Function‐Driven Versus Size‐Driven Decision‐Making: Real‐World Evaluation of the European Society of Endocrinology Criteria in Adrenal Surgery

ABSTRACT

Background

The increasing detection of adrenal incidentalomas has intensified the need for clearly defined surgical indications. The 2023 European Society of Endocrinology (ESE) guidelines introduced a paradigm shift from size‐based to function‐based criteria for adrenalectomy.

Methods

A retrospective cohort study was conducted including consecutive patients who underwent adrenal surgery between 2012 and 2023. Patients were reevaluated according to the ESE 2023 recommendations to determine whether historical surgical indications aligned with contemporary guideline‐defined criteria. Patients were classified as ESE‐positive (ESE YES) or ESE‐negative (ESE NO) based on hormonal activity and histopathological findings.

Results

The study included 797 consecutive patients who underwent adrenalectomy for adrenal masses. According to the ESE 2023 criteria, 541 (67.9%) patients were classified as ESE‐positive. Hormonal hypersecretion was present in 458 (57.8%) patients. Patients with clinically significant adrenal pathology were significantly more likely to have hormonally active tumors (81.7% vs. 4.3%, χ ² = 474.1, df = 1, p < 0.001). Median tumor diameter did not differ significantly between groups (4.5 cm [IQR 4.0–6.0] in the ESE‐positive group and 4.5 cm [IQR 3.5–6.0] in the ESE‐negative group (p = 0.118). Median age was similar between the ESE‐positive and ESE‐negative groups (55 years [IQR 44.5–63.0] vs. 56 years [IQR 41.0–62.0], p = 0.292).

Conclusion

Hormonal activity is strongly associated with clinically significant adrenal pathology according to the ESE 2023 criteria, whereas tumor size alone does not appear to reliably discriminate between patients who do and do not fulfill guideline‐defined indications for surgery. These findings provide real‐world evidence supporting function‐driven decision‐making and reinforce the contemporary paradigm shift away from size‐based surgical indications.

The increasing detection of adrenal incidentalomas has intensified the need for clearly defined surgical indications. The 2023 European Society of Endocrinology (ESE) guidelines introduced a paradigm shift from size‐based to function‐based criteria for adrenalectomy. Hormonal activity is strongly associated with clinically significant adrenal pathology according to the ESE 2023 criteria, whereas tumor size alone does not appear to reliably discriminate between patients who do and do not fulfill guideline‐defined indications for surgery. These findings provide real‐world evidence supporting function‐driven decision‐making and reinforce the contemporary paradigm shift away from size‐based surgical indications.

1. Introduction

The widespread use of cross‐sectional imaging has led to a substantial increase in the detection of adrenal incidentalomas, creating persistent challenges regarding their optimal management and indications for surgery [1, 2]. According to the most recent European Society of Endocrinology (ESE) guidelines, surgical treatment should be considered for all hormonally active adrenal tumors, adrenal metastases, and lesions demonstrating radiological suspicion of malignancy or significant growth during follow‐up, irrespective of tumor size [3]. Although earlier ESE recommendations incorporated tumor diameter among the criteria for surgery, the updated guidelines no longer support tumor size alone as an indication for adrenalectomy [4].

The aim of the present study was to determine whether patients who underwent adrenal surgery in a real‐world historical surgical cohort would meet the indications for surgery according to the ESE 2023 recommendations. In addition, we sought to assess the potential extent of discordance between historical surgical practice and contemporary guideline‐based criteria.

2. Material and Methods

This retrospective study included consecutive patients who underwent adrenalectomy for adrenal tumors at a tertiary referral center between 2012 and 2023. Data extraction was performed from the institutional database used for routine clinical documentation of all operated patients. The collected variables included age, sex, type of surgical approach (open, laparoscopic, or retroperitoneoscopic), tumor size, tumor laterality, preoperative hormonal evaluation, and final histopathological findings. Only patients undergoing primary adrenal surgery were included. Reoperations for recurrent disease were excluded.

During the study period, adrenalectomy was performed according to the contemporary clinical practice and multidisciplinary decision‐making at our institution. Surgical indications included hormonally active adrenal tumors, radiological suspicion of malignancy, interval tumor growth, large adrenal masses considered clinically significant, and selected indeterminate adrenal lesions after multidisciplinary evaluation. As this study spans more than a decade, surgical decision‐making reflected the recommendations and institutional practice applicable at the time of treatment.

