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Actas Urológicas Españolas
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Original article
Systemic immune-inflammation index as an independent predictor of malignancy in 4-6 cm adrenal incidentalomas
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Índice sistémico de inflamación e inmunidad como predictor independiente de malignidad en incidentalomas adrenales de 4-6 cm
E.M. Yorulmaz [Da,*,1, A. Gorgelb,1, S. Ozcanª, O. Koseª, S.N. Gorgela, Y. Akina a Departmento de Urología, Izmir Katip Celebi University, Karabaglar, Izmir, Turkey b Departmento de Endocrinología, Selcuk University, Selcuklu, Konya, Turkey
ARTICLE INFO
Keywords:
Adrenal incidentaloma
Adrenocortical carcinoma Inflammatory biomarkers Preoperative risk stratification Surgical decision-making Systemic immune-inflammation index
Palabras clave:
Biomarcadores Inflamatorios
Carcinoma suprarrenal
Decisión quirúrgica
Estratificación de riesgo preoperatoria
İncidentaloma suprarrenal Índice sistémico de Inflamación e Inmunidad
ABSTRACT
Introduction: Adrenal incidentalomas (AI) measuring 4-6 cm present a diagnostic challenge, as size alone inade- quately predicts malignancy and creates uncertainty in surgical decisions.
Objective: To evaluate the Systemic Immune-Inflammation Index (SII) as a predictor of malignancy in adrenal tumors ≥4 cm, with a focus on the 4-6 cm “gray zone.”
Methods: Retrospective single-center cohort of 91 adrenalectomy patients with AI ≥4cm (ACC n = 19, ACA n = 72). A predefined subgroup included 46 patients with 4-6 cm tumors (ACC n = 9, ACA n = 37). SII was calculated from preoperative complete blood counts (CBC) as platelets × neutrophils / lymphocytes. Predictive performance was assessed using ROC analysis and logistic regression.
Results: In the ≥4 cm cohort, SII was higher in ACC vs. ACA (1107.4 vs. 711.3, p < 0.001). SII independently predicted ACC (per 100-unit increase: OR 0.78, 95% CI 0.67-0.90; p = 0.002). SII showed AUC 0.778 with a cut-off of 811 (sensitivity 78.9%, specificity 73.6%). Tumor size was not predictive (AUC = 0.50). In the 4-6 cm subgroup, SII remained an independent predictor (per 100-unit increase: OR 0.61, 95% CI 0.45-0.82; p = 0.004), with AUC 0.898 at a cut-off of 945 (sensitivity 88.9%, specificity 83.8%).
Conclusions: SII-derived from routine CBC-is a low-cost, adjunctive biomarker that improves preoperative malignancy risk stratification beyond size in AI, particularly in 4-6 cm tumors. External prospective validation is warranted before routine implementation.
RESUMEN
Introducción: Los incidentalomas suprarrenales de 4-6 cm presentan un desafío diagnóstico, ya que el tamaño por sí solo predice de manera insuficiente la malignidad y genera incertidumbre en las decisiones quirúrgicas. Objetivo: Evaluar el Índice Sistémico de Inflamación e Inmunidad (IIS) como predictor de malignidad en tumores suprarrenales ≥4 cm, con especial atención a la “zona gris” de 4-6 cm.
Métodos: Cohorte retrospectiva unicéntrica de 91 pacientes sometidos a adrenalectomía por incidentalomas su- prarrenales ≥4 cm (carcinoma adrenocortical, CAC n = 19, adenoma adrenocortical, AAC n = 72). El subgrupo predefinido incluyó 46 pacientes con tumores de 4-6 cm (CAC n = 9, AAC n = 37). El IIS se calculó a partir de hemogramas completos preoperatorios (CBC) como plaquetas × neutrófilos / linfocitos. El rendimiento predictivo se evaluó mediante análisis ROC y regresión logística.
Resultados: En la cohorte ≥4 cm, el IIS fue mayor en CAC que en AAC (1107.4 vs. 711.3, p < 0.001). El IIS predijo de forma independiente la presencia de CAC (por cada incremento de 100 unidades: OR 0.78, IC 95% 0.67-0.90; p = 0.002). El IIS mostró un AUC 0.778 con un punto de corte de 811 (sensibilidad 78.9%, especificidad 73.6%).
