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Abstract

Importance

Salivary gland tumors (SGTs) are rare and heterogeneous, necessitating improved prognostic tools to optimize patient management.

Objective

To evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in distinguishing between benign and malignant SGTs, identifying tumor stage, and predicting survival and adverse events.

Design

Systematic review conducted according to PRISMA guidelines.

Setting

Published clinical studies from tertiary care centers and academic hospitals globally, retrieved from electronic databases (PubMed/MEDLINE, Embase, and Cochrane Library).

Participants

Included studies focused on adult and pediatric patients with histologically-confirmed SGTs. Eligibility criteria encompassed all original research articles reporting NLR values related to diagnosis or prognosis of SGTs.

Exposure

The exposure of interest was the NLR, evaluated pretreatment in relation to tumor type (benign vs malignant), tumor stage, survival, and adverse treatment outcomes.

Main Outcome Measures

Primary outcome: prognostic performance of NLR regarding overall survival and disease stage.

Results

Seventeen original studies were included, with a median cohort size of 123 patients (range: 20-1989). The mean NLR was 2.86 for distinguishing benign versus malignant SGTs, 2.23 for early-stage versus late-stage malignancy, and 3.62 across different malignant histologic subtypes. An NLR below the cutoff value of 2.51 was significantly associated with improved overall survival (P < .05). A higher cutoff of 3.95 correlated with the presence or absence of grade ≥3 adverse events (P < .05).

Conclusions

NLR shows promise as a cost-effective, noninvasive biomarker to stratify malignancy risk, assess tumor stage, and predict prognosis and treatment-related toxicity in both adult and pediatric SGT populations.

Relevance

These findings support the integration of NLR into routine pretreatment evaluation protocols for SGTs. Future prospective, multicenter studies are necessary to validate standardized cutoff values for clinical use and to further investigate its role in personalized treatment strategies.

Graphical Abstract

Keywords

neutrophils-lymphocyte ratio salivary gland neoplasms immunology inflammatory markers

Key Messages

A low neutrophil-to-lymphocyte ratio (NLR) is associated with improved overall survival in patients with salivary gland tumors.

NLR is a simple, cost-effective prognostic biomarker that can help distinguish between benign and malignant salivary tumors.

Further studies are needed to define standardized NLR cutoff values for clinical application.

Introduction

Salivary gland tumors (SGTs) are infrequent, comprising approximately 3% to 10% of all head and neck tumors and 0.5% of total malignancies, with an annual incidence of 0.5 to 2 patients per 100,000 individuals.^1-3 Despite their rarity, SGTs form a dynamically-evolving category of neoplasms, encompassing 15 benign and 21 malignant epithelial subtypes according to the 5th edition of the World Health Organization Classification of Head and Neck Tumors.⁴ Most of these subtypes share analogous histologic and clinical features, posing diagnostic and therapeutic challenges for clinicians.

The primary means of preoperative diagnosis are fine-needle aspiration (FNA) biopsy and radiographic imaging, including ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT). Due to the relative rarity of SGTs, FNA demands an experienced cytopathologist for precise diagnosis. The sensitivity and specificity of FNA range from 0.74 to 0.88 and 0.87 to 0.98, respectively—higher for benign lesions and lower for malignant tumors.^5-7 Accordingly, the pivotal step in SGT management is precise differentiation between nonneoplastic versus neoplastic, benign versus malignant, and low-grade versus high-grade tumors in order to optimally treat and guide surgery.

Malignant SGT, constituting up to 20% of overall SGTs, exhibit distinctive management strategies compared with their benign counterparts. The standard approach involves maximally-tolerated surgical resection, followed by adjuvant radiotherapy and, in some cases, chemotherapy or immunotherapy, depending on histological and molecular features.⁸ Limitations in costs and technological infrastructure have hindered the widespread use of tumor-distinguishing biomarkers in this clinical context, necessitating further investigation to identify prognostic biomarkers, particularly for immunotherapy in malignant SGTs.⁹

Various outcomes, such as distant metastasis-free survival (DMFS), have demonstrated correlations with the clinicopathological characteristics of SGTs. Identifying patients with unfavorable outcomes, such as poor DMFS, aids in selecting cases where outcomes could potentially improve with adjuvant therapy.¹⁰ A prognostic biomarker thus becomes a cornerstone for optimal SGT management.

Previous studies have identified the neutrophil-lymphocyte ratio (NLR)—which is basically the division of the neutrophil count measured in peripheral blood by the lymphocyte count—as a biomarker for systemic inflammation,¹¹ with higher NLR indicating a more inflammatory environment that may favor tumor progression, and metastasis.^12,13 Elevated NLR is associated with poorer outcomes in various cancers, as it suggests enhanced neutrophil activation and a suppressed lymphocyte response, impairing the immune system’s ability to target tumor cells effectively. Studies, such as Templeton et al, show that a higher NLR correlates with reduced survival in solid tumors.¹⁴ Furthermore, NLR may serve as an inflammatory marker to differentiate benign and malignant laryngeal lesions.¹⁵ Although NLR is a cost-effective and easily-accessible marker, it is influenced by treatment, disease progression, and other inflam matory conditions, requiring careful interpretation in clinical practice. NLR’s potential as a prognostic tool is valuable, but its use should be context-dependent.

