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Characteristic of Aldosterone-Producing adrenocortical carcinoma: review of the literature
Francesco Arcidiacono1D . Bianca Pellegrini2,3 . Antonio Prinzi1,4 . Ignazio Barca1 . Concita Trischitta2 . Rosario Pivonello2 . Pasqualino Malandrino1 . Maria Cristina De Martino2
Received: 4 August 2025 / Accepted: 29 November 2025 / Published online: 12 December 2025 @ The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025
Abstract
Adrenocortical carcinoma (ACC) is a rare tumor, and aldosterone-producing-ACCs are even less frequent. Data on aldo- sterone-producing ACC (APAC) are scarce and most of the current knowledge derives from case reports. Therefore, aim- ing to summarize the main clinical features described in this aggressive cancer, we conducted a review of the PubMed database on this topic from 2005 to 2024. We included only studies with histological confirmation of ACC and biochemi- cal evidence of aldosterone hypersecretion, identifying 27 reported cases of APAC. Epidemiological and radiological fea- tures of APACs resemble those of ACCs in general, whereas the median Ki67 index appears higher (25% vs. 10-14%) and the prevalence of ENSAT stage I greater (18% vs. 5-6%) compared with the overall ACC population, although a meaningful comparison would require a specifically designed prospective study. This is the first review assessing Ki67 and ENSAT stage in APACs based on previously published cases. To date, no significant differences have been described in morphological, clinical, or molecular aspects between these two types of ACC. Larger and higher-quality studies are needed to confirm these findings.
Keywords Adrenocortical carcinoma . Aldosterone . Ki67 . ENSAT · APAC . Aldosterone-producing adrenocortical carcinoma
Introduction
Primary hyperaldosteronism (PA) is a common and poten- tially curable cause of secondary hypertension [1]. In the general hypertensive population, the prevalence of PA
Francesco Arcidiacono and Bianca Pellegrini contributed equally to this work.
☒ Francesco Arcidiacono francescoarcidiacono.fa@gmail.com
1 Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi- Nesima Medical Center, Catania 95122, Italy
2 Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Naples, Italy
3 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende 87036, Italy
4 Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, Palermo, Italy
remains uncertain (ranging from 2% to 6%) [2, 3]. When hyperaldosteronism is diagnosed, instrumental investigation is recommended to exclude malignancy although adreno- cortical carcinoma (ACC) is a rare tumor, and aldosterone- producing-ACCs (APACs) are even less frequent [4, 5]. High resolution computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used to examine adrenal lesions in both symptomatic and asymptomatic patients [2]. The most recent ACC guidelines recommend biochemical screening for hyperaldosteronism in all ACC patients with hypertension or hypokalaemia [4].
ACC is a rare neoplasm with an incidence of 0.7-2.0 cases per million per year, and a poor prognosis [4]. Inci- dence of ACC is greater between 40 and 60 years, with female sex being more affected than male [6]. Most ACCs are hormone-secreting tumors (45-70%), mainly producing cortisol (50-80% of secreting-ACCs) or androgens (40- 60%) and less frequently estrogens (1-3% of male patients) [7]. APACs, either alone or in co-secretion with other hormones, account for approximately 2.5% of all ACCs 8]. A recent multicenter study on ACCs found isolated
mineralocorticoid excess in only 2 out of 145 conventional ACC patients, and in none of the 44 with oncocytic adre- nocortical carcinoma (OAC), which is consistent with the exceptional rarity of this condition [9]. However, since aldosterone is not systematically assessed, the true percent- age of APAC might be underestimated. Although APACs may differ from non-secreting ACC due to the presence of clinical features related to mineralocorticoid excess, to date, no significant morphological or molecular differences have been described between these two types of ACC.
Most of the current knowledge about APAC is primar- ily based on case reports. The present manuscript aims to review the main case reports published since 2005, when a previous review on the subject was published [10]. Another review was conducted in 2014 to summarize some of the data in literature [8]. With the aim of summarizing the clini- cal, biochemical, and histological characteristics, and to provide an updated overview of our knowledge over the last two decades, we conducted a narrative review to analyze the available literature on APAC.