DOI of original article: https://doi.org/10.1016/j.acuro.2025.501909
* Corresponding author.
E-mail address: enismert.yorulmaz@ikc.edu.tr (E.M. Yorulmaz).
1 These authors have contributed equally to this work.
https://doi.org/10.1016/j.acuroe.2026.501909
Received 4 August 2025; Accepted 16 September 2025
Available online 5 January 2026
El tamaño tumoral no fue predictivo (AUC ~ 0.50). En el subgrupo de 4-6 cm, el IIS siguió siendo un predictor independiente (por cada incremento de 100 unidades: OR 0.61, IC 95% 0.45-0.82; p = 0.004), con un AUC 0.898 y un punto de corte de 945 (sensibilidad 88.9%, especificidad 83.8%).
Conclusiones: El IIS-derivado de un hemograma rutinario-es un biomarcador complementario, de bajo costo, que mejora la estratificación preoperatoria del riesgo de malignidad más allá del tamaño en incidentalomas supra- rrenales, especialmente en tumores de 4-6 cm. Se requiere validación prospectiva externa antes de su aplicación rutinaria.
Introduction
Adrenal incidentalomas (AI) are increasingly detected due to the widespread use of radiological imaging [1]. Management becomes cha- llenging in tumors measuring 4-6 cm. Most incidental adrenal tumors are benign, non-functioning adenomas, but a small subset are malignant. Preoperative distinction is vital, especially for non-functional 4-6 cm tu- mors, where malignancy risk is intermediate and behavior unpredictable [2].
Adrenocortical carcinoma (ACC) accounts for ~2-6% of tumors ≤4 cm, 6-10% of 4-6 cm masses, and ~25% of those >6cm [3,4]. Although widely used, tumor size alone is an imperfect malignancy pre- dictor [5]. Many benign adenomas exceed 4 cm, while some ACCs are smaller, limiting size specificity [6].
Current guidelines and literature support size-based thresholds but recognize their limitations. Most guidelines suggest surveillance for <4 cm non-functional masses with benign imaging features but ack- nowledge limitations of size alone [7]. In contrast, adrenal tumors >6 cm - which carry a substantially higher likelihood of cancer - are usually recommended for prompt surgical resection [8]. The 4-6 cm “gray zone” requires individualized, multidisciplinary evaluation [9]. Indeed, contemporary guidelines emphasize that adrenal lesions falling in this indeterminate category should be discussed in a multidiscipli- nary setting to tailor the decision between continued observation and adrenalectomy [9]. Given the diagnostic uncertainty in 4-6 cm tumors, additional biomarkers for improved stratification are needed.
Inflammation-based markers like the Systemic Immune- Inflammation Index (SII = platelets x neutrophils/lymphocytes) reflect tumor-related immune imbalance [10]. SII reflects the balance between pro-tumor inflammatory response and host immune status. Elevated SII is linked to advanced disease and poor outcomes [11]. The premise is that malignant tumors often elicit systemic inflammation (e.g. neutrophilia, thrombocytosis) while suppressing lymphocyte-mediated immunity, and SII quantitatively captures this phenomenon.
Emerging data suggest SII may aid diagnosis in adrenal tumors. Pa- tients with ACC tend to exhibit a heightened systemic inflammatory state compared to those with benign adrenal adenomas [12]. Their ele- vation in adrenal cancer supports a link between tumor biology and immune response [13]. We hypothesize that SII may help distinguish malignant from benign adrenal masses preoperatively.
Given the limitations of tumor size as a sole criterion, we hypothesize that the SII may enhance the preoperative identification of patients at higher risk of malignancy among adrenal tumors. The primary objective of this study was to determine whether SII serves as an independent predictor of malignancy in AI ≥ 4 cm. The secondary objectives were to evaluate the performance of SII according to tumor size categories, with particular emphasis on the 4-6 cm “gray zone,” where clinical decision- making remains most challenging.
