Society for Endocrinology
Adrenal tumors in the elderly
Abel Decmann1,*, Peter Istvan Turai2,*, Pál Perge2,* and Peter Igaz®2,3,t
1Dr László Vass Health Center, Municipality of District XV, Budapest, Hungary
2Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
3Department of Endocrinology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
Correspondence should be addressed to P Igaz: igaz.peter@semmelweis.hu
*(A Decmann, P I Turai, and P Perge contributed equally to this work)
+P Igaz is an Associate Editor of Endocrine-Related Cancer, and was not involved in the review or editorial process for this paper This paper forms part of the themed collection Biology of Aging and Endocrine-Related Cancers: Shared Mechanisms and Interventions. The Guest Editors were Christin Burd and Mina Sedrak.
Graphical Abstract
Aging and adrenal tumors: Clinical and molecular insights
Molecular and cellular changes Aldosterone-producing micronodules accumulate with age
Benign and malignant tumors behave differently in elderly
Mechanisms: Senescence, inflammation, immune dysfunction
ACC has worse prognosis in elderly
Senescence-associated secretory phenotype suppresses tumor growth
Pheochromocytoma is rare, but more severe in elderly
Aging increases adrenal tumor incidence
Key findings
Sex differences: androgens enhance early anti-tumor effect, weaker in females
Aging reshapes adrenal tumor biology
Abstract
The incidence of adrenal tumors rises with age, but the link between adrenal aging and tumorigenesis is still not well defined. This mini-review summarizes age-related changes in both the adrenal cortex and medulla, including structural remodeling, altered steroidogenesis, and shifts in immune and cellular homeostasis. We then examine adrenocortical carcinoma (ACC), where clinical outcomes are poorer in older patients and where senescence, inflammation, and sex-specific immune differences may shape disease behavior. Limited information is available for other adrenocortical tumors, while pheochromocytomas in the elderly are described mainly in case reports, often with diagnostic and perioperative difficulties. For other rare adrenal neoplasms, data are fragmentary. Much of the mechanistic evidence
summarized here derives from preclinical models, and robust clinical validation remains limited; accordingly, translational inferences should be regarded as provisional. The evidence suggests that aging influences both the biology and clinical course of adrenal tumors, but systematic studies are lacking. This review brings together what is currently known and highlights many open questions. We hope this will serve as a starting point for further work on how aging affects adrenal function and tumor development and how this knowledge might be used to improve care of older patients.
Keywords: adrenal; aging; tumor; adrenocortical cancer; adenoma; pheochromocytoma
Introduction
The incidence of adrenal tumors rises with age (1, 2), reflecting both the widespread use of imaging techniques and biological changes in the aging adrenal, but the underlying mechanisms are mostly unknown (3). Beyond incidental detection, aging of the adrenal gland shows multiple structural and functional changes, described below. These age-dependent alterations provide a background in which both malignant and benign adrenal neoplasms may behave differently in older patients. Moreover, two clinically important entities, adrenocortical carcinoma (ACC) and pheochromocytoma, warrant special attention in the elderly (4, 5). This mini-review exclusively focuses on adult and elderly patients with adrenocortical carcinoma and pheochromocytoma/paraganglioma. Pediatric cases are outside the scope of this manuscript.
The risk of cancer rises significantly with age; the National Cancer Institute identifies advancing age as the single most significant risk factor for cancer development. However, mechanisms linking aging to tumorigenesis remain incompletely understood (6).
In this mini-review article, we summarize the main available findings associated with aging in adrenal tumors regarding both clinical and, where available, molecular features. The first step is to consider how aging affects the healthy adrenal gland itself and its pathology. Much of the current evidence linking aging processes to adrenal tumorigenesis derives from experimental and preclinical models, and clinical validation remains limited. To identify the most relevant data, we reviewed original studies and recent reviews published in peer-reviewed journals, located through PubMed and Scopus searches up to May 2025, using combinations of the terms ‘adrenal aging’, ‘adrenal incidentaloma’, ‘adrenocortical carcinoma’, ‘pheochromocytoma’, ‘paraganglioma’, and ‘elderly’. Additional papers were included when they provided clinically or mechanistically important information, with emphasis on studies addressing older adults or age-related mechanisms.
Both pediatric ACC and pheochromocytoma display clinical and molecular features that are different from their adult counterparts (7, 8, 9), but here we focus on
adrenal tumors in the elderly, and pediatric cases are not discussed.
Aging of the adrenal gland and changes in adrenal hormone levels in the elderly
Human data on adrenal aging are limited; much mechanistic insight comes from model organisms. Nevertheless, consistent structural and functional changes with age were described. Adrenal aging involves cortical thinning, sex-dependent changes in cell turnover, and increased immune infiltration accompanied by declining DHEAS/DHEA-S (dehydroepiandrosterone sulfate) production. These changes may predispose to nodule and tumor formation in older adults (4) (Fig. 1).
With aging, the adrenal cortex shows alterations that affect steroid production across its zones. In the zona glomerulosa, age-related atrophy contributes to a reduction in renin-dependent aldosterone production, whereas autonomous aldosterone production may increase because of the accumulation of aldosterone- producing micronodules (APMs). Owing to this balance of opposing influences, aldosterone levels often remain within a similar range in older and younger individuals (10, 11, 12). The APMs frequently harbor somatic mutations in the calcium voltage-gated channel subunit alpha 1 D (CACNA1D) gene - mutations that are rarely found in aldosterone-producing adenomas (APAs). In contrast, potassium inwardly rectifying channel subfamily J member 5 (KCNJ5) mutations - common in APAs - are only rarely detected in APMs. This pattern suggests that these age-dependent alterations are more likely to underlie hypertension not related to primary aldosteronism (12).
