Landscape of Adrenal Tumours in Patients with Congenital Adrenal Hyperplasia

Our aim is to update the topic of adrenal tumours (ATs) in congenital adrenal hyperplasia (CAH) based on a multidisciplinary, clinical perspective via an endocrine approach. This narrative review is based on a PubMed search of full-length, English articles between January 2014 and July 2023. We included 52 original papers: 9 studies, 8 case series, and 35 single case reports. Firstly, we introduce a case-based analysis of 59 CAH-ATs cases with four types of enzymatic defects (CYP21A2, CYP17A1, CYP17B1, and HSD3B2). Secondarily, we analysed prevalence studies; their sample size varied from 53 to 26,000 individuals. AT prevalence among CAH was of 13.3–20%. CAH prevalence among individuals with previous imaging diagnosis of AT was of 0.3–3.6%. Overall, this 10-year, sample-based analysis represents one of the most complex studies in the area of CAH-ATs so far. These masses should be taken into consideration. They may reach impressive sizes of up to 30–40 cm, with compressive effects. Adrenalectomy was chosen based on an individual multidisciplinary decision. Many tumours are detected in subjects with a poor disease control, or they represent the first step toward CAH identification. We noted a left lateralization with a less clear pathogenic explanation. The most frequent tumour remains myelolipoma. The risk of adrenocortical carcinoma should not be overlooked. Noting the increasing prevalence of adrenal incidentalomas, CAH testing might be indicated to identify non-classical forms of CAH.

Many countries have established CAH screening programs, and thus the early identification of the condition in most classic forms is at its birth [17,18].Prenatal diagnosis is also possible, underlying invasive methods such as analysis of the foetal hormones from amniotic fluid, chorionic villus sampling, and non-invasive procedures (cell-free foetal DNA from maternal blood) [1,19,20].Clinical presentation varies from classical CAH, either salt-wasting (SW-CAH), representing the most severe form, or simple virilizing (SV-CAH), to non-classical CAH (NC-CAH) [1,21].In countries without a valid neonatal screening protocol, SW-CAH is typically diagnosed at birth due to salt-wasting crises (manifested with vomiting, diarrhoea, severe dehydration, arrhythmias, and extremely low blood sodium levels).SV-CAH may be recognised later in life despite the early virilisation of the genital organs; a mild adrenal insufficiency may be associated, but there is no severe infantile hyponatremia.NC-CAH is often overlooked in daily practice; affected individuals usually present mild androgen excess symptoms [14,[22][23][24][25][26].
CAH may be associated with various adrenal tumours/masses, apart from the general imaging aspects of "adrenal hyperplasia" that sometimes mimic a nodular lesion (tumourlike presentation), and the distinction is mainly established upon post-adrenalectomy histological exam.Adrenal tumours have a prevalence of up to 30% according to some authors (myelolipomas being the most frequent type); common pathogenic traits between these masses and CAH are still a matter of debate [1,27,28].
Myelolipomas, also known as myeloid lipomas, are benign, small-growing tumours that have a fat tissue component and elements of myeloid cells.Typical imaging characteristics are related to the presence of fat.Their density varies with the fat-to-myeloid component ratio, while enhancement is low due to the poor blood flow [29][30][31][32].Sometimes they reach gigantic sizes, causing compression of nearby organs and local symptoms/signs such as abdominal pain, palpable mass, or urinary tract obstruction.Surgical treatment is electively performed in large and symptomatic tumours (those larger than 10 cm should undergo the standard approach, which is open surgery, rather than laparoscopic removal).Adrenalectomy may induce iatrogenic adrenal insufficiency, and thus a careful decision should be made [33][34][35][36][37][38].Surgery is not usually necessary in asymptomatic myelolipomas and a normal endocrine picture [39,40].
Overall, CAH remains a challenging condition in terms of best management, adequate hormonal substitution (to avoid both over and under treatment), and most practical surveillance protocol [41][42][43].Adrenal tumours in these patients are generally associated with a late CAH diagnosis and a poor disease control [28].Current guidelines do not recommend the use of ACTH assays during usual CAH monitoring [1,13].However, high persistent levels of plasma ACTH represent a potential pathogenic element of the adrenal tumours in CAH [27,28].
Moreover, in addition to myelolipomas, two other specifications should be made when it comes to the overall picture of adrenal tumours in CAH.Adrenocortical carcinoma is extremely rarely reported (and generally, it has a low prevalence in the general population, being considered an orphan disease); it is not yet clear whether the prevalence is higher in CAH than seen in the general population [1].Correct identification is mandatory, being based on a complex panel of assessments (including imaging findings, urine steroid metabolomics, and post-operatory histological and immunohistochemistry reports) [44,45].
The increasing use of different imaging techniques of diagnosis has identified a larger number of adrenal incidentalomas [46].It is still a matter of debate if their true frequency is higher in the CAH population or if these patients are the subject of an increased number of imaging evaluations (thus a false increase of their incidence involves individuals with CAH) [46].Even though NC-CAH poses lower risks compared with SW-CAH and SV-CAH, considering the need for adequate fertility management, genetic advice, and even prenatal treatment in NC-CAH, it is crucial to correctly identify these masses and a careful strategy of intervention or surveillance should be taken into consideration, mostly based on an individual decision according to a multidisciplinary team [47][48][49].The underlying pathological exam in CAH-related incidentalomas includes myelolipomas, adrenocortical adenomas (and even carcinomas), or typical/atypical hyperplasia [46][47][48][49].
Adrenalectomy is not routinely indicated due to the associated risks of the surgery itself and potential endocrine issues of developing adrenal insufficiency.The question of whether the benefits of adrenalectomy surpass the risks in patients with myelolipomas remains a current matter of interest, while generally incidentalomas need a complete hormonal workup and close surveillance in CAH subjects [46][47][48][49].