Material and methods
Study design
This retrospective single-center study included patients undergoing adrenalectomy for AI between 2015 and 2025. Approved by the Institu-
tional Ethics Committee, the study followed the Declaration of Helsinki, with informed consent obtained.
Patient selection
Among 173 patients who underwent adrenalectomy between 2015 and 2025, a total of 91 patients with adrenal tumors ≥4 cm and histologi- cally confirmed adrenocortical adenoma (ACA) or ACC were included in the study. A predefined subgroup analysis was performed for 46 patients with tumors measuring 4-6 cm.
All patients underwent contrast-enhanced computed tomography (CT) as the primary diagnostic imaging modality. In selected cases whe- re CT findings were equivocal, magnetic resonance imaging (MRI) was also performed. Radiological assessment followed standard criteria for adrenal incidentalomas, including: (i) detection of an adrenal mass in- cidentally during imaging not primarily intended for adrenal disease, (ii) size measurement in the largest axial diameter, and (iii) attenuation values and enhancement characteristics on CT/MRI to exclude obvious metastases or pheochromocytomas.
Inclusion criteria were: histopathological confirmation of ACA or ACC, tumor size ≥4 cm on preoperative imaging, availability of complete blood count (CBC) data including platelet, neutrophil, and lymphocy- te counts for SII calculation, and comprehensive hormonal evaluation to assess functional status of the tumor. Exclusion criteria included: adrenal metastases, missing hematological data, or comorbid conditions that could alter systemic inflammation such as active infections, hema- tological or autoimmune disorders, other active malignancies, severe cardiomyopathy, or use of glucocorticoids/immunomodulatory drugs. Patients undergoing major combined surgeries involving non-adrenal organs were also excluded.
Data collection
Data regarding demographics, comorbidities, imaging, hormonal sta- tus, and histopathology were retrospectively retrieved from patient records. Demographic variables included age, sex, and smoking status, while comorbidities such as diabetes mellitus and hypertension we- re systematically recorded. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2).
All patients underwent preoperative imaging with contrast-enhanced CT as the primary modality; MRI was performed in selected cases when CT findings were equivocal. Tumor size was defined as the largest axial diameter measured on imaging. Imaging characteristics were reviewed to confirm the diagnosis of adrenal incidentaloma and to exclude ob- vious metastases or pheochromocytoma.
Hormonal status was assessed using a standardized endocrine work- up, including the 1 mg overnight dexamethasone suppression test for cortisol secretion and plasma metanephrine levels for catecholamine activity. All tests were conducted within two weeks before surgery to ensure accurate preoperative evaluation. Non-functioning lesions were defined as those with normal results across all endocrine assessments.
The SII was calculated as platelets x neutrophils/lymphocytes using preoperative complete CBC performed within two weeks prior to sur- gery. Laboratory standardization was ensured: all cell counts were expressed in uniform units of 109/L, and all hematological analyses we-
re performed using the same automated analyzer in a single institutional laboratory, under the supervision of the same expert team.
Statistical analysis
Analyses were performed using Jamovi v2.4.8. Normality was tested via Shapiro-Wilk. Data were presented as mean + SD or median (IQR) and compared with t-test or Mann-Whitney U. Categorical data were analyzed with chi-square or Fisher’s test.
Receiver Operating Characteristic (ROC) analyses evaluated the dis- criminatory performance of SII, tumor size, and functional mass in distinguishing ACC from ACA, calculating area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predic- tive value (NPV), and Youden’s index. Cut-off values were determined by maximizing Youden’s index.
Logistic regression assessed predictors of ACC in tumors ≥4 cm and in the 4-6 cm subgroup (SII, size, function). Model fit was evaluated with deviance, AIC, and McFadden’s R2. Predictive accuracy was evaluated via ROC. Significance was set at p < 0.05.
Given the retrospective design, no a priori sample size calculation was performed. Instead, exact 95% confidence intervals (CIs) were re- ported for all odds ratios and AUCs as measures of estimator precision, acknowledging the limited number of ACC events. Although neutrophil, lymphocyte, and platelet counts were collected, NLR and PLR were not analyzed separately, as both indices are mathematical components of the SII. Including them alongside SII would introduce redundancy and collinearity, potentially distorting model interpretation.