Patients were retrospectively classified according to the 2023 European Society of Endocrinology (ESE) recommendations, and each patient was individually reviewed to ensure consistent classification according to predefined study criteria. Patients were classified as ESE‐positive if they fulfilled at least one of the following criteria: [1] documented preoperative hormone excess, including pheochromocytoma, primary aldosteronism, overt cortisol excess, or mild autonomous cortisol secretion (MACS); or [2] histopathologically confirmed malignant adrenal lesions, including adrenocortical carcinoma, adrenal metastases, and other primary malignant adrenal tumors. Because standardized retrospective reassessment of preoperative imaging studies was not feasible, histopathological confirmation of malignancy was used as a surrogate for lesions that would likely have fulfilled guideline‐based surgical indications. Benign nonfunctioning adrenal lesions, including rare adrenal lesions without hormonal activity, were classified as ESE‐negative (unless hormonal excess was documented). Thus, patient classification was based primarily on documented preoperative endocrine evaluation, whereas histopathological diagnosis was used only to identify malignant lesions.

Preoperative clinical, biochemical, and available imaging data were reviewed for all patients. Final histopathological findings were used to establish the definitive diagnosis of adrenal lesions. For analytical purposes, ESE‐positive patients were considered to have clinically significant adrenal pathology according to the 2023 ESE recommendations, whereas ESE‐negative patients represented lesions without contemporary guideline‐defined indications for adrenalectomy.

The primary outcome of the study was the presence of clinically significant adrenal pathology according to ESE criteria (ESE YES vs. ESE NO). Only univariate analyses were performed. Multivariable modeling was not undertaken, as hormonal activity constitutes an integral component of the ESE classification and would therefore introduce collinearity into adjusted analyses.

Continuous variables were assessed for normality and were presented as median and interquartile range (IQR) due to nonnormal distribution. Categorical variables are presented as absolute numbers and percentages. Comparisons between groups were performed using the Mann–Whitney U test for continuous variables. Categorical variables were compared using the χ² test or Fisher's exact test, as appropriate, when expected cell counts were < 5. A two‐sided p‐value < 0.05 was considered statistically significant. Statistical analyses were performed using JASP (version 0.95.4).

The study was approved by the institutional ethics committee (Approval No. 95/69 date 29.01.2026). Written informed consent was obtained from all patients for the surgical procedure, including consent for the use of anonymized clinical data for research purposes.

3. Results

The study included 797 patients who underwent adrenal surgery for adrenal tumors. Patient age ranged from 18 to 82 years, with a mean age of 53.3 ± 13.0 years. Of the included patients, 550 (69.0%) were women and 247 (31.0%) were men. Left‐sided tumors were identified in 388 (48.7%) patients, right‐sided tumors in 389 (48.8%), whereas 20 (2.5%) patients presented with bilateral disease.

Regarding the surgical approach, 148 (18.6%) patients underwent open adrenalectomy, 605 (75.9%) laparoscopic adrenalectomy, and 44 (5.5%) retroperitoneoscopic adrenalectomy. The proportion of open procedures reflects the early years of the study period, before minimally invasive adrenalectomy became the standard approach at our institution. Between 2013 and 2015, 112 open adrenalectomies were performed, whereas only 36 open procedures were undertaken between 2016 and 2023, mainly because of radiological suspicion of locally advanced disease, unfavorable tumor characteristics, or conversion during surgery.

Clinically significant adrenal pathology according to ESE criteria was identified in 541 (67.9%) patients. Hormonal hypersecretion, including mild autonomous cortisol secretion (MACS), was documented in 458 (57.5%) patients. Among 65 patients with histopathologically confirmed malignant adrenal tumors, only three (4.6%) presented with clinical evidence of hormone excess, whereas the remaining 62 (95.4%) underwent surgery because of radiological suspicion of malignancy and multidisciplinary clinical assessment.

The baseline demographic and clinical characteristics of the study population are summarized in Table 1.

TABLE 1.

Baseline characteristic of the patients surgically treated for adrenal tumors.

Variables	Overall cohort (n = 797)
Age, years	53.3 ± 13.0
Age range	18–82
Sex
Male	247 (31.0%)
Female	550 (69.0%)
Side of lesion
Left	388 (48.7%)
Right	389 (48.8%)
Bilateral	20 (2.5%)
Surgical approach
Open	148 (18.6%)
Laparoscopic	605 (75.9%)
Retroperitoneoscopic	44 (5.5%)
Hormonal activity
Yes	458 (57.5%)
No	339 (42.5%)
Clinically significant adrenal pathology according to ESE criteria
Yes	541 (67.9%)
No	256 (32.1%)

