Stesura Seveso 481Archivio Italiano di Urologia e Andrologia 2021; 93, 4 ORIGINAL PAPER No conflict of interest declared. INTRODUCTION Renal cancer represents 3% of all neoplasms in western Countries. During the last few years, its incidence increased by 2% due to an increased amount of inciden- tal radiological diagnosis, especially for small renal mass- es (< 4 cm of diameter) (1, 2), for which nephron sparing surgery is the treatment of choice (3). However, these small lesions can behave biologically different from other renal masses. It is estimated that 20-30% of small renal masses are benign and active surveillance is an acceptable tool that can be used to avoid the surgery and its related risks in this cohort of patients (2-4). The presence of ectopic adrenal tissue in the kidney, while benign, is a rare event that needs to be identified and distinguished from renal cancer. This condition can be divided into two entities based on the pathophysiological origin. First, “Ectopic adrenal tissue” or “adrenal rest”, initially described by Morgagni in 1740, is a congenital anomaly due to the migration, to other organs, of fragments of the primitive adrenal gland, and can be classified as “true” or “accessory” ectopy depending on the migration of the whole or part of the gland, respectively (5, 6). Second, “Adrenal-renal fusion”, first described by Rokitansky in 1855 (7), could be divided into a “congenital” form when it is caused by failure of the retroperitoneal mesenchymal cells to stimulate adrenal capsule formation, or “acquired” form when it is a consequence of inflammation of the peri- renal fat. Consequently the adrenal gland becoming fused with the renal parenchyma, and become anatomically indi- visible from the kidney (8). Most ectopic adrenal tissue is located along the migration path of the urogenital system but it could be present also at the level of celiac axis, broad ligament, spinal cord and other retroperitoneal parenchymatous organs (9). Ectopic adrenal tissue can be present in 50% of newborns, usual- ly regressing and persisting in only 1% of the adult pop- ulation (10). It is not a rare condition and can manifest clinically as endocrine abnormalities due to secretory activity, mass effect or neoplastic transformations. Additionally, due to the location where these lesions can arise, adrenal rest becomes part of the differential diagno- Introduction: Ectopic adrenal tissue in the kidney, including “Ectopic adrenal tissue” and “Adrenal-renal fusion”, is a rare event with a specific behavior which may be difficult to distinguish clinically from renal neoplasms. We performed a systematic review on ectopic adrenal tissue variants reported in the literature under- lining its clinical aspects. Methods: Manuscripts which presented a case report or case series of ectopic adrenal tissue in the kidney were included even if published in original articles, reviews, or letters to the editor. A specific search on SCOPUS®, PubMed®, and Web of Science® database was performed. Only English language papers pub- lished in a period ranging between August 1991 and April 2020 were considered. Additionally, a case we had at our institution is described, and its characteristics are included. Data on clini- cal presentation, type of adrenal anomaly, location, anato- mopathological and immune-histotype characteristics were col- lected. Results: We identified 888 manuscripts. Among these 29 were included in this systematic review. Overall, 39 patients with renal adrenal fusion or adrenal ectopia were considered. In most cases, the diagnosis was made incidentally, or following investi- gation for flank pain, abdominal pain, or endocrinological disor- ders. CT scan frequently identified a solid vascularized lesion that was difficult to distinguish from renal neoplasm. Adrenal fusion was mostly located at the level of the upper pole. Adrenal rest was found in the renal parenchyma, renal hilum, or retroperitoneum in close proximity to the renal peduncle. Often these ectopic adrenal tissue lesions follow a benign behavior and can be classified as functioning or non-functioning adenomas. Rarely, they may experience neoplastic degeneration. The most frequently positive markers were inhibin, vimentin, melan-A, synaptophysin and anti-p450 scc. Conclusions: Ectopic adrenal tissue