Result
Patients with Adrenal Masses ≥4 cm
The primary cohort included 91 patients (19 ACC, 72 ACA) with adrenal tumors ≥4 cm. Groups showed no significant differences in age, sex, comorbidities, smoking, or functionality, supporting comparability between ACC and ACA patients.
Tumors >6 cm were observed in 13 patients with ACC (68.4%) and in 32 patients with ACA (44.4%), with no statistically significant diffe- rence between groups (p = 0.063).
ACC cases had higher SII (1107.4 vs. 711.3, p < 0.001), higher plate- lets (348.2 vs. 255.1, p < 0.001), and lower lymphocytes (1.71 vs. 1.95, p = 0.053).
No significant differences were observed in age, BMI, neutrophils, hemoglobin, creatinine, or tumor size. The comparative distribution of variables between ACC and ACA groups is summarized in Table 1 .
In multivariate logistic regression including SII, tumor size, and fun- ctionality (Table 2 ), only SII remained an independent predictor of ACC (OR: 0.997, p = 0.002). The corresponding 95% CIs are reported to reflect estimator precision, acknowledging the limited number of ACC cases. The model’s AUC was 0.786 (sensitivity 95.4%, specificity 21.1%, accuracy 78.6%) (Fig. 1A).
SII alone had an AUC of 0.778 (cut-off 811; sensitivity 78.9%, speci- ficity 73.6%, PPV 44.1%, NPV 93.0%). Tumor size and function showed poor AUCs (0.502 and 0.481, respectively) (Fig. 1B).
Patients with Adrenal Masses 4-6 cm (Subgroup analysis - gray zone)
In the subgroup analysis of patients with adrenal masses measuring 4-6 cm (n = 46), including 9 patients with ACC and 37 with ACA, no sta- tistically significant differences were observed in categorical variables such as sex, comorbidities, smoking status, or functional tumor activity.
ACC patients had higher SII (1512.7 vs. 711.3, p < 0.001), platelets, and hemoglobin (p < 0.001), and lower lymphocytes (p = 0.015). Other variables were similar. Variable distributions are shown in Table 3 .
In the 4-6 cm subgroup (n = 46), binomial logistic regression sho- wed good model fit (deviance: 24.8; AIC: 32.8; McFadden’s R2: 0.455
SII was a significant independent predictor of ACC (OR = 0.995, 95% CI: 0.992-0.998, p = 0.004), whereas tumor size (p = 0.597) and functional mass (p = 0.780) were not (Table 4 ). Reporting exact 95% CIs high- lights the limited precision of these estimates due to the small number of events. AUC was 0.907 (sensitivity 97.3%, specificity 55.6%, accuracy 89.1%) (Fig. 2A).
SII alone showed AUC 0.898 (cut-off 945; sensitivity 88.9%, specifi- city 83.8%, PPV 57.1%, NPV 96.9%). Tumor size and function showed poor performance (AUCs 0.500 and 0.481, respectively) (Fig. 2B).
Discussion
Our study shows that SII distinguishes ACC from ACA in adrenal tumors ≥4 cm and is particularly effective in the 4-6 cm “gray zone.” SII levels were significantly higher in ACCs despite comparable tumor sizes and remained an independent predictor in multivariate analy- sis, whereas tumor size was not. In the 4-6 cm subgroup, SII retained discriminative power, supporting its role as a useful adjunct in risk stratification when size is unreliable. Clinically, SII may help identify borderline lesions that warrant surgery versus those suitable for obser- vation, addressing a critical gap in AI management.
Our findings support emerging evidence that systemic inflammation is elevated in adrenal malignancies. In our cohort, patients with ACC had significantly higher SII compared to those with ACA (1107.4 vs. 711.3, p < 0.001). ROC analysis showed that SII alone achieved an AUC of 0.778 with a cut-off value of 811 (sensitivity 78.9%, specificity 73.6%), while tumor size and functionality demonstrated poor discriminatory performance. In multivariate analysis including SII, tumor size, and fun- ctionality, only SII remained an independent predictor of ACC. These findings demonstrate that systemic inflammatory status, as captured by SII, has greater diagnostic relevance than conventional preoperative parameters.
