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Adrenal Rests in the Uro-genital Tract of an Adult Population
Enrico Costantino Falco1 . Lorenzo Daniele2 . Jasna Metovic3 . Enrico Bollito4 . Giovanni De Rosa2 . Marco Volante5 . Mauro Papotti3
Accepted: 28 May 2021 / Published online: 7 June 2021 The Author(s) 2021
Abstract
Ectopic adrenal rests are a rare condition which can be found in various sites, generally in the retroperitoneum or pelvis along the path of gonadal descent. Their real prevalence is unknown. Males are more commonly affected, at least in the pediatric age. Adrenal rests are usually clinically silent and incidentally found in surgical samples, mostly in the pediatric population, and rarely in adults. With the aim of increasing knowledge and estimating the prevalence of ectopic adrenocortical tissue in the adult population, 44 adrenal rests in the urogenital tract of 40 adults are described. These represent approximately 0.07% of the total number of urogenital and gynecological surgeries performed in the 22 considered years. Adrenal rests were identified in the spermatic cord (10 males) and in paraovarian, parasalpingeal, or infundibulopelvic ligament locations (30 females). All but one was incidental findings. One case regarded an adrenocortical carcinoma arisen in adrenal rests. A literature review of adrenal ectopia in the urogenital tract of adults identified 57 reported cases from 53 patients, with similar clinicopathological features as those of our series, with the exception of a lower incidence of parasalpingeal loca- tions. Despite their limited clinical implications, awareness of ectopic adrenal rests is essential also in adults for at least two reasons: (a) to correctly identify sources of adrenocortical hormone production in case of adrenal insufficiency or hormonal imbalance and (b) to avoid misinterpretations in the diagnostic workup of renal cell carcinoma, adrenocortical tumors, and rare gonadal neoplasms, including Sertoli/Leydig cell tumors.
Keywords Adrenal gland . Ectopia . Adrenal rests . Testis . Ovary . Neoplasia
Introduction
The adrenal glands develop at 28-30 days after concep- tion from two separate embryological tissues: the medulla derived from neural crest in proximity of dorsal aorta and the cortex from the intermediate mesoderm in the region between the genital ridge and the root of the mesentery [1]. During the 7th week, fusion between the two components
☒ Marco Volante marco.volante@unito.it
1 Pathology Unit, Department of Medical Sciences, Città Della Salute E Della Scienza Hospital, University of Turin, Turin, Italy
2 Pathology Unit, Mauriziano Hospital, Turin, Italy
3 Pathology Unit, Department of Oncology, Città Della Salute E Della Scienza Hospital, University of Turin, Turin, Italy
4 Pathology Unit, San Luigi Hospital, Orbassano, Turin, Italy
5 Pathology Unit, Department of Oncology at San Luigi Hospital, University of Turin, Orbassano, Turin, Italy
takes place by migration and penetration of neural crest cells into the unencapsulated cortex [2]. At birth, the fetal cortex forms the largest part (70-85%) of the adrenal cortex, but it quickly undergoes vascular engorgement and atrophy. At the same time, the outer permanent cortex begins to differentiate into the definitive three layers [3-5].
Adrenal ectopia is defined as the presence of adrenal tis- sue in a location other than the adrenal glands, including the region around the adrenal gland, the celiac plexus, the kidney, and the route of gonadal descent, comprising also hernia sacs [6-10]. In exceptional cases, it can also be found in bizarre sites, such as placenta [11], lung [12], or intrac- ranial cavity [13].
Ectopic adrenal nodules probably originate either from multiple primordia or from secondarily detached cortical fragments during the penetration of medullary cells into cortical anlage [14, 15]. Subsequently, these rests may remain close to the main gland or migrate, mostly in the pelvis or the groin region. The most frequent pelvic or groin location can be explained by the fact that the fetal
adrenal cortex is often unencapsulated and develops in close contact with the gonads.
Ectopic nodules usually contain cortical components, only [5]. However, in the area of the celiac plexus, ectopic adrenal nodules have been reported to contain both cortex and medulla in about 50% of cases [16]. Ectopia in unu- sual anatomic sites is more difficult to explain, and other theories have been proposed, including a possible origin from pluripotent cells [14].
