- Email: [email protected]
Testicular Adrenal Rest Tumor (TART) in congenital adrenal hyperplasia
Accepted Manuscript Testicular Adrenal Rest Tumor (TART) in congenital adrenal hyperplasia Hatice Ozisik, Banu Sarer Yurekli, Ilgin Yildirim Simsir, Ilker Altun, Utku Soyaltın, Ezgi Guler, Huseyin Onay, Banu Sarsik, Fusun Saygili PII:
S1769-7212(17)30098-8
DOI:
10.1016/j.ejmg.2017.06.009
Reference:
EJMG 3303
To appear in:
European Journal of Medical Genetics
Received Date: 13 February 2017 Revised Date:
30 June 2017
Accepted Date: 30 June 2017
Please cite this article as: H. Ozisik, B.S. Yurekli, I.Y. Simsir, I. Altun, U. Soyaltın, E. Guler, H. Onay, B. Sarsik, F. Saygili, Testicular Adrenal Rest Tumor (TART) in congenital adrenal hyperplasia, European Journal of Medical Genetics (2017), doi: 10.1016/j.ejmg.2017.06.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Testicular Adrenal Rest Tumor (TART) in congenital adrenal hyperplasia Hatice Ozisik1, Banu Sarer Yurekli1, Ilgin Yildirim Simsir1, Ilker Altun1, Utku Soyaltın1, Ezgi Guler2, Huseyin Onay3, Banu Sarsik4, Fusun Saygili1 1
Ege University, Faculty of Medicine, Department of Endocrinology and Metabolism Diseases, Turkey 2
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Ege University, Faculty of Medicine, Department of Radiology, Turkey
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Ege University, Faculty of Medicine, Department of Medical Genetics, Turkey
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Ege University, Faculty of Medicine, Department of Pathology, Turkey
Corresponding author
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Hatice Ozisik
Ege University, Division of Endocrinology and Metabolism, İzmir, TURKEY Ege University Hospital, Department of Endocrinology, Bornova, 35100 Izmir-Turkey
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Mobile phone number: +905068936521 Fax number: +902323904612
e-mail address: [email protected]
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-The work will not be submitted for publication elsewhere until the editorial board has decided whether
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to publish the article.
-TARTs are rarely seen so we would like to discuss about TARTs in the lights of literature. - We have received permission from the patients.
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The authors do not have any conflict of interest.
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Running head: Testicular adrenal rest tumor
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Key Words: Congenital adrenal hyperplasia, testicular adrenal rest tumor
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Abstract
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Congenital adrenal hyperplasia is one of the most common autosomal recessive genetic disorders. Testicular adrenal tumors are significant complications of congenital adrenal hyperplasia. We would like to present two patients of testicular adrenal rest tumors. Patient 1 24 year-old male, he was diagnosed with congenital adrenal hyperplasia at the age of 8 due to precocious puberty. He received hydrocortisone treatment until the age of 18. Testicular mass had been detected and right radical orchiectomy had been applied 6 months ago and reported as testicular adrenal rest tumor. In scrotal ultrasound, a mixed type mass lesion (6x4x3 cm) covering a large part of left testis was observed. The imaging findings were consistent with adrenal rest tumor. The patient took adrenocorticotropic hormone supressive therapy with dexamethasone 0.75 mg once a day. Patient 2, 38 year-old male, he had been followed-up as adrenal insufficiency for 35 years. He underwent right orchiectomy operation due to the testicular mass in 2010 and the pathological examination revealed Leydig cell tumor. In scrotal ultrasound, small multifocal lesions were detected on the left testis and resection was done. It was reported as testicular adrenal rest tumor. He is being followed-up with glucocorticoid treatment according to androgen and adrenocorticotropic hormone levels. Early diagnosis of testicular adrenal rest tumor is significant in preventing irreversible testicular damage and infertility. In the differential diagnosis, we should keep in mind that testicular adrenal rest tumor can mimic other testicular tumors such as primary germ cell tumors.
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Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive genetic disorders which is caused by a deficiency in CYP21 (21hydroxylase) enzyme in more than 90% of patients (White and Speiser, 2000). The prevalence is approximately 1 in 15.000 births. Individuals with CAH have impaired cortisol and aldosterone production, leading to increased adrenocorticotropic hormone (ACTH) production by the pituitary gland. Excess levels of ACTH cause adrenal hyperplasia and overproduction of adrenal androgens. CAH is classified as classic or non-classic. Classic form has a significant decrease in 21-hydroxylase activity, giving rise to total lack of cortisol and aldosterone. The classic simple virilizing form is seen in approximately 33% of patients with classic CAH and this form is related to 1% to 2% of normal 21-hydroxylase activity (White and Speiser, 2000). Non-classic CAH is defined as having 20% to 50% of 21-hydroxylase activity and has a milder phenotype (Witchel and Azziz, 2010). Testicular adrenal rest tumors (TARTs) were first defined in 1940. TARTs are significant complications of CAH (Stikkelbroeck et al., 2001). Though TARTs are usually benign, they can obstruct the seminiferious tubule, causing gonadal dysfunction (Claahsen-van der Grinten et al., 2007). Intensive glucocorticoid therapy can suppress ACTH secretion and can lead to the regression of the tumors. However, in some patients, surgical intervention may be needed. We would like to present two patients of TARTs with the challenges regarding to diagnosis and treatment.