Materials and methods
1. Study design and search strategy
This study is a narrative review of the PubMed database, performed by searching for the following keywords: (((adrenal cancer [Title/Abstract]) OR (adrenocortical car- cinoma [Title/Abstract]) OR (adrenal carcinoma [Title/
Records identified through Pubmed research from 2005 to 2024:
226 results
Records excluded from title and abstract screening: 188
Full text articles assessed for the eligibility:
38
Records excluded from full text screening:
12
Studies included in the analysis: 26
Patients finally included in the analysis:
27
Abstract])) AND ((hyperaldosteronism [Title/Abstract]) OR (aldosterone [Title/Abstract]))). All relevant articles written from 2005 to 2024, irrespective of the type of publication, were included in the search. The reference lists of studies of interest were manually reviewed for additional articles. Two reviewers (A.F., P.B.) independently screened the titles and abstracts of all publications identified by the database search. The remaining studies were reviewed in full text to determine their eligibility for inclusion and analysis.
2. Inclusion Criteria, Information selected
To be included in the current review, eligible studies had to satisfy the following criteria: (1) histological confirmation of ACC; (2) biochemical diagnosis of APAC.
We extracted all relevant available information including demographic, imaging, histopathological, immunohisto- chemical, hormonal, and clinical data, as well as informa- tion about treatment. A database was then constructed and used for analysis. The mean±standard deviation (S.D.), median, and range (min - max) values were calculated as appropriate. When measurements were expressed in differ- ent units, we converted them to the most common unit to facilitate calculation of median, mean, and range values.
Results
Study characteristics
As shown in Fig. 1, we identified 226 articles through a PubMed search between 2005 and 2024, and performed an initial selection based on the title and abstract content. A total of 188 studies were excluded because they did not include patients meeting the inclusion criteria described above. We then performed a full-text screening of the remaining articles: 12 studies were excluded because they did not include patients, did not have histologically con- firmed APAC, or lacked essential clinical data. The final number of the studies included in this review was 26, with a total of 27 patients. Included studies were predominantly case reports, with one case series comprising two patients.
Epidemiology
Among the 27 cases included in this review, the peak inci- dence was between 38.5 and 65 years, and the median was 52 years (range: 18-82). As shown in Tables 1 and 56% were females, and 44% males. Eighteen patients (67%) had pure hyperaldosteronism, 15 (26%) had aldosterone-cortisol co- secretion, and two (7%) of them exhibited triple hormonal
| Features | Patients (=27) |
|---|---|
| Sex, n. (m/f) | 12/15 |
| Age at diagnosis, years (median [IQR]) | 52 (18-82) |
| Tumor size, cm (median [IQR]) | 5.95 (2-20.2.2) |
| Potassium, mEq/L (mean±S.D.) | 2.5±0.7 |
| Signs | |
| Hypertension, n. (%) | 25 (93) |
| Uncontrolled hypertension, n. (%) | 17 (63) |
| Systolic blood pressure, mmHg (mean±S.D.) | 165±28 |
| Diastolic blood pressure, mmHg (mean±S.D.) | 92±14 |
| Hypokalaemia, n. (%) | 25 (93) |
| Symptoms reported | |
| Weakness, n. (%) | 8 (30) |
| Severe hypertension/hypertensive crisis, n. (%) | 6 (22) |
| Headache, n. (%) | 4 (15) |
| Loss of weight, n. (%) | 3 (11) |
| Palpitations/cardiac issue, n. (%) | 3 (11) |
| Fatigue, n (%) | 2 (7) |
| Loss of consciousness n. (%) | 2 (7) |
| Adrenal laterality, n. (%) | |
| Right | 13 (48) |
| Left | 12 (44) |
| Bilateral | 1 (4) |
| Unknown | 1 (4) |
| Hormonal secretion, n. (%) | |
| Aldosteron | 18 (72) |
| Mixed (Aldosteron, Cortisol) | 5 (20) |
| Mixed (Aldosteron, Cortisol, estradiol) | 1 (4) |
| Mixed (Aldosteron, Cortisol, androgen) | 1 (4) |
STAGE ENSAT Unknown 8%
Stage IV 22%
Stage I 18%
Stage II 22%
Stage III 30%
(aldosterone-cortisol-androgen [11] and aldosterone-corti- sol-estradiol [12]).