The distribution of final histopathological diagnoses is summarized in Table 2. Adrenocortical adenomas represented the most frequent finding, followed by pheochromocytomas. Malignant lesions, including primary malignant adrenal tumors and metastatic disease, accounted for a minority of cases. The category “other rare adrenal lesions” included adrenal cysts and pseudocysts, echinococcal cysts, adrenal oncocytomas, schwannomas, fibrolipomas, lymphangiomas, ganglioneuromas, and ectopic thyroid tissue within the adrenal gland. Histopathological data were unavailable in 40 patients (5.0%). Among these 21 patients fulfilled ESE criteria based on documented preoperative endocrine evaluation or clinical suspicion of metastatic disease (16 hormonal active tumors, and 5 with suspicion for carcinoma), whereas 19 did not fulfill ESE criteria.

TABLE 2.

Distribution of histopathological diagnoses and functional subclassification of adrenocortical adenomas and hyperplasia.

Pathological diagnoses	Frequency	Percent	Tumor size, cm, median (IQR)
Pheochromocytoma	145	18.2%	5 (3.5–7.0)
Clinically active	134	92.4%
Adrenocortical adenoma	424	53.2%	4 (3.5–5.0)
Overt cortisol‐producing adenoma	157	37.0%
MACS	51	12.1%
Aldosterone‐producing adenoma	59	13.9%
ACTH‐dependent Cushing’s syndrome	8	1.9%
Nonfunctioning adenoma	149	35.1%
Adrenocortical hyperplasia	46	5.8%	4 (3.0–5.0)
Overt cortisol‐producing hyperplasia	13	28.2%
MACS	5	10.9%
Aldosterone‐producing adenoma	5	10.9%
ACTH‐dependent Cushing’s syndrome	7	15.2%
Nonfunctioning hyperplasia	16	34.8%
Adrenocortical carcinoma and other primary malignant adrenal tumors	31	3.9%	9.5 (7.5–14.5)
Metastases	34	4.3%	7 (5.0–8.0)
Other rare adrenal lesions	77	9.6%	5 (4.0–6.0)
Missing	40	5%	—

Note: Other rare adrenal lesions included ganglioneuromas, schwannomas, oncocytomas, adrenal cysts, pseudocysts, and other uncommon benign adrenal lesions.

Abbreviation: MACS, mild autonomous cortisol secretion.

To provide greater granularity regarding histopathological diagnoses, both adrenocortical adenomas and adrenocortical hyperplasia were further subclassified according to their functional status. Nonfunctioning adenomas represented 34.7% of all adrenocortical adenomas. Among these patients, historical indications for surgery most commonly included larger tumor size, interval growth, younger patient age, and radiological features considered suspicious during multidisciplinary evaluation. Of the 65 histopathologically confirmed malignant adrenal tumors, only three (4.6%) presented with preoperative clinical evidence of hormone excess, whereas the remaining 62 (95.4%) underwent surgery primarily because of radiological suspicion of malignancy and multidisciplinary clinical assessment. As shown in Table 2, malignant adrenal tumors tended to have larger median tumor size than benign adrenal lesions.

Patients classified as ESE‐positive demonstrated a significantly higher prevalence of hormonal hypersecretion than ESE‐negative patients (81.7% vs. 4.3%, χ ² = 474.1, df = 1, p < 0.001). Median tumor size did not differ significantly between groups, measuring 4.5 cm (IQR 4.0–6.0) in the ESE‐positive group and 4.5 cm (IQR 3.5–6.0) in the ESE‐negative group (Mann–Whitney U test, p = 0.118). Tumor laterality differed significantly between the two groups (χ ² = 7.868, df = 2, p = 0.020). Median age was similar between the ESE‐positive and ESE‐negative groups (55 years [IQR 44.5–63.0] vs. 56 years [IQR 41.0–62.0], Mann–Whitney U test, p = 0.292). Sex distribution did not differ significantly between groups (χ ² = 0.451, df = 1, p = 0.502). These findings are summarized in Table 3.

TABLE 3.

Comparison of patients with and without clinically significant adrenal pathology according to ESE criteria.

Variable	ESE yes (n = 541)	ESE no (n = 256)	p‐value
Hormonal activity, n (%)	442 (81.7%)	11 (4.3%)	< 0.001
Tumor size, cm, median (IQR)	4.5 (4.0–6.0)	4.5 (3.5–6.0)	0.118
Side of lesion			0.020
Left, n (%)	267 (49.3%)	121 (47.3%)
Right, n (%)	255 (47.2%)	134 (52.3%)
Bilateral, n (%)	19 (3.5%)	1 (0.4%)
Age, years, median (IQR)	55 (44.5–63.0)	56 (41.0–62.0)	0.292
Female sex, n (%)	380 (70.2%)	170 (66.4%)	0.502

Continuous variables are presented as median (IQR) and were compared using the Mann–Whitney U test. Categorical variables were compared using the χ² test or Fisher's exact test, as appropriate.