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Patient 1
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24 year-old male, he was diagnosed with CAH at the age of 8 due to precocious puberty. He received hydrocortisone treatment until the age of 18. Testicular mass had been detected and right radical orchiectomy had been applied to him 6 months ago at another institution. Histopathological diagnosis was reported as testicular adrenal rest tumor. Pathological specimen was reevaluated by our pathologist. Histopathologic examination revealed a tumor with extensive eosinophilic cytoplasm, occasionally large nucleated cells, separated by fibrous septa around the rete testis. Focal fatty tissue metaplasia was detected in the tumor. In the immunohistochemical study, tumor cells were positive with CD56 and inhibin. In the presence of these findings, the tumor was evaluated as testicular adrenal rest tumor. He was admitted to our clinic owing to the presence of bilateral adrenal masses on the surrenal glands which were detected on abdominal computed tomography (CT). On physical examination, his height was 152 cm, weight was 47 kg, BMI was 20.3 kg/m2 . He was normotensive (120/70 mmHg). He had short fingers and short stature. There is no history of consanguineous marriage. In laboratory examination, 17hydroxyprogesterone (17-OHP): 122 ng/mL (0.6-3.3), ACTH:118 pg/mL (<46), free testosterone:34.4 pg/mL ), dehydroepiandrosterone (DHEAS):378.4 µg/dL (85-690), cortisol:5.2 µg/dL (4.82- 19.5), luteinizing hormone (LH):0.74 mIU/mL (1.24-8.62), follicle-stimulating hormone (FSH):2.39 mIU/mL (1.27-19.26) were detected. . Tumor markers as α-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase
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were negative. Semen analysis showed azoospermia. His serum electrolytes were normal. In scrotal ultrasound (US), a mixed type mass lesion (6x4x3 cm) covering a large part of left testes was observed. The patient underwent a magnetic resonance imaging (MRI) examination. In abdominal MRI, axial T2-weighted image and axial inphase image showed a 2.4 cm mass in the right adrenal gland and a 6 cm mass in the left adrenal gland. This scene in MRI was interpreted as nodular hyperplasia of adrenals. In MRI study of the testes, axial images showed a 4.4 cm lobulated mass in the left testis which is hypointense relative to the testes. The mass was isointense relative to the testes on axial T1-weighted image. Axial and coronal contrastenhanced T1-weighted images demonstrate diffuse enhancement of the mass. The findings are consistent with adrenal rest tumor (Figure 1 A,B,C,D).Mutation analysis revealed compound heterozygous mutations in CYP21A2 gene. Heterozygous NM_000500.7(CYP21A2):c.293-13C>G (legacy name: I2splice) was detected in one allele and heterozygous NM_000500.7(CYP21A2):c.923dup (p.(Leu308Phefs*6))(legacy name: L307 frameshift) mutation was detected on the other allele. To decrease the size of tumors on the left and to improve his hormonal profile, ACTH supressive therapy was initiated with dexamethasone 0.75 mg once a day. He is in the follow-up period. Patient 2
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38 year-old male, he had been followed-up as adrenal insufficiency for 35 years. He underwent the operation of right orchiectomy due to the testicular mass in 2010 and the pathological examination revealed Leydig cell tumor (LCT). In scrotal ultrasound, small multifocal lesions were detected on the left testis and testicular mass resection was done. Left testis mediastinum-localized tumors were examined in frozen specimens. When the frozen result was reported as benign, the residual mass was resected. Histopathologic examination revealed a tumor with extensive eosinophilic cytoplasm, occasionally large nucleated cells, separated by fibrous septa around the rete testis (Figure 2A,B). Focal fatty tissue metaplasia was detected in the tumor (Figure 2C). It was learned that right radical orchiectomy was performed and leydig cell tumor was diagnosed in 2010. When this material was re-evaluated, it was found that it was similar to the morphology of the left testis. In the immunohistochemical study, tumor cells were positive with CD56 (Figure 2D) and inhibin (Figure 2E), negative with calretinin and androgen receptor. In the presence of these findings, the tumor was evaluated as "testicular adrenal rest tumor". The diagnosis of LCT for the right testis changed into TART after reevaluation by the pathologist. He has been taking 30 mg hydrocortisone once a day. On physical examination, height was 174 cm, weight was 104 kg, BMI was 34.4 kg/m2 . In laboratory examination, 17-OHP: 157 ng/mL (0.6-3.3), ACTH:194 pg/mL (<46), free testosterone:31.6 pg/mL (57-178), DHEAS:123.5 µg/dL (85-690), cortisol:2.14 µg/dL (4.82-19.5), LH 3.34 mIU/mL(1.248.62), FSH 7.21 mIU/mL (1.27-19.26) were detected. Tumor markers as αfetoprotein, human chorionic gonadotropin and lactate dehydrogenase were negative. Semen analysis showed azoospermia. His electrolytes were normal. In
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abdominal CT, axial arterial and portal venous phase contrast enhanced CT images showed bilateral enlarged adrenal glands with nodular hyperplasia. In MRI study of testis, axial and coronal T2-weighted images showed a hypointense nodule in the left testis, axial and sagittal contrast enhanced T1-weighted images demonstrated 2.5 cm testicular nodules with diffuse enhancement (Figure 3 A,B,C,D). Mutation analysis revealed compound heterozygous mutations in CYP21A2 gene also in this patient. Heterozygous NM_000500.7(CYP21A2):c.92C>T (p.Pro31Leu)(legacy name: P30L)) mutation was detected in one allele and heterozygous NM_000500.7(CYP21A2):c.332_339del (p.(Gly111Valfs*21)) (legacy name: Del8bpE3) mutation was detected on the other allele. He is being followed-up with glucocorticoid treatment according to androgen and ACTH levels.
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Discussion
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Testicular adrenal rest tumors (TARTs) have been declared in 18% of undiagnosed CAH patients and can be the first symptom of CAH (Stikkelbroeck et al., 2001). Patients untreated or treated insufficiently with CAH can develop TARTs due to increased ACTH levels. TARTs have usually been reported in classic CAH but sometimes also in non-classic CAH as reported Falhammar H et al's article ( Falhammar et al.,2012). TART is very common in CAH, up to 94% will probably seen to have it if an ultrasound is done with an interested sonographer. TARTs are usually seen in adolescence and in early adulthood because increased LH levels can stimulate tumor growth in these periods (Jin et al., 2011). TARTs are supposed to derive from remnant adrenal cells that migrate to the scrotum throughout the descent of the testes or from pluripotent stem cells in the testes (Rich and Keating 2000). The adrenal rest tissue in the testes has ACTH specific receptors and is ACTH responsive, making steroid hormones and it may be hyperplastic (Smeets et al., 2015).