In terms of laterality, 13 (48%) patients had APAC in the right adrenal gland, 12 (44%) in the left, one (4%) had bilat- eral APAC, and in one (4%) the laterality was not reported. The median tumor size was 5.95 cm (range: 2-20.2).
Clinical aspects
Twenty-five patients (93%) were hypertensive, while only two (7%) had normal blood pressure. Hypertension was uncontrolled in 17 cases (63%), well controlled by medica- tion in five (18.5%), and not available in the remaining five (18.5%) (Table 1). Insufficient data were available regard- ing antihypertensive medication and duration of hyperten- sion. The mean systolic blood pressure was 165±28 mmHg, and the mean diastolic blood pressure was 92±14 mmHg. Hypokalaemia was observed in 25 cases (93%). Potassium levels were reported for 21 patients, with a mean value of 2.5±0.7 mEq/L.
The most reported symptoms were weakness, either gen- eralized or localized, and fatigue. Weakness was reported by eight patients (30%) whereas fatigue was reported by two patients. Other frequently recorded symptoms were related to hypertension: six patients (22%) presented with severe hypertension or hypertensive crisis, and four (15%) reported headache. Three patients (11%) described weight loss as the only sign of malignancy.
Two patients (7%) were admitted to the emergency department for loss of consciousness, and two (7%) expe- rienced palpitations due to severe hypokalaemia. A case of ventricular fibrillation associated with severe hypokalaemia in a hypertensive patient [13] and a case of sudden cardiac arrest in a patient with no known electrolyte abnormalities have also been reported [14].
Among the seven patients with aldosterone-cortisol co-secretion, one presented with facies lunata and other Cushingoid features [15], one had thin skin and easy bruis- ing without other Cushingoid signs [16], and the remaining five (72%) showed no physical signs of hypercortisolism. The ENSAT staging at diagnosis is shown in Fig. 2: five patients (18%) were stage I, six (22%) stage II, eight (30%) stage III, and six (22%) stage IV; staging data were not available for two cases [11, 17]. Figure 3 illustrates the localization of metastases in ENSAT III-IV disease.
Coexisting tumors were reported in four patients: colon carcinoma [8], papillary thyroid cancer [18] and a parathy- roid adenoma associated with hyperparathyroidism [23]. In the latter case, a diagnosis of multiple endocrine neopla- sia type 1 (MEN1) syndrome was suspected, although no molecular analyses were performed. An adrenal myeloli- poma adjacent to the ACC was also reported [24].
LOCALIZATION OF CANCER IN ENSAT III AND IV
70
67%
PERCENTAGE OF PATIENTS
60
50%
50
40
30
25%
25%
25%
20
12.5%
12.5%
10
0
Caval nodes
Local nodes
Undefined Kidney nodes
Renal vein
Lungs
Liver
STAGE III (8 PATIENTS)
STAGE IV (6 PATIENTS)
local nodes [19] and in another, the site was not specified [20]. In the remaining four patients (50%) infiltration of adjacent structures was described: in one patient, infiltration of renal parenchyma [21], in one infiltration of the renal vein [10] and in another both conditions were present [22]
Radiology
All 27 patients underwent radiological evaluation: a CT scan was performed in 22 cases (81%), MRI in one patient (4%) [21] and both CT and MRI scan in four cases (15%).
Regarding radiological features, the most frequently reported finding was heterogenous contrast enhancement, observed in nine patients (33%), whereas a homogeneous adrenal mass was described in only one patient [10]. The tumor margins were described in six patients (22%): three were irregular (50%) and three were well-defined. Calcifi- cation and necrosis were each reported in only two patients (7%). Tumor density was assessed in eight cases with a mean value of 29.25 ± 8.44 Hounsfield Unit (HU). All lesions had a density greater than 10 HU and seven had values greater than 20 HU. The presence of lipids in the adrenal nodule was described in four patients (15%): in three cases (75%) as lipid-poor masses, and in one case as lipid-rich (the tumor showed 32 HU on non-contrast CT but appeared lipid-rich on MRI) [17].