Aim
Our purpose is to update adrenal tumour profiles in patients diagnosed with CAH.This is a multidisciplinary, clinical perspective based on an endocrine approach.
The search strategy was dual: identifying adrenal tumours identified in CAH patients or CAH as the underlying diagnosis in patients already confirmed with different adrenal masses.We only included the papers in which the term adrenal "tumour" or "mass" was specified by the original authors and not the studies that introduced the usual adrenal hyperplasia imaging aspects in CAH.We included original studies in humans and excluded experimental, in vitro, and animal studies.
Notably, we kept the original terms "myelolipoma", "adrenocortical carcinoma", and "incidentaloma" that were introduced by the cited papers according the original authors, despite the fact that the first two can behave as an incidentaloma as well, but then the tumour should be further characterised based on imaging investigations, hormonal workups, histological reports (if available), etc. Statistical analysis was based on prior published data (original articles); we used mean, median, standard deviation, and ranges depending on the parameter.As mentioned, the included original articles were not restricted by the level of statistical significance.
Moreover, we mention that the cases diagnosed with CAH were included regardless of the fact that CAH diagnosis was established only based on the endocrine workup, but not genetically confirmed by the original authors (and we specified this aspect), since real life medicine showed us that in many centres genetic testing is not unanimously available, yet the diagnosis of CAH can be clearly established upon clinical and hormonal assessment [41][42][43].Of very important note, the adrenal tumours described in the patients diagnosed with CAH were not limited to the presence of the pathological report following adrenalectomy if the original authors specifically provided the imaging features of the tumour (in the absence of adrenal surgery).This is because we did not intend to restrict the search to the histological profile after surgery and since not all the clinicians agree that each tumour detected in one patient with CAH should be removed [1,27,28].

Results
After applying the mentioned strategy, we finally included a total of 52 original works: 9 studies, 35 single case reports, and 8 case series.We organised this samplebased, 10-year study according to two main sections: one is represented by a case-based analysis (3.1.)enrolling reports of CAH and adrenal tumours according to our strategy of search.We followed the genetic/enzymatic defects (CYP21A2 in Section 3.1.1.,CYP17A1 in Section 3.1.2., CYP17B1 in Section 3.1.3,and HSD3B2 deficiency in Section 3.1.4.) and analysed the clinical presentation, genetic testing results, hormonal work-up, as well as adrenal mass features such as size, histological report (if available), management, and outcome at the moment when these tumours were confirmed in CAH patients.
The second section, Section 3.2, includes larger original studies (not case reports or series) where the prevalence of the adrenal tumours in CAH or of CAH in adrenal tumours was reported amid different clinical, genetic, or imaging characteristics (prevalence studies) (Figure 1).