in the kidney is a rare event with specific clinical characteristics that need to be identified in order to arrive at a correct diagnosis and carry out appropriate treatment management. KEY WORDS: Intrarenal adrenal tissue; Ectopic adrenal tissue; Renal-adrenal fusion; Adrenal rest; Incidental renal masses; Renal cancer; Small renal mass. Submitted 19 September 2021; Accepted 23 September 2021 Ectopic adrenal tissue in the kidney: A systematic review Davide De Marchi 1*, Alessandro Tafuri 2-4*, Guglielmo Mantica 5, Aliasger Shakir 6, Federico Scarfò 7, Giovanni Passaretti 1, Salvatore Smelzo 1, Silvia Proietti 1, Lorenzo Rigatti 1, Roberta Luciano 7, Alessandro Antonelli 3, Vincenzo Pagliarulo 2, Rosario Leonardi 1, Guido Giusti 1, Franco Gaboardi 1 1 Department of Urology, San Raffaele Hospital, Milan, Italy; 2 Department of Urology, “Vito Fazzi” Hospital, Lecce, Italy; 3 Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy; 4 Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy; 5 Department of Urology, University of Genova, Ospedale San Martino, Genova, Italy; 6 USC Institute of Urology, Catherine and Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA; 7 Department of Pathology, San Raffaele Hospital, Milan, Italy. * Equal contribution. DOI: 10.4081/aiua.2021.4.481 Summary Archivio Italiano di Urologia e Andrologia 2021; 93, 4 D. De Marchi, A. Tafuri, G. Mantica, et al. 482 sis along with renal cell carcinoma and for this reason it must be correctly diagnosed (11). Here, we report a sys- tematic review of the literature on ectopic adrenal tissue while underlining its main clinical aspects. METHODS We performed a systematic review limited to case reports, case series and all formats reporting a case description on our specific topic. The purpose of this literature review is to describe the salient features of adrenal ectopia in order to assist the differential diagnosis process with renal neo- plasms. For this reason, we considered only adrenal ectopias located at the renal level or in the retroperi- toneum in close proximity to the renal pelvis in the study. A specific search on SCOPUS®, PubMed®, and WEB OF SCIENCE® database was performed including “[(intrarenal adrenal tissue) OR (ectopic adrenal tissue)] OR [(renal - Box 1. Case report. In November 2017, a 66 year-old man with a previous history of diabetes mellitus, hypertension, and benign prostatic hyperplasia came to our Institution. Due a single episode of hyperpyrexia associated with left flank pain, he performed an abdomen ultrasound with incidental finding of a left renal mass, and a following abdomen CT scan which confirmed the presence of an exophytic solid lesion of 10 x 14 mm, in the middle lateral margin of the left kidney (R.E.N.A.L. score 6A; P.A.D.U.A. 7 A), (Figure 2 A-B-C-D). Both adrenal glands had regular morphology, size and location. Complete blood count, creatinine, urine analysis values were all within normal limits. Given the small size of the neoformation, active surveillance of the neoformation was proposed to the patient but he preferred to remove the mass, and robot assisted left partial nephrectomy was performed in January 2018. A clampless enucleoresection was performed with a continuous suture on the resection bed by sliding suture technique with Hem-O-Lok. The post-operative period was regular and uncomplicated. The patient was discharged after three days. The definitive anatomopathological report reports “ectopic adrenal gland with renal tissue where occasional tubular thyroidization and minimal interstitial chromic nephritis” (Figure 3 A-B). The follow up was negative. Ultrasound of the abdomen and blood test with kidney function evaluation was negative. Figure 1. PRISMA flowchart. 