In addition, extra-adrenal disease, as a manifestation of malignancy, was reported in six patients (22%) on CT scan: liver metastases in two cases [25, 26], infiltration of the inferior vena cava in two cases [27, 28], lymph node involvement in one case [15], and displacement of the ipsi- lateral kidney in another [23].
Biochemical aspects
Among the patients included in this review, aldosterone levels were reported in 25 of 27 cases (93%). Values were expressed as a percentage of the upper limit of the reference range (ULR). The median aldosterone increase was 300% of the ULR (range: - 46% - +53122%).
Renin was measured in three cases (11%) as direct renin concentration (DRC), in 21 cases (78%) as plasma renin activity (PRA), and was not available in three cases. We evaluated in how many cases PRA and DRC were sup- pressed, considering cut-offs of 0.6 ng/ml/h for PRA and 5 mIU/L for DRC, as reported by Faconti et al. in a recent guideline [2]. DRC or PRA were suppressed in 17 of 24 (71%) patients.
The aldosterone-to-renin ratio (ARR) was evaluated in 21 patients (78%) with available PRA values. The median ARR was 575 ng/ml/h (range: 27.38-479,000). A confirmatory test was performed in only seven cases (26%): the captopril test in two cases, the saline infusion test in three cases, and adrenal venous sampling (AVS) in five cases. More than one confirmatory test was performed in two patients. The 1-mg dexamethasone suppression test (1-mg DST) and 24-hours urinary free cortisol (UFC) were not performed in all cases. The 1-mg DST was carried out in nine cases (33%), of which eight (89%) showed absent suppression. In one patient, cor- tisol suppression was considered normal, although it should
probably have been interpreted as abnormal [29]. UFC was measured in 14 (52%) patients, with positive results in nine (64%).
Adrenal androgens were measured in 12 cases (44%): the most frequently assessed was dehydroepiandrosterone-sul- fate (DHEA-S), performed in all 12 cases. Androstenedione was performed in three patients and 17-OH-progesterone in one case. DHEA-S was within the normal range in all cases except two: in one case it was increased [16], and in another decreased [13].
Total testosterone was evaluated in five cases (19%): it was increased in one case due to androgen production by the tumor [11], and decreased in another probably due to the older age [25].
Histological, immunohistochemical and molecular aspects
Regarding histological features, we examined Ki67, Weiss score, vascular invasion, mitotic index, and necrosis. Ki67 was available only in eleven of 27 patients (41%) with a median value of 25% (range: 8-90), calculated for patients with ENSAT stages I-III. The Weiss score was reported in 10 cases (37%): the original Weiss score [30] was used in four studies, and the modified Weiss score [31] in six. The median original Weiss score was 6.5 out of 9 (range: 3-9), while the median modified Weiss score was 5 out of 7 (range: 4-6).
Vascular invasion and necrosis were described in 13 cases (48%): among these, vascular invasion was present in 11 (85%) and absent in two (15%); necrosis was pres- ent in 11 (85%), and absent or not evident in two patients. Regarding mitotic index, we distinguished between high mitotic rate (>20 mitoses per 50 high-power fields [HPF]) and low mitotic rate (< 20 mitoses per 50 HPF), as recom- mended when Ki67 is not reported to define tumor grade [4]. Mitotic rate was reported in 12 patients: a high mitotic ☒ rate was described in seven of them (58%), and a low rate in the remaining five (42%).
Immunohistochemical analyses were reported in 14 of 27 patients (52%). The most frequently expressed mark- ers were: inhibin (43%), synaptophysin (36%), vimentin (21%), and CYP11B1/CYP11B2 (21%). Molecular data were available in only two studies [10, 19]: one described cDNA amplification using primers for the housekeep- ing gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH); the other reported heterozygous mutations in TP53 (c.1051 A >G) and MEN1 (c.1003 C >A), both of unknown pathogenicity.