Results
After applying the mentioned strategy, we finally included a total of 52 original works: 9 studies, 35 single case reports, and 8 case series.We organised this sample-based, 10-year study according to two main sections: one is represented by a case-based analysis (3.1.)enrolling reports of CAH and adrenal tumours according to our strategy of search.We followed the genetic/enzymatic defects (CYP21A2 in Section 3.1.1.,CYP17A1 in Section 3.1.2., CYP17B1 in Section 3.1.3,and HSD3B2 deficiency in Section 3.1.4.) and analysed the clinical presentation, genetic testing results, hormonal work-up, as well as adrenal mass features such as size, histological report (if available), management, and outcome at the moment when these tumours were confirmed in CAH patients.
Long-term outcomes are poorly reflected by the published data.Following adrenalectomy, an event-free course at 6 and 12 months follow-up were mentioned in one case [54], respectively, and another subject was offered hydrocortisone and the adrenal mass remained stationary during long-term surveillance [53].Treatment with glucocorticoids such as dexamethasone was associated with a favourable outcome in another subject with tumour decrease.This is the report of Buitenwerf et al. [55] introducing a 43-year-old male with a left adrenal incidentaloma of 5.2 by 4.4 cm that was accidentally discovered on a computed tomography scan.CAH diagnosis was based on biochemical evaluation, including the response to the ACTH stimulation test.Genetic testing confirmed compound heterozygous genetic variants: c.518T>A (p.Ile173Asn) and c.710T>A, c.713T>A, c.719T>A (p.lIe237Asn), (p.Val238Glu), (p.Met240Lys).After dexamethasone administration (0.5 mg/day) for 1 year, the tumour decreased to 4.4 by 2.9 cm [55].
Paradoxically, a 61-year-old male was diagnosed with CAH after the discovery of bilateral myelolipomas (of 18.2 and 7.8 cm maximum diameter, respectively) in association with persistent increased testosterone despite the fact that he was under antiandrogen treatment (leuprolide and bicalutamide) for prostate cancer.The patient received dexamethasone therapy due to lethargy and fatigue, with prompt improvement of symptoms and a decrease in testosterone levels.Genetic testing revealed a CYP21A2 deficiency through bi-allelic genetic variants in the CYP21A2 gene: complete gene deletion on one allele and a C518T>A (I172N) genetic variant on the other [56].
Urinary tract symptoms represent an alternative to the clinical (abdominal) features on first admission.For example, Hui et al. [57] introduced a 65-year-old individual with late CAH diagnosis; the phenotypically male presented lower urinary tract symptoms.Further on, the clinical examination revealed an empty scrotum and small penile length as well as short stature.Increased 17-hydroxyprogesteron and estradiol levels as well as the urinary profile of the steroid metabolites suggested a CYP21A2 deficiency, confirmed by genetic testing (compound heterozygous: p.Ile172Asn, p.Arg483Pro, and p.Met485Trpfs*56 genetic variants); chromosome testing confirmed a 46,XX karyotype.The patient underwent right adrenalectomy due to the discovery of a right adrenal mass of 5.8 cm maximum diameter on computed tomography imaging (that was initially performed in search of intra-abdominal gonads).Pathological examination confirmed adrenal hyperplasia with a mild atypia [57] (Table 3).

