Testicular adrenal rest tumours (TARTs) are rare benign tumours and as the name itself is explanatory, they arise from the resting adrenal cells in the testis. Previously, it was hypothesized that adrenal cells migrate with the testicular cells and remain dormant. However, it is now believed that they may originate from a pluripotent steroidogenic cell in utero [1,2]. Early and prolonged exposure to ACTH is necessary for the hyperplasia of these cells. The defect in the steroidogenesis pathway in CAH results in hypersecretion of ACTH. This leads to the hyperplasia of zona fasciculata as well as the resting adrenal cells. TARTs are reported in other acquired conditions such as childhood Cushing’s disease, Nelson syndrome, and Addison’s disease [3,4]. However, they are not seen in adult males after bilateral adrenalectomy despite high ACTH levels, as prolonged exposure is required for the development of TART [5].

The patient noticed enlarged testicles for the last four to five months. It was painless and gradually progressive. He searched online and found out that it could be a testicular cancer. Out of fear, he consulted the surgeon and wanted to get rid of it as early as possible to prevent the progression of the disease. He was in his twenties, married, and sexually active. There were no symptoms such as pain, tenderness, or fever. There was no loss of libido or erectile dysfunction. Upon questioning, he declined any history of chronic disease, trauma, or the use of any off-label medications. Upon local examination, both testes were enlarged and had a firm consistency, with no local rise in temperature. Cord structures were palpable separately from the swellings. There was no inguinal lymphadenopathy. Systemic examination was unremarkable. His scrotal ultrasound detected irregularly shaped masses in both testes, well demarcated from the testis. They were hypoechoic and eccentrically located. Colour Doppler showed increased vascularity. These findings raised a suspicion of malignancy. He underwent bilateral testicular exploration, which revealed irregular, firm masses arising from the mediastinum testis. They were distinct from testicular parenchyma. The lesions were excised with the preservation of adjacent testicular tissue. On gross examination, the lesions were reddish-brown with grey areas in between (Figure 1).

Figure 1: Gross appearance of the Testicular Adrenal Rest Tumours (TARTs).

Microscopic examination showed large polygonal cells with moderate to abundant finely granular eosinophilic cytoplasm arranged in sheets, cords, and lobules with round to oval vesicular nuclei with prominent nucleoli. Characteristic brown-coloured vacuoles were noted in some of the cells, which were consistent with the lipofuscin pigment (Figure 2). Focal lymphocytic infiltration of the rete testis was noted, along with intervening fibrous stroma (Figure 3). The surrounding testicular parenchyma showed markedly atrophic and hyalinised seminiferous tubules (Figure 4). These features were consistent with stage 3 TARTs as per the Claahsen-van der Grinten classification [2].

Figure 2: Microscopic image (H&E, ×400) showing nests and trabeculae of large polygonal tumour cells with abundant eosinophilic granular cytoplasm, vesicular nuclei, prominent nucleoli, and intracytoplasmic lipofuscin pigment (red arrow), features consistent with steroid-producing adrenal rest cells.

Figure 3: Low-power histology (H&E, ×100) demonstrating tumour infiltration into the rete testis (green arrow), surrounded by fibro-adipose stroma and a mild lymphocyte infiltrate.

Figure 4: Adjacent testicular parenchyma (H&E, ×100) revealing markedly atrophic and hyalinised seminiferous tubules (green arrows) with interstitial fibrosis, consistent with chronic compression and impaired spermatogenesis due to expanding TART mass.

He was referred to the endocrinology department for further management. After detailed history taking, he admitted to having been diagnosed with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in childhood. He was non-compliant with the medications but started taking them regularly in the last two months. On physical examination, he was averagely built with typical male secondary sexual characteristics. Pubertal assessment corresponded to Tanner stage 5 with reduced testicular volume (approximately 10 mL on Prader orchidometer). There was no gynecomastia. There were no signs of adrenal insufficiency, such as hyperpigmentation or postural hypotension.

Hormonal tests were ordered, which showed mildly elevated LH (8.3 IU/L; normal range: 1.2-7.8 IU/L) with normal FSH and testosterone levels (Table 1), suggestive of partial Leydig cell dysfunction with preserved Sertoli cell function. 17-hydroxy progesterone was 1.9 ng/mL, suggestive of adequate biochemical control. Semen analysis revealed oligoasthenozoospermia, characterized by a sperm count of 8.5 million/mL and motility of 26%. He was initiated on prednisolone 7.5 mg/day and fludrocortisone 100 µg/day, with plans for further dose titration.

Scrotal Ultrasound

Right Testis

Volume: 10.5 mL (normal adult range: 12-25 mL).

Irregular eccentric hypoechoic lesion of size 3.0 × 1.0 × 1.2 cm located in the mediastinum testis with coarse internal echoes.

Left Testis:

Volume: 9.5 mL

Irregular hypoechoic lesion seen in the mediastinum testis, measuring 2.8 × 1.0 × 1.1 cm with coarse internal echoes.

Both epididymides were normal in size.

No significant fluid collection noted.

Doppler Study

Preserved vascular flow in both testes with mildly increased vascularity in the lesions.

Hormonal Evaluation:

Table 1: Hormonal and Biochemical Profile.

Leydig Cell Tumour (LCT): Considered but unlikely due to bilateral presentation, absence of Reinke crystals [10,11].

