Diagnostic accuracy of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in the differential diagnosis of adrenocortical carcinoma: a retrospective study

Introduction

Adrenocortical carcinoma (ACC) is one of the most aggressive malignancies, with a median overall survival of about 3.21 years at the time of diagnosis (1). A functional hormonal hypersecretion affecting 40–60% of patients with ACC may be identified by a number of distinct clinical manifestations, such as Cushing’s syndrome (CS), feminization/masculinization, and hyperaldosteronism (2,3). As ACC is a highly rare endocrine malignancy with an annual incidence rate of 0.7–2.0 cases/million (4,5), most medical facilities have limited experience with this condition. Accurate preoperative diagnosis is crucial for referring the patients to a specialized ACC multidisciplinary center to improve the prognosis (6). This is particularly important as even after complete resection, ACC has a high recurrence and mortality rate, necessitating effective adjuvant therapies (7). Recent advances in molecular profiling have also uncovered distinct molecular subtypes of ACC, providing deeper insights into tumor biology (8). Therefore, identifying widely available and cost-effective clinical indicators for the preoperative diagnosis of ACC is of considerable clinical value.

Inflammation plays a vital role at different stages of tumor growth. Systemic tumor-related inflammation has been reported to be related to the prognosis of patients with a variety of solid malignancies (9). Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), in addition to novel markers such as C-reactive protein and interleukin-6 (IL-6), are widely investigated for their utility in tumors (10-13). Neutrophils and lymphocytes have distinct roles in cancer-related inflammation. Patients with tumors often exhibit decreased lymphocyte counts, which can result in a diminished immune response and an elevated risk of tumor recurrence. Conversely, elevated neutrophil counts may foster tumorigenesis and tumor progression through the secretion of angiogenic and growth factors. Consequently, both neutrophil and lymphocyte counts are recognized as valuable prognostic indicators. The NLR is advantageous as it offers greater stability and less variability across different clinical settings and studies. Elevated platelet counts in patients with cancer may facilitate tumor progression via enhanced angiogenesis and the synthesis of adhesion molecules (14). The PLR, akin to the NLR, is not only clinically convenient but also exhibits enhanced stability and reduced heterogeneity. An increased PLR has been correlated with poorer outcomes in patients with several types of cancer. Unlike molecular diagnostic tests, the NLR and PLR are cost-effective and readily accessible, and thus are suitable for use in studies focused on inflammation and immunology across patient populations.

The diagnostic efficacy of NLR and PLR for ACC has been preliminarily investigated. Mochizuki et al. (15) reported that malignant adrenal tumors exhibited elevated NLR as compared to benign tumors. Furthermore, patients with ACC and an elevated NLR have significantly poorer survival rates than those with a lower NLR. We hypothesized that NLR and PLR, as markers of systemic inflammation, could serve as accessible and cost-effective adjuncts to imaging features like tumor size for the preoperative diagnosis of ACC. Given the variability in the NLR and PLR reference values across different ethnicities, the objective of this study was to determine the utility of these ratios in diagnosing ACC within the Chinese population. We present this article in accordance with the STARD reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-727/rc).

Methods

Patients

A total of 578 patients were included in this study, including 45 patients with pathologically confirmed ACC and 533 patients with non-ACC tumors. The data of inpatients who were diagnosed with ACC in The First Affiliated Hospital of Xi’an Jiaotong University from January 1985 to December 2020 were retrospectively collected. Moreover, data from inpatients diagnosed with non-ACC tumors—including pheochromocytoma, CS, aldosteronoma, and nonfunctioning adrenocortical adenoma (ACA)—at The First Affiliated Hospital of Xi’an Jiaotong University between January 2018 and December 2020 were included as the control group. Due to the retrospective and exploratory nature of this study on a rare disease, a formal sample size calculation was not performed prior to data collection. The study aimed to include all eligible cases within the specified timeframe to maximize statistical power. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2021LSK-153). The requirement for informed consent was waived due to the retrospective nature of the study.

