Case Report
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Testicular Adrenal Hyperplasia
Testicular Adrenal Rest Hyperplasia due to 21-Hydroxylase Deficiency: A Case Report Seyda Erdogan, MD,1 Melek Ergin, MD,1 Filiz Cevlik, MD,1 Bilgin Yuksel, MD,2 Recep Tuncer, MD,3 Nurdan Tunali, MD,1 and Sait Polat, MD4 Abstract Bilateral testicular tumors are a rare complication of congenital adrenal hyperplasia. It can be extremely difficult to distinguish histologically between Leydig cell tumors and adrenocortical rest hyperplasia, which may lead in some cases to unnecessary orchidectomy. A 7-yr-old boy was admitted because of precocious puberty and enlargement of testicles. Hormonal studies established the diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Testicular biopsy revealed interlacing strands, cords, and rests of cells resembling interstitial (Leydig) cells but with no Reinke crystalloids. Here we report a case of testicular adrenal rest hyperplasia in congenital adrenal hyperplasia and discuss the pathological and clinical features and origin of this rare lesion by using immunohistochemical evaluation. Key Words: Testicular adrenal hyperplasia; 21-hydroxylase deficiency.
Introduction
Cukurova University, Medical Faculty, Departments of 1Pathology, 2Pediatrics, 3 Pediatric Surgery, and 4Histology–Embryology, Turkey. Address correspondence to Dr. Seyda Erdogan, Cukurova University, Medical Faculty, Department of Pathology, 01330 Balcali Adana, Turkey. E-mail:
[email protected] Endocrine Pathology, vol. 17, no. 1, 83–88, Spring 2006 © Copyright 2006 by Humana Press Inc. All rights of any nature whatsoever reserved. 1046-3976/1559-0097 (Online)/ 06/17:83–88/$30.00
Congenital adrenal hyperplasia (CAH) is the result of an autosomal recessive enzyme defect, with more than 90% of cases caused by a deficiency of 21-hydroxylase. The secretion of ACTH by the pituitary gland is increased because of impaired cortisol and aldosterone synthesis. The diagnosis of CAH is confirmed in male individuals with “pubertas praecox” and the presence of a high 17-OH progesterone concentration [1,2]. In nonclassic forms, it can be present with bilateral testicular masses in 18% of the cases, which can easily be misdiagnosed as Leydig cell tumor [3]. The presence of testicular tumors, so-called adrenal rest tumors, in male patients was already described in 1940 by Wilkins et al. [4]. We report a case of testicular adrenal rest (TAR) hyperplasia in congenital adrenal
hyperplasia and discuss the pathological, clinical features, and origin of this rare lesion. Case Report A 7-yr-old boy was admitted to the Hospital of Çukurova University Medical Faculty with evidence of precocious puberty and hyperpigmentation. Physical examination revealed bilateral testicular masses and virilization (Fig. 1). Scrotal USG showed bilateral multifocal masses in the testicles. The largest one was 13 × 6 mm in diameter on the right side. The patient was operated on with the suspicion of Leydig cell neoplasm or adrenal rest hyperplasia. On gross examination, three biopsies taken from the right testicle, one from the left testicle, and each spermatic cord were yellow-brown and firm. Their 83
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Fig. 1. Precocious virilization and testicular enlargement were noted.
Fig. 2. The nodular lesion and adjacent intact tubules of the testis.
sizes were ranged from 0.4 to 2.5 cm in diameter. On microscopic examination, these six nodules were composed of cells having centrally located nuclei, eosinophilic large cytoplasm, and thin fibrovascular stroma. Some cytomegalic nuclei,
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cytoplasmic lipid vacuoles, and also stromal lymphocytic infiltration were noted (Figs. 2–4). Only a few intratubular calcifications were observed in the testicular parenchyma. There were no Reinke crystalloids in the cytoplasms and spermatogenesis in the testicles both in hematoxylene-eosin and Masson trichrome stains. When laboratory findings showed a 21-hydroxylase deficiency combined with these morphologic features, the diagnosis of testicular adrenal rest tissue hyperplasia was made. ACTH (Nova Castro, UK, 1/50), MelanA (Dako, USA, 1/30), β-HCG (NeoMarkers, USA, 1/50), FSH (Dako, USA, 1/50), and LH (Dako, USA, 1/80) hormones were performed on the paraffin sections by immunohistochemistry in order to clarify the origin of these cells. There was diffuse staining with Melan-A (Fig. 5), β-HCG, and focal positivity with ACTH (Fig. 6). No positivity was observed with FSH and LH. For electron microscopic examination, a paraffin-embedded tissue sample was transferred to Karnovsky’s fixative after being immersed in xylol, graded series of ethanol, and rinsed in cacodylate buffer for 10 min. Tissue sample was rinsed in 1% osmium tetraoxide, dehydrated by graded series of ethanol, and finally embedded in epon. Semithin (1 µm) sections were cut on a Reichart ultramicrotome and stained with toluidine blue. The lesion was further cut into thin sections, supported with 200-mesh copper grids, and stained with uranyl acetate and lead citrate. Ultrastructural examination was performed with a Zeiss 900 EM transmission electron microscope. Ultrastructurally, cytoplasmic, abundant membrane-limited, steroidsecreting cells were identified by their vesicles that contain a very dense core (Fig. 7). Crystals of Reinke were not observed.