483Archivio Italiano di Urologia e Andrologia 2021; 93, 4 Ectopic adrenal tissue in the kidney adrenal fusion) OR (adrenal rest)] AND [(kidney cancer) OR (renal cancer) OR (renal cell carcinoma)]” MeSh terms. Only manuscripts in English language published in a period ranging between August 1991 and April 2020 were considered (Figure 1). All the manuscripts which presented a case report or case series were included even if published in original articles, reviews, or letters to the editor. Two authors (D.D.M.) and (G.M.) independently reviewed the literature using inclusion and exclusion criteria. All dis- agreements about eligibility were resolved by discussion with a third reviewer (A.T.) until consensus was reached. This study was performed using guidelines set out by Preferred Reporting Items for Systematic Reviews and meta- analysis (PRISMA) statement (12). Additionally, a case at our institution is described, and its characteristics are included in the following evidence syn- thesis (Box 1, Tables 1-2). Table 1. Clinical and pathological characteristics of adrenal ectopias findings in the included studies. Author Type of article N° of case Clinical Presentations Adrenal abnormalities AP report Markers Goren et al. 1991 (14) Case report 1 case Left lumbar pain Adrenal rest Ectopic adrenocortical adenoma NS Chin et al. 1994 (6) Case report 1 case Incidental finding in patient with kidney neoplasia True heterotopia ectopic adrenocortical adenoma Anti-P450 scc+ Colberg et al. 1998 (15) Case report 1 case abdominal pain and weight loss Adrenal renal fusion Adrenocortical adenoma Pan cytokeratin - cytokeratin 7- Ayala et al. 2000 (16) Case report 1 case Cushing’s syndrome Adrenal rest Ectopic adrenocortical adenoma NS Souverijns et al. 2000 (17) Case report 1 case Hypertension Adrenal rest Ectopic adrenocortical adenoma Vimentin + Szumera et al. 2003 (11) Case report 1 case NS Adrenal rest Ectopic adrenocortical adenoma Vimentin + synaptophysin + cytokeratin- EMA - Fan et al. 2004 (18) Case report 1 case Incidental findings in patients with metabolic syndrome Adrenal renal fusion Atrophic adrenal gland and renal cyst NS Hsu et al. 2005 (19) Case report 1 case Incidental findings in Patient with kidney neoplasia Adrenal rest Ectopic adrenocortical adenoma NS Claahsen-van der Grinten Case report 1 case Abdominal pain in patient with congenital Adrenal rest Adrenal rest tumour cytokeratins 8/18 + inhibin + et al. 2008 (20) adrenal hyperplasia AE1/AE3 - epithelial membrane antigen - CD68 - CD10 - placental-like alkaline phosphatase - Baydar et al. 2008 (32) Case series 2 cases Abdominal pain Adrenal rest Ectopic adrenocortical adenoma melan-A + inhibin + calretinin + EMA- pancytokeratin - Eterotopic adrenal cortical tissue melan-A + synaptophysin + calretinin + EMA- CD68- LInder et al. 2009 (21) Case report 1 case Incidental finding Renal adrenal fusion Adrenocortical adenoma MART-1 + MAK-6 + inhibin + CD10 - hmb-45 – AE1/3 - SMA - Mahadevia et al. 2009 (22) Case report 1 case Abdominal pain Adrenal renal fusion Adrenocortical adenoma NS Ye et al. 2009 (12) Retrospective 9 cases - 7 adrenal rest Ectopic adrenocortical adenoma NS cases series 2 adrenal renal fusion Louiset et al. 2010 (23) Case report 1 case ACTH-independent Cushing’s Bilateral adrenocortical micronodular Bilateral adrenocortical 17-α hydroxylase+ syndrome due to PPNAD hyperplasia and adrenal rest micronodular hyperplasia and 21-α hydroxylase+ ectopic adrenocortical adenoma Brč ić et al. 2011 (15) Case report 1 case Incidental finding Adrenal rest Ectopic adrenocortical adenoma HMB-45 + SMA + melan-A + inhibin + Calretinin+ AE1/3 - CD10 - EMA - Cardinalli et al. 2012 (24) Case report 1 case Incidental finding in Beckwith–Wiedemann syndrome Adrenal rest ectopic adrenocortical adenoma NS Wang et al. 2012 (9) Case report 1 case Cushing’s syndrome Adrenal rest ectopic adrenocortical adenoma NS Yokoyama et al. 2013 (25) Case report 1 case Incidental finding Adrenal rest adrenocortical carcinoma P450c17 + SF-1 + DHEA-ST + 3β-HSD + Tong et al. 2014 (26) Case report 1 case Cushing’s syndrome Adrenal rest Ectopic adrenocortical adenoma Melan-A+ HSD3B2+ CYP17A1+ Godin et al. 2014 (27) Case report 1 case Incidental finding Adrenal rest Oncocytic adrenocortical adenoma NS Griffin et al. 2015 (28) Case report 1 case Hypertension Adrenal renal fusion Multinodular adrenal cortical hyperplasia NS Clair et al. 2015 (29) Case report 1 case Abdominal pain Adrenal renal fusion Adrenocortical adenoma NS Liu et al. 2016 (33) Case report and review 1 case Endocrinological Disorders: Adrenal rest Ectopic adrenocortical adenoma Vimentin + Inhibin α+ Amenorrhea and virilization and Melan-A + Synaptophysin + obstruction urinary output NSE + CD56 + AE1/AE3 +/- PAX 8 – S100 – Chromogranin A - Zhang et al. 2016 (10) Case report and review 1 case Hypertension and bilateral limb weakness Adrenal rest Ectopic