Data collection

Demographic, clinical, laboratory, and pathological data were retrospectively collected. The NLR and PLR were calculated with the use of data from preoperative routine blood tests. None of the patients had an active infection, sepsis, nor coexisting inflammatory conditions such as hematological or autoimmune disorders.

Statistical analysis

Statistical analysis was performed with SPSS version 23.0 software (IBM Corp., Armonk, NY, USA). Normally distributed measurement data were presented as mean ± standard deviation (x±SD) and were compared between the two groups with the t-test. Nonnormally distributed data were expressed as the median and interquartile range [M (Q1, Q3)], and comparisons between groups for two independent samples were performed with the Mann-Whitney U test. For multiple group comparisons, the Kruskal-Wallis test was applied, followed by pairwise comparisons. Categorical data were expressed as the frequency (percentage), and group comparisons were conducted via the Chi-squared test or the Fisher exact test, as appropriate. The critical value was determined from the receiver operating characteristic (ROC) curve, and binary logistic regression analysis was conducted with this critical value to further investigate the influencing factors. GraphPad Prism software version 9 (Dotmatics, Boston, MA, USA) was employed for graphical representation. All P values were two-sided, and a value of less than 0.05 (P<0.05) was considered to indicate statistical significance. The area under the curve (AUC) of ≥0.70 was considered to indicate potentially useful diagnostic performance for clinical application, while values below this threshold would suggest limited utility.

Results

Baseline characteristics of patients

This study included 45 patients diagnosed with ACC, among whom 11 were diagnosed with CS. For ACC patients, 1 (2.22%), 8 (17.78%), 22 (48.89%), and 14 (31.11%) had European Network for the Study of Adrenal Tumors stage I, II, III, and IV disease, respectively. An additional 533 patients with non-ACC diseases were also enrolled, consisting of 23 patients (4.32%) with CS due to ACA, 80 (15.01%) with pheochromocytoma, 148 (27.77%) with aldosteronoma, and 282 (52.91%) with nonfunctioning ACA. Table 1 provides a summary of the basic clinical features of patients with ACC and four other non-ACC diseases.

NLR and PLR for the differential diagnosis of ACC from non-ACC diseases

As shown in Table 1, the NLR was significantly higher in patients with ACC than in those without ACC [4.28 (2.58–5.71) vs. 2.43 (1.76–3.38), P<0.001]. Similarly, the median PLR was significantly elevated in ACC patients [182.72 (142.55–211.45) vs. 135.26 (106.77–178.97), P<0.001] as compared to the non-ACC patients. A detailed comparison of the NLR and PLR between different subgroups (ACA with CS, aldosteronoma, nonfunctioning ACA, and pheochromocytoma) is summarized in Tables 2,3, respectively. Of note, ACA with CS and ACC did not show significant differences in terms of NLR [4.85 (3.94–6.75) vs. 4.28 (2.58–5.71)] or PLR [169.52 (137.28–303.10) vs. 182.72 (142.55–211.45), P>0.99], and thus neither NLR nor PLR can facilitate differential diagnosis (Tables 2,3).

To investigate the effectiveness of NLR, PLR, and tumor size in detecting ACC, an ROC curve was constructed based on the significant differences observed between ACC and non-ACC patients. As shown in Figure 1, the areas under the curve were 0.742 [95% confidence interval (CI): 0.67–0.82, P<0.001] for NLR, 0.696 (95% CI: 0.63–0.77, P<0.001) for PLR, and 0.986 (95% CI: 0.98–1.00, P<0.001) for tumor size (Figure 1). Table 4 provides different cutoff values for these parameters, along with their corresponding sensitivity and specificity for facilitating the diagnosis of ACC. The cutoff values of the NLR previously reported by Mochizuki et al. (15) and Ma et al. (16) were also evaluated and are listed in Table 4. After adjustments were made for gender and tumor location, the independent factors for diagnosing ACC were identified to be NLR (>3) [odds ratio (OR) =2.819, P=0.04], PLR (>140) (OR =3.238, P=0.03), and tumor size (>48 mm) (OR =565.600, P<0.001).