Testicular Adrenal Hyperplasia
Fig. 3. The lesion in the testis has centrally located nuclei, eosinophilic large cytoplasm, thin fibrovascular stroma (H&E, ×100).
Fig. 4. Some cytomegalic nuclei, cytoplasmic lipid vacuoles were noted (H&E, ×200).
Discussion TAR is most commonly reported in patients with congenital adrenal hyperplasia who have clinically detectable testicu-
85 lar masses, usually in adolescence or early adulthood. These lesions are hormone dependent and are not considered as true autonomous tumors [1–3,5,6]. In prenatal life, both gonads and adrenals develop from adrenogenital ridge and do not separate until the adrenal groove becomes prominent. Before separation, adrenal cortical tissue may adhere to the gonad. Adrenal rest tissue can be found on the way of normal testicular descent and can be detected in 50% of newborns. These remnants are usually found in extratesticular locations like connective tissue of the spermatic cord, adjacent to the epididymis and rete testis, and near the hilum of the testis. They are less common within the testis [5–7]. Shanklin et al. supposed that this rest tissue originates from a pluripotential cell that atrophies during early infancy. In the case of adrenogenital syndrome, the elevated adrenocorticotrophic hormone causes the hyperplasia of these adrenal remnants that presents as testicular masses [7]. They may also occur in other patient groups characterized by elevated plasma ACTH levels, such as Nelson’s syndrome and Addison’s disease [2,3]. Histologically, the differentiation of testicular nodules due to CAH and Leydig cell tumor may be very difficult, but it is important to assessment to preserve fertility. Reinke crystalloids are present in 40% of Leydig cell tumors, whereas they are absent in adrenal cortical rests. Testicular nodules due to CAH are usually bilateral and multifocal; however, Leydig-cell tumors are often unilateral [7,8]. A biochemical profile including 17-hydroxyprogesterone, 11-desoxycortisol, dehydroepiandrosterone, androstenedione, and testerone levels should be performed for differentiating the two conditions. Leydig cell tumors of the testis are more likely to present unilaterally and 17-ketosteroid
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Fig. 5. Melan A positivity at the adrenal rest (Immunohistochemistry, ×400).
Fig. 6. ACTH positivity at the adrenal rest within the testis (Immunohistochemistry, ×400).
levels are not suppressed by steroid administration [6–8]. The precise origin of TAR is controversial. The hypothesis includes derivation from adrenocortical cells or from peculiar
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ACTH-dependent Leydig cells or from undifferentiated stromal cells that differentiate to either adrenal-like cells or Leydiglike cells [6–8]. In our case, we performed Melan-A, ACTH, β-HCG, LH, FSH to the testicular nodules by immunohistochemistry in order to clarify the tissue origin of TAR. All the nodules were positive with Melan-A and β-HCG and where as negative for LH and FSH. Focal positivity was detected with ACTH at the nodules located within the testis. Absence of Reinke crystalloids, bilaterality, immunopositivity with Melan-A and ACTH suggests an adrenal origin in the present case. Additionally, ultrastructural features like membrane-limited dense granular cores (norepinephrine-secreting cells) and absence of Reinke crystals strongly favor adrenal origin rather than testis. However, the intratesticular location, β-HCG positivity by IHC, and high serum testerone level argues against an adrenal rest cell origin. So our case provides evidence suggesting that the testicular nodules associated with CAH are neither intestitial nor adrenal cortical cell origin but originate from a pluripotential cell. As mentioned above the cell origin of testicular nodules due to CAH arises in utero at the gonadal–adrenal border zone, descends with the testis, and progresses under chronically elevated ACTH stimulation into a detectable mass [7–9]. This would explain their bilaterality, mixed histology, and immunohistochemical features. Thus, although histological, immunohistochemical, and ultrastructural examination may be helpful, more sophisticated techniques are also needed to clarify the cell origin of this lesion. The suppression of high ACTH by replacement steroid therapy usually causes rapid regression in tumor size in 75% of cases. Immediate orchiectomy for the pre-
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References
Fig. 7. Ultrastructurally steroid-secreting cells are identified by their vesicles which contain a very dense core (EM, ×10,000).
sumed diagnosis of Leydig cell tumor is unwarranted [3,9]. In conclusion, the adrenogenital syndrome must be ruled out in any child who presents with bilateral testicular tumors and precocious puberty. If the masses do not respond to steroid replacement, biopsy must be performed to confirm pathological diagnosis of TAR and followed by observation only.
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