adrenocortical adenoma Synaptophysin + CD56 + Vimentin + Ki-67 +(2%) Inhibin α+ Calretinin + chromogranin A - CD117- CD10 - CK7 - EMA - CK-pan - melan-A - Sappal et al. 2016 (34) Case report and review 1 case Incidental finding Adrenal rest Ectopic adrenocortical adenoma Melan-A + PAX 8 - Zhao et al. 2018 (30) Case report 1 case Cushing’s syndrome Adrenal rest Adrenocortical adenoma with NS myelolipoma metaplasia Lee et al. 2018 (31) Case report 1 case Back pain Adrenal rest Adrenocortical carcinoma Inhibin α+ Vimentin + Synaptophysin + Melan A focal + Bamford et al. 2018 (8) Case report 1 case Incidental finding in patient with bladder neoplasia Adrenal renal fusion - - Lu et al. 2018 (35) Case report and review 1 case ACTH-independent Cushing’s syndrome Adrenal rest Ectopic adrenocortical adenoma Inhibition + Melan-A + Synaptophysin + Vimentin + AE1/AE3 + HMB45 +/- CD34 + Current case Case report and systematic review 1 case Incidental finding Adrenal rest Heterotopic adrenocortical adenoma NS Archivio Italiano di Urologia e Andrologia 2021; 93, 4 D. De Marchi, A. Tafuri, G. Mantica, et al. 484 RESULTS Our online search identified 888 publications. Sixty-five had all the inclusion criteria, and 29 were included in this systematic review. Among these, 22 were single case reports (6, 8, 9, 13-31), 2 articles reported more than one case (11, 32), 4 were literature reviews with case report (10, 33-35), and 1 article was a letter to the publisher including a case reports (5). We therefore compared the cases present in the literature with one that happened in our center in January 2018 (Box 1), evaluating the main characteristics. Overall, 39 patients with renal adrenal fusion or adrenal ectopia were considered. The main aspects examined in this review of the literature were the clinical presentation, the type of adrenal anom- aly found, the location of this anomaly, the definitive anatomopathological report and the presence of immune- histotypic markers (Table 1). Type of adrenal anomalies “Adrenal rest” were present in 29 patients, “adrenal renal fusion” was present in 9 patients (Table 1). All cases had adrenal cortex tissue, in the absence of heterotopia with regard to the medullary portion. We found 1 case of “true heterotopia” as published by Chin Table 2. CT characteristics characteristics of adrenal ectopias findings in the included studies. Author Location CT-presentation Native adrenals HU MRI Differential diagnosis Goren et al. 1991 (14) Left renal hilum 8 cm solid mass with contrast enhancement NS NS NS Oncocytoma, RCC Chin et al. 1994 (6) Right upper pole NS Normal NS NS NS Colberg et al. 1998 (15) Right upper pole 2.9 cm solid mass NS NS NS NS Ayala et al. 2000 (16) Left renal hilum 3.5 cm mass Normal NS NS Ureteral tumor Souverijns et al. 2000 (17) Retroperitoneal mass close 5.5 cm mass with inhomogeneous to left renal vein peripheral contrast enhancement NS NS NS Lymph node metastasis Szumera et al. 2003 (11) Left upper pole cystic lesion of 7 cm NS NS NS RCC Fan et al. 2004 (18) Right upper pole Cystic renal mass (Bosniak II) WISP-like and thin 9-10 NS Cystic RCC Hsu et al. 2005 (19) Retroperitoneal paracaval mass 5 cm contrast enhancing paracaval mass NS NS NS Lymph node metastasis Claahsen-van der Grinten Retroperitoneal mass beside 5 cm retroperitoneal mass et al. 2008 (20) Rx left kidney with multinodular aspect NS NS NS NS Baydar et al. 2008 (32) Right upper pole 1.5 cm solid mass Normal NS NS RCC Left upper pole 2 mm mass at upper pole NS NS NS RCC LInder et al. 2009 (21) Right upper pole 4.5 cm solid mass with minimal amount of fat NS NS NS AML, RCC Mahadevia et al. 2009 (22) Left upper pole 2 cm mass with low attenuation Normal Basal: -19A. and heterogeneity Phase: +58V. Phase: +22 NS AML, RCC Ye et al. 2009 (12) 1 Mid pole left kidney, 6 superior pole NS NS NS NS RCC 2 superior pole NS NS NS NS RCC Louiset et al. 2010 (23) Right pararenal adrenal rest close 3.8 cm pararenal mass Previous bilateral 28 NS NS to the renal hilum adrenalectomy Brč ić et al. 2011 (15) Right upper pole 2 cm cystic and solid mass with contrast enhancement NS NS NS AML, RCC Cardinalli et al. 2012 (24) Left renal hilum NS NS NS NS NS Wang et al. 2012 (9) Left upper pole NS Bilateral adrenal NS 3 cm mass with fatty component NS atrophy and plentiful vascular supply