Figure 1 ROC curves for the NLR, PLR, and tumor size in differentiating ACC from non-ACC diseases. ACC, adrenocortical carcinoma; AUC, area under the curve; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; ROC, receiver operating characteristic.

Special circumstances

Patients with CS

The demographic and clinical characteristics of patients with CS caused by either ACC or ACA are summarized in Table 5. There were no significant differences in gender, age, or tumor location; however, the median tumor size in patients with ACC [76.00 (51.00–131.00) vs. 27.00 (24.00–30.00), P<0.001] was significantly larger than that in the patients with ACA. In terms of clinical and laboratory parameters, fasting blood glucose and systolic and diastolic blood pressure were similar between the two groups, while total cholesterol was notably lower in patients with ACC than in those with ACA (4.61±1.23 vs. 5.71±1.35 mmol/L, P=0.03). Patients with ACC had a higher level of plasma cortisol (both at 8 AM and 4 PM) than those with ACA (P=0.002). There were no significant differences in patients with ACC and ACA in terms of NLR [5.07 (4.38–7.35) vs. 4.85 (3.94–6.75), P=0.90] nor PLR [193.83 (165.42–246.56) vs. 169.52 (137.29–303.10), P=0.62] (Table 5).

ACC and pheochromocytoma with capsule invasion

A similarity in CT features, such as uneven density, necrosis, and calcification, can occasionally lead to the misdiagnosis of ACC as pheochromocytoma, particularly in cases involving capsule invasion. Therefore, the potential of the NLR and PLR in distinguishing between the two conditions warrants further investigation. As shown in Table 6, when capsule invasion was present, there were no significant differences in sex, age, or tumor location between the two groups. However, the tumor size of ACC [140.00 (81.00–160.00) vs. 57.50 (41.00–79.25), P<0.001] was notably larger than that of pheochromocytoma. Furthermore, the NLR of patients with ACC [4.56 (3.11–6.31) vs. 2.24 (1.18–4.25), P=0.003] was significantly higher compared to that in patients with pheochromocytoma and capsule invasion, whereas no significant difference in PLR was observed between the two groups (Table 6).

Discussion

ACC has a high degree of malignancy, rapid progression, and a poor prognosis (17-19). Complete tumor resection remains the only potential cure for patients (2). The annual incidence rate of ACC is only 0.7–2.0 cases/million (4), which contributes to the scarcity of diagnostic and therapeutic expertise in the majority of medical facilities. Referring patients with ACC to a specialized ACC multidisciplinary center can aid in optimizing the prognosis of patients (6) but that heavily relies on accurate preoperative diagnosis. Although recent advancements in the identification of molecular markers for ACC have significantly improved pathological diagnosis, performing preoperative puncture biopsies is not recommended due to its inherent risks, including tumor capsule rupture, needle tract metastasis, hemorrhage, pneumothorax, and other complications. Consequently, the preoperative diagnosis of ACC has predominantly been reliant on imaging studies. However, it is not uncommon for some ACC imaging manifestations to be misdiagnosed as benign tumors or pheochromocytomas. Therefore, the development of clinical detection indicators that can be carried out in the majority of hospitals and that can assist in the preoperative diagnosis of ACC may provide substantial clinical value.

Chronic inflammation has been recognized to play a significant role in the development and advancement of tumors. Several studies have reported that neutrophil count, lymphocyte count, and platelet count, as markers of tumor-related inflammation, can serve as prognostic indicators (10,11).

