the prognostic values of NLR and LMR in patients with penile cancer undergoing partial or total penectomy. We show that NLR could be a good independent predictor of PFS. These findings need external and prospective validation.

Conflict of Interest

The authors declare no competing interests.

Informed Consent
Informed consent was obtained from all the subjects involved in the study.

Funding

This study was sponsered by the Health Research Program of Shanghai Pudong New District Health Committee(PW2023B-05); Top-level Clinical Discipline Project of Shanghai Pudong(No.PWYgf 2021-06)

Author Contribution

SX and PXS performed the experiments and collected the data. SX, LY and CZK analyzed the data. YJB and SX wrote the manuscript. CZK conceived the study and coordinated the research. All authors contributed to editorial changes in the manuscript. All authors read and approved the finial manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Availability of Data and Materials

Data will be provided from the corresponding author upon reasonable request.

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No competing interests reported.

Preoperative neutrophil-lymphocyte and lymphocyte-monocyte ratios predict prognosis in patients with penile cancer undergoing partial or total penectomy

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusions

Figures

Introduction

Materials and methods

Study subjects

Statistical analysis

Results

Discussion

Declarations

Conflict of Interest

Informed Consent
Informed consent was obtained from all the subjects involved in the study.

Funding

Author Contribution

Availability of Data and Materials

References

Additional Declarations

Status:

Version 1

Preoperative neutrophil-lymphocyte and lymphocyte-monocyte ratios predict prognosis in patients with penile cancer undergoing partial or total penectomy

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusions

Figures

Introduction

Materials and methods

Study subjects

Statistical analysis

Results

Discussion

Declarations

Conflict of Interest

Informed Consent Informed consent was obtained from all the subjects involved in the study.

Funding

Author Contribution

Availability of Data and Materials

References

Additional Declarations

Status:

Version 1

Informed Consent
Informed consent was obtained from all the subjects involved in the study.