Macroscopically, ectopic adrenal tissue looks like a round, yellow, and well-defined node, usually smaller than 1 cm. Ectopic cortex shows normal morphology with the typical zonation, and responds to physiological ACTH stimulation. Therefore, although these rests are usually clinically silent, they may undergo hyperplasia in condi- tions associated with excessive adrenocorticotropic hor- mone (ACTH) production, such as in patients with Cush- ing’s disease or Nelson’s syndrome following bilateral adrenalectomy [17]. Ectopic adrenal nodules could also give rise to malignant tumors. Moreover, in congenital adrenal hyperplasia (CAH), an autosomal recessive dis- ease that causes adrenal cortical dysfunction, the increased ACTH levels induce adrenocortical hyperplasia of ortho- topic and heterotopic adrenal tissue [18].
The real incidence of adrenal rests is unknown, but they are reported to be much more frequent in infants than in adults. In intrauterine life, the adrenal glands are propor- tionally 20 times larger than those in adulthood, so ectopic tissue is also likely larger and more readily identified in infants and children. In fact, they are found in about 50% of newborns near the adrenal gland and in 7.5-15% of cases in the inguinal region, while their incidence drops to 1% in adults, as they are believed to degenerate or undergo atrophy within a few years [10, 14, 15].
The majority of ectopic adrenal tissues are described as incidental findings during surgical procedures in the uro- genital tract of male children. Moreover, they are identified mostly by the pathologist in surgical material, whereas 14% of cases, only, are discovered by the surgeon, due to their small size and fat-like appearance [10]. In the adult population, adrenal ectopia is a rare occurrence.
Both in pediatric and in adult patients, the presence of ectopic adrenal tissue in the inguinal region is associated with undescended testis, probably because of a thorough dissection and careful examination of the spermatic cord. However, an alternative hypothesis suggest that inadequate or late migra- tion of primordial germ cells could lead to closer interactions with adrenal cortical cells affecting the right location [19, 20].
Based on the above, the aim of the present study was to review a large retrospective series of adrenal ectopia in the urogenital tract in adults.
Materials and Methods
We retrospectively collected all cases of adrenal ectopia in the urogenital tract close to the gonads detected in surgically resected specimens of adult patients (age> 18 years) between 1999 and 2020 in three academic hospitals of Torino, Italy (Mauriziano, San Luigi and Città della Salute e della Scienza University Hospitals). In the considered timeframe, 53,983 urogenital and gynecological surgical specimens were submitted to histopathological examination. In particular, 39,286 and 14,697 surgical procedures were performed in women and in men, respectively. Histological reports were retrieved from the pathological databases of the three pathology divisions and were then integrated with data from the clinical and surgical databases. Data about sex, age, relevant medical history, reason for surgery, location, and morphological features of the ectopic rests were recorded. The study was approved by the Institutional Review Board of the San Luigi Hospital (Protocol AMPRECCO, No. 128/2010). After anonymization of pathology slides and blocks by a pathology staff member not involved in this study, all specimens were reviewed to confirm the diagnosis of ectopic adrenal tissue and to evaluate the specific histopathological features. In some cases, immunohistochemical stains for Melan-A/MART-1 (clone A103, Benchmark AutoStainer Ventana Medical Systems, AZ, USA) and for alpha-inhibin (clone R1, Ventana) were performed using a Ventana Roche immunohistochemistry platform (Fig. 1).
Moreover, the previous literature was reviewed to compare the morphological features of adrenal ecto- pia in the urogenital tract of the adult population. A search was set up in the PubMed database using the terms “ectopic adrenal,” “accessory adrenal,” “adre- nal heterotopia,” “adrenal rests,” browsing titles, and abstracts in English language. All the articles reporting well-documented cases in adult patients (age> 18 years) and localized in the urogenital region near the gonads were included.
Results
Forty cases of ectopic adrenal nodules in the urogenital region adjacent to the gonads were collected and reviewed. One case (No. 9) had already been described as part of a single case report of a testicular seminoma associated to adrenal rests [21], and case No. 14 was a consultation case reviewed by one of us (EB) (Fig. 2).
a
b
General Information and Clinical Findings
Overall, adrenal rests were detected in 0.07% of urogenital tract surgical specimens in adults. The clinicopathologi- cal results are summarized in Table 1. Ectopic rests were found in 10 (25%) men and 30 women (75%), with a mean age of 54.6 years (range 26-86). Females had a mean age of 57.2 years, while males of 45.9 years. The nodules had a mean size of 3.0 mm (1-8 mm). In 37 patients, a single adrenal rest was identified, whereas multiple small nodules were found in three women, either in the adipose tissue close to the ovaries or in the infundibulopelvic ligament. The nodules were almost equally distributed on the right and left side (20 and 19, respectively; in one case, the
information was missing), but with a difference between sexes. Indeed, a right-side preference was observed in men (6/9, 66.7%; missing information in one case), but not in women (14/30, 46.7%).