Prior studies have reported similar observations. Mangone et al., in their large cohort of 61 ACC and 429 ACA patients, found significantly higher SII, Neutrophil-to-Lymphocyte Ratio (NLR), and Platelet-to- Lymphocyte Ratio (PLR) in ACC compared to adenomas (p < 0.001), with an AUC of approximately 0.84 for SII-closely matching our AUC of 0.778 [12].
Earlier, Mochizuki et al. had also identified NLR as a useful biomar- ker: in a series of 59 patients, NLR was significantly higher in ACC than in non-malignant adrenal tumors [13]. Sisman et al. found elevated NLR and PLR in ACC as well [14]. While NLR and PLR have been frequently investigated as inflammatory indices in adrenal tumors, their predictive value overlaps with SII, which mathematically incorporates both ratios. For this reason, we emphasized SII in our analysis, as it provides a mo- re integrative marker and, in our cohort, outperformed its individual components.
Elevated SII likely reflects tumor-induced immune changes. ACCs may secrete cytokines (e.g., IL-6, TNF-a, TGF-B) that drive neutrophi- lia, thrombocytosis, and lymphopenia [15]. This creates a pro-tumor inflammatory milieu and an immune evasion environment, manifesting as a high SII value in peripheral blood. In our cohort, ACC patients had markedly higher platelet counts and slightly lower lymphocyte counts than adenoma patients, explaining the SII differences, even though neu- trophil counts were similar. It is notable that SII differentiated ACC from ACA independently of tumor size - a significant finding because size has long been the main preoperative criterion.
Clinically, incorporating SII into the preoperative assessment may enhance malignancy detection in borderline-size AIs. Although many adrenal masses >4 cm are benign, surgery is often pursued due to perceived cancer risk [16,17]. As a result, some patients undergo adrenalectomy-despite inherent surgical risks-only to discover a benign adenoma. Our findings suggest that SII may refine this decision- making process. For instance, a 5 cm mass with elevated SII may indicate higher malignancy risk and warrant surgery, while a similar-sized mass
| Variable | ACA n, % | ACC n, % | p |
|---|---|---|---|
| Gender | |||
| Male | 54 (59.3%) | 14 (15.4%) | 1.000ª |
| Female | 18 (19.8%) | 5 (5.5%) | |
| HT | |||
| Yes | 35 (38.5%) | 10 (11.0%) | 0.755b |
| No | 37 (40.7%) | 9 (9.9%) | |
| DM | |||
| Yes | 24 (26.4%) | 5 (5.5%) | 0.783ª |
| No | 48 (52.7%) | 14 (15.4%) | |
| Smoking | |||
| Yes | 45 (49.5%) | 11 (12.1%) | 0.714b |
| No | 27 (29.7%) | 8 (8.8%) | |
| Functional Mass | |||
| Yes | 24 (26.4%) | 2 (2.2%) | 1.000ª |
| No | 60 (67.4%) | 17 (19.1%) | |
| According to Tumor Size | |||
| 4-6 cm | 40 (50.5%) | 6 (6.6%) | 0.063b |
| >6 cm | 32 (35.2%) | 13 (14.3%) | |
| [10pt] | Mean + SD | Mean + SD | p |
| Age (Years) | 59.36 +11.90 | 58.74 +12.48 | 0.841€ |
| SII | 711.27 + 342.27 | 1107.39 + 452.70 | <0.001ª |
| BMI (kg/m2) | 28.55 +5.58 | 27.27 ±6.41 | 0.922° |
| PLT (109/L) | 255.13±62.62 | 348.16 ±103.06 | <0.001c |
| NEU (109/L) | 5.06 ±1.14 | 5.18±1.24 | 0.700€ |
| LYM (109/L) | 1.95 +0.47 | 1.71 ±0.46 | 0.053€ |
| HB (g/dL) | 13.15±2.23 | 12.38 +3.15 | 0.229€ |
| Creatinine (mg/dL) | 1.27 +0.95 | 1.02+0.32 | 0.485ª |
| Tumor Size (mm) | 64.06 ± 24.54 | 60.78 +13.25 | 0.979ª |
DM: Diabetes Mellitus, HT: Hypertension, BMI: Body Mass Index, HB: Hemoglobin, LYM: Lymphocyte, NEU: Neutrophil, PLT: Platelet, SII: Systemic Immune- Inflammation Index.