Cortisol secretion may also change with age (13, 14), although evidence is limited and mechanisms remain unclear (15, 16, 17). The aging cortex may be prone to autonomous cortisol production, resulting in abnormal dexamethasone suppression test (18). In contrast, adrenal
A
B
Aging adrenal cortex:
Adrenal weight Į Immune infiltration ț Focal hyperplasia/nodules
Cortisol
Aldosterone
zG: CYP11B2 Į Aldosterone Į APMs f zF: variable changes, cortisol ++ / 1 zR: marked atrophy, DHEA/DHEA-S Į
Catecholamines
DHEA / DHEA-S
Adrenal medulla:
-
si
- Mitochondrial DNA deletions > dysfunction
- Catecholamin production Į
- Apoptosis, fibrosis, inflammation
- Shorter telomeres
Adrenal aging
C
p16/p21 1 Telomere shortening
8
Somatic mutations e.g. CACNA1D - APMs DIX
O2
Myeloid infiltration
ROS Mitochondrial dysfunction
androgens exhibit a consistent age-related decline, linked to degenerative changes in the zona reticularis (19, 20).
Alongside cortical atrophy, multiple focal hyperplasias (nodules), such as APMs or steroid-producing nodules (SPNs), appear more frequently with aging (5, 21). One hypothesis proposes that most cortical cells undergo senescence and lose proliferative capacity, while a minority retain the ability to divide and may form these focal growths (5, 22). Typically, one of the nodules enlarges while the surrounding cortex atrophies (4). In APAs, the adjacent zona glomerulosa shows a higher p21 and p16 expression compared with the adenoma itself and the zona fasciculata and zona reticularis, inducing cell cycle arrest or senescence (23). The mechanism determining why a single nodule enlarges remains unknown.
Age-related changes are observed in the adrenal medulla as well, although this area has been far less studied. A decline in medullary function has long been recognized (24). Recent data indicate that catecholamine metabolism can lead to mitochondrial DNA deletions, not only in dopaminergic cells (25) but also in medullary tissue during aging. These changes contribute to mitochondrial dysfunction and subsequent apoptosis of adrenal medullary cells. Inflammation and fibrosis may accompany this process (26, 27). Telomere shortening in medullary cells has also been reported with advancing age (28), and additional structural alterations can be triggered by external factors, such as chronic ultraviolet exposure (29).
At the cellular level, several of these age-related alterations may arise from senescence-associated mechanisms, including telomere erosion and oxidative stress. These processes may contribute to age-dependent
vulnerability to disease and tumor formation in the adrenal gland (5, 30, 31).
These mechanisms might explain the hormonal and cellular changes of the adrenal gland, but they do not account for the higher incidence of adrenal tumors in older people. Evidence comparing adrenal tumors between younger and older adults is limited. While these endocrine and structural alterations shed light on normal adrenal aging, they only partially explain why malignant tumors, such as ACC, are more frequent and more aggressive in older patients. The next section therefore focuses on ACC, where the influence of senescence and immune remodeling has been studied most.
Adrenocortical tumors in the elderly
Adrenocortical cancer and molecular features of aging
Although several experimental studies have begun to delineate age-related mechanisms in ACC, these remain largely confined to model systems. Current molecular and immunologic insights should therefore be interpreted cautiously until validated in larger, clinical cohorts. ACC shows a bimodal age distribution, with incidence peaks in the first and fifth decades of life (32).
Many studies report results using a ≥60 vs <60 years split for comparability; we retain authors’ categories for accuracy but emphasize that age effects are likely continuous rather than reflecting a biological threshold. According to data analyzed from the Surveillance, Epidemiology, and End Results (SEER) database,
five-year overall survival (OS) rates decline considerably with advancing stage, with survival at 55, 31, and 8% for localized, locally advanced, and metastatic ACC cases, respectively (33). In contrast, the age- and sex-matched general-population controls, generated one-to-one via Monte Carlo/Markov simulation from SSA (Social Security Administration) life tables, exhibited consistently high survival rates (92-94%). Notably, even patients with localized disease experienced a 39% reduction in life expectancy compared to the control cohort, with survival deficits increasing to 61 and 84% for locally advanced and metastatic stages, respectively (33). This background benchmark means that the excess- mortality estimate reflects the composite burden of ACC and its management, not tumor biology alone. SEER lacks tumor functional status; therefore, the analysis is not stratified by secretory phenotype (e.g., cortisol vs androgen). Another study from SEER compared the surgical prognosis and survival between younger adults (<60 years, excluding those <18 years) and elderly (≥60 years) as commonly reported categories of ACC patients (34). Among the elderly cohort, the 1- and 5-year OS rates were 46 and 20%, respectively, compared to 65 and 35% in younger patients. Similarly, cancer- specific survival was significantly lower in the elderly group, with 1- and 5-year rates of 54 and 28%, respectively, versus 69 and 39% in the younger cohort. These disparities highlight the pronounced challenges in managing ACC among older adults, compounded by their lower rates of surgery (59% in elderly vs 69% in younger patients) and lymph node dissection (12% in elderly vs 20% in younger patients) (34).