All but one case was clinically silent, and none of them was recognized by surgeons during excision: in three cases, ectopic nodules were incidentally discovered at the time of macroscopic dissection in the pathology laboratory, while most of them were recognized at the time of microscopic analysis, only. None of the patients had primary adrenal diseases or symptoms related to hormonal excess, and no hormonal deficits resulted from the excision of the acces- sory tissue. Among males, the ectopic nodules were found in the spermatic cord after surgery performed for hernia
| No | Sex/Age | Cause of surgery | Adrenal rests | |||
|---|---|---|---|---|---|---|
| Laterality/Location | Macro/ microscopic finding | Size (mm) | Histology | |||
| 1 | M/48 | Cryptorchidism in single congenital kidney | L/Spermatic cord | Micro | 4 | Normal cortex |
| 2 | F/49 | Uterine leiomyomas | NA/Parasalpingeal tissue | Micro | 2 | Normal cortex |
| 3 | F/75 | Endometrial carcinoma | L/Paraovarian tissue | Micro | 1 | Normal cortex |
| 4 | F/65 | Endometrial carcinoma | L/Parasalpingeal tissue | Micro | 2 | Normal cortex |
| 5 | F/46 | Endometriotic cyst | NA/Parasalpingeal tissue | Micro | 3 | Normal cortex |
| 6 | F/68 | Uterine prolapse | 1R-2L/Paraovarian tissue | Micro | 1/2/2 | 3 nodules, normal cortex |
| 7 | F/47 | Prophylactic adnexectomy | R/Paraovarian tissue | Micro | 3 | Normal cortex |
| 8 | M/56 | Inguinal hernia and cryptorchidism | R/Spermatic cord | Micro | 3 | Normal cortex |
| 9 | M/43 | Seminoma | R/Spermatic cord | Macro | 3 | Normal cortex |
| 10 | F/32 | Ovarian cystadenoma | R/Ovarian hilus | Micro | 2 | Normal cortex |
| 11 | M/37 | Mixed malignant germ cells tumor | R/Spermatic cord | Micro | 1 | Normal cortex |
| 12 | M/28 | Mixed malignant germ cells tumor | R/Spermatic cord | Macro | 3 | Normal cortex |
| 13 | F/52 | Ovarian cystadenofibroma | L/Paraovarian tissue | Micro | 2 | Normal cortex |
| 14 | M/NA | Inguinal mass | NA/ Spermatic cord | Macro | NA | Carcinoma |
| 15 | M/29 | Seminoma | L/Spermatic cord | Micro | 2 | Normal cortex |
| 16 | M/26 | Mixed malignant germ cells tumor | R/Spermatic cord | Micro | 4 | Normal cortex |
| 17 | F/60 | Pelvic leiomyosarcoma | NA/Paraovarian tissue | Micro | 5 | Normal cortex |
| 18 | F/50 | Endometrial stromal sarcoma | L/Parasalpingeal tissue | Micro | 8 | Normal cortex |
| 19 | F/55 | Ovarian carcinoma | Peritoneum L/paracolic gutter | Micro | 3 | Normal cortex |
| 20 | F/67 | Salpingeal adenocarcinoma | R/Infundibulopelvic ligament | Micro | 4 | Normal cortex |
| 21 | F/61 | Endometrial carcinoma | R/Infundibulopelvic ligament | Micro | 3/5 | 2 nodules, normal cortex |
| 22 | F/71 | Bladder urothelial carcinoma | L/Paraovarian tissue | Micro | 4 | Normal cortex |
| 23 | F/85 | Ovarian borderline cystadenoma | NA/Parasalpingeal tissue | Micro | 5 | Normal cortex |
| 24 | F/55 | Vaginal carcinoma | R/Parasalpingeal tissue | Micro | 3 | Normal cortex |
| 25 | F/52 | Ovarian carcinoma | R/Infundibulopelvic ligament | Micro | 2/2 | 2 nodules, normal cortex |
| 26 | F/54 | Endometrial carcinoma | L/Parasalpingeal tissue | Micro | 3 | Normal cortex |
| 27 | F/54 | Endometriotic cyst | R/Parasalpingeal tissue | Micro | 2 | Normal cortex |
| 28 | F/56 | Ovarian cystadenoma | L/Ovarian hilus | Micro | 2 | Normal cortex |
| 29 | F/75 | Endometrial carcinoma | L/Infundibulopelvic ligament | Micro | 1 | Normal cortex |
| 30 | F/51 | Adult granulosa cell tumor | L/Parasalpingeal tissue | Micro | 2 | Normal cortex |
| 31 | F/86 | Bladder urothelial carcinoma | R/Parasalpingeal tissue | Micro | 3 | Normal cortex |
| 32 | F/60 | Ovarian cystadenoma | R/Parasalpingeal tissue | Micro | 1 | Normal cortex |