a Fisher’s exact test.
b x2 test.
c Independent Samples t-test.
d Mann-Whitney U test.
| Predictor | Estimate | SE | Z | p | Odds ratio | 95% Confidence Interval | |
|---|---|---|---|---|---|---|---|
| Lower | Upper | ||||||
| Intercept | 4.12877 | 1.3628 | 3.030 | 0.002 | 62.102 | 4.296 | 897.658 |
| SII | -0.00253 | 8.00e-4 | -3.159 | 0.002 | 0.997 | 0.996 | 0.999 |
| Functional Mass | 0.32371 | 0.8547 | 0.379 | 0.705 | 1.382 | 0.259 | 7.380 |
| Tumor size (mm) | -0.01145 | 0.0131 | -0.872 | 0.383 | 0.989 | 0.963 | 1.014 |
Note. Estimates represent the log odds of Pathological Type = ACAvs. Pathological Type = ACC: SII: Systemic Immune-Inflammation Index.
with normal SII might be monitored. Given its low cost and accessibility, SII is a practical tool to complement current assessments. By reducing reliance on size alone, SII-based stratification could help avoid unneces- sary surgery in low-risk patients while guiding appropriate intervention in high-risk cases. Incorporating SII into multidisciplinary evaluations may enhance preoperative malignancy prediction alongside imaging and hormonal data.
A prospective validation study on urinary steroid metabolomics concluded that combining tumor size, imaging features, and steroid pro- filing improves ACC detection, may expedite surgery in malignant cases, and helps avoid unnecessary surgery in benign tumors [18]. Advan-
ced tests like steroid metabolomic profiling (e.g., EURINE-ACT) offer high diagnostic accuracy for distinguishing ACC from adenomas but are costly and not widely accessible. In contrast, SII is a simple, inexpen- sive marker derived from routine blood counts. While not diagnostic on its own, our findings suggest that SII can support risk stratification alongside imaging-especially in resource-limited settings or general practice, where decisions often rely on basic parameters like tumor size.
This study has several limitations. First, it is a single-center retrospec- tive analysis with a limited number of ACC cases (19 ACC vs. 72 ACA), reflecting the rarity of the disease. The small sample size-particularly
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| Variable | ACA n, % | ACC n, % | p |
|---|---|---|---|
| Gender | |||
| Male | 29 (63.0%) | 7 (15.2%) | 1.000ª |
| Female | 8 (17.4%) | 2 (4.3%) | |
| HT | |||
| Yes | 23 (50.0%) | 4 (8.7%) | 0.456ª |
| No | 14 (30.4%) | 5 (10.9%) | |
| DM | |||
| Yes | 14 (30.4%) | 4 (8.7%) | 0.721ª |
| No | 23 (50.0%) | 5 (10.9%) | |
| Smoking | |||
| Yes | 26 (56.5%) | 6 (13.0%) | 1.000ª |
| No | 11 (23.9%) | 3 (6.5%) | |
| Functional Mass | |||
| Yes | 7 (15.2%) | 1 (2.2%) | 1.000ª |
| No | 30 (65.2%) | 8 (17.4%) | |
| [10pt] | Mean + SD | Mean + SD | p |
| Age (Years) | 59.50 ± 12.90 | 58.60 ±13.90 | 0.840b |
| SII | 711.27 + 342.27 | 1512.67 + 554.962 | <0.001b |
| BMI (kg/m2) | 30.38 ±6.36 | 27.12+5.29 | 0.163b |
| PLT (109/L) | 264.49 +62.63 | 367.89 +74.64 | <0.001b |
| NEU (109/L) | 5.53 +1.09 | 5.96 ±1.24 | 0.302b |
| LYM (109/L) | 1.97 ±0.42 | 1.56 ±0.51 | 0.015b |
| HB (g/dL) | 13.25+1.97 | 10.48 ±1.89 | <0.001b |
| Creatinine (mg/dL) | 1.27 +1.05 | 1.38 +1.25 | 0.570€ |
| Tumor Size (mm) | 49.81 ±7.14 | 46.67 + 11.18 | 0.368€ |
DM: Diabetes Mellitus, HT: Hypertension, BMI: Body Mass Index, HB: Hemoglobin, LYM: Lymphocyte, NEU: Neutrophil, PLT: Platelet, SII: Systemic Immune- Inflammation Index.