In this systematic review, we systematically review literature on the role of NLR in SGTs, encompassing its significance in subtype determination, predictive value for treatment response, and correlation with clinical outcomes.

Methods

A comprehensive systematic review of the existing literature was conducted to identify case series involving patients diagnosed with SGTs and reported NLR. The methodology was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the PICO strategy as follows: (P) Patients were individuals with SGT, (I) Intervention was the NLR assessment, (C) Comparison between malignant versus benign SGTs, and (O) Outcome was the correlation with prognosis.¹⁶

The search strategy was based on the PubMed, Embase, and Cochrane databases performed in April 2025. The search query included variations of NLR and SGT terms: ([neutrophils to lymphocytes ratio] OR [Neutrophil/lymphocyte ratio]) AND ([salivary gland tumor] OR [salivary gland malignancy] OR [salivary gland carcinoma] OR [adenoid cystic carcinoma] OR [mucoepidermoid carcinoma] OR [salivary adenocarcinoma]). All identified publications underwent rigorous title and abstract screening by S.E.Z., S.H., and R.B., and the reference lists of eligible publications were scrutinized to unveil additional pertinent studies.

Inclusion criteria for the systematic review dictated that articles must be full-text, available in English, with a confirmed neoplasm in the salivary glands and a special investigation of NLR correlation with the histopathology class, the treatment modality, or the clinical outcome(s).

After selection, the following articles were excluded from the full-text analysis: those not involving human subjects; those not addressing the NLR and/or SGTs; those in which data specific to NLR and/or SGTs could not be extracted separately from other inflammatory markers or tumor sites, respectively; and clearly-duplicated articles. No age restriction was applied. A language restriction to English and French was implemented.

To facilitate a comprehensive review of articles, we established a standardized data extraction table. This table encompasses key variables, including patient age (categorized as adult or pediatric), tumor malignancy, salivary tumor location, T category (ranging from T0 to T4), and tumor overall staging (I-II defined as “early” and III-IV defined as “late” stages), following the 8th edition of the American Joint Committee on Cancer (AJCC) guidelines for Major Salivary Glands.¹⁷

We examined the significance of NLR in differentiating between malignant and benign tumors, as well as between early-stage and late-stage tumors. Adjuvant therapy details such as chemotherapy, radiotherapy, or immunotherapy were documented, along with NLR thresholds for tumor responsiveness and prognostic factors. We also considered NLR thresholds for the significance of prognostic factors and assessed the presence or absence of a significant difference between study groups based on sex and age composing a bias analysis. Risk of bias due to missing results was considered.

Subsequently, we condensed the information into more concise and reader-friendly tables derived from the main collection table, with a focus on highlighting the primary study objectives.

Due to the limited number of available articles on the topic, statistical analysis of the extracted data proved unfeasible.

Based on the range of NLR cutoff values reported across the included studies, and their documented associations with malignancy status, treatment response, and prognostic outcomes, a prediction tree was constructed. The process involved identifying the most-frequently-used and statistically-significant NLR cutoff, categorizing them by clinical, prognostic, or diagnostic relevance.

PROSPERO registration number was 1044342.

Results

Study Characteristics

In totality, data from 17 distinct original studies were collated for comprehensive analysis (PRISMA flow diagram in Figure 1), with the inclusive articles spanning publication dates from 2014 to 2025 (Table 1). The scrutinized articles comprised 15 retrospective^10,18-31 and 2 prospective studies.^8,9 Among them, 4 studies primarily examined the role of NLR in discriminating between different tumor types, while 9 studies assessed the predictive capacity of NLR for clinical outcomes. Additionally, 4 studies evaluated the impact of NLR on therapy response.

Figure 1.

Flow chart. Systematic review exploring NLR as a valuable prognostic tool in SGTs management conducted with PRISMA methodology performed in April 2025. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis; NLR, neutrophil-lymphocyte ratio; SGT, salivary gland tumor.

Table 1.

Study Characteristics.