Yokoyama et al. 2013 (25) Retroperitoneal mass between inferior 6,5 cm retroperitoneal mass Normal NS NS NS vena cava and right kidney Tong et al. 2014 (26) Left renal hilum 2.7 mass in the left renal hilum Atrophic NS NS NS Godin et al. 2014 (27) Left upper pole NS NS NS 4,8 cm heterogeneously RCC, enhancing mass pheocromocytoma Griffin et al. 2015 (28) Right superior pole NS NS NS NS Cystic RCC Clair et al. 2015 (29) Left upper pole 2.5 cm heterogeneous mass NS NS Hypointense on T2 Papillary RCC, with contrast enhancing than renal cortex AML, RCC Liu et al. 2016 (33) Left renal hilum 2.7 cm well-circumscribed soft-tissue mass Atrophic 35 to 161 NS AML, oncocytoma, with contrast enhancement with atrophic paraganglioma bilateral adrenals and RCC Zhang et al. 2016 (10) Right renal hilum 3*3 cm mass with contrast enhancement Normal NS NS NS Sappal et al. 2016 (34) Right upper pole 2.7 cm mass with contrast enhancement Lesions appeared inseparable NS NS RCC from the right adrenal gland Zhao et al. 2018 (30) Right renal hilum 3.6 cm solid mass with contrast enhancement. Normal NS NS NS Adrenal gland were normal Lee et al. 2018 (31) Mid pole right kidney 13 cm heterogeneous mass NS NS NS RCC Bamford et al. 2018 (8) Bilateral superior pole Symmetrical well-defined low-attenuation No demonstrable fat plan between 55 NS NS subcapsular lesions each measuring 2.3 cm renal lesions and adrenals Lu et al. 2018 (35) Left renal hilum 3 cm well-circumscribed Atrophic NS NS NS mass with athrophic bilateral adrenal glands Current case Mid pole of the left kidney 10 x 14 mm, in the middle lateral margin Normal Basal: - 5A. NS RCC, AML of the left kidney Phase: +90 V. Phase: +60 485Archivio Italiano di Urologia e Andrologia 2021; 93, 4 Ectopic adrenal tissue in the kidney et al. in 1994 (6). In this case, the absence of an adrenal gland on the right side and the presence of normal left gland on the preoperative CT scan suggests a true hetero- topia. From our review, it emerged, that the most fre- quent form of adrenal heterotopia is the adrenal rest, and in alignment with these findings, our clinical case also had this form of adrenal abnormality. Clinical presentation In 11 patients the diagnosis was incidental, in 8 patients the mass was found after clinical investigation was per- formed for flank or abdominal pain, in 7 patients pre- sented with manifestations of endocrinological disorders, and in 3 patients, it was diagnosed during imaging evalu- ations which were performed for arterial hypertension refractory to therapy or metabolic syndrome. The onset of symptomatology was not reported in 9 patients derived from a retrospective case series (11). Most of the clinical cases in the literature have been acci- dentally diagnosed during clinical investigations for abdom- inal or lower back pain, high blood pressure, or during diagnostic routines for concomitant neoplasms. Seven cases showed endocrinological disorders such as Cushing syn- drome, primary hyperaldosteronism or were present in the context of congenital anomalies such as Beckwith- Wiedemann syndrome (9, 16, 20, 23, 24, 26, 30, 33, 35). Abdominal pain may be due to an ureteropelvic obstruc- tion due to the mass effect of the neoplasm, as in the case presented by Goren et al. (14) and Lee et al. (31). In another five cases the abdominal pain was not moti- vated by the size or the location of the adrenal abnormal- ities (15, 20, 22, 29, 32). Cushing syndrome was the most frequent clinical presen- tation when a secreting ectopic adrenal adenoma was reported (9, 16, 23, 26, 30, 35). The clinical presentation included moon facies, hirsutism, easy bruising and weak- ness, polydipsia and polyuria. Elevated blood pressure refractory to anti-hypertensive drugs was also present. In these patients, surgical removal of the adrenal adenoma led to a regression of symptoms except for the case pub- lished by Suverijns et al. in which the pressure remained high (10, 17, 28). In one case described by Cardinalli et al. in 2012 the adre- nal rest was diagnosed during complementary radiologi- cal studies in a patient with Beckwith-Wiedemann Syndrome (BWS) (24). BWS is a growth disorder characterized by macrosomia, macroglossia, organomegaly, abnormalities of the ears, an increased risk for development of embryonal tumors and disorders of the