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TART is a detectable and mostly treatable lesion, but it could be misdiagnosed as Leydig cell tumor (LCT). In some conditions, patients with CAH had undergone unnecessary testicular surgery. Karakus et al (Karakuş et al., 2014) reported a 7year-old boy with CAH who had TART and stated that it was difficult to make differential diagnosis with LCT. Furthermore, Olpin et al. (Olpin and Witt, 2014) declared that 27-year-old male with CAH who was diagnosed at age 3 weeks presented bilateral testicular mass. Although he was thought to have TART according to ultrasound findings, pathological report revealed LCT initially. But, later on, diagnosis was established as TART eventually with the further consultation. In our patient 2, right orchiectomy material was reevaluated by the pathologist in our institution. The diagnosis was thought to be TART rather than LCT in the light of clinical and hormonal data. Histopathologically, TARTs can be misdiagnosed as LCTs. TARTs are negative for Reinke crystals (cytoplasmic rod-like crystalloids) which are seen in LCTs (Budzyńska and Beń-Skowronek, 2011, Cakir et al., 2012). Both tumors consist of polygonal cells with abundant eosinophilic or granular cytoplasm in cord-like arrangements divided by dense fibrotic tissue. TARTs are
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generally not painful, they are bilateral and they exist near the hilum of the testis. In fact, they can response to steroid treatment and the size of tumors can be reduced with the treatment (Rich and Keating, 2000). On the contrary, though they are also usually painless, LCTs are unilateral and they do not regress with corticosteroid treatment. They are localized in the interstitial tissue of testis adjacent to seminiferous tubules (Claahsen-van der Grinten et al., 2007). When TART is compared to LCT, it can be seen that lack of cytological atypia, low mitotic activity, dense fibrous septa, lymphoid aggregates, adipose metaplasia and prominent lipochrome pigment are more prevalent in TART. Immunohistochemically, TART displays strong and diffuse positivity for CD56, focal or diffuse strong reactivity for synaptophysin and negative reactivity for the androgen receptor. On the contrary, LCT shows focal weak or negative reactivity for CD56 and synaptophysin while showing positive reactivity for the androgen receptor (Ashley et al., 2007). Inhibin A may be a sensitive and a specific immunohistochemical marker only for LCTs (Iczkowski et al., 1998) (Table 1). As in our second patient, pathological examination should be performed carefully with the aid of clinical, laboratory and endocrinological evaluations.
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Imaging is essential and important in the diagnosis and follow-up period for TARTs. First step is US due to its cost-effectiveness. The vast of these lesions are hypoechoic and sharply marginated but enormous lesions can be hyperechoic. In Doppler US, these lesions are usually hypervascular (Avila et al., 1996, Stikkelbroeck et al., 2003). MR imaging has not been completely approved. Some scientists report that the edges of TART can be well defined at MR. If testis sparing surgery is planned, MR is superior and more preferable than US in describing extent and margins of TART (Walker et al., 1997). On T1-weighted sequences, TARTs are usually isointense, while they are usually hypointense on T2-weighted sequences (Nagamine et al., 2005).
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Despite no malignant characteristics of TARTs, they may inflict serious testicular damage by pushing down the seminiferous tubules, resulting in obstructive azoospremia. In the literature, prevalence of TART was 34% and that of oligospermia was 66%, reported in the largest series with 219 male subjects (Bouvattier et al., 2015). Chronic obstruction of the tubules may cause irreversible testicular damage.(Claahsen-van der Grinten et al., 2007). Thus, early diagnosis and treatment is vital for good prognosis. Tumors greater than 2 cm can be detectable by palpation but tumors of small-size can not be detected without US. Ultrasound is thought to be as sensitive as MRI in detecting small TARTs (Stikkelbroeck et al., 2003). Fertility rates are lower in CAH reported in recent studies as 67%, 51% and 23% (Arlt et al., 2010, Bouvattier et al., 2015, Reisch et al., 2009). Infertlity in male patients may result from TART and hypogonadotrophic hypogonadism, leading to testicular failure. Excess adrenal androgens cause negative feedback at the pituitary level wtih the result of low LH and FSH. Decreased LH levels generally return back to normal levels
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Intensive glucocorticoid treatment is effective, first line treatment in TART and can help regression of tumors. Dexamethasone has a longer half-life than hydrocortisone and more effectively supresses the hypothalamic-pituitary axis (Claahsen-van der Grinten et al., 2007). It is important to prescribe appropriate doses to suppress ACTH levels to patients with TARTs (Vanzulli et al., 1992). Because if the treatment is not adequate, these lesions may develop in extent and number. As mentioned above, untreated TARTs may cause compression and distortion resulting in low testosterone production and infertility. If the tumors do not respond to the treatment and the patient has chronic testicular pain, surgical intervention may be needed. These patients may undergo partial or total orchiectomy (Walker, et al., 1997). Kavoussi et al. (Kavoussi et al., 2016) offer sperm retrieval during TART resection in azoospermic CAH patients. This procedure could be an option for infertility in CAH subjects.
References
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In differential diagnosis, it should be kept in mind that other testicular tumors such as primary germ cell tumors or gonadal (sex cord) tumors may also be present in adult patients. Nevertheless, primary testicular tumors are usually unilateral and fewer in number when they are compared with TARTs (Woodward et al., 2002). In conclusion, patients with CAH due to 21-hydroxylase deficiency have a risk for TARTs. So, early diagnosis of TART is significant in preventing irreversible testicular damage and infertility. It is crucial to detect small-sized tumors for these patients. Therefore digital palpation and US is very important in the surveillance.
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Arlt W., D. S. Willis, S. H. Wild, et. al., 2010. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J. Clin. Endocrinol. Metab. 95, 5110-5121.
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Ashley R. A., S. M. McGee, P. A. Isotaolo, et. al., 2007. Clinical and pathological features associated with the testicular tumor of the adrenogenital syndrome. J. Urol. 177, 546-549; discussion 549. Avila, N. A., A. Premkumar, T. H. Shawker et. al., 1996. Testicular adrenal rest tissue in congenital adrenal hyperplasia: findings at Gray-scale and color Doppler US. Radiology. 198, 99-104. Bouvattier, C., L. Esterle, P. Renoult-Pierre, et. al., 2015. Clinical Outcome, Hormonal Status, Gonadotrope Axis, and Testicular Function in 219 Adult Men Born With Classic 21-Hydroxylase Deficiency. A French National Survey. J. Clin. Endocrinol. Metab.100, 2303-2313. Budzyńska, E., I. Beń-Skowronek., 2011. Testicular adrenal rest tumours in boys with congenital adrenal hyperplasia: case report and literature review. Pediatr. Endocrinol. Diabetes Metab. 17, 239-242.
ACCEPTED MANUSCRIPT Cakir, E. D., F. S. Mutlu, E. Eren et. al., 2012. Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia. J. Clin. Res. Pediatr. Endocrinol. 4, 94100.