First author	Year	Country	Study period	Study population	N	Study focus	Design	Other data
Yang	2025	China	2008-2014	Adults	310	Clinical outcomes	Retrospective	None
Feng	2023	China	2003-2020	Adults	162	Clinical outcomes	Retrospective	None
Lee	2023	USA	2016-2017	Adults	20	Therapy response	Retrospective	Clinical outcomes
Committeri	2023	Italy	2015-2022	Adults	117	Tumor discrimination	Retrospective	None
Yan	2022	China	2004-2020	Adults	418	Clinical outcomes	Retrospective	None
Abbate	2022	Italy	2011-2018	Adults	74	Clinical outcomes	Retrospective	None
Barcellini	2022	Italy	2015-2021	Adults	49	Therapy response	Retrospective	Clinical outcomes
Pan	2022	USA	2015-2021	Adults	25	Therapy response	Prospective	Clinical outcomes
Abbate	2021	Italy	2016-2020	Adults	328	Tumor discrimination	Retrospective	None
Gao	2020	China	1991-2018	Pediatric	88	Clinical outcomes	Retrospective	Tumor discrimination
Niwa	2020	Japan	NR	Adults	24	Therapy response	Prospective	Clinical outcomes
Kuzucu	2019	Turkey	2010-2018	Adults	228	Tumor discrimination	Retrospective	None
Seng	2019	China	1995-2016	Pediatric	123	Clinical outcomes	Retrospective	Tumor discrimination
Brkic	2018	Austria	1996-2016	Adults	31	Clinical outcomes	Retrospective	None
Damar	2016	Turkey	2010-2015	Adults	198	Tumor discrimination	Retrospective	None
Kawakita	2016	Japan	NR	Adults	140	Clinical outcomes	Retrospective	None
Ma	2014	China	1989-2011	Adults	1989	Clinical outcomes	Retrospective	None

Most of the investigations (15 out of 17) were predominantly oriented toward adults. Studies exploring the prognostic significance of NLR in SGTs exhibited a differential contribution when considering the country of publication.

The median cohort size across the studies was 123, with participant numbers ranging from 20 to 1989, reflecting a considerable variability in sample sizes. Three pillars of SGTs management were identified: tumor discrimination, treatment responsiveness, and clinical outcome prediction.

Impact of NLR on Diagnosis

Table 2 displays studies in which the discriminatory potential of NLR was assessed. The median number (range) of patients included per study with benign tumors and malignant tumors was 47 (28-123) and 103 (0-191), respectively. Among the 11 studies where tumor discrimination was either a primary or secondary aim, 4 demonstrated significant discriminatory capacity between malignant and benign SGTs.^21,24,26,29 Three studies exhibited significant discrimination between early-stage and late-stage malignant SGTs,^25,27,29 while only one study achieved significant discrimination among SGT subtypes based on a specific NLR value.²¹

Table 2.

Neutrophils-to-Lymphocytes Rates Discriminate Tumor Malignancy Status and Histological Subtype.

Reference	Malignant tumors (M)	Benign tumors (B)	Significant discrimination M/B	Significant discrimination early/late	Significant discrimination between histological subtypes	NLR M/B cutoff
Kuzucu et al	42	103	Yes	No	—	—
Damar et al	58	124	Yes	Yes^a	—	1.86
Committeri et al	28	89	Yes	—	Yes	3.62
Abbate et al	47	191	Yes	—	—	3.11
Seng et al^b	123	0	—	Yes	—	2.51
Gao et al^b	88	0	—	Yes	—	2.32

Abbreviation: NLR, neutrophils-to-lymphocytes ratio.

Parotid tumors only.

Pediatric population.

The mean NLR values for discriminating between benign and malignant SGTs, early-stage and late-stage malignant SGTs, and different SGT subtypes were 2.86, 2.23, and 3.62, respectively (Table 2).

Impact of Neutrophils-to-Lymphocytes Ratio on Prognosis

Table 3 summarizes the relationship between NLR values and various prognostic endpoints. Among the 11 studies evaluating NLR in relation to prognosis—as either a primary or secondary outcome—10 reported that a specific NLR cutoff was significantly associated with at least 1 clinical endpoint.^{8,19,20,22,23,25,27,28,30,31} Reported prognostic outcomes included recurrence-free survival (RFS), disease-specific survival (DSS), DMFS, overall survival (OS), disease-free survival (DFS), time-to-second recurrence, mortality rate, recurrence rate, multiple recurrence rate (MRR), progression-free survival (PFS), local control, metastasis-free survival, and objective response rate.

Table 3.

Relationship Between NLR Rates and Prognostic Factors.

Reference	Prognostic factor	Significant effect on prognosis	Prognosis NLR cutoff	NLR as an independent prediction factor
Yang et al^a	OS	No	1.65	No
Feng et al^a	OS	Yes	0.223	Yes
Lee et al	OS and PFS	Yes	5.0	Yes
Gao et al^b	RFS and DSS	Yes (RFS)	2.32	Yes
Yan et al	DMFS	No	2.45	No
Abbate et al	OS	Yes	3.95	—
Seng et al^b	RFS and DSS	Yes (both)	2.51	Yes (both)
Ma et al	OS	Yes	4.0	Yes
Brkic et al	OS, DFS, TTSR, MR, RR and MRR	Yes (MRR)	2.0	—
Niwa et al	OS, PFS	Yes (Both)	2.6 (OS), 5.9 (PFS)	—
Barcellini et al	DFS, LC, MFS, OS	Yes (DFS)	2.5	Yes (DFS)
Pan et al	ORR, PFS, OS	Yes (PFS, OS)	3.95	—
Kawakita et al	PFS, OS	Yes (OS)	2.5	—

Abbreviations: DFS, disease-free survival; DMFS, distant metastasis-free survival; DSS, disease-specific survival; LC, local control; MFS, metastasis-free survival; MR, mortality rate; MRR, multiple recurrence rate; NLR, neutrophils-to-lymphocytes ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RFS, recurrence-free survival; RR, recurrence rate; TTSR, time-to-second recurrence.