The use of the NLR and PLR presents distinct advantages, including improved stability and reduced heterogeneity across different centers and studies. The potential utility of the NLR and PLR may extend beyond diagnosis to treatment selection, particularly as multikinase inhibitors combined with immuno-oncology agents show promising efficacy in advanced ACC (20). Furthermore, inflammatory markers such as IL-6 are not as widely implemented in routine blood tests due to higher costs and the need for specialized laboratory equipment. In addition, while IL-6 is produced in various tissues, including tumors, it may not be the optimal choice as a systemic inflammatory response marker when compared to neutrophils and platelets, which are predominantly produced in myeloid tissues. As NLR and PLR are mainly related to the late systemic inflammatory state of tumors, the bulk of related studies have focused on the application of NLR and PLR to predict tumor prognosis. And thus, the prognostic value of the NLR and PLR has been investigated in patients with ACC (21-25).

In light of the fact that the majority of patients with ACC are diagnosed at an advanced stage, this study aimed to assess the diagnostic utility of NLR and PLR in differentiating ACC from non-ACC tumors. Mochizuki et al. (15) and Ma et al. (16) conducted analogous studies, examining the NLR in patients with adrenal space-occupying lesions, including ACA and pheochromocytoma. Their research identified boundary values of 3.15 and 2.65 for differentiating benign and malignant tumors, respectively. However, those studies involved several limitations, such as a comparatively small sample size and a lack of separate evaluation for patients with CS.

In our study, we compared the NLR and PLR of various adrenal or adjacent masses, including patients with ACA with CS, aldosteronoma, nonfunctioning ACA, and pheochromocytoma. The findings suggest that NLR >3.07 and PLR >139.74 can be used as sensitive and specific markers for differential diagnosis, except when the tumor size is considered capable of distinguishing between benign and malignant tumors. In the multivariate logistic regression, tumor size (>48 mm) was an overwhelmingly strong predictor (OR =565.600, P<0.001). It is important to note that this exceptionally high odds ratio indicates a scenario of quasi-complete separation in the data, underscoring the near-perfect discriminatory power of tumor size within this specific cohort but suggesting caution in interpreting the precise magnitude of the effect estimate. While tumor size demonstrated outstanding discriminatory power (AUC =0.986), NLR and PLR showed more modest performance (AUCs 0.742 and 0.696), suggesting that their role is complementary rather than primary. Furthermore, our NLR result aligns closely with the study by Mochizuki et al. (15), who reported a value of 3.15. The discrepancy between our results and those reported by Ma et al. (16), may be attributed to the earlier disease stage of their ACC cohort, as well as differences in cohort composition—particularly the proportion of patients with ACA and CS. In order to facilitate the future clinical implementation, we propose the use of NLR >3 and PLR >140 as diagnostic thresholds for ACC.