Sixteen ESE‐positive patients with documented preoperative hormonal hypersecretion were excluded from the analyses presented in Table 3 because final histopathological reports were unavailable, precluding complete clinicopathological comparison. Consequently, hormonal activity in the ESE‐positive group was assessed in 442 patients.

Temporal trends in patient characteristics across the study period are summarized in Table 4. The proportion of patients undergoing open adrenalectomy decreased markedly over time, from 49.4% during 2012–2015 to 4.2% in 2016–2019 and 7.9% in 2020–2023, reflecting the adoption of minimally invasive adrenal surgery at our institution. The proportion of patients with hormonally active tumors remained relatively stable across the three study periods (63.3%, 50.9%, and 58.7%, respectively). Similarly, the proportion of patients classified as ESE‐positive showed only modest variation over time (72.1%, 65.3%, and 66.9%, respectively). Median tumor size demonstrated a slight increase during the study period, from 4.0 cm (IQR 3.5–5.0) in 2012–2015 to 5.0 cm (IQR 3.8–6.0) in 2020–2023.

TABLE 4.

Evolution of surgical characteristics during the study period.

Variable	2012–2015	2016–2019	2020–2023
Number of patients	229	265	303
Open approach (%)	113 (49.4)	11 (4.2)	24 (7.9)
Laparoscopic (%)	116 (50.6)	254 (95.8)	279 (92.1)
Hormonal activity (%)	145 (63.3)	135 (50.9)	178 (58.7)
ESE positive (%)	165 (72.1)	173 (65.3)	203 (66.9)
Tumor size median (IQR)	4 (3.5–5.0)	4.5 (3.5–6.0)	5 (3.8–6.0)

4. Discussion

In this study, 797 patients who underwent adrenal surgery were included, with a mean age of 53.3 ± 13.0 years; the majority were female (69.0%). Almost two‐third of operated patients (67.9%) fulfilled the criteria for clinically significant adrenal pathology according to the 2023 ESE recommendations [3]. This distribution suggests that most surgically treated patients demonstrated pathology consistent with guideline‐defined indications.

These findings provide insight into historical surgical decision‐making and illustrate how the application of contemporary ESE criteria may influence patient selection for adrenalectomy.

Although the ESE 2023 recommendations were formulated based on extensive prior literature, data evaluating how these criteria perform when retrospectively applied to real‐world historical surgical cohorts remain limited. This distinction is clinically relevant, as guidelines are ultimately intended to influence decision‐making in precisely such patient populations.

Adrenocortical adenomas represented the most frequent histopathological finding, accounting for 53.2% of cases, followed by pheochromocytomas (18.2%), whereas adrenocortical carcinoma (ACC) was identified in 3.8% of patients. The distribution of pathological diagnoses observed in our cohort is consistent with previous reports. Staubitz et al. reported cortical adenomas and pheochromocytomas in 41% and 28% of patients, respectively, with ACC diagnosed in 6% of cases [5]. Similarly, Aydin et al. observed that 61.1% of operated patients had hormonally active tumors, with cortical adenomas and pheochromocytomas accounting for 73% and 18.3%, respectively, whereas ACC was present in 3.8% of patients [6].

Several surgical series have previously emphasized tumor size as a factor associated with malignancy risk. Bozkurt et al. reported a higher incidence of malignancy in larger adrenal tumors; however, their definition of large tumors included lesions up to 8 cm in diameter, representing a substantially higher cutoff than those commonly encountered in clinical practice [7]. Rossi et al. demonstrated that although adrenal tumors ≥ 6 cm are associated with a higher rate of perioperative complications, minimally invasive adrenalectomy remains a feasible and preferred surgical approach in selected patients [8].

Earlier surgical series frequently incorporated tumor size as a key determinant in surgical decision‐making, although reported cutoff values varied widely across studies. Sturgeon et al. demonstrated that at a tumor size threshold of ≥ 4 cm, the likelihood of malignancy approximately doubled, whereas it increased more than ninefold for tumors ≥ 8 cm [9]. Although earlier ESE guidelines incorporated tumor size as a criterion for surgical decision‐making, the 2023 update represents a paradigm shift by removing tumor size as a standalone indication for adrenalectomy in homogeneous adrenal lesions with benign imaging characteristics [3, 4]. Importantly, our findings did not demonstrate a significant difference in tumor diameter between patients classified as ESE‐positive and ESE‐negative. This observation is particularly noteworthy given the historical reliance on tumor size as a surrogate marker of malignancy risk, suggesting that tumor diameter alone may have limited discriminatory value when considered independently of functional status. According to the contemporary ESE recommendations, a proportion of patients with benign nonfunctioning adrenal lesions included in this historical surgical cohort might have been managed conservatively rather than surgically. Nevertheless, historical surgical decision‐making frequently incorporated tumor size, interval tumor growth, younger patient age, and radiological findings considered suspicious during multidisciplinary evaluation.