The decline in survival highlights the challenges posed by ACC in elderly patients, where cellular senescence, chronic inflammation, and immune dysfunction can synergize with advancing age to accelerate disease progression. These findings emphasize the need to understand how senescence-associated mechanisms influence the trajectory of ACC, particularly in aging adrenal tissues, where the dual roles of senescence as both a tumor-suppressive and tumor-promoting force become evident. Addressing these dynamics could provide critical insights into improving outcomes for this vulnerable population.
Cellular senescence represents an important mechanism of aging and tumorigenesis, particularly in age-associated ACC, a rare but aggressive malignancy (6). This process - hallmarked by irreversible cell cycle arrest and activation of the senescence-associated secretory phenotype (SASP) - drives changes in the tissue microenvironment that shape tumor behavior (35). In the context of aging, senescence emerges as a barrier to early tumorigenesis and tumorigenesis may stem from cells that circumvent senescence or from cells that subsequently exit the senescence program (4). Complementing these concepts, a recent multi-cohort transcriptomics study developed and externally validated a four-gene senescence-related risk score
(HJURP, CDK1, FOXM1, and CHEK1) that independently predicts OS in ACC. High-score tumors showed an immune-cold microenvironment with fewer cytotoxic T cells and a lower predicted benefit from immune checkpoint therapy, but greater predicted sensitivity to several cell cycle and growth-pathway agents (for example, BI-2536, OSI-027, tozasertib, daporinad, and linsitinib) (36).
The link between senescence and ACC has been extensively studied, e.g., in murine models deficient in ZNRF3, an E3 ubiquitin ligase frequently mutated in human ACC (37, 38, 39). ZNRF3 loss of function mutations disrupt the regulation of Wnt signaling, which is frequently upregulated in ACC, making cells hypersensitive to Wnt ligands and predisposing them to tumorigenesis (39, 40). In ZNRF3-deficient adrenal tissues, senescence plays a key role in modulating tumor progression, initially restraining hyperplasia by inducing immune surveillance (6). This anti-tumor effect is mediated by the recruitment of myeloid cells, particularly macrophages and dendritic cells observed especially in male tissues, driven in part by androgens, which help clear senescent cells and limit early-stage tumor growth in a sex-dimorphic manner. By contrast, females show a weaker immune response, characterized by reduced myeloid recruitment and an increased propensity for metastatic disease. Females exhibit early recruitment of predominantly nonphagocytic myeloid cells with scarce macrophages and absent SASP/phagocytosis signatures, consistent with impaired efferocytosis and subsequent progression (41). In contrast, androgens in males trigger senescence and SASP, driving the recruitment and fusion of highly phagocytic MERTK/TREM2+ macrophages that clear preneoplastic cells. Consistently, a phagocytic macrophage gene signature is enriched in male ACC patients and associates with favorable prognosis. These findings mirror clinical observations in human ACC, where females have a higher incidence of metastatic tumors and poorer overall outcomes compared to males (42). Androgens in males may amplify the acute immune response triggered by SASP, leading to a more effective elimination of tumor cells before they can establish a supportive microenvironment. These changes sometimes preceded the development of adrenal tumors in some mice, which occurred between 12 and 18 months of age - ages that correspond to the incidence of ACC in humans (6, 42, 43). This heightened immunosurveillance prevents progression to the phase of senescence-driven tumorigenesis, characterized by chronic inflammation and pro-tumorigenic SASP activity. The sex-specific immune modulation highlights a protective role of androgens in early tumor suppression and offers potential avenues for targeted therapeutic strategies. However, as aging progresses, chronic activation of the SASP leads to persistent inflammation and a gradual exclusion of these
A
Cellular senescence in ACC
ZNRF3 deficiency
Wnt
B Immune response over time
Senescence
SASP
IL-9 TNF-a MMPs
Early phase Suppression of tumor growth
Adrenal cortex cell
Tumor cells
CD68+ myeloid cells
Androgens enhance early response
C
Therapeutic strategies
Senolytic drugs
Recruitment of myeloid cells
Late phase
Active cell
chronic inflammation
Senescent cell
IL-9, TNF-a, MMPs
Apoptotic cell
Tumor suppression
protective immune cells, fostering a permissive environment for tumor progression (Fig. 2).
This transition from tumor suppression to promotion is a hallmark of senescence-associated cancers and pronounced in aging tissues (44). The pro-tumorigenic phase is driven by SASP components, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), and matrix metalloproteinases, which remodel the extracellular matrix (ECM), alter cell-cell interactions, and promote angiogenesis (6). These changes support tumor cell proliferation and create pathways for metastasis, a critical factor in the poor prognosis of ACC. Importantly, the depletion of CD68+ myeloid cells, observed in both murine models and human ACC patients, correlates with increased tumor aggressiveness and worse clinical outcomes, suggesting that immune cell dynamics play a central role in determining disease trajectory (6). This framing is consistent with the broader SASP literature on tissue-dependent, time-dependent effects (35, 45), and with the myeloid exclusion patterns reported in Warde et al. (6), but does not imply direct proof of SASP-driven causality in late ACC progression.
The dual role of senescence in ACC presents both significant challenges and opportunities. Enhancing the recruitment and function of myeloid cells within the tumor microenvironment may help restore immune surveillance and suppress tumor progression (4). At the same time, targeting senescent cells through senolytic agents, which selectively eliminate these cells, could mitigate the pro-tumorigenic effects of chronic SASP
activation. Strategies aimed at modulating the SASP to balance its anti- and pro-tumorigenic effects are also being explored, with the goal of leveraging its early protective functions while minimizing its later harmful consequences (46, 47).