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Claahsen-van der Grinten, H. L., B. J. Otten, F. C. Sweep et. al., 2007. Repeated Successful Induction of Fertility after Replacing Hydrocortisone with Dexamethasone in a Patient with Congenital Adrenal Hyperplasia and Testicular Adrenal Rest Tumors. Fertil. Steril. Vol. 88, No. 3, pp. 705.e5-8. Claahsen-van der Grinten, H. L., F. C. Sweep, J. G. Blickman et. al., 2007. Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21- hydroxylase deficiency. Eur. J. Endocrinol.157, 339-344. F., Ekström
U., Granberg
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al.,2012.
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Falhammar H., Nyström H. J Endocrinol. 166, 441-449
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Iczkowski, K. A., D. G. Bostwick, P. C. Roche et. al., 1998. Inhibin A is a sensitive and specific marker for testicular sex cord-stromal tumors. Mod. Pathol. 11, 774-779. Jin, H. Y., J. H. Choi, G. H. Kim et. al., 2011. Testicular adrenal rest tumors in a patient with untreated congenital adrenal hyperplasia. Korean J. Pediatr.54, 137-140. Karakuş, E., M. N. Azılı, T. Tiryaki., 2014. Testicular adrenal rest tumor mimicking leydig cell tumor in a patient with congenital adrenal hyperplasia. APSP J. Case Rep. 5, 10.
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Kavoussi, P. K., R. B. Summers-Colquitt, K. C. Odenwald et. al., 2016. Sperm retrieval and concomitant tumor resection in azoospermic men with congenital adrenal hyperplasia and bilateral testicular adrenal rest tumors: a case report. J Assist Reprod Genet. 33, 545-548.
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King, T. F., M. C. Lee, E. E. Williamson et. al., 2016. Experience in optimizing fertility outcomes in men with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. Clin. Endocrinol. (Oxf). 84, 830-836. Nagamine, W. H., S. V. Mehta, A. Vade. 2005. Testicular adrenal rest tumors in a patient with congenital adrenal hyperplasia: sonographic and magnetic resonance imaging findings. J. Ultrasound Med. 24, 1717-1720. Olpin, J. D., B. Witt. 2014. Testicular adrenal rest tumors in a patient with congenital adrenal hyperplasia. J. Radiol. Case Rep. 8, 46-53. Reisch, N., L. Flade, M. Scherr et. al., 2009. High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 94, 1665-1670. Rich, M. A., M. A. Keating., 2000. Leydig cell tumors and tumors associated with congenital adrenal hyperplasia. Urol. Clin. North Am. 27, 519-28, x.
ACCEPTED MANUSCRIPT Smeets, E. E., P. N. Span, A. E. van Herwaarden et. al., 2015. Molecular characterization of testicular adrenal rest tumors in congenital adrenal hyperplasia: lesions with both adrenocortical and Leydig cell features. J. Clin. Endocrinol. Metab. 100, E524-30.
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Stikkelbroeck, N. M., B. J. Otten, A. Pasic et. al., 2001. High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 86, 5721-5728. Stikkelbroeck, N. M., H. M. Suliman, B. J. Otten et. al., 2003. Testicular adrenal rest tumours in postpubertal males with congenital adrenal hyperplasia: sonographic and MR features. Eur. Radiol.13, 1597-1603.
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Vanzulli, A., A. DelMaschio, P. Paesano et. al., 1992. Testicular Masses in Association with Adrenogenital Syndrome: Us Findings'. Radiology Vol. 183, No. 2, pp. 425-429. Walker, B. R., S. J. Skoog, B. H. Winslo et. al., 1997. Testis sparing surgery for steroid unresponsive testicular tumors of the adrenogenital syndrome. J. Urol. 157, 1460-1463. White, P. C., P. W. Speiser. 2000. Congenital adrenal hyperplasia due to 21hydroxylase deficiency. Endocr. Rev.21, 245-291.
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Witchel, S. F., R. Azziz. Nonclassic congenital adrenal hyperplasia. Int. J. Pediatr. Endocrinol., 2010, 625105.
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Woodward, P. J., R. Sohaey, M. J. O'Donoghue et. al., 2002. From the Archives of the Afip: Tumors and Tumorlike Lesions of the Testis: Radiologic-Pathologic Correlation. Radiographics Vol. 22, No. 1, pp. 189-216.
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Figure Legends.
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Figure 1. 24-year-old male with a history of right orchiectomy (Patient 1). Axial T2weighted image (A) show a 4.4 cm lobulated mass in the left testis which is hypointense relative to the testis. The mass is isointense relative to the testis on axial T1-weighted image (B). Axial (C ) and coronal (D) contrastenhanced T1-weighted images demonstrate diffuse enhancement of the mass (arrows). The findings are consistent with adrenal rest tumor.
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Figure 2. Histological features of tumors located around rete testes (Patient 2). (A) Large polygonal tumor cells with abundant eosinophilic cytoplasm, occasionally large nucleated cells (HE, x200). (B) Diffuse growth pattern intersected by dense fibrous tissue (HE, x40). (C) Focal fatty tissue metaplasia was seen in the tumor (HE, x200). (D) Immunohistochemical features of tumor. Tumor cells were positive with CD56. (E) Immunohistochemical features of tumor. Tumor cells were positive with inhibin. Figure 3. 38-year-old male with a history of right orchiectomy (Patient 2). Axial (A) and coronal (B) T2- weighted images show a hypointense nodule in the left testis (arrows). Axial (C) and sagittal (D) contrast enhanced T1-weighted images demonstrate testicular nodules with diffuse enhancement.
