Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders due to enzyme deficiency in the biosynthesis of adrenal steroids. These cause elevated adrenocotropic hormone (ACTH) levels and adrenocortical hyperplasia.[
] CAH may be divided into two basic types, the classic and the nonclassic one. The most common cause is 21-hydroxylase deficiency with an incidence 1/5.000–145.000 births, which blocks in the production of aldosterone and cortisol, leads to high plasma ACTH, causing virilizing syndrome, cortisol deficiency, and variable salt-wasting syndrome, depending on the extension of enzyme defect. 1
Testicular adrenal rest tumors (TARTs) develop from islands of ectopic adrenal tissue within gonads, stimulated by ACTH hypersecretation, as the compilation of CAH, with a prevalence ranging from 27% to 47%.[
] They are benign tumors presenting as palpable mass. Tissue biopsy is recommended and surgical removal may be performed to exclude a malignant neoplasm. 2
We report a case of bilateral synchronous TART associated with myelolipoma in a CAH patient and the dilemma of bilateral orchiectomy or not.
A 34-year-old male who was known to have the CAH classic salt-wasting type diagnosed since birth was being treated insufficiently with fludrocortisone and hydrocortisone. He presented to the urology clinic with synchronous bilateral testicular masses and mild orchialgia in the right testis. He mentioned precocious development of secondary sexual characteristics at an early age and short stature.
Table 1] presents the laboratory tests of the patient. He underwent an Ultrasound study and an Abdomen – Thorax computerized Tomography. Table 1:
Testicular parenchymal abnormality of ultrasound imaging with excessive blood supply. The right testis appeared to be larger than normal, with inhomogeneity of the whole parenchyma. The upper pole of the left testis also appeared inhomogeneity [
Figure 1]. Figure 1:
Right and left testis ultrasonography
Abdomen-thorax computerized tomography
The right testis appeared to be lobar with increased contrast mediaabsorption. Furthermore, the left testis had some similar suspicious imaging characteristics. Mesenteric or retroperitoneal lymph nodes were not detected. The rest of the abdomen organs appeared to be normal [
Figure 2]. Figure 2:
Abdomen and pelvic computed tomography
Furthermore, computed tomography of the thorax had not revealed any metastatic masses.
Considering the possibility of malignant testicular neoplasm, the patient underwent right testicular biopsy and left orchiectomy. Macroscopically, the specimen (brown, firm mass) from the right testis measured 2.2 cm × 1 cm × 1 cm. with no evidence of necrosis or hemorragia. The left testis was oval with prominent vessels in the surface, measured 5.8 cm × 3.5 cm × 3 cm, with a segment of spermatic cord 9 cm long. The cut surface revealed a well-circumscribed 4.3 cm lesion, pale tan fleshy with areas of hemorrhage. No tumor was noted in the epididymis or spermatic cord.
Microscopic examination of the first material showed sheets or nests of large round and polygonal cells with abundant eosinophilic granular cytoplasm and round central nuclei, with rare gigantic hyperchromatic figures, separated by bands of fibrous tissue. The cells contained golden brown pigment consistent with lipochrome. No Reinke's crystals were identified. No testicular parenchyma was present.
The left testicular lesion comprised sheets or nests of cells histologically similar to the described ones of the right testicular biopsy. It must be mentioned that the cellular population were separated by myeloid and erythroid precursor cells in different stages of maturation with numerous scattered megakaryocytes admixed with apidocytes.
Immunohistochemical analyses were performed: positive staining for Melan A, inhibin, CD56, and negative staining of AR, PLAP, CD30, AFP, and HCG. The Ki67 index was low.
Based on the findings, a diagnosis of bilateral TART associated with myelolipoma was established.