In human ACC, the relevance of these findings is underscored by data from The Cancer Genome Atlas (TCGA) and other clinical studies (37). Tumors with high myeloid infiltration, as measured by markers such as CD68, ITGAM, and MSR1 are associated with better outcomes, while those with low myeloid signatures show increased proliferation and poorer survival rates (6). These observations align with the patterns seen in ZNRF3-deficient models and underline the translational relevance of preclinical findings. Moreover, the identification of SASP components and immune cell markers as prognostic biomarkers offers promising tools for patient stratification and personalized therapy.
Other adrenocortical tumors
Compared with ACC, data on other functional adenomas are more limited, yet age-related molecular patterns can still be recognized. These are briefly summarized below.
Aldosterone-producing adenomas
APAs most frequently harbor mutations in the KCNJ5 gene and relatively less frequently in the CACNA1D, ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1), and ATPase plasma membrane Ca2+ transporting 2 (ATP2B3) genes (48). Around 36% of APAs harbor KCNJ5 mutations,
with even higher frequencies reported in Asian cohorts (up to 73%) (49, 50). These tumors present usually along with a larger diameter, higher plasma aldosterone level, and lower potassium level in younger age than in KCNJ5 wild-type APAs (45-47 vs 52-57 years) (51, 52). Considering that APMs, which become more prevalent with age, mostly harbor non-KCNJ5 mutations, this might be related to the observation that APAs harboring these mutations develop later in life (53), compared to APAs with KCNJ5 mutation, which are seen more infrequently in APMs, but more frequently in APAs arising in younger age.
Cortisol-producing adenomas (CPAs)
CPAs are usually associated with somatic mutations in guanine nucleotide binding protein, alpha stimulating activity polypeptide (GNAS), protein kinase A catalytic subunit (PRKACA), and catenin beta 1 (CTNNB1) genes (48, 54). These mutations can lead to adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome or mild autonomic cortisol excess (55). Cells in the adrenal cortex harboring a GNAS mutation can clonally expand to form SPNs - analogous to APMs in primary aldosteronism - and are hypothesized to evolve into CPAS (55). CPAs with PRKACA mutation are associated with younger presenting age and overt Cushing’s syndrome relative to tumors without the mutation or with CTNNB1 mutation (37 vs 53 and 59 years, respectively) (56), a finding confirmed in additional cohorts (57, 58). A study comparing CPAS with PRKACA or GNAS mutation to adenomas without these alterations also reported a younger presenting age (45 vs 52 years) (59).
Beyond these canonical somatic drivers, recent molecular studies have identified additional genetic alterations in cortisol-producing adrenal disease. Loss-of-function mutations in the genes coding for lysine-specific histone demethylase 1A (KDM1A) and armadillo repeat- containing protein 5 (ARMC5) are well established in primary bilateral macronodular adrenal hyperplasia and hereditary food-dependent Cushing’s syndrome, where they promote nodular growth and autonomous cortisol secretion (60). Although these mutations are more typical for bilateral macronodular disease than for solitary CPAs, they broaden the spectrum of predisposing molecular lesions that should be considered in adults with cortisol excess.
Although age-related differences are subtle compared to ACC, these mutational patterns suggest that aging shapes not only tumor incidence but also the spectrum of mutations observed.
Pheochromocytoma
Pheochromocytomas and paragangliomas (PPGLs) are uncommon neuroendocrine tumors that exhibit the highest known heritability rate (30-40%) among all
human neoplasms (8, 61). It originates predominantly from the adrenal medulla; however, approximately one-fifth of all cases are located extra-adrenally (paraganglioma). The catecholamine hormones secreted from the tumor cells can lead to various clinical manifestations (62).
Pheochromocytoma is usually diagnosed in middle-aged (fourth to fifth decade of life) adults; however, the disease has also been described in elderly patients. Germline mutations are significantly more frequent in younger patients (<60 years). In older patients, the sporadic form is more frequent and, sometimes, diagnosed incidentally. Surgical treatment is more complex, and prognosis is worse in elderly patients (63, 64). Elderly patients more often required vasoactive medications, had a longer intensive care treatment, experienced more frequent complications, and had longer overall hospitalization (65).
Unlike ACC, to the best of our knowledge and following an extensive literature search, no molecular studies have addressed age-specific features of pheochromocytoma, underlining how underexplored this field is.
Recent observations indicate that glycemic disturbances may persist in patients with PPGLs, even after tumor removal, but current data do not support hyperglycemia as a predisposing factor. The underlying molecular mechanisms remain to be elucidated (66).
Based on a comprehensive literature review, we have found some case reports published on the occurrence of pheochromocytoma in elderly patients. One of the earliest case reports that investigated the manifestation of pheochromocytoma in the elderly was published more than 70 years ago. In this publication, the authors described the case of an 81-year-old white female patient. The symptoms were characteristic for pheochromocytoma; however, the diagnosis was not set prior to the death of the patient (67). A few other publications also emphasize the complicated clinical scenarios to diagnose pheochromocytoma in the elderly (68, 69, 70, 71, 72, 73).