Leyding Cell Tumor
Age
-Adolescence -Young Adulthood -20-40
-Any age -5-10 -30-60
Localization of tumor
- near the hilum of the testis
-in the interstitial tissue of testis adjacent to seminiferous tubules
Clinical Characteristics
-bilateral -painful -usually benign -can regress with corticosteroid treatment -endocrine atypia+ -low mitotic activity+ -lipochrome pigment+ -Reinke crystals-
-unilateral -painless -%10 malign -can not regress with corticosteroid treatment -endocrine atypia-high mitotic activity+ -lipochrome pigment-Reinke crystals+
-synaptophysin+ -Inhibin A+/-CD 56+
- synaptophysin- Inhibin A+ -CD56-
Pathological Features
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-Immunohistochemical
Imaging Findings -Ultrasound
- usually hypoechoic - cystic areas, hemorrhage, or necrosis -vascularity +/-
-isointense-hyperintense on T1 weighted images -hypointense on T2 weighted images
-isointense on T1 weighted images -hypointense on T2 weighted images -Radical orchiectomy
-Hormone replacement (glucocorticoid and mineralocorticoid) -partial or total orchiectomy -usually benign
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Prognosis
-usually hypoechoic -usually hypovascular
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-MRI
Treatment
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Testicular Adrenal Rest Tumor
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-usually benign
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S1769-7212(17)30098-8
DOI:
10.1016/j.ejmg.2017.06.009
Reference:
EJMG 3303
To appear in:
European Journal of Medical Genetics
Received Date: 13 February 2017 Revised Date:
30 June 2017
Accepted Date: 30 June 2017
Please cite this article as: H. Ozisik, B.S. Yurekli, I.Y. Simsir, I. Altun, U. Soyaltın, E. Guler, H. Onay, B. Sarsik, F. Saygili, Testicular Adrenal Rest Tumor (TART) in congenital adrenal hyperplasia, European Journal of Medical Genetics (2017), doi: 10.1016/j.ejmg.2017.06.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Testicular Adrenal Rest Tumor (TART) in congenital adrenal hyperplasia Hatice Ozisik1, Banu Sarer Yurekli1, Ilgin Yildirim Simsir1, Ilker Altun1, Utku Soyaltın1, Ezgi Guler2, Huseyin Onay3, Banu Sarsik4, Fusun Saygili1 1
Ege University, Faculty of Medicine, Department of Endocrinology and Metabolism Diseases, Turkey 2
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Ege University, Faculty of Medicine, Department of Radiology, Turkey
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Ege University, Faculty of Medicine, Department of Medical Genetics, Turkey
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Ege University, Faculty of Medicine, Department of Pathology, Turkey
Corresponding author
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Hatice Ozisik
Ege University, Division of Endocrinology and Metabolism, İzmir, TURKEY Ege University Hospital, Department of Endocrinology, Bornova, 35100 Izmir-Turkey
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Mobile phone number: +905068936521 Fax number: +902323904612
e-mail address: [email protected]
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-TARTs are rarely seen so we would like to discuss about TARTs in the lights of literature. - We have received permission from the patients.
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The authors do not have any conflict of interest.
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Running head: Testicular adrenal rest tumor
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Key Words: Congenital adrenal hyperplasia, testicular adrenal rest tumor
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Abstract
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Congenital adrenal hyperplasia is one of the most common autosomal recessive genetic disorders. Testicular adrenal tumors are significant complications of congenital adrenal hyperplasia. We would like to present two patients of testicular adrenal rest tumors. Patient 1 24 year-old male, he was diagnosed with congenital adrenal hyperplasia at the age of 8 due to precocious puberty. He received hydrocortisone treatment until the age of 18. Testicular mass had been detected and right radical orchiectomy had been applied 6 months ago and reported as testicular adrenal rest tumor. In scrotal ultrasound, a mixed type mass lesion (6x4x3 cm) covering a large part of left testis was observed. The imaging findings were consistent with adrenal rest tumor. The patient took adrenocorticotropic hormone supressive therapy with dexamethasone 0.75 mg once a day. Patient 2, 38 year-old male, he had been followed-up as adrenal insufficiency for 35 years. He underwent right orchiectomy operation due to the testicular mass in 2010 and the pathological examination revealed Leydig cell tumor. In scrotal ultrasound, small multifocal lesions were detected on the left testis and resection was done. It was reported as testicular adrenal rest tumor. He is being followed-up with glucocorticoid treatment according to androgen and adrenocorticotropic hormone levels. Early diagnosis of testicular adrenal rest tumor is significant in preventing irreversible testicular damage and infertility. In the differential diagnosis, we should keep in mind that testicular adrenal rest tumor can mimic other testicular tumors such as primary germ cell tumors.
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Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive genetic disorders which is caused by a deficiency in CYP21 (21hydroxylase) enzyme in more than 90% of patients (White and Speiser, 2000). The prevalence is approximately 1 in 15.000 births. Individuals with CAH have impaired cortisol and aldosterone production, leading to increased adrenocorticotropic hormone (ACTH) production by the pituitary gland. Excess levels of ACTH cause adrenal hyperplasia and overproduction of adrenal androgens. CAH is classified as classic or non-classic. Classic form has a significant decrease in 21-hydroxylase activity, giving rise to total lack of cortisol and aldosterone. The classic simple virilizing form is seen in approximately 33% of patients with classic CAH and this form is related to 1% to 2% of normal 21-hydroxylase activity (White and Speiser, 2000). Non-classic CAH is defined as having 20% to 50% of 21-hydroxylase activity and has a milder phenotype (Witchel and Azziz, 2010). Testicular adrenal rest tumors (TARTs) were first defined in 1940. TARTs are significant complications of CAH (Stikkelbroeck et al., 2001). Though TARTs are usually benign, they can obstruct the seminiferious tubule, causing gonadal dysfunction (Claahsen-van der Grinten et al., 2007). Intensive glucocorticoid therapy can suppress ACTH secretion and can lead to the regression of the tumors. However, in some patients, surgical intervention may be needed. We would like to present two patients of TARTs with the challenges regarding to diagnosis and treatment.