Adenoid cystic carcinoma only.

Pediatric population.

Among these, RFS, OS, DSS, MRR, PFS, and DFS were significantly impacted by NLR in the included studies. The mean cutoff value associated with a statistically-significant prognostic difference was 2.51 (range: 0.223-5.9). Four studies identified NLR as an independent prognostic factor for RFS, DSS, OS, or DFS.^23,25,27,31

Influence of NTL Ratio on Responsiveness to Therapy

Table 4 details the association between pretreatment NLR values and responsiveness to adjuvant therapies. Three types of therapies were investigated across 4 studies: immune checkpoint inhibitors [nivolumab (Bristol-Myers Squibb©, New York, NY, USA), pembrolizumab (Merck & Co©, Inc, Rahway, NJ, USA), and pembrolizumab with vorinostat (Merck & Co©, Inc)] and carbon ion radiotherapy (CIRT).^8,9,23 Specific NLR thresholds were found to correlate with treatment-related outcomes.

Table 4.

NLR Rates and Response to Adjuvant Therapy.

Reference	Treatment	Significant effect on treatment response	Treatment NLR cutoff
Lee et al	Pembrolizumab	Yes	—
Pan et al	Pembrolizumab and vorinostat	Yes (G ≥3AE)	3.95
Barcellini et al	CIRT	Yes (DFS)	2.5
Niwa et al	Nivolumab	Yes (OS, PFS)	2.6 (OS), 5.9 (PFS)

Abbreviations: CIRT, carbon ion radiotherapy; DFS, disease-free survival; G ≥3AE, grade ≥3 adverse events; NLR, neutrophils-to-lymphocytes ratio; OS, overall survival; PFS, progression-free survival.

An NLR cutoff of 3.95 significantly predicted the presence or absence of grade ≥3 adverse events.⁸ In addition, NLR values greater than 2.5 were associated with improved DFS, and cutoffs of 2.6 and 5.0 were significantly associated with OS and PFS, respectively.^8,19,20,23 These findings suggest that NLR may hold potential as a predictive biomarker for treatment response when measured prior to therapy initiation.

Sex and Age in Different Study Groups

Table 5 outlines the assessment of bias risk associated with patients’ sex and age, considering variations across different studies.

Table 5.

Risk of bias consideration in the included studies.

Bias	Taken into consideration	Not taken into consideration
Patients’ sex bias	Kuzucu et al, Damar et al, Barcellini et al, Abbate et al, Abbate et al,^a Lee et al, Feng et al, Yang et al	Committeri et al, Pan et al, Brkic et al, Kawakita et al
Patients’ age bias	Kuzuku et al, Damar et al, Barcellini et al. Kawakita et al, Lee et al, Feng et al, Yang et al	Committeri et al, Abbate et al, Pan et al, Brkic et al, Abbate et al
Age and sex influence the outcome	Yan et al, Abbate et al (Age), Feng et al (Age)
Age and sex did not influence the outcome	Seng et al, Gao et al, Ma et al, Niwa et al, Lee et al, Yang et al
Risk of bias due to missing results	Kuzucu et al, Damar et al, Barcellini et al, Abbate et al, Abbate et al,^a Lee et al, Feng et al, Yang et al Committeri et al, Pan et al,⁹ Brkic et al, Kawakita et al	—

For the benign and malignant salivary glands tumors but not the healthy controls.

Several investigations incorporated a conscientious evaluation of the potential impact of age and sex disparities on the observed results, while others omitted such considerations.

The impact of age on outcomes was demonstrated to be significant in Yan et al,¹⁰ Abbate et al,²⁴ and Feng et al.¹⁹ Sex was also significant for Yan et al.¹⁰ Conversely, in studies by Seng et al,²⁷ Gao et al,²⁵ Ma et al,³¹ Niwa et al,⁸ and Lee et al,²⁰ Yang et al,¹⁸ age and sex did significantly influence study outcomes.

Implementation of NLR Rate in Patient Treatment Assessment

Figure 2 illustrates an NLR-based tree designed to predict tumor malignancy, therapy responsiveness, and clinical outcomes based on specific NLR values, in the parotid gland.

Figure 2.

NLR-based predictive tree for malignancy in parotid salivary gland tumors. NLR-based treatment and outcome assessment in patients with SGTs. NLR, neutrophils-to-lymphocytes ratio; OS, overall survival; PFS, progression-free survival; G ≥3AE, grade 3 and greater adverse events; P&V, pembrolizumab and vorinostat; SGT, salivary gland tumor.