Treatment and response
Among the patients reported in the literature, 21 (84%) out of 25 with available data underwent surgery as the first-line treatment. The remaining four patients initially received medical treatment: mitotane in three cases, one of which in combination with chemotherapy. Data on adjuvant ther- apy were available for 18 cases (67%): adjuvant treatment was not performed in three patients and administered in 15 (83%). Mitotane was the most commonly used agent (10 of 15; 67%). Response to treatment was favourable (partial and complete response) in 7 out of 19 cases (37%) and unfa- vourable in 63%. Relapse was reported in 15 patients (79%). The site of relapse was reported in 16 patients (59%): the most common was the liver (56%), followed by the lungs (37%), peritoneum (12%), and lymph nodes (12%).
A change in hormonal secretion profile was observed in some metastases: in two cases from aldosterone to cortisol [21, 29], and in another, from cortisol and aldosterone to aldosterone only [15].
Discussion
APAC is a very rare disease, representing 2.5% of all ACCs, and its current management and understanding do not sub- stantially differ from other types of ACC. Seccia et al. [10] conducted a review summarizing all information available at that time. However, that review lacked several key data now considered essential, such as Ki67 and other histologi- cal findings, ENSAT stage, treatment response, and particu- larly the comparison with non-secreting ACCs. We therefore aimed to explore these aspects to gain a deeper insight into this rare disease.
Although a direct comparison with general ACC popula- tion is not possible due to the nature of the available data, it is possible to speculate a parallelism between APACs and ACCs to further explore APACs characteristics. Neverthe- less, any direct comparison should be interpreted cautiously, since cohorts of ACC patients often include APAC cases. Considering epidemiology APACs do not appear to differ from ACCs in terms of peak incidence [4, 32], sex distri- bution [33], and their frequent association with cortisol co- secretion [34].
The most frequent clinical sign was hypertension, reported in 93% of patients, and poorly controlled in 77% of those with available data. Hypertension has always been considered one of the most characteristic features of PA: indeed, both previous [5] and recent guidelines [2] still list it among the key screening criteria, especially when resis- tant to drugs, uncontrolled, or occurring in young individu- als. Regarding symptoms, APACs can cause signs related
to hypertension and hypokalaemia, such as hypertensive crisis, headache, palpitation, cardiac issues and loss of con- sciousness, as well as general symptoms due to malignancy (e.g., weakness, fatigue, weight loss). The latter do not dif- fer from those seen in non-functioning ACCs [35], while the former, although more specific to APACs, are not consid- ered pathognomonic but should be included in the overall clinical picture [34].
At diagnosis APACs tended to present with a lower ENSAT-stage in comparison with general ACC population, who typically present with a large primary tumour mass and are classified ENSAT stage I, II, III, or IV in 5-6%, 33-50%, 10-26% or 21-35% of cases, respectively [36, 37]. The higher frequency of stage I in APACs could be related to the symptomatic nature of mineralocorticoid excess. Stage II appeared underrepresented in the present cohort, while stages III and IV were consistent with published data. These differences may also be related to the small cohort size, which reflects the rarity of the disease. Radiologi- cally APACs closely resemble ACCs: in both conditions, the most common features were heterogeneous contrast enhancement and lipid-poor nodules [32, 35]. The density values in all cases exceeded the 10 HU cut-off reported in current guidelines [4, 38]. This cut-off has high sensitivity (97%) but low specificity (52%) [39]. Increasing the thresh- old to 20 HU improves specificity and positive predictive value [40]. In our review, the 87% of cases exceeded this higher threshold. Interestingly, clear tumor margins, usually considered atypical for ACC, were seen in half of the APAC cases [35].