a Fisher’s exact test.
b Independent Samples t-test.
· Mann-Whitney U test.
in the 4-6 cm subgroup (only 9 ACC cases)-may limit statistical po- wer and generalizability. Second, inclusion was restricted to surgically treated patients, introducing potential selection bias by excluding non- operated, likely benign tumors, which may overestimate malignancy rates in 4-6 cm lesions. Third, although patients with overt confounders
were excluded, SII is a non-specific marker that may be influenced by un- measured factors such as subclinical infections, other malignancies, or cortisol-induced neutrophilia [12]. In our cohort, hormone-producing tumors were rare and similarly distributed between ACC and ACA, but the potential influence of cortisol on immune markers warrants
| Predictor | Estimate | SE | Z | p | Odds ratio | 95% Confidence Interval | |
|---|---|---|---|---|---|---|---|
| Lower | Upper | ||||||
| Intercept | 8.24787 | 4.47835 | 1.842 | 0.066 | 3819.494 | 0.589 | 2.48e+7 |
| SII | -0.00497 | 0.00172 | -2.890 | 0.004 | 0.995 | 0.992 | 0.998 |
| Tumor size (mm) | -0.03533 | 0.06689 | -0.528 | 0.597 | 0.965 | 0.847 | 1.101 |
| Functional Mass | 0.35456 | 1.27037 | 0.279 | 0.780 | 1.426 | 0.118 | 17.192 |
Note. Estimates represent the log odds of Pathological Type = ACAvs. “Pathological Type = ACC”. SII: Systemic Immune-Inflammation Index.
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further investigation in larger studies. Additionally, we did not extensi- vely assess other inflammatory indices (e.g., NLR, PLR), as the focus was on SII; however, combining multiple markers may enhance dia- gnostic accuracy. Moreover, we did not establish a definitive SII cut-off for clinical use. Although our ROC analysis supports its discriminati- ve value, threshold validation in prospective cohorts is needed. Future multicenter studies should confirm our findings and evaluate how in- corporating SII into existing models influences decision-making and outcomes. Additionally, prospective research could assess whether SII correlates with ACC stage or prognosis and whether interventions- such as preoperative anti-inflammatory strategies-might impact its levels.
Conclusion
In conclusion, our study indicates that SII is a useful biomar- ker for distinguishing ACC from benign adenomas, particularly in the 4-6 cm “gray zone” where clinical decisions are most difficult. SII re- flects tumor-driven systemic inflammation, and elevated levels may suggest malignancy even when size is inconclusive. These findings support incorporating simple inflammatory markers into adrenal inci- dentaloma evaluation. By aiding preoperative risk stratification, SII may help avoid unnecessary surgery in benign cases while enabling timely intervention for ACC. However, these results require validation in pros- pective multicenter cohorts before routine clinical application can be recommended.
CRediT authorship contribution statement
All authors have made substantial contributions to the conception, design, data acquisition, analysis, interpretation, and manuscript pre- paration. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work.
Ethical considerations
This study was conducted in accordance with the Declaration of Hel- sinki, relevant national laws, and institutional guidelines. The study protocol was approved by the Institutional Ethics Committee of Iz- mir Katip Çelebi University (Application No: 2025-SAEK-0655, Date: 29.06.2025).
Informed consent
No patient identifiable data or images are included in this article.
Declaration of Generative AI and AI-assisted technologies in the writing process
During the preparation of this work, the authors did not use genera- tive AI or AI-assisted technologies in the writing process.
Funding
The authors declare that no funding was received for this study.
Declaration of competing interest
None.
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