CYP17A1 Deficiency
A total of six patients, all phenotypically female, but one with a 46,XY karyotype 7, were identified with CYP17A1 deficiency across three single case reports and one case series of five patients with myelolipomas (out of fifteen individuals tested for CAH genetic variants belonging to two unrelated families), and three of them were identified with the mentioned enzymatic defect [60,[68][69][70].
The average age at presentation was 33.1 years, with a median of 34.The youngest subject was 27 years old [69], while the oldest was 37 [60].Five out of six individuals presented myelolipomas [60,69,70]; one subject out of six was confirmed with an adrenocortical adenoma [68]; 50% (N = three) of the sample-based cohort had bilateral tumours [60,69].All unilateral tumours (N = three subjects) were on the left adrenal gland [60,68,70].The largest adrenal tumour was found by Liu et al. [60] (20 by 15 by 10 cm).This patient had giant bilateral tumours and shared a compound heterozygous genetic variant (c.1118A>T, p.H373L, c.1459_1467del9, and p.D487_F489del) with two of her sisters [60].The dimensions of the adrenal mass in an individual harbouring a tumour are 10 by 6.3 by 8.6 cm, associated with a compound heterozygous genetic variant for p.Tyr329fs (c.985_987delTACinsAA) and a missense genetic variant p.His373Leu (c.1118A>T) [68].Moreover, Chang et al. [70] reported a left adrenal mass of 5 by 9 cm associated with a genetic profile of a heterozygous variant of c.985_987delinsAA (p.Y329Kfs*90) and the p.R96W genetic variant [70].
Five of six patients with CYP17A1 deficiency had hypokalaemia at the moment when the adrenal tumour was confirmed [60,69,70].Arterial hypertension was also noted in three cases (50%) [60,70]; other symptoms included headaches and fatigue [60]; only one individual had abdominal pain due to a tumour of >10 cm [68].
All subjects (N = 6) had high ACTH or high normal ACTH, with values ranging from 41.56 pg/mL [69] and 1250 pg/mL [60], with an average of 394.5 pg/mL; the highest ACTH value was found in the patient with the largest tumour [60].However, an ACTH-tumour size correlation was not confirmed due to a small sample size.Plasma cortisol levels were provided in five of six persons, all of whom had low values [60,[68][69][70].Aldosterone was increased in two cases (if available) [68,70].Data regarding 17-hydroxyprogesterone were provided for one female who presented with a very low level of < 0.05 ng/mL [69].
Five of six subjects underwent adrenal surgery [60,68,70]; one patient out of six was managed with dexamethasone 0.75 mg per day and showed a reduction of the adrenal tumour diameter [69].
In terms of outcome, five of six patients had an adrenal tumour removal [60,68,70].The patient of Lee et al. [68] postoperatively developed nausea, weakness in association with elevated ACTH, and blunted cortisol response to stimulation test.At the 3-year follow-up, progression of the right adrenal hyperplasia was associated with high ACTH levels and poor compliance with glucocorticoid treatment [68] (Table 5).Abbreviations: F = female; NA = not available.

CYP11B1 Deficiency
We identified one case report with a CYP11B1 deficiency.Ozbas et al. [71] presented a 35-year-old female with genital reconstruction during childhood who suffered from hypertension science at the age of 12.She had a left adrenal mass of 7.4 cm associated with hypokalaemia, high ACTH, and androstenedione.Adrenalectomy had a favourable outcome, with post-surgery confirmation of a myelolipoma.Genetic analysis revealed a homozygous missense genetic variant: c.1385T>C L462P variant (NM_000497.3) in the CYP11B1 gene [71] (Table 6).Abbreviations: C = case; NA = not available, 21OHD = 21-hydroxylase deficiency (* data on C4 were not specifically addressed).