| 33 | F/41 | Cervical adenocarcinoma | R/Parasalpingeal tissue | Micro | 3 | Normal cortex |
| 34 | M/80 | Spermatocytic tumor | L/Parafunicular fat | Micro | 3 | Normal cortex |
| 35 | F/57 | Endometrial carcinoma | L/Parasalpingeal tissue | Micro | 4 | Normal cortex |
| 36 | M/66 | Prostate adenocarcinoma | R/Parafunicular fat | Micro | 5 | Normal cortex |
| 37 | F/46 | Salpingitis | L/Parasalpingeal tissue | Macro | 6 | Normal cortex |
| 38 | F/39 | Salpingo-ovarian abscess | L/Paraovarian tissue | Micro | 4 | Normal cortex |
| 39 | F/60 | Metastatic gastric carcinoma | R/Parasalpingeal tissue | Micro | 2 | Normal cortex |
| 40 | F/48 | Uterine leiomyomas | L/Parasalpingeal tissue | Micro | 2 | Normal cortex |
F female, M male, R right, L left, NA not available
repair, prostate carcinoma, cryptorchidism, or testicular tumors, while in females, they were discovered in parao- varian or paratubal location after surgery for gynecologi- cal neoplasms or bladder carcinoma. Case No. 14 was a
carcinoma strictly related to adrenal rests identified in the periphery of the tumor and close to the testis. The patient underwent surgery for inguinal pain, and multiple nodules were found along the spermatic cord. A hepatic node was
also excised, whereas no abnormalities were detected in the adrenal glands. Benign rests in males were associated with testicular malignancy (six cases), prostate adenocarcinoma (one case), and with undescended testis (the remaining two cases). Interestingly, in one of such cases (#1), cryptorchid- ism was associated with a congenital solitary kidney, ipsi- lateral to the cryptorchid testis. Among females, fourteen cases were associated with gynecological malignancies (two leiomyosarcomas, six endometrial, four ovarian/salpingeal, one cervical, and one vaginal carcinomas), three cases with extra-gynecological malignancies (two bladder and one gastric carcinomas), and one borderline ovarian tumor. The other twelve cases were associated with benign gynecologi- cal conditions including four ovarian cystadenomas, two leiomyomas, two endometriotic cysts, two salpingitis, and one uterine prolapse, the remaining case being a prophylac- tic bilateral adnexectomy in a BRCA mutated breast carci- noma patient.
Pathological Findings
Macroscopically, adrenal rests presented as circumscribed round to oval small nodules, with a tan-yellow color, and different in consistency from the surrounding adipose tis- sue. The microscopic analysis revealed well-defined nod- ules composed of adrenal cortex, only, surrounded by a thin fibrous capsule. They had all a comparable morphology, with cells arranged in two or three layers. Zona fasciculata was predominant in all cases, followed by zona reticularis. Glomerulosa cells were present in small clusters beneath the capsule in larger nodules and absent in smaller ones. The cells had a cord-like arrangement with a minimal inter- posed stroma, and were large and polygonal, with abundant vacuolated granular and eosinophilic cytoplasm and small nuclei. Conversely, in both testicular and hepatic lesions of case No. 14, a solid proliferation of moderately atypical polygonal cells with a high mitotic count and foci of necrosis was identified. A diagnosis of adrenocortical carcinoma in ectopic adrenal rests with liver metastasis was rendered in this case. In addition to the routine hematoxylin and eosin, immunostaining for Melan-A (in case 11, 15, 16, 29, and 30) and for alpha-inhibin (in case 13) were also performed, confirming the adrenocortical nature of the tissue. Notably, all cases in our series were correctly identified in the original diagnosis as ectopic adrenal cortical tissue, irrespective of the location and pathology associated.