Treatment

Surgical: Bilateral testis-sparing tumour excision

Medical: Prednisolone 7.5 mg and fludrocortisone 100 µg/day, with monitoring of ACTH and 17-OHP

Outcome and Follow-Up

The patient was clinically stable postoperatively, and examination did not reveal any recurrence of the TARTs.A semen analysis is planned for 3 months. Fertility counselling and the option of sperm banking were discussed. The patient was advised to have regular endocrine follow-up for dose titration and monitoring for recurrence.

Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders that are caused by defects in the enzymes responsible for adrenal steroid production. The most common type of CAH is due to 21-hydroxylase deficiency, which occurs with an incidence of approximately one in every 10,000 to 20,000 births [1]. It is classified into three types based on the residual activity of the enzyme [2].

• Classic salt-wasting: It is the most severe form, resulting from complete loss of enzyme activity, leading to an adrenal crisis in the neonatal period and a marked elevation of ACTH and androgens.
• Simple virilising: In this type, 1-2% of enzyme activity is present, which prevents adrenal crisis but is associated with virilization in early childhood due to excessive adrenal androgens.
• Non-classic: This is the mildest form, characterized by 30-50% residual enzyme activity. Patients may present with signs such as hirsutism, acne, and menstrual irregularity.

Testicular adrenal rest tumours (TARTs), as the name suggests, arise from the resting adrenal cells in the testis. It was previously thought that during adrenogonadal development, aberrant adrenal cells migrate to the testes or ovaries. However, it is now hypothesized that TARTs originate from a more pluripotent steroidogenic cell in utero [2]. Loss of adrenal steroidogenesis results in increased ACTH stimulation due to the loss of negative feedback inhibition, causing hyperplasia of the adrenal cortex, as well as the resting adrenal cells [3]. It is traditionally believed that poorly controlled CAH patients will develop TARTs; however, this is not entirely accurate, as TARTs can also occur in patients with well-controlled CAH [2]. Early and prolonged exposure to elevated ACTH is necessary for the proliferation of pluripotent cells into TARTs. Various acquired conditions associated with excess ACTH include childhood Cushing's disease, Nelson syndrome, and Addison's disease [4]. However, it is not seen in adult males with Addison disease or after bilateral adrenalectomy despite having high ACTH levels supporting the hypothesis of early and prolonged stimulation [5]. Other compounds, such as LH and angiotensin 2, may also contribute to the development of TART, as these receptors have been found in TART [6]. Manon Engels et al. summarized 33 original studies that have reported on TART prevalence in the last 10 years. The prevalence ranged from 14% to 86%, depending on age and genotype, with summed prevalence of 37% [2]. Although there is an increase in the prevalence with age, the youngest child described was 1.8 years old [6].

Most patients present with painless enlargement of the testis, and some are diagnosed on the evaluation for infertility. Ultrasound imaging is the preferred initial investigation, as it is readily available and cost-effective and can detect TARTs of sizes less than 2 cm. Most TARTs are hypoechogenic but can be isogenic or hyperechogenic [6]. MRI imaging reveals hypointensity in T2-weighted images compared with normal testicular parenchyma [7]. TARTs are usually bilateral and located near or within the mediastinum testis [8].

Macroscopically, they are sharply demarcated from the normal testicular tissue and are round to oval in shape with firm consistency [9]. Microscopically, TARTs contain sheets or cords of hyperplastic cells separated by bands of fibrous tissue, which gives them a characteristic rubbery consistency [9]. The cells are large, polygonal, with round nuclei and abundant cytoplasm, consistent with steroid-secreting cells, such as Leydig cells [10]. TARTs may compress the rete testis or seminiferous tubules, leading to infertility. The staging of Testicular Adrenal Rest Tumours (TARTs) is based on ultrasound and clinical findings, as proposed by Claahsen-van der Grinten et al. It is used to classify tumour progression and guide treatment decisions.

TARTs are often misdiagnosed as Leydig cell tumours (LCTs) due to similar morphological and histological characteristics. These can be distinguished based on the combination of clinical and histological characteristics. Furthermore, TARTs are bilateral in 77% of cases, whereas more than 90% of LCTs are unilateral [11]. Immunohistochemistry helps distinguish TART from Leydig cell tumours (LCTs). TARTs are negative for sex cord-stromal markers (EMA, S100, and PAX8) and Leydig cell markers (INSL3, Reinke crystalloids, calretinin) but show variable positivity for vimentin, synaptophysin, and NCAM1. Adrenal markers such as inhibin A, DLK1, and enzymes like 21-hydroxylase, 11β-hydroxylase, and 3β-HSD are consistently positive, supporting the adrenal origin of TART [12,4].

In this case, the patient had a known case of congenital adrenal hyperplasia (CAH) diagnosis but had been on irregular glucocorticoid therapy since adolescence. This likely resulted in the chronic elevation of adrenocorticotropic hormone (ACTH), which, in turn, contributed to the development of bilateral testicular adrenal rest tumours (TARTs). The case highlights the importance of considering TART in males with CAH presenting with testicular masses. Early recognition and adequate steroid replacement may prevent progression to advanced stages and preserve fertility.

• TARTs should be considered in males with CAH presenting with testicular masses.
• They may occur even in well-controlled patients due to earlier ACTH overexposure.
• Timely imaging and staging are essential for preserving fertility.
• Differentiation from malignancy is critical to avoid unnecessary intervention.
• Regular endocrine follow-up and steroid titration are key to prevention.

Patient’s Perspective

“I was too worried because of the testicular swelling. Thank god, it wasn't cancer. Now I will take the medications regularly and do a regular follow-up.”

Acknowledgements

Nil

Conflict of Interest

Nil

Financial Support

Nil