HSD3B2 Deficiency
We mention an analysis coming from a larger study on HSD3B2 deficiency.Ladjouze et al.
[72] studied 14 out of 273 patients with classic CAH who suffered from HSD3B2 deficiency.Out of these 14 individuals (coming from 10 families), 3 females had adrenal tumours and SW-CAH (all with a history of consanguinity).CAH diagnosis was established early (13,15, and 16 years, respectively; two of them were sisters).Both siblings carried the p.(Thr152_Pro155del) genetic variant.One of them had a large left adrenal mass of 6.3 by 5.2 by 5.1 cm.Histological examination following adrenalectomy proved an adrenocortical hyperplasia in one case, while her sister presented a smaller left adrenal mass of 2.5 cm and she continued surveillance.The third patient, harbouring a p.(Pro222Gln) pathogenic variant, had a right adrenal mass (of 3 cm) with necrotic areas that was removed due to a high malignancy suspicion; however, the histological report also showed an adrenal hyperplasia.This patient was associated with an ovarian adrenal rest tumour [72].
Overall, the topic of the adrenal tumours/masses in cases with CYP11B1 and HSD3B2 defects remains at a low level of statistical evidence and awareness is necessary, while no clear hormonal-adrenal tumour correlations can be established so far (Table 7).Abbreviations: DHEA-S = dehydroepiandrosterone-sulfate; K = potassium; Na = sodium; 170HP = 17hydroxyprogesterone; 170HPreg = 17-hydroxypregnenolone; NA = not available; = decrease; = increase.
The scenario of detecting an adrenal tumour starts from an adrenal imaging scan; an individual decision is taken with respect to adrenalectomy.For example, we mention a 26-year-old patient who presented with hypertension and hypokalaemia who was diagnosed with 17α-hydroxylase/17,20-lyase deficiency according to biochemical and endocrine findings (low plasma cortisol, 17-hydroxyprogesteron, respectively, high ACTH and deoxycorticosterone, as well as hypogonadotropic hypogonadism).Genetic testing for CYP17A1 genetic variants was unavailable.The patient's karyotype was 46,XY.Magnetic resonance imaging did not reveal any gonads.Glucocorticoids and oestrogens were initiated.A left adrenalectomy was performed due to an asymmetrical enlargement of the left adrenal and associated persistent abdominal pain.A pathological examination confirmed a myelolipoma [89].
Data regarding the outcomes in these individuals (N = 22) are relatively scarce, varying from a good evolution with symptoms remission [76,83], disease-free following adrenalectomy [82] to rapid relapse (one patient had a nodularity at the adrenal bed at 3-month follow-up) [88].
A study investigating the relationship between CAH control and adrenal imaging aspects was conducted by Kim et al. [96]; the retrospective cohort included 90 adults with 21-hydroxlase deficiency and 270 healthy controls; 12/90 (13.3%) subjects were diagnosed with adrenal tumours: unilateral (N = 9/12) and bilateral (N = 3/12).Except for one adrenocortical adenoma, all tumours were identified as myelolipomas based on radiologic (computed tomography) findings.Higher levels of ACTH, 11β-hydroxyandrostenedione, and progesterone sulphate levels were associated with the presence of these masses, but no correlation between hormonal values and tumour size was established [96].Similarly, a retrospective study on 88 patients with classic CAH revealed a myelolipoma prevalence of 12.5% (N = 11), respectively, of benign adenomas of 9% (N = 8); one pheochromocytoma was reported as well (this represents the only case reported during the latest 10 years) [95].Another study regarding long-term consequences of CAH (CYP21A2 deficiency) followed 20 subjects (among a total of 53) via adrenal ultrasound: 3/20 subjects with SV-CAH had adrenal adenomas; 1/20 cases of SV-CAH was associated with adrenocortical carcinoma at the age of 15; 1/20 patients with SV-CAH presented a myelolipoma [93].
The prevalence of CAH in subjects diagnosed with adrenal incidentalomas varied between 0.3% and 3.6% [90][91][92]94,[97][98][99].Kiedrowickz et al. [91] analysed the prevalence of NC-CAH among adults with adrenal incidentalomas (N = 100).The most common genetic variants of CYP21A2 were tested; 8/100 (0.8%) persons had CYP21A2 pathogenic variants (and 3/8 of them exceeded the cut-offs for stimulated 17-hydroxyprogesterone).When compared to a control group of healthy neonates (as a substitute for the prevalence of these genetic variants in the general population), the CYP21A2 genetic variant prevalence was statistically significantly higher in patients confirmed to have incidentalomas (N = 3 subjects with P30L, N = 3 with P453S, and N = 2 with V281L).The mean tumour size was 2.4 cm (between 1.6 cm and 3.7 cm) [91].Similarly, Patrova et al. [92] analysed 637 patients with adrenal incidentalomas from the perspective of underlying CAH; 2/637 (0.3%) were confirmed to have CAH; both cases have been previously reported [51,100].A bias of interpretation of this rate came from the fact that not all the patients were specifically tested for CAH.Yet, a subgroup was assessed either by urinary steroids profile (N = 26) or by 17-hydroxyprogesterone assays (N = 47), and thus CAH prevalence increased to 2.9% [92].A prospective cohort of 228 adrenal incidentalomas identified late-onset CAH in 1.8% of them (N = 4) [94].Sahlander et al. [97] analysed CAH prevalence in 320 subjects with adrenal incidentalomas by using an ACTH stimulation test and genetic confirmation; 8/222, representing 3.6%, had NC-CAH (only this subgroup of 222 individuals was assessed via the mentioned dynamic test; a cut-off of 17-hydroxyprogesterone of ≥30 nmol/L was applied) based on an ACTH stimulation test and not basal levels (with negative genetic testing with respect to CYP21A2 gene).Fifty percent of the individuals with NC-CAH based on an ACTH stimulation test had bilateral adrenal tumours (and the others had unilateral masses).A larger size was correlated with a positive stimulation test, with diameters ranging from 1.6 to 6.6 cm (median of 3.8 cm) [97].