Review of the Literature
The English literature review identified 37 articles reporting 57 ectopic adrenal nodules in the urogenital tract (excluding the kidney) of 53 adult patients (27 men and 26 women). Demographic and clinic-pathological data are summarized
in Table 2. Almost all studies are single-case reports (33/37 papers), with the largest series being those by Falls and Gutowski (11 and 5 cases, respectively) [6, 16]. The mean age was 41.8 years (range 19-78 years). Females had a mean age of 38.2 years, while males of 45.5 years. The nodules had a mean size of 15 mm (range 0.4-145 mm). In 3 patients (2 females and 1 male), bilateral nodules were found, while two ectopic rests were located in the same hernia sac in a man. In the other 49 patients, a single adrenal rest was iden- tified. Overall, the majority of nodules were identified on the right side (36/56, 64.3%; the information was not available in one case). Among men, ectopic tissue was found in the spermatic cord, in hernia sacs, and in paratesticular loca- tion. In women, the most frequent locations were the broad ligament and the paraovarian region, followed by the wall of ovarian cysts and a single case in the appendiceal tissue adherent to mesovarium. Only the nodule found in the wall of an ovarian serous cystadenoma had both adrenal cortical and medullary components, while in all the other cases, in both males and females, adrenal cortical tissue, only, was identified. The majority of cases were asymptomatic and incidentally found after surgical exploration of the pelvic region for different reasons. Of the 54 cases with this infor- mation available, 42 were recognized at the time of surgical excision or during the macroscopic gross evaluation of the specimen and 12 were identified at the microscopic analy- sis. Nine cases were associated to an adrenocortical tumor, namely, six clinically silent adenomas and three carcinomas with Cushing’s syndrome.
Discussion
In this study, we reported a series of 44 adrenal rests found in the peri-gonadal location of the urogenital tract in an adult population of 40 patients, with a female predominance. A PubMed review of the English literature disclosed 57 pub- lished cases, for a total of 101 ectopic adrenal nodules in the path of gonadal descent, supporting the notion that adrenal ectopia is a rare, but not exceptional, occurrence in adults.
After birth, this accessory tissue undergoes involution, and in the presence of a normal hormonal function of the main glands, the ectopic nodes are believed to undergo complete atrophy and eventually disappear [14]. During the atrophic process, small adrenal rests are relatively common in the pediatric age, especially in male children undergoing urogenital surgery or hernia repair, often in the presence of congenital adrenal hyperplasia.
In adults, small adrenal rests may occasionally remain close to urogenital tract organs, and in exceptional condi- tions of hormonal deficits or abnormal stimulation, they could increase in size and become the source of adrenocorti- cal hormone production. Adrenal rests are usually identified
| No | Author [reference] | Sex/Age | Cause of surgery | Adrenal rests | |||
|---|---|---|---|---|---|---|---|
| Laterality/Location | Macroscopic/ microscopic finding | Size (mm) | Histology | ||||
| 1 | Gualtieri [22] | M/31 | Scrotal mass | L/Spermatic cord | Macro | 40 | Adenoma |
| 2 | Janovski [23] | F/42 | Cervical carcinoma | R/Mesosalpinx | Macro | 15 | Choristoma |
| 3 | Schechter [14] | M/19 | Inguinal hernia | L/Hernia sac | Macro | 2 | Normal cortex |
| 4 | Morimoto [24] | M/57 | Scrotal mass in Cushing's syndrome | L/Paratesticular | Macro | 50 | Carcinoma |
| 5 | Gutowski 6] | M/58 | Inguinal hernia | R/Hernia sac | Micro | 4 | Normal cortex |
| 6 | Gutowski [6] | M/66 | Inguinal hernia | R/Hernia sac | Macro | 10 | Normal cortex |
| 7 | Gutowski 6] | M/44 | Inguinal hernia | R/Hernia sac | Macro | 2/5 | 2 nodules, normal cortex |