When managing SGTs, an initial differentiation is made based on the anatomical location, particularly identifying whether it is a parotid tumor. If the tumor is parotid in origin, attention is then directed to the NLR value. For cases where NLR is <1.86, the parotid tumor is deemed likely benign or early-stage malignant, signifying a favorable prognosis and a positive response to therapy. Conversely, if the NLR value exceeds 1.86, the parotid tumor is indicative of a high-grade malignant nature, necessitating prognosis and treatment responsiveness assessment contingent upon the precise NLR value (refer to Tables 3 and 4).

In cases where the SGT pertains to glands other than the parotid, a parallel approach is adopted. If the NLR value is <3.62, as per Committeri et al’s²¹ findings (study-specific tumor discrimination NLR values summarized in Table 2), the tumor is likely benign, associated with favorable OS and PFS, and devoid of grade 3 adverse events related to pembrolizumab and vorinostat (P&V) administration. Other prognostic factors and responsiveness to alternative therapies are contingent on the NLR value and the specific study parameters. Conversely, if the NLR exceeds 3.62, the tumor is likely-high-grade malignant, portending a less favorable prognosis, except for OS and PFS, which remain dependent on the specific NLR level. Additionally, a diminished responsiveness to therapy is anticipated in such cases.

For pediatric malignancies, an NLR value below 2.32 strongly indicates a low-grade histology with favorable RFS and DSS. However, the prognostic implications and discrimination between early and late grades at higher NLR values are contingent upon the specific study under consideration (Tables 1 and 2).

Discussion

This is the first PRISMA-based systematic review exploring the potential of NLR as a valuable prognostic tool in SGT management. This review underscores the utility of NLR in discerning the malignancy, stage, and subtype of SGTs, revealing mean cutoff values of 2.86, 2.23, and 3.62, respectively. These findings resonate with prior investigations focused on the applicability of NLR in analogous contexts for other head and neck tumors.

In 2025, Migliorelli et al³² highlighted in a scoping review the potential of inflammatory biomarkers—particularly NLR—in improving diagnosis and prognosis of malignant SGT. Elevated NLR, along with other markers such as the platelet-to-lymphocyte ratio, the systemic immune-inflammation index, and the systemic inflammation response index, has been associated with malignancy and poor clinical outcomes in both adults and children. However, their clinical application remains limited due to the lack of standardized cutoff values and the fact that the authors did not follow a systematic review methodology. To date, only 3 systematic reviews have explored the prognostic value of the NLR in head and neck carcinomas, and none have provided dedicated insight into SGTs. Mascarella et al³³ specifically excluded SGTs from their analysis, but reported that elevated NLR was associated with poorer OS in patients with head and neck squamous cell carcinomas. Similarly, Kumarasamy et al³⁴ did not include SGTs in their dataset, although this exclusion was not explicitly stated in their methodology. Takenaka et al³⁵ did mention SGTs alongside head and neck squamous cell carcinomas but ultimately included no SGT-specific studies in their final review. While these studies were valuable in establishing the prognostic relevance of NLR in Head & Neck Squamous Cell Carcinoma (HNSCC), their limited or absent focus on SGTs underscores a significant gap in the literature. This gap reinforces the relevance and necessity of the present systematic review, which is, to our knowledge, the first to exclusively investigate the role of NLR in the context of SGTs.

Beyond reviews and meta-analyses, Seretis et al¹⁷ observed a markedly-higher mean NLR in patients afflicted with papillary thyroid carcinoma (PTC) than in those with benign goiter. This hints at the prospect of using a high NLR as a marker to identify coexisting PTC in benign goiters. Kum et al¹⁵ identified an elevated NLR in laryngeal squamous cell carcinomas in contrast to benign and premalignant laryngeal lesions, proposing NLR as a valuable inflammatory marker for differentiating between benign and malignant laryngeal lesions. Liu et al³⁶ put forth the notion that a higher mean NLR (2.28 for PTC vs 1.98 for nodular goiter) and a lower lymphocyte count could serve as a valuable prognostic tool, aiding in the stratification of patients with thyroid goiters and the identification of older patients at risk of PTC. These collective findings corroborate the broader applicability of NLR as an informative marker in SGTs.

Subsequently, we established a correlation between NLR and several pivotal clinical factors, RFS, OS, DSS, MRR, PFS, and DFS. These findings are consistent with previous studies across diverse tumor types, extending beyond the head and neck region.^37-40 Consistently, a meta-analysis³⁸ involving 5475 cases of head and neck cancers underscored a shorter DFS (HR: 2.18, 95% CI: 1.46-3.24; P < .001) and an increased risk of mortality (HR: 1.84, 95% CI: 1.53-2.23; P < .001) in cases characterized by higher NLR values. Another meta-analysis,³⁵ incorporating 19 studies encompassing 3770 patients with head and neck cancer, concurred, demonstrating also that elevated NLR is associated with shorter DFS. NLR was also recognized as an independent predictive factor for RFS, DSS, OS, and DFS.