adrenal gland. In this particular case the presence of ectopic adrenal tissue at the level of left renal hilum was associated with a myelolipoma but the authors concluded that a clear relationship between BWS, adrenal adenoma and myelolipoma is unclear (24). In our case, the diagnosis was incidental during routine investigation. In fact, the patient did not report abdomi- nal pain, and did not manifest any endocrinological abnormalities or elevated blood pressure. Location and CT-presentation CT is considered the gold standard for the characteriza- tion of renal cancers. Multiphase CT has a sensitivity of 90% to 99% and a specificity of 99% to 100%. In our review, MRI was the method of choice for the study of renal mass only in two cases (9, 27). However, small kid- ney masses can exhibit similar behaviors making the dif- ferential diagnosis process difficult. Renal adrenal fusion as described by Rokitansky is due to the absence of adipose tissue that normally separates the adrenal gland and the upper pole of the kidney. In our review we identified 9 cases of renal adrenal fusion all located at the upper renal pole (Table 2). Among the 29 patients with adrenal rest, 17 had a local- ization at the kidney, 7 at the level of the renal hilum and 5 at the level of the retroperitoneum in close proximity to the renal peduncle (Table 2). In patients with localization at the kidney, the lesion most commonly occurred in the upper pole, while only 3 patients, including our case, had a lesion located in the middle third of the kidney (11, 31). In this subgroup of patients, the differential diagnosis included clear cell renal cell carcinoma (ccRCC), angiomy- olipoma (AML), oncocytoma, papillary renal cell carcinoma (pRCC) and cystic RCC. In the remaining case reports with extra renal localization the differential diagnosis included lymph node metastases and ureteral tumors (Table. 2). Only 3 case reports present in our review reported the Hounsfield Units (HU) of the neoplasms. Fan et al. found that the lesion had a HU of 9-10. In this case, given the radiographic characteristics of the lesion, the differential diagnosis included a cystic renal neoplasm (18). Mahadevia et al. found a variation in HU depending on the phase of the study from -19 to +58 and +22. In this case the differential diagnosis was between AML and RCC (22). Liu et al., reported a change in HU from 35 to 161. In this case the differential diagnosis included AML, Oncocytoma, Paraganglioma and RCC (33). In our case, the neoplasm showed a behavior similar to that described by Mahadevia. In fact, the neoplasm had differ- ent HU -5, +90 and +60 according to the different phas- es of the CT study. Also, in our case, the main differential diagnoses were AML and RCC. Anatomopathological report More frequently these adrenal changes have a benign behavior and can be classified as functioning or non- functioning adenomas. However, in some cases, they may experience neoplastic degeneration as published by Yokoyama et al. and Lee et al. (25, 31). Godin et al. in 2014 published the first case of adrenocorti- cal heterotopic oncocytoma of the kidney. As reported, the additional cases present in the literature had extrarenal locations being localized at the spinal or retroperitoneum level (27). Our case, according with the literature is one with a non-functioning adrenocortical adenoma (Box 1 - Table 1). Additionally, the absence or poor presence of fibrous tissue between the kidney and heterotopic tissue was commonly reported, and a contact between the adrenal tissue and the renal parenchyma is frequently described. This feature is also present in our case (Figure 2). Immune-histotypic markers The immunohistochemistry has a pivotal role in the final Archivio Italiano di Urologia e Andrologia 2021; 93, 4 D. De Marchi, A. Tafuri, G. Mantica, et al. 486 diagnosis. In our review, 17 studies investigated the use of immunohistochemistry in the diagnostic phase. Chin et al. in 1994, first used immunohistochemistry to establish the steroidogenic potential of the sample under examination (6). The kidney was incubated with adrenal ectopic tissue and specific antibodies for cytochrome p 450 scc (a mitochondrial enzyme implicated in the syn- thesis of steroid hormones), and a high response to the adrenal ectopic tissue was