| 8 | Gutowski 6] | M/45 | Inguinal hernia | L/Hernia sac | Macro | 3 | Normal cortex |
| 9 | Gutowski 6] | M/34 | Inguinal hernia | R/Hernia sac | Micro | 2 | Normal cortex |
| 10 | Anderson 15] | F/62 | Acute appendicitis | R/Appendiceal mesentery | Macro | 10 | Normal cortex |
| 11 | Anderson [15] | M/53 | Inguinal mass | R/Spermatic cord | Macro | 10 | Normal cortex |
| 12 | Lodeville [25] | M/21 | Nodule of the spermatic cord | R/Spermatic cord | Macro | 1.5 | Normal cortex |
| 13 | Czaplicki [26] | M/34 | Cryptorchidism and sterility | R/Paratesticular | Macro | 5 | Adenoma |
| 14 | Czaplicki [26] | M/34 | Cryptorchidism and sterility | L/Paratesticular | Micro | NA | Normal cortex |
| 15 | Van Ingen [27] | F/41 | Testosterone-producing tumor | L/Mesovarium | Macro | 40 | Adenoma |
| 16 | Sasano [28] | F/43 | Uterine leiomyoma | R/Broad ligament | Macro | 50 | Adenoma |
| 17 | Ventura [29] | M/42 | Scrotal trauma | R/Spermatic cord | Macro | 5 | Normal cortex |
| 18 8 | Mari [21] | M/43 | Seminoma | R/Spermatic cord | Macro | 3 | Normal cortex |
| 19 | Usta [30] | F/21 | Ovarian cystadenoma | L/Ovary | Macro | 2 | Normal cortex and medulla |
| 20 | Iyengar [8] | M/54 | Inguinal hernia | R/Hernia sac | Micro | 0.4 | Normal cortex |
| 21 | Ors [31] | F/44 | Paraovarian mass | R/Paraovarian | Macro | 20 | Adenoma |
| 22 | Jain [32] | M/65 | Testicular masses in Cushing's syndrome | R-L/Paratesticular | Macro | 31 / 85 | 2 nodules, carcinoma |
| 23 | El Demellawy [7] | M/78 | Inguinal hernia | L/Hernia sac | Macro | 7 | Normal cortex |
| 24 | Yasar [33] | F/50 | Granulosa cell tumor | L/Ovary | NA | NA | Normal cortex |
| 25 | Rabie [34] | M/26 | Undescended testis | L/Paratesticular | Micro | NA | Normal cortex |
| 26 | Zhong [35] | F/56 | Ovarian cystadenoma | R/Paraovaric | Micro | 2 | Normal cortex |
| 27 | Müllhaupt [36] | M/44 | Varicocele | NA/Spermatic cord | Macro | 9 | Normal cortex |
| 28 | Floyd [37] | M/45 | Seminoma in undescended testis | R/Spermatic cord | Macro | 5 | Normal cortex |
| 29 | Takeuchi [38] | M/52 | Lipoma of spermatic cord | R/Spermatic cord | Micro | NA | Normal cortex |
| 30 | Kasajima [39 | F/29 | Pelvic mass in oligomenorrhea | L/Broad ligament | Macro | 65 | Adenoma |
| 31 | Niveditha [40] | M/64 | Inguinal hernia | R/Hernia sac | Macro | 4 | Normal cortex |
| 32 | Raman [41] | M/28 | Undescended testis | R/Paratesticular | Micro | 2 | Normal cortex |
| 33 | Sangeeta [42] | M/21 | Undescended testis | R/Paratesticular | Macro | NA | Normal cortex |
| 34 | Khandakar [43] | F/26 | Ovarian cystadenoma | R/Paratubal | Micro | 6 | Normal cortex |
| 35 | Chentli [44] | F/34 | Pelvic mass in Cushing's syndrome | R/Ovary | Macro | 145 | Carcinoma |
| 36 | Senescende [10] | M/44 | Inguinal hernia | R/Hernia sac | Macro | 10 | Normal cortex |
| No | Author [reference] | Sex/Age | Cause of surgery | Adrenal rests | |||
|---|---|---|---|---|---|---|---|
| Laterality/Location | Macroscopic/ microscopic finding | Size (mm) | Histology | ||||
| 37 | Billone [45] | F/22 | R/hydrosalpinx and torsion | L/Infundibulopelvic ligament | Macro | 3 | Normal cortex |
| 38 | Chew [46] | F/22 | Ovarian cystadenoma | L/Ovary | Micro | NA | Normal cortex |
| 39 | Kassaby [47] | M/56 | Inguinal hernia | L/Hernia sac | Micro | 1.5 | Normal cortex |
| 40 | Sahin [48] | F/65 | Ovarian cystadenoma | L/Ovary | NA | NA | Normal cortex |
| 41 | Tingi [49] | F/48 | Dysmenorrhea | L/Fallopian tube | NA | NA | Normal cortex |
| 42 | Alimoradi [50] | M/37 | Bilateral inguinal hernia | R/Hernial sac | Micro | NA | Normal cortex |
| 43 | Falls [16] 13 cases in 11 consecutive pts | F/35.7 | Endometrial carcinoma, leiomyomas, polycystic ovaries, ruptured tubal | 8R, 1L, 2 Bilateral/ Broad ligament | Macro | 2 (1-4) | Normal cortex |
F female, M male, R right, L left, NA not available, pts patients