TART is a rare benign tumor in the testis that occurs secondary in patients with CAH. CAH is a group of autosomal recessive disorders related to enzyme deficiencies in the adrenal steroidogenesis pathway, which leads to impaired corticosteroid biosynthesis. Mutation of the steroid-hydroxylase gene (CYP21A2) located at chromosome 6p21 is responsible for 95% of the CAH cases.[
CAH has two major forms depending on the extension of the enzyme defect: Classic form, which includes salt wasting and simple virilizing and nonclassic, which is the mild form of disease.[
3 ] In over 90%, the deficient enzyme is 21-hydroxylase.[ 4 ] The level of ACTH driven by negative feedback regulation increases and leads to hypertrophy of the adrenal glands.[ 5 5 ] 6
During embryonic adrenogonadal development, abnormal adrenal cells end up within the testis. Such cells are reported to exist in the testis of 15% healthy neonates.[
1 ] These cells lead to the development of TART because of high ACTH levels, particularly in those of inadequate long hormone control stimulating their proliferation,[ 6 ] gonadal dysfunction, and infertility.[ 7 6 ] As far as the relationship of ACTH level and TARTS's size is concerned, some studies reported that TART cells have ACTH receptors while other studies suggested the involvement of other growth-promoting factors.[ 8 ] 6
The reported prevalence of TARTs in patients with CAH ranges from 27% to 47%. These lesions are typically located within the rete testis and are bilateral, synchronous, nodular, and multiple. Lesions are palpable and/or ultrasound detectable.
Histopathologically, TARTs resemble adrenocortical tissue, with large polygonal cells with abundant granular eosinophilic cytoplasm arranged in strands, cords or lobules, containing lipochrome pigment.[
] The mitotic activity is low. Reinke crystals are absent. The adjacent testicular parenchyma is atrophic with reduced or absent spermatogenesis.[ 9 ] Immunohistochemically, TART shows diffuse and strong positivity for CD56, focal or diffuse reactivity for synaptophysin and negative reactivity for the androgen receptor and inhibin.[ 8 ] 3
TART should be suspected not only in CAH patients but also in all men with potentially high ACTH levels (Cushing syndrome, Addison's disease, adrenalectomy).[
] In some cases, doctors misdiagnose them as malignancies. It is necessary to discriminate TART from Leydig cell tumors (LCT) because they are closely related and share morphological characteristics. TARTs have benign behavior, being removed only after severe orchialgia or testicular parenchymal damage from large tumors. LCTs are less commonly bilateral (3%) and nonresponsive to corticosteroid therapy, with the presence of Reinke crystals. 10% of them are malignant.[ 5 ] LCT displays negative reactivity for CD56 and synaptophysin but positive reactivity for the androgen receptor. 3
Medical management is preferred since TARTs are potentially reversible by the reduction in plasma ACTH level after sufficient steroid therapy.[
5 ] 9
Myelolipoma is an uncommon benign neoplasm of the adrenal gland, composed of apidose tissue and benign hematopoietic elements.[
] The hematopoietic elements contain myeloid, erythroid, and megakaryocytic lineages showing normal maturation. Rarely, foci of metaplastic ossification may be observed, and areas of infarction, hemorrhage, or thrombosis can occur. Myelolipomas are usually incidental findings, accounting for up to 9% of adrenal incidentalomas. They are asymptomatic and vary considerably in size, but some are quite large, causing compressive symptoms. They may also occur in other extra-adrenal sites. 3
The origin of adrenal myelolipoma is not clear. It has been suggested the differentiation of ectopic hematopoietic stem cells or cells of the mesenchyme of ectopic adrenal tissue.[
Myelolipomas have been reported in patients with CAH, supporting the role of hormonal stimuli in their formation.[
] The majority is localized in the adrenal gland, but there are references of myelolipomas in other locations, such as testis.[ 11 ] Specifically, the finding of testicular myelolipoma-associated TARTs, as in our case, suggests that other intrinsic factors related to the presence of adrenal cortical (like) cells play a role in the formation of myelolipoma. There is an association between ACTH excess[ 12 ] and the development of adrenal myelolipoma, but the direct causal link remains to be established. The prevalence of myelolipomas in CAH is 7.4%.[ 11 ] 3
The knowledge of the histological and immunohistochemical features of TART, in association with the patient's history, may allow preservation of fertility and avoidance of unnecessary surgical procedures in the case of testicular tumors. Testicular imaging is necessary to monitor males with CAH and should initially be performed in early adolescence.
Ultrasound is recommended as an imaging modal choice in detecting and monitoring these lesions. While computed tomography may be useful for some individuals who require extremely accurate preoperative assessment.
Imaging findings are nonspecific and difficult to differentiate from malignancy. Histologically, TART may look similar to Leydig cell hyperplasia, causing a diagnostic dilemma in these cases and leading to unnecessary surgery.
It is necessary to distinguish TART tumors from LCT because they are closely related and share morphological features. TARTs have good behavior, they are removed only after severe orchial pain or testicular damage to the parenchyma.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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