From Case-Sample Analysis to Prevalence Studies
The analysis of published case reports and series showed, as expected, that the majority of data concerned 21-hydroxylase deficiency (13 single case reports and 5 case series, with a maximum of 5 patients per paper with respect to 27 subjects diagnosed with synchronous CAH that was genetically confirmed and adrenal tumours), followed by CYP17A1 deficiency (3 single case reports, 1 case series with 3 patients/paper, N = 6), CYP11B1 deficiency (1 single case report, N = 1), and HSD3B2 deficiency (1 case series; N = 3); respectively, there were cases of CAH without a specific genetic confirmation (18 case reports and 1 case series; N = 22), and thus there was a total of 59 patients across 43 original papers (Figure 2).Most patients with genetically confirmed CAH were diagnosed after the discovery of the adrenal tumours , while the majority of the individuals without a genetic confirmation had a known (prior) diagnosis of CAH at presentation for the adrenal mass [64,[73][74][75][76]78,[85][86][87][88].SV-CAH was the most prevalent form in both mentioned groups (with genetic confirmation and without).The highest rate among tumours was for myelolipoma (N = 42), and all patients with CYP17A1 deficiency and the one with CYP11B1 deficit had this type; however, two-thirds of subjects with HSD3B2 deficiency actually had adrenocortical hyperplasia.Incidentaloma (N = 18) was the second-most frequent tumour, but this radiological term might underline different histological reports (if surgery is decided), including myelolipomas [51,52,55,59,[64][65][66]79,80,82,84].Although rare, adrenocortical carcinoma was reported in three patients [52], and it has been reported before our timeframe of research [99].The largest diameter was 40 cm (in a case of a myelolipoma) [67].
The most common presentation in both groups included abdominal symptoms such as abdominal discomfort, pain, distension, nausea, and vomiting (either caused by a large adrenal mass or by adrenal insufficiency) [57,59,62,75,77,83].In terms of treatment, most patients underwent surgery, especially for adrenal lesions larger than 10 cm.
In both groups, ACTH values (if available) were increased in most subjects; ACTH values did not correlate with tumour size.17-hydroxyprogesterone was elevated as well, and it seemed higher in individuals with larger tumours (with regard to both groups of genetically confirmed and unconfirmed CAH).
Considering that genetic confirmation is not always commonly available, there are still many reports of patients diagnosed with CAH based on hormonal profiles or ACTH stimulation tests.Some of them, however, were diagnosed at birth with SW-CAH forms.Current findings suggest an under diagnosis of SV-CAH, especially in patients with concurrent adrenal tumours.Lack of treatment leading to increased ACTH (sometimes clinically expressed as hyperpigmentation) [58] may induce a tumour growth up to very large diameters of over 10 cm, affecting nearby organs, including kidney compression [58].Patients suffering from SV-CAH may benefit from an early diagnosis and treatment, including the scenario of developing an adrenal mass.
Regarding laterality, the left side seemed more affected in cases of unilateral lesions or larger on the left adrenal in cases of bilateral tumours.A bias in recognition due to anatomical differences was suggested as a potential explanation [100][101][102][103][104]. Another explanation may be related to the morphological differences, leading to a predisposition for left adrenal tumours.These include a higher volume and therefore a larger pool of cells, asymmetries of the vascular supply and drainage, as well as differences in gland innervation [101].
Moreover, as mentioned, prevalence studies showed that awareness of CAH and adrenal tumour combination is necessary, either starting from patients who received a diagnosis of an adrenal tumour (particularly, of an incidentaloma) or of CAH.Two prospective and seven retrospective (including a registry-based cohort) studies have addressed the present topic, thus providing a good level of statistical evidence, enrolling from 53/88 patients (the smallest sample sizes) to more than 26,000 individuals, depending on the study design.Among CAH cases, adrenal tumours were reported in up to 13.3% of them [96], respectively, 20% [95], while among individuals with previous imaging diagnosis of an adrenal tumour/incidentaloma, the rate of detecting CAH was 0.3% [92], 0.53% [90], 0.8% [91], 1.8% [94], 2.9% [92], 3.6% [97], and 0.75‰ [98].An important aspect remains the lack of systematic genetic confirmation in many of these patients.