in specimens of gynecological surgery or in the context of inguinal hernia repair or orchidopexy procedures [14, 26, 34]. In the present case series, undescended testis in male patients was the unique non-neoplastic associated pathol- ogy, with 2 out of 10 cases. Interestingly, the association of adrenal ectopia with cryptorchidism and ipsilateral con- genital solitary kidney in case #1 highlights the embryo- logical relationship between fetal adrenal and genitourinary structures. Renal agenesis is reported to be associated with absence or ectopia of adrenal gland in about 10% of cases [51], and cryptorchidism could be associated with minor or major urinary tract abnormalities such as single kidney, unilateral renal hypoplasia, ureterocele, or ureteric stenosis, usually ipsilateral to the undescended testis [52]. However, in our case, the urological anomaly was contralateral to the cryptorchid testis (left undescended testis and right kidney agenesis). No other cases of ectopic adrenal tissue associ- ated with undescended testis and concomitant renal agenesis have been described in adults, so far. One case in a man was a primary adrenocortical carcinoma from ectopic adrenal tissue in the spermatic cord, associated with liver metasta- ses. A literature search revealed only three previous cases of carcinoma arising in ectopic adrenal rests of the urogenital tract in the adult population, all associated with Cushing’s syndrome [24, 32, 44]. The remaining seven male patients were affected by testicular (six cases) or prostatic (one case) malignancies. To the best of our knowledge, only three cases associated with testicular tumors in adults are on record in the English literature [21, 25, 37].
In female patients, the majority of surgical specimens derived from hysterectomies or ovariectomies, with a remarkable finding of adrenal rests in ovarian and salpingeal ligaments (9 and 16 cases, respectively), the remaining cases
being located in the infundibulopelvic ligament or paracolic tissue.
In our adult series of adrenal ectopia, the sex distribu- tion and overall anatomical sites, including the absence of a predominant right location, are opposed to those of the literature. A possible explanation could be that in the pedi- atric population, surgical procedures more frequently are performed in males and involve the groin region, leading to a higher detection of clinically silent adrenal rests along the spermatic cord or rete testis [10, 19, 53, 54]. Indeed, in adults, gonadal resection is more likely to occur in women, thus explaining the higher number of adrenal rests in female patients of the current series. However, if we compare the number of ectopic nodules with the number of surgical procedures performed in the same time interval, we get the same incidence rate (0.07%) in both sexes. A very old study on a consecutive series of hysterectomies showed that an extensive sampling of the broad ligaments allowed to iden- tify adrenal rests (having a median size of 2 mm) in up to 25% of cases [16]. Therefore, the evaluation of the exact incidence and sex distribution of adrenal rests in the general population and in adults in particular, seems to suffer from numerous biases, precluding a precise estimate.
Regarding right-side predominance of adrenal ectopia, this is well documented in the male pediatric population, but not in adults, due to the lack of large series [10, 19]. Considering the currently reported cases, the right-side preferential location seems to occur also in adults, espe- cially in male patients, being negligible in females. In any case, a selection bias linked to the type of pathology specimens analyzed cannot be excluded: in fact, inguinal hernias are the main reason for groin region exploration in children and they typically develop far more commonly
on the right side than in the left [55]. Moreover, also cryp- torchidism and testicular cancer are reported to have a right-side predominance and, therefore, adrenal rests may well be incidentally detected in the same location [56].