In the present study, hormonally active tumors were significantly more frequent among patients with clinically significant adrenal pathology according to ESE criteria (81.7% vs. 4.3%, p < 0.001). This strong association underscores the central role of hormonal hypersecretion in surgical decision‐making within a highly selected surgical cohort. In contrast, tumor size did not differ significantly between patients with and without clinically significant adrenal pathology, supporting the concept that tumor size alone is insufficient to guide surgical indications. These findings are in line with the 2023 ESE recommendations, which emphasize a function‐driven rather than size‐driven approach to adrenal surgery.

Although tumor laterality differed significantly between groups, this finding is unlikely to be clinically meaningful and probably reflects characteristics of the study cohort rather than a true determinant of surgical indication. Neither patient sex nor age differed significantly between groups, suggesting that these variables do not appear to substantially influence the likelihood of fulfilling ESE criteria for clinically significant adrenal pathology.

Although other professional societies, such as the American Association of Endocrine Surgeons, have issued guidelines for adrenalectomy, these recommendations are largely concordant with the ESE guidelines. Both frameworks emphasize hormonal activity and malignant potential as the principal determinants of surgical decision‐making, rather than tumor size alone [10].

This study has several limitations inherent to its retrospective design. First, the analysis was conducted within a single‐center surgical cohort, which may limit the generalizability of the findings to nonoperated or conservatively managed patients. Second, surgical decision‐making reflected historical clinical practice and multidisciplinary judgment rather than predefined ESE criteria, potentially introducing selection bias. Third, because malignant adrenal tumors were classified as ESE‐positive based on histopathological confirmation, this retrospective study cannot determine how many malignant lesions would have been missed if contemporary ESE criteria had been applied prospectively.

Additionally, detailed imaging characteristics, including Hounsfield unit measurements and washout parameters, were not uniformly available for all patients.

Nevertheless, the large sample size and real‐world nature of the cohort represent important strengths, enabling meaningful evaluation of contemporary guideline recommendations within routine surgical practice. From a clinical perspective, these results reinforce the rationale underlying contemporary guideline recommendations and provide empirical support for function‐driven decision‐making. In an era increasingly focused on minimizing unnecessary surgical interventions, such data may help contextualize the evolving role of adrenalectomy.

5. Conclusion

In conclusion, our findings demonstrate that hormonal activity is strongly associated with clinically significant adrenal pathology according to the 2023 ESE criteria, whereas tumor size alone does not appear to reliably discriminate between patients who do and do not fulfill guideline‐defined indications for surgery.

Two‐thirds of patients in this historical surgical cohort would have met the criteria for adrenalectomy according to the updated ESE recommendations, emphasizing the clinical relevance of function‐driven assessment. These results provide real‐world evidence supporting the contemporary paradigm shift from size‐based to function‐based decision‐making in adrenal surgery.

Importantly, these findings do not challenge the validity of contemporary guidelines, but rather illustrate how guideline‐driven frameworks align with real‐world surgical pathology when applied to historical clinical practice.

Author Contributions

Matija Buzejic: conceptualization, investigation, writing – original draft, data curation, formal analysis. Milan Jovanovic: investigation, methodology, software, writing – review and editing. Branislav Rovcanin: investigation, formal analysis, data curation, validation. Marina Stojanovic: data curation, supervision, writing – review and editing, formal analysis. Katarina Tausanovic: methodology, validation, project administration, formal analysis. Nikola Slijepcevic: investigation, visualization, project administration, writing – review and editing. Jovan Ilic: investigation, data curation, software, formal analysis. Vladan Zivaljevic: conceptualization, methodology, writing – review and editing, project administration.

Funding

The authors have nothing to report.

Ethics Statement

The study was approved by the institutional ethics committee (Approval No. 95/69 date 29.01.2026.).

Consent

Written informed consent was obtained from all patients for the surgical procedure, including consent for the use of anonymized clinical data for research purposes.

Conflicts of Interest

The authors declare no conflicts of interest.

Statement of Human Rights

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.