Hypokalaemia is typically considered a key biochemical parameter in the screening of patients with PA. Although it is not specific to APAC and is absent in some PA cases [2], severe hypokalaemia is often found in APACs [5, 40]. It is worth noting that hypokalaemia in ACC more commonly results from massive cortisol excess, which overwhelms the renal 11ß-hydroxysteroid dehydrogenase type 2 system [4]. For the detection of PA, ARR remains the most commonly used tool. However, its interpretation is subject to various pitfalls (electrolyte abnormalities, medications, circadian rhythm, and posture) [2, 5]. Therefore, it is recommended to evaluate ARR alongside its individual components and the overall clinical context. Patients included in this review had a high median ARR, and 95% exceeded the standard cut- off of 30 ng/mL/h. The sensitivity and specificity of ARR depend on the cut-off chosen: when a higher threshold (e.g., >50 ng/mL/h) is applied, sensitivity markedly decreases (to about 10%). Thus, ARR is more suitable for ruling in rather than ruling out patients [41]. It would have been interest- ing to assess whether the method of aldosterone measure- ment (mass spectrometry vs. immunoassay) influenced the reliability of ARR, but this information was not available
in the included studies. Nevertheless, a recent review [42] found no significant differences between these two analyti- cal methods. In this review, confirmatory tests were per- formed only in 26% of cases. It is important to remember that, according to current guidelines, confirmatory testing can be omitted when a florid PA phenotype is present (i.e., clearly elevated ARR, elevated aldosterone concentration, and hypokalaemia) [2, 5]. According to available histologi- cal data, Ki67, considered the single most powerful prog- nostic marker in both localized and advanced ACC, was higher in APACs than in historical ACC cohorts, where median values for comparable ENSAT stages range from 10 to 14% [33, 43-46]. In our review, the median Ki67 value was 25%. Necrosis was observed in 85% of cases, compa- rable to that reported for ACC (81%) [43], while vascular invasion appeared slightly more frequent in APACs. Data on systemic treatments for APAC remain very limited, and no specific therapeutic regimens beyond those used for ACC have been reported [36]. Available evidence suggests that mitotane remains the standard adjuvant and palliative ther- apy, with reported response rates of approximately 30-35%, consistent with conventional ACC. This further supports the need for international registries and collaborative stud- ies to improve understanding of treatment outcomes in such rare tumors. Recommendations for mitotane use do not dif- fer from those for other ACCs: it is suggested in patients at high risk of recurrence (stage III, R1 resection, or Ki67 >10%) [4].
Strengths and limitations
This review has several important strengths that enhance understanding of this disease. In particular, it is the first review on APACs to include analyses of Ki67 and ENSAT stage, two parameters crucial for prognostic evaluation. Moreover, it provides a comprehensive overview of the clinical, biochemical, pathological, and radiological fea- tures of this very rare tumor, despite relying exclusively on case reports and small case series. We believe that summa- rizing all reported APAC cases in the literature is valuable for promoting early recognition and better management, while providing insights for future research. However, sev- eral limitations must be acknowledged. The most significant is the low quality and heterogeneity of the available studies, which, to our knowledge, are limited to single case reports or small series. No multicenter or larger studies including the parameters evaluated here were found. This limitation, combined with the small number of patients due to the rarity of the condition, precludes drawing firm conclusions, allow- ing only speculative interpretation of clinical, biochemical, and radiological characteristics. The findings presented
therefore remain primarily descriptive and should ideally be validated by future studies involving larger cohorts.
Conclusion
APAC is a very rare disease that shares many features with ACC from both radiological and epidemiological perspec- tives. Clinical manifestations, combining symptoms of ACC and those specific to hyperaldosteronism, along with biochemical findings, are crucial for early diagnosis.
Ki67 appears to be higher in APACs compared with the general ACC population, suggesting a potentially greater proliferative capacity. Interestingly, the prevalence of ENSAT stage I appears higher, possibly reflecting earlier diagnosis due to more specific symptoms compared to con- ventional ACCs. Further large-scale, high-quality studies are warranted to better characterize the clinical presentation and biological behaviour of these patients.
Author contributions M. C. De Martino and P. Malandrino had the idea for the article. F. Arcidiacono and B. Pellegrini performed the literature search and data analysis, with the former drafting the article. M. C. De Martino, P. Malandrino, A. Prinzi, I. Barca, C. Trischitta, R. Pivonello critically revised the work suggesting edits and improve- ments.
Data availability No datasets were generated or analysed during the current study.
Declarations
Conflict of interest The authors have no competing interests to declare that are relevant to the content of this article. On behalf of all authors, the corresponding author states that there is no conflict of interest.
Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent For this type of study formal consent is not required.
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