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Patient 1
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24 year-old male, he was diagnosed with CAH at the age of 8 due to precocious puberty. He received hydrocortisone treatment until the age of 18. Testicular mass had been detected and right radical orchiectomy had been applied to him 6 months ago at another institution. Histopathological diagnosis was reported as testicular adrenal rest tumor. Pathological specimen was reevaluated by our pathologist. Histopathologic examination revealed a tumor with extensive eosinophilic cytoplasm, occasionally large nucleated cells, separated by fibrous septa around the rete testis. Focal fatty tissue metaplasia was detected in the tumor. In the immunohistochemical study, tumor cells were positive with CD56 and inhibin. In the presence of these findings, the tumor was evaluated as testicular adrenal rest tumor. He was admitted to our clinic owing to the presence of bilateral adrenal masses on the surrenal glands which were detected on abdominal computed tomography (CT). On physical examination, his height was 152 cm, weight was 47 kg, BMI was 20.3 kg/m2 . He was normotensive (120/70 mmHg). He had short fingers and short stature. There is no history of consanguineous marriage. In laboratory examination, 17hydroxyprogesterone (17-OHP): 122 ng/mL (0.6-3.3), ACTH:118 pg/mL (<46), free testosterone:34.4 pg/mL ), dehydroepiandrosterone (DHEAS):378.4 µg/dL (85-690), cortisol:5.2 µg/dL (4.82- 19.5), luteinizing hormone (LH):0.74 mIU/mL (1.24-8.62), follicle-stimulating hormone (FSH):2.39 mIU/mL (1.27-19.26) were detected. . Tumor markers as α-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase
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were negative. Semen analysis showed azoospermia. His serum electrolytes were normal. In scrotal ultrasound (US), a mixed type mass lesion (6x4x3 cm) covering a large part of left testes was observed. The patient underwent a magnetic resonance imaging (MRI) examination. In abdominal MRI, axial T2-weighted image and axial inphase image showed a 2.4 cm mass in the right adrenal gland and a 6 cm mass in the left adrenal gland. This scene in MRI was interpreted as nodular hyperplasia of adrenals. In MRI study of the testes, axial images showed a 4.4 cm lobulated mass in the left testis which is hypointense relative to the testes. The mass was isointense relative to the testes on axial T1-weighted image. Axial and coronal contrastenhanced T1-weighted images demonstrate diffuse enhancement of the mass. The findings are consistent with adrenal rest tumor (Figure 1 A,B,C,D).Mutation analysis revealed compound heterozygous mutations in CYP21A2 gene. Heterozygous NM_000500.7(CYP21A2):c.293-13C>G (legacy name: I2splice) was detected in one allele and heterozygous NM_000500.7(CYP21A2):c.923dup (p.(Leu308Phefs*6))(legacy name: L307 frameshift) mutation was detected on the other allele. To decrease the size of tumors on the left and to improve his hormonal profile, ACTH supressive therapy was initiated with dexamethasone 0.75 mg once a day. He is in the follow-up period. Patient 2
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38 year-old male, he had been followed-up as adrenal insufficiency for 35 years. He underwent the operation of right orchiectomy due to the testicular mass in 2010 and the pathological examination revealed Leydig cell tumor (LCT). In scrotal ultrasound, small multifocal lesions were detected on the left testis and testicular mass resection was done. Left testis mediastinum-localized tumors were examined in frozen specimens. When the frozen result was reported as benign, the residual mass was resected. Histopathologic examination revealed a tumor with extensive eosinophilic cytoplasm, occasionally large nucleated cells, separated by fibrous septa around the rete testis (Figure 2A,B). Focal fatty tissue metaplasia was detected in the tumor (Figure 2C). It was learned that right radical orchiectomy was performed and leydig cell tumor was diagnosed in 2010. When this material was re-evaluated, it was found that it was similar to the morphology of the left testis. In the immunohistochemical study, tumor cells were positive with CD56 (Figure 2D) and inhibin (Figure 2E), negative with calretinin and androgen receptor. In the presence of these findings, the tumor was evaluated as "testicular adrenal rest tumor". The diagnosis of LCT for the right testis changed into TART after reevaluation by the pathologist. He has been taking 30 mg hydrocortisone once a day. On physical examination, height was 174 cm, weight was 104 kg, BMI was 34.4 kg/m2 . In laboratory examination, 17-OHP: 157 ng/mL (0.6-3.3), ACTH:194 pg/mL (<46), free testosterone:31.6 pg/mL (57-178), DHEAS:123.5 µg/dL (85-690), cortisol:2.14 µg/dL (4.82-19.5), LH 3.34 mIU/mL(1.248.62), FSH 7.21 mIU/mL (1.27-19.26) were detected. Tumor markers as αfetoprotein, human chorionic gonadotropin and lactate dehydrogenase were negative. Semen analysis showed azoospermia. His electrolytes were normal. In
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abdominal CT, axial arterial and portal venous phase contrast enhanced CT images showed bilateral enlarged adrenal glands with nodular hyperplasia. In MRI study of testis, axial and coronal T2-weighted images showed a hypointense nodule in the left testis, axial and sagittal contrast enhanced T1-weighted images demonstrated 2.5 cm testicular nodules with diffuse enhancement (Figure 3 A,B,C,D). Mutation analysis revealed compound heterozygous mutations in CYP21A2 gene also in this patient. Heterozygous NM_000500.7(CYP21A2):c.92C>T (p.Pro31Leu)(legacy name: P30L)) mutation was detected in one allele and heterozygous NM_000500.7(CYP21A2):c.332_339del (p.(Gly111Valfs*21)) (legacy name: Del8bpE3) mutation was detected on the other allele. He is being followed-up with glucocorticoid treatment according to androgen and ACTH levels.
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Discussion
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Testicular adrenal rest tumors (TARTs) have been declared in 18% of undiagnosed CAH patients and can be the first symptom of CAH (Stikkelbroeck et al., 2001). Patients untreated or treated insufficiently with CAH can develop TARTs due to increased ACTH levels. TARTs have usually been reported in classic CAH but sometimes also in non-classic CAH as reported Falhammar H et al's article ( Falhammar et al.,2012). TART is very common in CAH, up to 94% will probably seen to have it if an ultrasound is done with an interested sonographer. TARTs are usually seen in adolescence and in early adulthood because increased LH levels can stimulate tumor growth in these periods (Jin et al., 2011). TARTs are supposed to derive from remnant adrenal cells that migrate to the scrotum throughout the descent of the testes or from pluripotent stem cells in the testes (Rich and Keating 2000). The adrenal rest tissue in the testes has ACTH specific receptors and is ACTH responsive, making steroid hormones and it may be hyperplastic (Smeets et al., 2015).