A widely-acknowledged consensus indicates that the systemic inflammatory response plays a pivotal role in facilitating tumor metastasis, microvascular regeneration, and the proliferation of tumor cells.^41,42 Additionally, NLR stands out as a reliable and precise inflammatory marker. Elevated NLR has been consistently linked to significantly-poorer survival outcomes in various solid cancers.^43,44 These encompass but are not limited to head and neck squamous cell carcinoma, breast cancer, and prostate cancer. Notably, recent research has extended this association with SGTs. This systematic review gathers the previously-published studies investigating the implication of NLR in the management of SGTs in adult and pediatric populations.

NLR emerges as a valuable predictor for assessing responsiveness to adjuvant therapies, notably exhibiting significant associations with nivolumab (Bristol-Myers Squibb©), pembrolizumab (Merck & Co©, Inc), P&V (Merck & Co©, Inc) and CIRT. The delineated NLR cutoff values, signifying significant associations with grade 3 adverse events or higher, as well as DFS, OS, and PFS, were identified as 3.95, 2.5, 2.6, and 5.0, respectively. Concordant findings in the context of other head and neck tumors bolster the broader relevance of these observations. In 2018, Foster et al⁴⁵ examined a cohort of 114 patients with metastatic head and neck cancer undergoing anti-PD-1 therapy, revealing an inverse correlation between high baseline NLR and both OS and PFS. Similarly, in a small retrospective review, Nishikawa et al⁴⁶ observed that elevated baseline percent neutrophils and diminished percent lymphocytes were linked to an unfavorable prognosis in the treatment of platinum-refractory recurrent/metastatic head and neck tumors with nivolumab.

Furthermore, the associated direct and indirect costs related to the diagnosis of and treatment for these tumors are notably substantial. Jacobson et al underscored this financial burden, revealing that the overall cost for salivary gland cancers in the United States ranges from approximately $96,520 to $153,892 per patient, a figure linked to the intricacies of treatment.⁴⁷ Considering this economic burden, the development of a prognostic system characterized by rapidity and cost-effectiveness is needed. Such a system is essential to efficiently stratify patients based on their risk profile, thus facilitating optimal clinical decision-making and resource allocation. These insights prompt a compelling suggestion for prospective investigations into the potential role of NLR as a cost-effective biomarker. Specifically, such studies could focus on its utility in tumor discrimination, grading, and, notably, for enhanced pretreatment risk stratification in patients diagnosed with SGTs.

This study endeavors to formulate a comprehensive management tree aimed at providing valuable guidance to clinicians managing SGTs. The observed variations in NLR cutoff values can be ascribed to the inherent heterogeneity within the cohorts of each study, particularly concerning the histological subtypes of the tumors. However, it is essential to acknowledge that these differences might also stem from unaddressed confounding factors present in these studies.

These results are insufficient for altering surgical decision-making. FNA cytology and imaging remain the standard tools for the diagnostic evaluation of SGTs. However, both techniques present limitations. FNA cytology can yield inconclusive or nonspecific results, especially when differentiating between low-grade malignancies and benign lesions. Similarly, imaging lacks sufficient resolution for precise histological characterization.^5-7 In certain cases, surgical excision is pursued precisely because of this diagnostic uncertainty. In this context, the NLR may offer complementary diagnostic and prognostic value. Its accessibility, low cost, and association with tumor behavior suggest potential utility as a noninvasive adjunct to better inform preoperative risk assessment—particularly without disrupting current clinical workflows. The present findings underscore the need for further prospective studies to explore the integration of NLR into routine practice.

Conclusion

In the first systematic review of NLR in SGTs, NLR was efficacious in children and adults as a discriminative tool for distinguishing between malignant versus benign tumors, as well as early-stage versus late-stage neoplasms. Furthermore, NLR emerged as a valuable predictor of prognosis, both in the presence and in the absence of adjuvant therapy. The implications of our findings support the integration of NLR assessment in the clinical landscape, potentially enhancing the precision of diagnosis and prognosis of SGTs.

Footnotes

Acknowledgements

None.

Author Note

This manuscript has been reviewed by US academic medical editorial staff.

Author Contributions

Saïf Eddine Zaidi: Substantial contributions to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; drafting the work; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Stéphane Hans: Substantial contributions to the conception or design of the work; the interpretation of data for the work; revising the paper critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Kevin J. Contrera: Substantial contributions to the conception or design of the work; the interpretation of data for the work; revising the paper critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Jose S. Zevallos: Substantial contributions to the conception or design of the work; the interpretation of data for the work; revising the paper critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Robin Baudouin: Substantial contributions to the conception or design of the work; the interpretation of data for the work; revising the paper critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Research Involving Participants and/or Animals

IRB approval was not required for this study.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Robin Baudouin

References

VSH

Chan

JYW

Tsang

RKY

Wei

. Review of salivary gland neoplasms. ISRN Otolaryngol. 2012;2012:872982.

Ansari

MH.

Salivary gland tumors in an Iranian population: a retrospective study of 130 cases. J Oral Maxillofac Surg. 2007;65:2187-2194.