Histological Profile of CAH-Associated Adrenal Tumours
The most frequent tumour in CAH was myelolipoma, in accordance with prior published data [105,106].Even though computed tomography-based aspects of myelolipomas consist of fat density, usually negative, there are cases of myelolipomas with a heterogeneous appearance resembling an adrenocortical carcinoma.Differential diagnosis is crucial in these cases [66].Of note, non-adrenal sites of myelolipoma have been reported as well (for example, mediastinal or renal) in non-CAH patients [107,108]; also, adrenocortical adenoma with myelolipomatous metaplasia should be taken into consideration as an alternative differential diagnosis [109].
Adrenocortical carcinoma was reported in 3 out of 59 patients according to the samplebased analysis (5.2%) [52,78,81], this rate being 10 times more frequent than in the general population [44].For instance, a reported case was associated with bilateral myelolipomas on a 32-year-old patient with SW-CAH diagnosed as a neonate, presented with rapidly growing bilateral masses and poor hormonal control.The largest lesion was on the left adrenal side, exceeding 19 cm.A left adrenalectomy was performed and a histological exam identified an adrenocortical carcinoma.Moreover, the patient had a history of testicular adrenal rest tumour.Mitotane was initiated while waiting for the right adrenalectomy (no genetic test was available) [78].Generally, the condition is extremely aggressive, and it requires particular attention due to its highly aggressive potential, regardless of CAH co-presence [110,111].Larger studies are necessary to establish if adrenocortical carcinoma is indeed more frequent among CAH patients or if it is a mere coincidence.According to current data and considering the severity of this disease, the possibility of an adrenal tumour in a patient with CAH being carcinoma should not be overlooked [52,78,81].
Whether hormonal panels, particularly high ACTH and 17-hydroxyprogesterone, are part of the pathogenic elements in CAH-associated tumours is yet to be established.A link between CAH control and the development of adrenal tumours was based on the observations that a high prevalence of late diagnosis and non-compliance with treatment was registered among these patients.In subjects with 3BHSD deficiency, 17-hydroxypregnenolone might be a better predictor of disease control and tumour risk than 17-hydroxyprogesterone [71,72].
Another subject of controversy might be claimed by continuing changes of the terminology and classifications in the area of adrenal tumours [112].Our decade-based analysis included the original terms (from the publications), since it is difficult to adjust them to current names and this might come as a potential source of bias.As mentioned, we did not include CAH cases with typical adrenal hyperplasia at initial imaging assessment unless a tumour was particularly diagnosed (despite the fact that some post-adrenalectomy reports in fact showed an adrenal hyperplasia in some tumours, as they had been identified at computed tomography or magnetic resonance exams) [52,67] (Figure 3).we did not include CAH cases with typical adrenal hyperplasia at initial imaging assessment unless a tumour was particularly diagnosed (despite the fact that some post-adrenalectomy reports in fact showed an adrenal hyperplasia in some tumours, as they had been identified at computed tomography or magnetic resonance exams) [52,67] (Figure 3).Finally, from our perspective, one of the greatest pitfalls of touching the topic of adrenal tumours in CAH is represented by addressing the term "adrenal incidentaloma".Generally, an accidentally detected tumour at any organ subscribes to this name; however, the strictly endocrine perspective also means a negative endocrine profile and a slow growth rate (actually, the most common endocrine incidentaloma is a thyroid nodule, but the term is not usually applied to this gland in daily practice, but rather for adrenals and pituitary glands) [113,114].Yet, as seen in mentioned studies, incidentalomas in CAH were not always harmless and the histological reports were heterogeneous, and Finally, from our perspective, one of the greatest pitfalls of touching the topic of adrenal tumours in CAH is represented by addressing the term "adrenal incidentaloma".Generally, an accidentally detected tumour at any organ subscribes to this name; however, the strictly endocrine perspective also means a negative endocrine profile and a slow growth rate (actually, the most common endocrine incidentaloma is a thyroid nodule, but the term is not usually applied to this gland in daily practice, but rather for adrenals and pituitary glands) [113,114].Yet, as seen in mentioned studies, incidentalomas in CAH were not always harmless and the histological reports were heterogeneous, and thus the presence of an incidentaloma in CAH remains an open chapter and awareness of its particular significance is needed.Also, it might seem that CAH patients are more frequently assessed and thus it increases the risk of detecting an adrenal tumour, but, as already shown, many adrenal masses were found in poorly controlled and uncompliant cases; that is why a general conclusion is debatable.Moreover, our 10-year sample-based study included the COVID-19 pandemic period (between March 2020 and the first months of 2023); it is difficult to establish if fewer imaging investigations have been performed in these patients due to the medical and social regulations amid first waves.However, as seen in other medical and surgical domains, the pandemic impact should be noted when referring to the incidence of tumours, including adrenal incidentalomas [115][116][117][118][119][120].