found. Subsequently, further markers were used in the differential diagnosis. The most frequently positive markers were inhibin, vimentin, melan-A, synaptophysin and anti-p450 scc (Table 1). Our case report did not pose a diagnostic doubt and therefore, was not investigated with immunohistochemistry (Figure 2). Adrenal heterotopia is a rare condi- tion, present in about 1% of the adult population. The main locations are celiac axis, broad ligament, spinal cord and other retroperitoneal parenchymatous organs and this is due to the embryological develop- ment of the adrenal gland. Adrenal heterotopia is a benign and asymptomatic condition; however, it can become evident clinically when endocrinological disorders manifest, neoplastic transformation occurs, or mass effect arises. In most cases it presents itself as an incidental finding during routine examinations performed for other causes and can mimic a solid lesion affecting parenchymatous organs, a retroperitoneal lesion compatible with a neoplasm or a metastasis if diag- nosed during diagnostic investiga- tions for other malignancies. Having a heightened clinical suspicion for these neoplasms in the setting of small renal masses will improve detection and allow more appropriate therapeutic planning with impor- tant clinical implications. In this review, we considered the clinical characteristics of a subgroup of adrenal heterotopias such as those located at the renal, perirenal and retroperi- toneal level in order to identify the main differences that can guide clinicians towards to a correct preoperative diagnosis. As we reported, clinical presentation can be very varied. In most cases, it is silent and diagnosed during routine exams. In other cases, if the adenoma is secreting hormones, it manifests itself with endocrinological disorders, hyperten- sion refractory to medical therapy or abdominal pain. The most frequently occurring location of this lesion is at the level of the upper pole of the kidney with a typical mor- phology of solid lesion with fat con- tent, and a hyper-vascularized pattern which includes differential diagnoses of AML or ccRCC (Table 2). In these, an attenuation of -10 HU or less is similar to AML. A strong con- trast during CMP with HU values greater than 100 with subsequent wash-out during the nephrogenic phase is similar to ccRCC. Also, pRCC has a more subtle enhancement pattern than ccRCC, further compli- cating the list of differentials (36). Finally, it can also present itself as a complex cyst as published by Fan et al. and, in this case the differential diagnosis is with cystic RCC (18). More frequently the anatomopatho- logical report is a benign adenoma, however an adrenocortical neoplasm or other histological subtypes may be Figure 2. “A-B”: renal neoformation localized to the middle third of the left kidney; “C-D”: adrenal glands with regular size, morphology and localization. Figure 3. Histopathological findings of an ectopic adrenal gland. Normal kidney parenchyma with glomeruli and tubules can be seen (BLUE SQUARE). The right side is occupied by normal tissue of the adrenal gland, where cells belonging to the fasciculata and the reticularis can be spotted (YELLOW STAR). While the orthotopic adrenal gland is embedded and separated by the renal parenchyma by a fibrous capsule most of the time, in this case the glandular tissue appears to be embedded directly in the renal parenchyma, since it is directly adjacent to it without any visible capsule or connective tissue. 487Archivio Italiano di Urologia e Andrologia 2021; 93, 4 Ectopic adrenal tissue in the kidney present sporadically as published by Godin et al. in 2014 (27). In many of the cases present in this review, immuno- histochemical markers were used, in fact the histological structure was not always correctly reported. This is espe- cially true for cases of adrenocortical carcinoma and rarer histological subtypes. The characteristics that our clinical case carried, corre- spond to clinical characteristics presented in the litera- ture. The diagnosis was incidental during routine investi- gation, no painful or endocrinological symptoms were present. When the definitive anatomopathological report showed a well differentiated adrenal adenoma, further immunohistochemical investigations could have been avoided. The main feature