Jones

TM.

Tumour-infiltrating lymphocytes in the risk stratification of squamous cell carcinoma of the head and neck. Br J Cancer. 2014;110:269-270.

Skalova

Mehrotra

Skalova

A HM

Mehrotra

, eds. WHO Classification of Tumours Editorial Board. In: Head and Neck Tumours. 5th ed.; 2022. Accessed May 1, 2025. https://tumourclassification.iarc.who.int/chapters/52

Peravali

Bhat

HHK

Upadya

Agarwal

Naag

Salivary gland tumors: a diagnostic dilemma!

J Maxillofac Oral Surg. 2015;14:438-442.

Ronchi

Montella

Zito Marino

, et al Diagnostic accuracy of FNA cytology for diagnosis of salivary gland tumors in pediatric patients. Cancer Cytopathol. 2019;127:529-538.

Dell’Aversana Orabona

Salzano

Abbate

, et al Malignant tumours of the parotid gland: management of the neck (including the clinically negative neck) and a literature review. Br J Oral Maxillofac Surg. 2021;59:665-671.

Niwa

Kawakita

Nagao

, et al Multicentre, retrospective study of the efficacy and safety of nivolumab for recurrent and metastatic salivary gland carcinoma. Sci Rep. 2020;10:16988.

Pan

Voutsinas

, et al Neutrophil to lymphocyte ratio and peripheral blood biomarkers correlate with survival outcomes but not response among head and neck and salivary cancer treated with pembrolizumab and vorinostat. Head Neck. 2023;45:391-397.

10.

Yan

Shen

A nomogram involving immune-inflammation index for predicting distant metastasis-free survival of major salivary gland carcinoma following postoperative radiotherapy. Cancer Med. 2023;12:2772-2781.

11.

Ozdemir

Akin

Sucullu

Balta

Yucel

Pretreatment neutrophil/lymphocyte ratio as a prognostic aid in colorectal cancer. Asian Pac J Cancer Prev. 2014;15:2647-2650.

12.

Coussens

Werb

Inflammation and cancer. Nature. 2002;420:860-867.

13.

Kao

SCH

Pavlakis

Harvie

, et al High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res. 2010;16:5805-5813.

14.

Templeton

McNamara

Šeruga

, 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.

15.

Kum

Ozcan

Baklaci

, et al Elevated neutrophil-to-lymphocyte ratio in squamous cell carcinoma of larynx compared to benign and precancerous laryngeal lesions. Asian Pac J Cancer Prev. 2014;15:7351-7355.

16.

Moher

Liberati

Tetzlaff

Altman

Group

TP.

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

17.

Amin

Greene

Edge

, et al The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67:93-99.

18.

Yang

Wang

, et al Preoperative platelet-to-lymphocyte ratio and lymphocyte-to-monocyte ratio predict poor prognosis in patients diagnosed with salivary gland adenoid cystic carcinoma. J Craniomaxillofac Surg. 2025;53:970-976.

19.

Feng

Sun

Huang

Zhang

Chen

Deng

A low systemic inflammatory response index is associated with improved survival in adenoid cystic carcinoma patients. J Oral Maxillofac Surg. 2024;82:999-1007.

20.

Lee

Truong

, et al The neutrophil-to-lymphocyte ratio in salivary gland cancers treated with pembrolizumab. Head Neck. 2024;46:129-137.

21.

Committeri

Barone

Salzano

, et al Support tools in the differential diagnosis of salivary gland tumors through inflammatory biomarkers and radiomics metrics: a preliminary study. Cancers (Basel). 2023;15:1876.

22.

Abbate

Barone

Troise

, et al The combination of inflammatory biomarkers as prognostic indicator in salivary gland malignancy. Cancers (Basel). 2022;14:5934.

23.

Barcellini

Fontana

Filippini

, et al Exploring the role of neutrophil-to-lymphocyte ratio and blood chemistry in head and neck adenoid cystic carcinomas treated with carbon ion radiotherapy. Radiother Oncol. 2022;177:143-151.

24.

Abbate

Orabona

GDA

Barone

, et al Relevance of inflammatory biomarkers in salivary gland cancers management. Eurasian J Med Oncol. 2021;5:311-317.

25.

Gao

Sun

Significance of pretreatment neutrophil-to-lymphocyte ratio in mucoepidermoid carcinoma of pediatrics: a multicenter study. Front Pediatr. 2020;8:96.

26.

Kuzucu

Güler

Kum

Baklacı

Özcan

. Increased neutrophil lymphocyte ratio and platelet lymphocyte ratio in malignant parotid tumors. Braz J Otorhinolaryngol. 2020;86:105-110.

27.

Seng

Fang

Liu

Prognostic value of the pretreatment neutrophil-to-lymphocyte ratio in pediatric parotid cancer. Front Pediatr. 2019;7:207.

28.