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TART is a detectable and mostly treatable lesion, but it could be misdiagnosed as Leydig cell tumor (LCT). In some conditions, patients with CAH had undergone unnecessary testicular surgery. Karakus et al (Karakuş et al., 2014) reported a 7year-old boy with CAH who had TART and stated that it was difficult to make differential diagnosis with LCT. Furthermore, Olpin et al. (Olpin and Witt, 2014) declared that 27-year-old male with CAH who was diagnosed at age 3 weeks presented bilateral testicular mass. Although he was thought to have TART according to ultrasound findings, pathological report revealed LCT initially. But, later on, diagnosis was established as TART eventually with the further consultation. In our patient 2, right orchiectomy material was reevaluated by the pathologist in our institution. The diagnosis was thought to be TART rather than LCT in the light of clinical and hormonal data. Histopathologically, TARTs can be misdiagnosed as LCTs. TARTs are negative for Reinke crystals (cytoplasmic rod-like crystalloids) which are seen in LCTs (Budzyńska and Beń-Skowronek, 2011, Cakir et al., 2012). Both tumors consist of polygonal cells with abundant eosinophilic or granular cytoplasm in cord-like arrangements divided by dense fibrotic tissue. TARTs are
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generally not painful, they are bilateral and they exist near the hilum of the testis. In fact, they can response to steroid treatment and the size of tumors can be reduced with the treatment (Rich and Keating, 2000). On the contrary, though they are also usually painless, LCTs are unilateral and they do not regress with corticosteroid treatment. They are localized in the interstitial tissue of testis adjacent to seminiferous tubules (Claahsen-van der Grinten et al., 2007). When TART is compared to LCT, it can be seen that lack of cytological atypia, low mitotic activity, dense fibrous septa, lymphoid aggregates, adipose metaplasia and prominent lipochrome pigment are more prevalent in TART. Immunohistochemically, TART displays strong and diffuse positivity for CD56, focal or diffuse strong reactivity for synaptophysin and negative reactivity for the androgen receptor. On the contrary, LCT shows focal weak or negative reactivity for CD56 and synaptophysin while showing positive reactivity for the androgen receptor (Ashley et al., 2007). Inhibin A may be a sensitive and a specific immunohistochemical marker only for LCTs (Iczkowski et al., 1998) (Table 1). As in our second patient, pathological examination should be performed carefully with the aid of clinical, laboratory and endocrinological evaluations.
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Imaging is essential and important in the diagnosis and follow-up period for TARTs. First step is US due to its cost-effectiveness. The vast of these lesions are hypoechoic and sharply marginated but enormous lesions can be hyperechoic. In Doppler US, these lesions are usually hypervascular (Avila et al., 1996, Stikkelbroeck et al., 2003). MR imaging has not been completely approved. Some scientists report that the edges of TART can be well defined at MR. If testis sparing surgery is planned, MR is superior and more preferable than US in describing extent and margins of TART (Walker et al., 1997). On T1-weighted sequences, TARTs are usually isointense, while they are usually hypointense on T2-weighted sequences (Nagamine et al., 2005).
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Despite no malignant characteristics of TARTs, they may inflict serious testicular damage by pushing down the seminiferous tubules, resulting in obstructive azoospremia. In the literature, prevalence of TART was 34% and that of oligospermia was 66%, reported in the largest series with 219 male subjects (Bouvattier et al., 2015). Chronic obstruction of the tubules may cause irreversible testicular damage.(Claahsen-van der Grinten et al., 2007). Thus, early diagnosis and treatment is vital for good prognosis. Tumors greater than 2 cm can be detectable by palpation but tumors of small-size can not be detected without US. Ultrasound is thought to be as sensitive as MRI in detecting small TARTs (Stikkelbroeck et al., 2003). Fertility rates are lower in CAH reported in recent studies as 67%, 51% and 23% (Arlt et al., 2010, Bouvattier et al., 2015, Reisch et al., 2009). Infertlity in male patients may result from TART and hypogonadotrophic hypogonadism, leading to testicular failure. Excess adrenal androgens cause negative feedback at the pituitary level wtih the result of low LH and FSH. Decreased LH levels generally return back to normal levels
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Intensive glucocorticoid treatment is effective, first line treatment in TART and can help regression of tumors. Dexamethasone has a longer half-life than hydrocortisone and more effectively supresses the hypothalamic-pituitary axis (Claahsen-van der Grinten et al., 2007). It is important to prescribe appropriate doses to suppress ACTH levels to patients with TARTs (Vanzulli et al., 1992). Because if the treatment is not adequate, these lesions may develop in extent and number. As mentioned above, untreated TARTs may cause compression and distortion resulting in low testosterone production and infertility. If the tumors do not respond to the treatment and the patient has chronic testicular pain, surgical intervention may be needed. These patients may undergo partial or total orchiectomy (Walker, et al., 1997). Kavoussi et al. (Kavoussi et al., 2016) offer sperm retrieval during TART resection in azoospermic CAH patients. This procedure could be an option for infertility in CAH subjects.
References
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In differential diagnosis, it should be kept in mind that other testicular tumors such as primary germ cell tumors or gonadal (sex cord) tumors may also be present in adult patients. Nevertheless, primary testicular tumors are usually unilateral and fewer in number when they are compared with TARTs (Woodward et al., 2002). In conclusion, patients with CAH due to 21-hydroxylase deficiency have a risk for TARTs. So, early diagnosis of TART is significant in preventing irreversible testicular damage and infertility. It is crucial to detect small-sized tumors for these patients. Therefore digital palpation and US is very important in the surveillance.
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Arlt W., D. S. Willis, S. H. Wild, et. al., 2010. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J. Clin. Endocrinol. Metab. 95, 5110-5121.
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Ashley R. A., S. M. McGee, P. A. Isotaolo, et. al., 2007. Clinical and pathological features associated with the testicular tumor of the adrenogenital syndrome. J. Urol. 177, 546-549; discussion 549. Avila, N. A., A. Premkumar, T. H. Shawker et. al., 1996. Testicular adrenal rest tissue in congenital adrenal hyperplasia: findings at Gray-scale and color Doppler US. Radiology. 198, 99-104. Bouvattier, C., L. Esterle, P. Renoult-Pierre, et. al., 2015. Clinical Outcome, Hormonal Status, Gonadotrope Axis, and Testicular Function in 219 Adult Men Born With Classic 21-Hydroxylase Deficiency. A French National Survey. J. Clin. Endocrinol. Metab.100, 2303-2313. Budzyńska, E., I. Beń-Skowronek., 2011. Testicular adrenal rest tumours in boys with congenital adrenal hyperplasia: case report and literature review. Pediatr. Endocrinol. Diabetes Metab. 17, 239-242.
ACCEPTED MANUSCRIPT Cakir, E. D., F. S. Mutlu, E. Eren et. al., 2012. Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia. J. Clin. Res. Pediatr. Endocrinol. 4, 94100.