that distinguishes our clinical case is the localization at the level of the middle third of the kidney on the lateral margin which is present only in two other clinical cases (11, 31). In our case, we proposed active surveillance, given the size of the mass, however the patient chose surgery to relieve the anxiety of carrying a cancer diagnosis. We had not proposed a renal biopsy and the EAU guidelines do not recommend a renal biopsy on a mass with contrast enhancement, given the high diagnostic accuracy of radi- ographic imaging. Furthermore, biopsy is not currently a requirement for initiating active surveillance (3). In a recent systematic review, Mir et al. found that less than 30% of patients included in retrospective active surveil- lance studies had a confirmatory biopsy (4). The diag- nostic accuracy and safety of the method, previously con- troversial, are currently supported by a recent meta- analysis (37). In the absence of a definitive histology, active surveillance is based on initial dimensions and on its growth estimat- ed as linear grow rate (cm/yr) but unfortunately growth is not an indicative parameter of the biology of a lesion, as even benign lesions can have a volumetric increase (4). On the contrary, a retrospective study done at Columbia University showed that low growth rate lesions do not progress to metastatic disease (38). Although it is a rare condition, adrenal heterotopia at the renal level presents itself as a contrast-enhancing neo- plasm and therefore worthy of biopsy to avoid unneces- sary surgery. Certainly, in the presence of a lesion suspected of renal neoplasia, it is difficult to include within the differential diagnosis a condition with such a low incidence, but,the presence of endocrinological disorders, hypertension refractory to medical therapy can guide the differential diagnosis process. Other symptoms such as abdominal pain, appear to be of lesser help in the diagnostic phase as it is linked to the localization of the neoplasm and to its size and not to a peculiar characteristic of the adrenal anomaly. The main location of the adrenal fusion is at the level of the superior pole, and adrenal rest can also be present in the retroperitoneum adjacenct to the renal pelvis. However, in some cases, such as ours, the adrenal ecotopia can also be localized at the level of the lateral margin of the kidney. This systematic review has intrinsic limitations such as the fact that it examines case series and case reports and the non-homogeneity of the cases taken into considera- tion. However, it underlines the main characteristics of the types of adrenal ectopic tissue in the kidney. The astute clinician should be cognizant of this condition in the evaluation of small renal masses due to its benign behavior, and its differentiation by renal cancer could require a renal biopsy because active surveillance is indi- cated in these patients. CONCLUSIONS The increase in the incidence of small renal masses due to the diffusion of radiological imaging has led to a better understanding of the behavior of these neoformations. Ectopic adrenal tissue in the kidney is a rare event with specific clinical characteristics which can clinically mimic a renal neoplasia and needs to be known in order to arrive at a correct diagnosis and carry out appropriate treatment management. REFERENCES 1. 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Correspondence Davide De Marchi, MD Federico Scarfò, MD Giovanni Passaretti, MD Salvatore Smelzo, MD Silvia Proietti, MD Lorenzo Rigatti, MD Leonardi Rosario, MD Guido Giusti, MD Franco Gaboardi, MD Department of Urology, San Raffaele Hospital, Milan (Italy) Alessandro Tafuri, MD (Corresponding Author) tafuri.alessandro@gmail.com Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Piazzale Stefani 1, 37126, Verona (Italy) Guglielmo Mantica, MD Department of Urology, University of Genova, Ospedale San Martino, Genova (Italy) Aliasger Shakir, MD USC Institute of Urology, Catherine and Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA (USA) Roberta Luciano, MD Department of Pathology, San Raffaele Hospital, Milan (Italy) Alessandro Antonelli, MD Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona (Italy) Vincenzo Pagliarulo, MD Urology and Andrology Unit - Azienda Ospedaliera 'Vito Fazzi', Lecce, Italy