To account for the potential influence of hypercortisolemia on NLR, we conducted additional analysis by excluding patients with CS. The findings indicated that NLR >3 and PLR >140 remained valid for differentiating between ACC and non-ACC cases in patients without CS (data not shown). However, in patients with CS, NLR and PLR were unable to distinguish ACC from ACA, and it was observed that those with larger tumor volumes and elevated cortisol levels were more likely to be diagnosed with ACC. These findings indicate that elevated cortisol levels may have a potential effect on the NLR and this aligns with recent reviews emphasizing the complex management of CS in patients with ACC. In these patients, hypercortisolemia itself can alter systemic inflammatory responses and immune function (26), potentially confounding the interpretation of inflammatory markers such as the NLR and PLR. Conversely, the PLR cannot serve as a distinguishing factor between patients with CS caused by ACA or ACC. Additionally, apart from cortisol levels, abnormal sex hormones, particularly androgens originating from female adrenal glands, may be useful in differentiating between ACC and ACA in these patients. However, during data collection, we observed that a significant number of patients who underwent initial surgical diagnosis did not have their sex hormone levels analyzed, underscoring the importance of implementing multidisciplinary collaboration in the diagnosis and treatment of ACC prior to surgery. Another critical aspect of the preoperative differential diagnosis of ACC involves differentiating it from pheochromocytoma, as both tumors are often located near the adrenal gland and exhibit similar imaging characteristics, such as uneven density and necrosis. Misdiagnosis of ACC as pheochromocytoma can occur, particularly in cases with evidence of capsular invasion. To address this challenge, we conducted a comparative analysis between ACC and pheochromocytoma, revealing that ACC had significantly higher NLR and PLR than pheochromocytoma. To account for potential confounding factors, such as capsular invasion, vascular invasion, and distant metastasis, which might affect the NLR and PLR, we conducted a focused analysis on cases with pathologically confirmed capsular invasion in both diseases. Notably, in the absence of local invasion, vascular invasion, and distant metastasis in pheochromocytoma, we did not include a comparative analysis for these factors. Our findings indicated that patients with ACC nonetheless demonstrated a significantly higher NLR than those with pheochromocytoma. To further ensure the accuracy of our results, we excluded patients with ACC presenting with a cortisol phenotype to eliminate the potential interference of hypercortisolemia. Despite this exclusion, the observed differences in the NLR and PLR persisted (data not shown). These findings suggest that when imaging studies are inconclusive in differentiating between ACC and pheochromocytoma, an elevated NLR may suggest a diagnosis of ACC.

This paper introduces several novel contributions to the field: (I) NLR was examined hierarchically with respect to its combination with hypercortisolemia for distinguishing between benign and malignant conditions and for prognostic forecasting; (II) the roles of hypercortisolemia and tumor-induced immune dysregulation in the elevation of NLR and PLR in patients with ACC were analyzed. However, several important limitations of our study must be acknowledged. First, the retrospective collection of ACC cases over a 35-year period [1985–2020], compared to the more recent non-ACC control group [2018–2020], introduces a potential temporal bias. Although laboratory standards for complete blood counts have been maintained, the evolution of diagnostic technologies and clinical practices over this extended timeframe could influence the comparability of the cohorts and the generalizability of our findings. The rarity of ACC necessitated this extended accrual period to achieve a meaningful sample size, but this design limitation underscores the preliminary nature of our results and the critical need for validation in prospective, contemporaneous cohorts. Additionally, the heterogeneous non-ACC control group may influence the diagnostic performance estimates of NLR and PLR. These limitations underscore the preliminary nature of our findings. Furthermore, the lack of an external validation cohort is another important limitation. The diagnostic performance metrics and the proposed cut-off values for NLR and PLR were derived from and applied to the same dataset, which inherently risks model overfitting and optimism bias. Therefore, our results and the suggested thresholds must be considered preliminary and require rigorous validation in future, multicenter studies before any potential clinical application. Future research endeavors will aim to build upon the preliminary findings of this study via large-scale, multicenter, retrospective, and prospective studies to achieve more comprehensive and precise conclusions. Future studies should also explore the integration of inflammatory markers with molecular profiling (8,27,28) and emerging therapeutic approaches (29,30) to develop more comprehensive diagnostic and prognostic models for ACC.

Conclusions

In summary, for the rapid differential diagnosis of ACC from ACA, the initial step should be to assess for the presence of hypercortisolism. In its absence, tumor size, NLR, and PLR may collectively indicate the tumor’s nature. NLR >3 and PLR >140 may serve as supplementary, but not definitive, diagnostic indicators for ACC in selected clinical scenarios. For hypercortisolemic lesions, tumor size and cortisol levels are important for differential diagnosis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-727/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-727/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-727/prf

Funding: This work was supported by the Key Research and Development Program of Shaanxi Province (grant Nos. 2023-ZDLSF-40 and 2021LL-JB-06). No funding body participated in the design of the study; the collection, analysis, and interpretation of data; or the writing of the manuscript.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-727/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2021LSK-153). The requirement for informed consent was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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