Adrenal medulla was not found in any of the cases of the current series and only in one case among those described in the literature, with an overall prevalence of 1% (1/101). This finding contrasts with the data of some early literature that reported the presence of medulla in up to 50% of cases of adrenal rests in the celiac-plexus area [16]. This discordance may be explained by a differ- ent time of adrenal tissue displacement, with the nodules in the celiac-plexus area, localized close to the adrenal glands, arising in a late phase of embryonic development (after the fusion between cortex and medulla), while those found far away being displaced at early (pre-fusion) stages.
Regarding hormonal function of adrenal rests, although such ectopic tissue is generally devoid of clinical rele- vance, it is to be noticed that it is hormonally active and able to respond to external stimuli. Thus, as also reported in animal models, after adrenocortical failure or injury, compensatory hormonal function of ectopic rests has been reported [16, 57]. ACTH-mediated hyperplasia of acces- sory nodules could also account for refractory Cushing’s syndrome, replacing adrenal hormonal production [58]. On the other hand, adrenal insufficiency can follow ectopic tissue excision, if this was the only functional adrenal tis- sue of the patient [10].
All but one (the ectopic adrenocortical carcinoma) cur- rently reported case was clinically silent and incidentally found. Nevertheless, tumors arising from adrenal rests are on record, often benign and non-functioning. In a few cases, ectopic tissue may be directly responsible for Conn’s syndrome [59] or ACTH-independent Cushing ‘s syndrome, due to adenomas [27, 28, 39, 60, 61] and excep- tionally to carcinomas [32, 62, 63]. Indeed, adenoma is not easily differentiated from normal ectopic tissue, except for an aberrant hormonal production or a large size. Carcino- mas are conversely more easily recognizable, based on the Weiss score parameters, as observed in the single malig- nant case of our series. Other neoplasms of gonadal ori- gin including steroid producing tumors [44, 64-66] have a gross and microscopic resemblance to adrenocortical tumors, determining differential diagnosis problems from overgrown adrenal rests, although the location of gonadal neoplasms is intraparenchymal, while adrenal rests gener- ally occur in the periphery of the gonad [67]. In addition, in the rete testis of CAH patients, adrenal rests can expand in up to 40% of cases leading to the so called testicu- lar adrenal rest tumor (TART), that can cause infertility because of compressive/obstructive events [68, 69]. Such TART nodules are functionally and histologically simi- lar to adrenocortical tissue, and may result from ectopic
adrenal cell proliferation or from a totipotent embryonic cell type in the testis [5].
In conclusion, the actual prevalence of ectopic adrenocor- tical rests in the adult population is probably much higher than reported, but the low clinical relevance and the small size of ectopic nodules cause that most of them are not rec- ognized. Awareness of the occurrence of ectopic adrenal tissue is important because of hyperplasia and even neoplas- tic transformation of such rests in patients with symptoms caused by hypersecretion of adrenocortical hormones, which can well be ectopically produced. In addition, ectopic adre- nal tissue must be differentiated from urogenital tumors, in particular its mimickers, such as renal cell carcinoma and Sertoli Leydig cell tumor, that also partially share the immu- nophenotypic markers of the adrenal cortex (Melan-A, SF-1, inhibin). Indeed, misinterpretation of ectopic adrenal tissue is unlikely, and morphology and appropriate immunohisto- chemistry are adequate for addressing a correct diagnosis in most cases.
Author Contribution Conceptualization: De Rosa Giovanni, Volante Marco, Papotti Mauro; Data collection and analysis: Falco Enrico Costantino, Daniele Lorenzo, Metovic Jasna, Bollito Enrico, De Rosa Giovanni, Volante Marco, Papotti Mauro; Writing-original draft preparation: Falco Enrico Costantino; Writing-review and editing: Papotti Mauro, Volante Marco, De Rosa Giovanni; Supervision: Papotti Mauro. All authors edited, reviewed and approved the manuscript.
Funding Open access funding provided by Università degli Studi di Torino within the CRUI-CARE Agreement.
Availability of Data and Material The datasets generated and/or ana- lyzed during the current study are not publicly available due to privacy reasons but are available from the corresponding author on reasonable request.
Declarations
Ethics Approval The study was conducted in accordance with The Code of Ethics of the World Medical Association (Declaration of Hel- sinki) and was approved by the Institutional Review Board of the San Luigi Hospital (Protocol AMPRECCO, No. 128/2010).
Conflict of Interest The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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