There are only a few case reports published regarding metastatic pheochromocytoma in elderly patients (Table 1). In this cohort, metastatic pheochromocytoma was first described in a case report from 1956. The diagnosis was set post-mortem. Thirty years passed by when four further cases were diagnosed. In this publication, four patients over 70 years of age were diagnosed with pheochromocytoma, and two of them had metastatic pheochromocytoma (74).
Recurrence of pheochromocytoma has also been described in a 60-year-old man initially treated by laparoscopic adrenalectomy. Ten years later, the development of metastatic pheochromocytoma was detected (78).
| No. of cases included | Age | Sex (M:F) | Germline mutation | Diagnosis established as % | Diameter (mm) | MIBG- positivity (%) | Metastatic | References | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Incidentaloma | Typical symptoms | Atypical symptoms | ||||||||
| 10 | 69.6 (avg) | 5:5 | No | 40 | 30 | 30 | 53.1 (avg) | 90 | No | (61) |
| 4 | 75.5 (avg) | 0:4 | n.d. | 100 | 75 (avg) | 100 | Two cases | (70) | ||
| 1 | 81 | M | n.d. | 100 | 135 | n.d. | Yes | (72) | ||
| 1 | 60 | M | n.d. | 100 | 78* | n.d. | Yes | (71) | ||
| 1 | 84 | M | No | 100 | 94 | n.d. | No | (75) | ||
| 1 | 87 | M | SLC25A11 | n.d. | n.d. | Yes | (76) | |||
| 1 | 86 | M | No | 100 | 58 | n.d. | No | (77) | ||
| 1 | 83 | M | No | 100 | 90 | n.d. | Yes | (73) | ||
| 1 | 77 | F | n.d. | n.d. | n.d. | n.d. | (64) | |||
| 1 | 81 | F | n.d. | n.d. | n.d. | n.d. | (69) | |||
avg, average; n.d., no data.
*Recurrent tumor.
To date, the oldest patient reported with metastatic pheochromocytoma was an 81-year-old man. After the curative surgical removal, no post-operative complications, tumor recurrence, or distant metastasis was found (79).
Although PPGLs are most commonly diagnosed in middle- aged adults, they also occur in older people. Systematic, age-stratified molecular studies are lacking, and much of the literature focused on older patients consists of case reports or small series (80).
Other benign adrenal tumors
The relevant literature on age-dependent changes in rare benign adrenal masses is scarce. Some ganglioneuromas (GNs) arise in the adrenal gland. Only a small minority of these develop in adults. Since the majority of GNs are found in pediatric patients, the disease might be associated with genetic predisposition, but this hypothesis has not been confirmed yet (75). Adrenal myelolipomas usually present in the middle decades of life. Their pathogenesis is yet to be fully elucidated. Altered mesenchymal stem cell function and hormonal stimuli, including ACTH and erythropoietin, have been suggested (76). A higher incidence of myelolipomas is found in congenital adrenal hyperplasia patients; thus, higher ACTH levels might contribute to the development of myelolipomas in younger patients (77).
Conclusions
By integrating findings from molecular studies, clinical data, and immune profiling, we might clarify how cellular senescence contributes to age-associated adrenal pathologies. In ACC, its potential dual role as both a tumor suppressor and promoter underscores the complex interplay between immune modulation, hormonal
changes, and genetic alterations. Similarly, in pheochromocytoma and other adrenal tumors, age-dependent shifts in cellular function and tumor biology highlight the need for refined diagnostic and therapeutic strategies tailored to elderly patients. Overall, most evidence currently rests on preclinical observations or small retrospective cohorts, which limits the strength of clinical extrapolation. Future research targeting senescence-associated pathways and immune microenvironment dynamics may offer novel avenues to improve patient outcomes in these challenging malignancies.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this work.
Funding
The authors acknowledge support from the Hungarian National Research, Development and Innovation Office (NKFIH) (grant K146906 to PI) and TKP2021-EGA-24 from the National Research, Development and Innovation Fund by the Ministry of Innovation and Technology of Hungary financed under the TKP2021-EGA funding scheme.