A Matter of Surgery or Surgery Matters
Most patients were managed surgically (38/59), especially those with the largest tumours and the symptomatic subjects.The question of whether adrenalectomy may be postponed remains open, considering the fact that the majority of the adrenal masses were myelolipomas, slow-growing, benign tumours that had clear characteristics on computed tomography imaging.However, the gigantic sizes of up to 40 cm indicate that the subjects should be monitored to identify and remove in time such large tumours, which can possibly cause compression of nearby organs, which indicates adrenalectomy [121].Whether the adrenal removal will be performed via a traditional approach or the laparoscopic route (that is preferred nowadays) represents a strictly surgical decision based on prior endocrinological and imaging assessments, as generally seen in other areas of adrenal tumours [122,123].
When choosing surgery, it is important to know whether patients with adrenal tumours may suffer from CAH, due to the risk of developing adrenal insufficiency [59,77].Sometimes, adrenal failure occurs years after (unilateral) surgery [77].Currently, the decision of adrenal removal is based on an individual decision rather than a guideline indication.Falhammar et al. [124] showed in 2016 according to a meta-analysis (n = 36 articles) with respect to CAH or carrier status in patients with adrenal incidentalomas that bilateral tumours "were frequent in CAH" (but bilateral lesions did not predict the most frequent CAH deficiency, namely CYP21A2) [124].Consequently, the decision of tumour removal is even more challenging in these cases.

Limits of the Topic and Further Expansion
We are aware of the potential bias that comes with a narrative review, but we intended to cover a heterogeneous panel of issues in the area of adrenal tumours and CAH and not restrict the research.Also, the level of statistical significance of the cited papers varied from a single case report to studies with large sample sizes.Whether disease control or high ACTH levels are contributors to the development of such adrenal tumours in CAH is yet to be explored as a potential pathogenic link.Another potential bias may be the fact that the incidental detection of a tumour in a patient diagnosed with CAH does not necessarily mean causality, only a co-existence and that further studies are necessary.Also, the largest tumours are usually referred to adrenalectomy, and thus a potential bias with respect to the histological report of the entire panel of different tumours is expected.As mentioned, the term "incidentalomas" is not associated with any pathological report, and that is why the exact imaging-histological picture is difficult to assess in the absence of surgery.Another open issue remains the selection of adrenalectomy candidates and the exact protocol of imaging surveillance in CAH.

Biomedicines 2023 ,
11,  x FOR PEER REVIEW 22 of case reports and 1 case series; N = 22), and thus there was a total of 59 patients across original papers (Figure2).

Figure 3 .
Figure 3. Bilateral adrenal hyperplasia (red arrows) according to computed tomography exam on a prior unreported case of a 26-year-old female diagnosed with HSD3B2 deficiency and SV-CAH form (no tumour was suspected in this case since the imaging aspect is rather usual in this situation).

Figure 3 .
Figure 3. Bilateral adrenal hyperplasia (red arrows) according to computed tomography exam on a prior unreported case of a 26-year-old female diagnosed with HSD3B2 deficiency and SV-CAH form (no tumour was suspected in this case since the imaging aspect is rather usual in this situation).