Brkic

Kadletz

Jank

, et al Pretreatment assessment of hematologic and inflammatory markers in adenoid cystic carcinoma: neutrophil/lymphocyte ratio is associated with multiple recurrences. Oral Surg Oral Med Oral Pathol Oral Radiol. 2019;127:408-416.

29.

Damar

Dinç

Erdem

, et al Pretreatment neutrophil-lymphocyte ratio in salivary gland tumors is associated with malignancy. Otolaryngol Head Neck Surg. 2016;155:988-996.

30.

Kawakita

Tada

Imanishi

, et al Impact of hematological inflammatory markers on clinical outcome in patients with salivary duct carcinoma: a multi-institutional study in Japan. Oncotarget. 2017;8:1083-1091.

31.

Lin

Wang

, et al Primary lymphoepithelioma-like carcinoma of salivary gland: sixty-nine cases with long-term follow-up. Head Neck. 2014;36:1305-1312.

32.

Migliorelli

Manuelli

Ciorba

Stomeo

Pelucchi

Bianchini

The role of blood inflammatory markers in salivary gland carcinoma: a scoping review. J Clin Med. 2025;14:1762.

33.

Mascarella

Mannard

Silva

Zeitouni

Neutrophil-to-lymphocyte ratio in head and neck cancer prognosis: a systematic review and meta-analysis. Head Neck. 2018;40:1091-1100.

34.

Kumarasamy

Tiwary

Sunil

, et al Prognostic utility of platelet–lymphocyte ratio, neutrophil–lymphocyte ratio and monocyte–lymphocyte ratio in head and neck cancers: a detailed PRISMA compliant systematic review and meta-analysis. Cancers. 2021;13:4166.

35.

Takenaka

Oya

Kitamiura

, et al Prognostic role of neutrophil-to-lymphocyte ratio in head and neck cancer: a meta-analysis. Head Neck. 2018;40:647-655.

36.

Liu

Fan

, et al The neutrophil-to-lymphocyte ratio correlates with age in patients with papillary thyroid carcinoma. ORL J Otorhinolaryngol Relat Spec. 2015;77:109-116.

37.

Aneja

Ghossein

Katabi

Salivary gland epithelial neoplasms in pediatric population: a single-institute experience with a focus on the histologic spectrum and clinical outcome. Hum Pathol. 2017;67:37-44.

38.

Ashok

Keener

Rubenstein

, et al Consequences of interleukin 1β-triggered chronic inflammation in the mouse prostate gland: Altered architecture associated with prolonged CD4+ infiltration mimics human proliferative inflammatory atrophy. Prostate. 2019;79:732-745.

39.

Peinado

Lavotshkin

Lyden

The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol. 2011;21:139-146.

40.

Kano

Homma

Hatakeyama

, et al Pretreatment lymphocyte-to-monocyte ratio as an independent prognostic factor for head and neck cancer. Head Neck. 2017;39:247-253.

41.

Xiong

Dong

Cheng

Neutrophils in cancer carcinogenesis and metastasis. J Hematol Oncol. 2021;14:173.

42.

Wang

Yan

, et al Pretreatment neutrophil to lymphocyte ratio in determining the prognosis of head and neck cancer: a meta-analysis. BMC Cancer. 2018;18:383.

43.

Howard

Kanetsky

Egan

KM.

Exploring the prognostic value of the neutrophil-to-lymphocyte ratio in cancer. Sci Rep. 2019;9:19673.

44.

Price

Mistry

Betts

, et al Pretreatment lymphocyte count predicts benefit from concurrent chemotherapy with radiotherapy in oropharyngeal cancer. J Clin Oncol. 2022;40:2203-2212.

45.

Foster

Kochanny

Khattri

, et al Association of a baseline neutrophil-to-lymphocyte ratio (NLR) with progression-free and overall survival in head and neck cancer patients receiving anti-PD-1 therapy. J Clin Oncol. 2018;36:6038.

46.

Nishikawa

Suzuki

Koide

, et al Prognostic markers in head and neck cancer patients treated with nivolumab. Cancers (Basel). 2018;10:466.

47.

Jacobson

Epstein

Eichmiller

, et al The cost burden of oral, oral pharyngeal, and salivary gland cancers in three groups: commercial insurance, Medicare, and Medicaid. Head Neck Oncol. 2012;4:15.

Prognostic Significance of Neutrophil-Lymphocyte Ratio in Salivary Gland Neoplasms: A Systematic Review

Abstract

Importance

Objective

Design

Setting

Participants

Exposure

Main Outcome Measures

Results

Conclusions

Relevance

Keywords

Key Messages

Introduction

Methods

Results

Study Characteristics

Impact of NLR on Diagnosis

Impact of Neutrophils-to-Lymphocytes Ratio on Prognosis

Influence of NTL Ratio on Responsiveness to Therapy

Sex and Age in Different Study Groups

Implementation of NLR Rate in Patient Treatment Assessment

Discussion

Conclusion

Footnotes

Acknowledgements

Author Note

Author Contributions

Research Involving Participants and/or Animals

Declaration of Conflicting Interests

Funding

ORCID iD

References