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Claahsen-van der Grinten, H. L., B. J. Otten, F. C. Sweep et. al., 2007. Repeated Successful Induction of Fertility after Replacing Hydrocortisone with Dexamethasone in a Patient with Congenital Adrenal Hyperplasia and Testicular Adrenal Rest Tumors. Fertil. Steril. Vol. 88, No. 3, pp. 705.e5-8. Claahsen-van der Grinten, H. L., F. C. Sweep, J. G. Blickman et. al., 2007. Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21- hydroxylase deficiency. Eur. J. Endocrinol.157, 339-344. F., Ekström
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Iczkowski, K. A., D. G. Bostwick, P. C. Roche et. al., 1998. Inhibin A is a sensitive and specific marker for testicular sex cord-stromal tumors. Mod. Pathol. 11, 774-779. Jin, H. Y., J. H. Choi, G. H. Kim et. al., 2011. Testicular adrenal rest tumors in a patient with untreated congenital adrenal hyperplasia. Korean J. Pediatr.54, 137-140. Karakuş, E., M. N. Azılı, T. Tiryaki., 2014. Testicular adrenal rest tumor mimicking leydig cell tumor in a patient with congenital adrenal hyperplasia. APSP J. Case Rep. 5, 10.
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Kavoussi, P. K., R. B. Summers-Colquitt, K. C. Odenwald et. al., 2016. Sperm retrieval and concomitant tumor resection in azoospermic men with congenital adrenal hyperplasia and bilateral testicular adrenal rest tumors: a case report. J Assist Reprod Genet. 33, 545-548.
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King, T. F., M. C. Lee, E. E. Williamson et. al., 2016. Experience in optimizing fertility outcomes in men with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. Clin. Endocrinol. (Oxf). 84, 830-836. Nagamine, W. H., S. V. Mehta, A. Vade. 2005. Testicular adrenal rest tumors in a patient with congenital adrenal hyperplasia: sonographic and magnetic resonance imaging findings. J. Ultrasound Med. 24, 1717-1720. Olpin, J. D., B. Witt. 2014. Testicular adrenal rest tumors in a patient with congenital adrenal hyperplasia. J. Radiol. Case Rep. 8, 46-53. Reisch, N., L. Flade, M. Scherr et. al., 2009. High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 94, 1665-1670. Rich, M. A., M. A. Keating., 2000. Leydig cell tumors and tumors associated with congenital adrenal hyperplasia. Urol. Clin. North Am. 27, 519-28, x.
ACCEPTED MANUSCRIPT Smeets, E. E., P. N. Span, A. E. van Herwaarden et. al., 2015. Molecular characterization of testicular adrenal rest tumors in congenital adrenal hyperplasia: lesions with both adrenocortical and Leydig cell features. J. Clin. Endocrinol. Metab. 100, E524-30.
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Stikkelbroeck, N. M., B. J. Otten, A. Pasic et. al., 2001. High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 86, 5721-5728. Stikkelbroeck, N. M., H. M. Suliman, B. J. Otten et. al., 2003. Testicular adrenal rest tumours in postpubertal males with congenital adrenal hyperplasia: sonographic and MR features. Eur. Radiol.13, 1597-1603.
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Vanzulli, A., A. DelMaschio, P. Paesano et. al., 1992. Testicular Masses in Association with Adrenogenital Syndrome: Us Findings'. Radiology Vol. 183, No. 2, pp. 425-429. Walker, B. R., S. J. Skoog, B. H. Winslo et. al., 1997. Testis sparing surgery for steroid unresponsive testicular tumors of the adrenogenital syndrome. J. Urol. 157, 1460-1463. White, P. C., P. W. Speiser. 2000. Congenital adrenal hyperplasia due to 21hydroxylase deficiency. Endocr. Rev.21, 245-291.
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Woodward, P. J., R. Sohaey, M. J. O'Donoghue et. al., 2002. From the Archives of the Afip: Tumors and Tumorlike Lesions of the Testis: Radiologic-Pathologic Correlation. Radiographics Vol. 22, No. 1, pp. 189-216.
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Figure Legends.
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Figure 1. 24-year-old male with a history of right orchiectomy (Patient 1). Axial T2weighted image (A) show a 4.4 cm lobulated mass in the left testis which is hypointense relative to the testis. The mass is isointense relative to the testis on axial T1-weighted image (B). Axial (C ) and coronal (D) contrastenhanced T1-weighted images demonstrate diffuse enhancement of the mass (arrows). The findings are consistent with adrenal rest tumor.
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Figure 2. Histological features of tumors located around rete testes (Patient 2). (A) Large polygonal tumor cells with abundant eosinophilic cytoplasm, occasionally large nucleated cells (HE, x200). (B) Diffuse growth pattern intersected by dense fibrous tissue (HE, x40). (C) Focal fatty tissue metaplasia was seen in the tumor (HE, x200). (D) Immunohistochemical features of tumor. Tumor cells were positive with CD56. (E) Immunohistochemical features of tumor. Tumor cells were positive with inhibin. Figure 3. 38-year-old male with a history of right orchiectomy (Patient 2). Axial (A) and coronal (B) T2- weighted images show a hypointense nodule in the left testis (arrows). Axial (C) and sagittal (D) contrast enhanced T1-weighted images demonstrate testicular nodules with diffuse enhancement.
Leyding Cell Tumor
Age
-Adolescence -Young Adulthood -20-40
-Any age -5-10 -30-60
Localization of tumor
- near the hilum of the testis
-in the interstitial tissue of testis adjacent to seminiferous tubules
Clinical Characteristics
-bilateral -painful -usually benign -can regress with corticosteroid treatment -endocrine atypia+ -low mitotic activity+ -lipochrome pigment+ -Reinke crystals-
-unilateral -painless -%10 malign -can not regress with corticosteroid treatment -endocrine atypia-high mitotic activity+ -lipochrome pigment-Reinke crystals+
-synaptophysin+ -Inhibin A+/-CD 56+
- synaptophysin- Inhibin A+ -CD56-
Pathological Features
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-Immunohistochemical
Imaging Findings -Ultrasound
- usually hypoechoic - cystic areas, hemorrhage, or necrosis -vascularity +/-
-isointense-hyperintense on T1 weighted images -hypointense on T2 weighted images
-isointense on T1 weighted images -hypointense on T2 weighted images -Radical orchiectomy
-Hormone replacement (glucocorticoid and mineralocorticoid) -partial or total orchiectomy -usually benign
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Prognosis
-usually hypoechoic -usually hypovascular
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Treatment
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Testicular Adrenal Rest Tumor
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-usually benign
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