References
1 Sherlock M, Scarsbrook A, Abbas A, et al. Adrenal incidentaloma. Endocr Rev 2020 41 775-820. (https://doi.org/10.1210/endrev/bnaa008)
2 Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2023 189 G1-G42. (https://doi.org/10.1093/ejendo/lvad066)
3 Barzon L, Sonino N, Fallo F, et al. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003 149 273-285. (https://doi.org/10.1530/eje.0.1490273)
4 Warde KM, Smith LJ & Basham KJ. Age-related changes in the adrenal cortex: insights and implications. J Endocr Soc 2023 7 bvad097. (https://doi.org/10.1210/jendso/bvad097)
5 Hornsby PJ. Aging of the human adrenal cortex. Ageing Res Rev 2002 1 229-242. (https://doi.org/10.1016/s1568-1637(01)00007-1)
6 Warde KM, Smith LJ, Liu L, et al. Senescence-induced immune remodeling facilitates metastatic adrenal cancer in a sex-dimorphic manner. Nat Aging 2023 3 846-865. (https://doi.org/10.1038/s43587-023-00420-2)
7 Kuhlen M, Schmutz M, Kunstreich M, et al. Targeting pediatric adrenocortical carcinoma: molecular insights and emerging therapeutic strategies. Cancer Treat Rev 2025 136 102942. (https://doi.org/10.1016/j.ctrv.2025.102942)
8 Casey RT, Hendriks E, Deal C, et al. International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents. Nat Rev Endocrinol 2024 20 729-748. (https://doi.org/10.1038/s41574-024-01024-5)
9 Turin CG, Crenshaw MM & Fishbein L. Pheochromocytoma and paraganglioma: germline genetics and hereditary syndromes. Endocr Oncol 2022 2 R65-R77. (https://doi.org/10.1530/eo-22-0044)
10 Nanba K, Vaidya A & Rainey WE. Aging and adrenal aldosterone production. Hypertension 2018 71 218-223. (https://doi.org/10.1161/hypertensionaha.117.10391)
11 Baudrand R, Guarda FJ, Fardella C, et al. Continuum of renin- independent aldosteronism in normotension. Hypertension 2017 69 950-956. (https://doi.org/10.1161/hypertensionaha.116.08952)
12 Omata K, Anand SK, Hovelson DH, et al. Aldosterone-producing cell clusters frequently harbor somatic mutations and accumulate with age in normal adrenals. J Endocr Soc 2017 1 787-799. (https://doi.org/10.1210/js.2017-00134)
13 Kern W, Dodt C, Born J, et al. Changes in cortisol and growth hormone secretion during nocturnal sleep in the course of aging. J Gerontol A Biol Sci Med Sci 1996 51 M3-M9. (https://doi.org/10.1093/gerona/51a.1.m3)
14 Gaffey AE, Bergeman CS, Clark LA, et al. Aging and the HPA axis: stress and resilience in older adults. Neurosci Biobehav Rev 2016 68 928-945. (https://doi.org/10.1016/j.neubiorev.2016.05.036)
15 Gupta D & Morley JE. Hypothalamic-pituitary-adrenal (HPA) axis and aging. Compr Physio/ 2014 4 1495-1510. (https://doi.org/10.1002/j.2040-4603.2014.tb00585.x)
16 Ferrari E, Cravello I, Muzzoni B, et al. Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates. Eur J Endocrinol 2001 144 319-329. (https://doi.org/10.1530/eje.0.1440319)
17 Wilkinson CW, Peskind ER & Raskind MA. Decreased hypothalamic- pituitary adrenal axis sensitivity to cortisol feedback inhibition in human aging. Neuroendocrinology 1997 65 79-90. (https://doi.org/10.1159/000127167)
18 Ciftel S & Mercantepe F. Relationship between overnight dexamethasone suppression test and aging. Cureus 2023 15 e48383. (https://doi.org/10.7759/cureus.48383)
19 Parker CR, Mixon RL, Brissie RM, et al. Aging alters zonation in the adrenal cortex of men. J Clin Endocrinol Metab 1997 82 3898-3901. (https://doi.org/10.1210/jcem.82.11.4507)
20 Labrie F, Bélanger A, Cusan L, et al. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 1997 82 2396-2402. (https://doi.org/10.1210/jcem.82.8.4160)
21 Dobbie JW. Adrenocortical nodular hyperplasia: the ageing adrenal. J Pathol 1969 99 1-18. (https://doi.org/10.1002/path.1710990102)
22 Martin GM. Clonal attenuation: causes and consequences. J Gerontol 1993 48 B171-B172. (https://doi.org/10.1093/geronj/48.5.b171)
23 Pieroni J, Yamazaki Y, Gao X, et al. Cellular senescence in human aldosterone-producing adrenocortical cells and related disorders. Biomedicines 2021 9 567. (https://doi.org/10.3390/biomedicines9050567)
24 McCarty R. Age-related alterations in sympathetic-adrenal medullary responses to stress. Gerontology 1986 32 172-183. (https://doi.org/10.1159/000212785)
25 Neuhaus JFG, Baris OR, Hess S, et al. Catecholamine metabolism drives generation of mitochondrial DNA deletions in dopaminergic neurons. Brain 2014 137 354-365. (https://doi.org/10.1093/brain/awt291)
26 Neuhaus JFG, Baris OR, Kittelmann A, et al. Catecholamine metabolism induces mitochondrial DNA deletions and leads to severe adrenal degeneration during aging. Neuroendocrinology 2016 104 72-84. (https://doi.org/10.1159/000444680)
27 Maldonado-Rengel R, Sócola-Barsallo Z & Vásquez B. Impact of aging on the morphology of the adrenal gland in rats. Int J Morpho/ 2024 42 1102-1110. (https://doi.org/10.4067/s0717-95022024000401102)
28 Nonaka K, Aida J, Takubo K, et al. Correlation between telomere attrition of Zona fasciculata and adrenal weight reduction in older men. J Clin Endocrinol Metab 2020 105 dgz214. (https://doi.org/10.1210/clinem/dgz214)
29 Lim HS, Yoon KN, Chung JH, et al. Chronic ultraviolet irradiation to the skin dysregulates adrenal medulla and dopamine metabolism in vivo. Antioxidants 2021 10 920. (https://doi.org/10.3390/antiox10060920)
30 Gao X, Li F, Liu B, et al. Cellular senescence in adrenocortical biology and its disorders. Cells 2021 10 3474. (https://doi.org/10.3390/cells10123474)
31 Neville AM & O’Hare MJ. Histopathology of the human adrenal cortex. Clin Endocrinol Metabol 1985 14 791-820. (https://doi.org/10.1016/s0300-595x(85)80078-5)
32 Wooten MD & King DK. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 1993 72 3145-3155. (https://doi.org/10.1002/1097-0142(19931201)72:11<3145 :: aid- cncr2820721105>3.0.co;2-n)
33 Jannello LMI, Baudo A, Scheipner L, et al. Differences in life expectancy of adrenocortical carcinoma patients vs age- and sex-matched population controls. Int Urol Nephrol 2024 57 107-113. (https://doi.org/10.1007/s11255-024-04180-9)
34 He S, Huang X, Zhao P, et al. The prognosis difference between elderly and younger patients with adrenocortical carcinoma. Front Genet 2023 13 1029155. (https://doi.org/10.3389/fgene.2022.1029155)
35 Coppe JP, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008 6 e301. (https://doi.org/10.1371/journal.pbio.0060301)
36 Peng H, Chen Q, Ye L, et al. A senescence-associated gene signature for prognostic prediction and therapeutic targeting in adrenocortical carcinoma. Biomedicines 2025 13 894. (https://doi.org/10.3390/biomedicines13040894)
37 Zheng S, Cherniack AD, Dewal N, et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 2016 29 723-736. (https://doi.org/10.1016/j.ccell.2016.04.002)
38 Assié G, Letouzé E, Fassnacht M, et al. Integrated genomic characterization of adrenocortical carcinoma. Nat Genet 2014 46 607-612. (https://doi.org/10.1038/ng.2953)
39 Hao HX, Xie Y, Zhang Y, et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 2012 485 195-202. (https://doi.org/10.1038/nature11019)
40 Koo BK, Spit M, Jordens I, et al. Tumour suppressor RNF43 is a stem- cell E3 ligase that induces endocytosis of Wnt receptors. Nature 2012 488 665-669. (https://doi.org/10.1038/nature11308)
41 Wilmouth JJ, Olabe J, Garcia-Garcia D, et al. Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development. Sci Adv 2022 8 eadd0422. (https://doi.org/10.1126/sciadv.add0422)
42 Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev 2014 35 282-326. (https://doi.org/10.1210/er.2013-1029)
43 Flurkey K, Currer JM & Harrison DE. Chapter 20: Mouse Models in Aging Research. The Mouse in Biomedical Research (2nd Edition) 2007 III 637-672. (https://doi.org/10.1016/B978-012369454-6/50074-1)
44 Krtolica A, Parrinello S, Lockett S, et al. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A 2001 98 12072-12077. (https://doi.org/10.1073/pnas.211053698)
45 Lau L, Porciuncula A, Yu A, et al. Uncoupling the senescence-associated secretory phenotype from cell cycle exit via interleukin-1 inactivation unveils its protumorigenic role. Mol Cell Biol 2019 39 e00586-18. (https://doi.org/10.1128/mcb.00586-18)
46 Myrianthopoulos V, Evangelou K, Vasileiou PVS, et al. Senescence and senotherapeutics: a new field in cancer therapy. Pharmacol Ther 2019 193 31-49. (https://doi.org/10.1016/j.pharmthera.2018.08.006)
47 Zhang L, Pitcher LE, Prahalad V, et al. Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. FEBS J 2023 290 1362-1383. (https://doi.org/10.1111/febs.16350)
48 Zennaro MC, Boulkroun S & Fernandes-Rosa F. Genetic causes of functional adrenocortical adenomas. Endocr Rev 2017 38 516-537. (https://doi.org/10.1210/er.2017-00189)
49 Nanba K, Yamazaki Y, Bick N, et al. Prevalence of somatic mutations in aldosterone-producing adenomas in Japanese patients. J Clin Endocrinol Metab 2020 105 1-8. (https://doi.org/10.1210/clinem/dgaa595)
50 Kitamoto T & Nishikawa T. Clinical translationality of KCNJ5 mutation in aldosterone producing adenoma. Int J Mol Sci 2022 23 9042. (https://doi.org/10.3390/ijms23169042)
51 Lenzini L, Rossitto G, Maiolino G, et al. A meta-analysis of somatic KCNJ5 K+ channel mutations in 1636 patients with an aldosterone- producing adenoma. J Clin Endocrinol Metab 2015 100 E1089-E1095. (https://doi.org/10.1210/jc.2015-2149)
52 Yang Y, Gomez-Sanchez CE, Jaquin D, et al. Primary aldosteronism: KCNJ5 mutations and adrenocortical cell growth. Hypertension 2019 74 809-816. (https://doi.org/10.1161/hypertensionaha.119.13476)
53 Nishimoto K, Tomlins SA, Kuick R, et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci U S A 2015 112 E4591-E4599. (https://doi.org/10.1073/pnas.1505529112)
54 Sato Y, Maekawa S, Ishii R, et al. Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome. Science 2014 344 917-920. (https://doi.org/10.1126/science.1252328)
55 Fukumoto T, Umakoshi H, Iwahashi N, et al. Steroids-producing nodules: a two-layered adrenocortical nodular structure as a
precursor lesion of cortisol-producing adenoma. EBioMedicine 2024 103 105087. (https://doi.org/10.1016/j.ebiom.2024.105087)
56 Thiel A, Reis AC, Haase M, et al. PRKACA mutations in cortisol- producing adenomas and adrenal hyperplasia: a single-center study of 60 cases. Eur J Endocrinol 2015 172 677-685. (https://doi.org/10.1530/eje-14-1113)
57 Di Dalmazi G, Kisker C, Calebiro D, et al. Novel somatic mutations in the catalytic subunit of the protein kinase a as a cause of adrenal Cushing’s syndrome: a European multicentric study. J Clin Endocrinol Metab 2014 99 E2093-E2100. (https://doi.org/10.1210/jc.2014-2152)
58 LiX, Wang B, Tang L, et al. Clinical characteristics of PRKACA mutations in Chinese patients with adrenal lesions: a single-centre study. Clin Endocrinol 2016 85 954-961. (https://doi.org/10.1111/cen.13134)
59 Goh G, Scholl UI, Healy JM, et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet 2014 46 613-617. (https://doi.org/10.1038/ng.2956)
60 Yanase T. Recent progress in pathophysiology of cortisol-producing adrenal tumor. Endocr J 2025 73 1-12. (https://doi.org/10.1507/endocrj.EJ25-0207)
61 Hall CBM, Watson EM, Prasad T, et al. Hereditary and clinical insights into paraganglioma and pheochromocytoma. Endocr Oncol 2024 4 e240029. (https://doi.org/10.1530/EO-24-0029)
62 Nolting S, Bechmann N, Taieb D, et al. Personalized management of pheochromocytoma and paraganglioma. Endocr Rev 2022 43 199-239. (https://doi.org/10.1210/endrev/bnab019)
63 Lenders JWM, Eisenhofer G, Mannelli M, et al. Phaeochromocytoma. Lancet 2005 366 665-675. (https://doi.org/10.1016/s0140-6736(05)67139-5)
64 Seabrook A, Vasudevan A, Neville K, et al. Genotype-phenotype correlations in paediatric and adolescent phaeochromocytoma and paraganglioma: a cross-sectional study. Arch Dis Child 2023 109 201-208. (https://doi.org/10.1136/archdischild-2023-325419)
65 Srougi V, Chambo JL, Tanno FY, et al. Presentation and surgery outcomes in elderly with pheocromocytoma: a comparative analysis with young patients. Int Braz J Uro/ 2016 42 671-677. (https://doi.org/10.1590/s1677-5538.ibju.2015.0503)
66 Fischer A, Remde H, Pamporaki C, et al. Long-term persistence of glycemic dysregulation in patients with a history of pheochromocytoma/paraganglioma. J Clin Endocrinol Metab 2025 110 e2966-e2976. (https://doi.org/10.1210/clinem/dgae901)
67 Berkheiser SW & Rappoport AE. Unsuspected pheochromocytoma of the adrenal; report of five cases. Am J Clin Pathol 1951 21 657-665. (https://doi.org/10.1093/ajcp/21.7.657)
68 Radziszewski J, Kabat M & Szostek M. [A case of pheochromocytoma in a 77-year old female patient]. Pol Tyg Lek 1991 46 668-669.
69 Tsutsui A, Omoto K, Eto M, et al. Unsuspected pheochromocytoma of the urinary bladder in an 81-year-old woman. Acta Urol Jpn 2006 52 577-579.
70 Szmidt L, Symonides B, Poor HF, et al. [Pheochromocytoma in a 81 year old woman treated with surgery - case report]. Pol Arch Med Wewn 1997 97 157-160.
71 Lassnig E, Weber T, Auer J, et al. Pheochromocytoma crisis presenting with shock and tako-tsubo-like cardiomyopathy. Int J Cardiol 2009 134 e138-e140. (https://doi.org/10.1016/j.ijcard.2008.03.012)
72 Fullerton CW, Sutton JC & Milne IG. A case of secreting paraganglioma of the organ of Zuckerkandl. Ann Intern Med 1954 40 1212-1217. (https://doi.org/10.7326/0003-4819-40-6-1212)
73 Zakrzewska A, Makowska AM, Górnicka B, et al. [Dramatic symptoms of pheochromocytoma in old woman during antiarrhythmic therapy with sotalol: case report]. Pol Merkur Lek 2003 15 95-97.
74 Cooper ME, Goodman D, Frauman A, et al. Phaeochromocytoma in the elderly: a poorly recognised entity? Br Med J 1986 293 1474-1475. (https://doi.org/10.1136/bmj.293.6560.1474-a)
75 Deflorenne E, Peuchmaur M, Vezzosi D, et al. Adrenal ganglioneuromas: a retrospective multicentric study of 104 cases from the COMETE network. Eur J Endocrino/ 2021 185 463-474. (https://doi.org/10.1530/eje-20-1049)
76 Decmann Á, Perge P, Tóth M, et al. Adrenal myelolipoma: a comprehensive review. Endocrine 2018 59 7-15. (https://doi.org/10.1007/s12020-017-1473-4)
77 Nermoen I & Falhammar H. Prevalence and characteristics of adrenal tumors and myelolipomas in congenital adrenal hyperplasia: a systematic review and meta-analysis. Endocr Pract 2020 26 1351-1365. (https://doi.org/10.4158/ep-2020-0058)
78 Susheela AT, Eldib H, Vinnakota D, et al. Recurrent pheochromocytoma in an elderly patient. Medicina 2020 56 1-7. (https://doi.org/10.3390/medicina56060316)
79 Ma C, Sun E & Lu B. Giant malignant pheochromocytoma in an elderly patient: a case report. Medicine 2018 97 e0614. (https://doi.org/10.1097/md.0000000000010614)
80 Mazza A & Rubello D. Malignant pheochromocytoma in the elderly: which is the best management in clinical practice? Nucl Med Commun 2015 36 1159-1164. (https://doi.org/10.1097/mnm.0000000000000386)