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Home , Leydig cell tumour, Precocious puberty, Testicle

Atypical Leydig Tumor in Children: Report of 2 Cases Chiara Mameli, MD,a Giorgio Selvaggio, MD, b Chiara Cerini, MD, c Gaetano Bulfamante, MD, d Cristina Madia, MD,a Giovanna Riccipetitoni, MD,b Gian Vincenzo Zuccotti, MDa

Leydig cell tumors (LCTs) are rare cord-stromal tumors that may occur in abstract testis or and may produce or . The majority has been found in men between the ages of 20 and 60 years. Adults with -secreting LCTs are usually asymptomatic; feminizing syndromes may result from the production of or the peripheral aromatization of . In children, LCTs usually present between 5 and 10 years of age with isosexual precocious pseudopuberty or . We report 2 cases of LCT in prepubertal boys presenting with advanced unilateral and testicular volume asymmetry. Both subjects had normal size for age; no axillary hair or other signs of were present. Height velocity was normal, and was coincident with chronological Departments of aPediatrics, and bPediatric Surgery, age. Androgen levels were normal, as well as , corticotropin, and Children’s Hospital “V. Buzzi,” University of Milan, Milan, Italy; cDivision of Infectious Diseases, Children’s Hospital concentration. Testicular demonstrated a testicular Los Angeles, Los Angeles, California; and dHuman Pathology mass. Histology examination revealed a well-differentiated LCT. This is Unit, Department of Health Sciences, San Paolo Hospital, University of Milan, Milan, Italy the first report of 2 pediatric patients with LCT presenting with advanced pubarche in absence of systemic . We hypothesize Dr Mameli conceptualized the study, collected that the neoplastic cells may locally produce high levels of androgens or cases, and drafted the initial manuscript; Dr Selvaggio collected cases and reviewed and revised androgen-like bioactivity molecules that are responsible for the clinical the manuscript; Drs Cerini and Madia drafted manifestation. We suggest that a testicular ultrasound should be obtained the manuscript; Dr Bulfamante performed the in all children presenting with unilateral pubarche, with or without histological analysis; Drs Riccipetitoni and Zuccotti critically reviewed the manuscript; and all authors hyperandrogenism. approved the fi nal manuscript as submitted. DOI: 10.1542/peds.2016-0151 Accepted for publication Jul 6, 2016 tumors (LCTs) are rare G proteins may excessively stimulate Address correspondence to Chiara Mameli, MD, 3 cord-stromal gonadal tumors. LCTs Leydig cells and induce oncogenesis. Department of Pediatrics, Children’s Hospital are -secreting tumors releasing In pediatric subjects, LCTs are rarely “V. Buzzi, ” Via Castelvetro 32, University of Milan, androgens, classically testosterone, reported.4 – 6 Overall, LCTs account Milan, Italy. E-mail: [email protected] but they can also produce estrogens for 0.4% to 9% of all testis tumors in PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, either by direct production of prepubertal males. 1098-4275). estradiol or peripheral aromatization Copyright © 2016 by the American Academy of of the testosterone. 1 In children, LCTs usually present Pediatrics between 5 and 10 years of age, with FINANCIAL DISCLOSURE: The authors have LCTs typically affect males between isosexual precocious pseudopuberty indicated they have no fi nancial relationships 20 and 60 years of life. Malignant or gynecomastia in boys or virilizing relevant to this article to disclose. transformation is rare, and given the syndromes in girls, due to their FUNDING: No external funding. 7 slow growth, prognosis is generally hormonal activity. - POTENTIAL CONFLICT OF INTEREST: The authors 2 good. dependent have indicated they have no potential confl icts of associated with accelerated growth interest to disclose. The etiology of LCTs remains and bone maturation, may develop unknown. Some authors hypothesized after surgical therapy. 8 that a disorder of the hypothalamic- To cite: Mameli C, Selvaggio G, Cerini C, et al. pituitary axis or structural changes of Radical inguinal is still Atypical Leydig Cell Tumor in Children: Report of 2 Cases. Pediatrics. 2016;138(5):e20160151 the luteinizing receptors and recommended as standard treatment.

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 138 , number 5 , November 2016 :e 20160151 CASE REPORT FIGURE 1 1, Patient 1. 2, Patient 2. A, Clinical fi ndings. A1, Patient 1: monolateral curled on left testis. A2, Patient 2: monolateral testicular hair adult type. B, Testicular ultrasound. Hypoechoic testicular mass. C, Histology. Hematoxylin and eosin staining, ×4. Neoplastic cells with abundant eosinophilic cytoplasm, distinct cell borders arranged in nests and cords. D, Histology. Hematoxylin and eosin staining, ×40.

TABLE 1 Hormonal Assessment Subject LH, IU/L FSH, IU/L Testosterone, ng/mL 17-OH-, Androstenedione, DHEAS, ng/mL ng/mL ng/mL 1 <0.1 (0.1–6) 0.5 (0.5–3.7) 0.01 (<5) 0.5 (0.59–3.44) 0.2 (0.6–3.10) 0.8 (0.3–2.5) 2 0.3 (0.1–6) 1.6 (0.5–3.7) <0.20 (<5) 0.45 (0.59–3.44) 0.61 (0.6–3.10) 1.8 (0.3–2.5) Data are mean (normal range); testosterone is mean (normal level for prepubertal children).

However, to preserve male 2 mL and 3 mL, respectively. negative surgical margins ( Fig 1). , in the past decade a more Neither testis had a palpable mass. One month after surgery, pubic hair conservative testis-sparing approach Height and weight were at 50th in the left decreased, and has been successfully chosen for percentile for sex and age; height resolved. young adults and children. 9 velocity was normal. Gynecomastia was absent. The hormonal We report 2 cases of LCTs in Patient 2 is a 11-year-old who assessment documented normal prepubertal boys presenting with presented with advanced unilateral androgen, estradiol, corticotropin, unilateral advanced pubarche, right pubarche and testicular and cortisol levels. LH, FSH, without hyperandrogenism. asymmetry for 1 month. Physical testosterone, 17-OH-progesterone, examination revealed testicular androstenedione, and hair adult in type, prepubertal CASE REPORTS sulfate penis, and no axillary hair ( Fig 1). (DHEA-S) plasma levels are The right and left were Patient 1 is a 6-year 10-month-old shown in Table 1. Tumor markers of 3.5 mL and 3 mL volume, boy who presented with unilateral α-fetoprotein and β-human chorionic respectively, with normal position premature pubarche and history of gonadotropin were unremarkable. and no palpable masses. Height pubic hair development on the left Bone age was 6 years. and weight were at 75th percentile scrotum since age 6-years 4-months, for sex and age; height velocity associated with unilateral testicular Testicular ultrasound of the was normal. Gynecomastia was swelling. left identified a 0.3 cm absent. The hormonal assessment Physical examination revealed dark, hypoechoic mass located at the documented normal androgen, coarse, and curled pubic hair without inferior pole and grade III varicocele. estradiol, corticotropin, and cortisol axillary hair and normal penis size A left-testis-sparing surgery was levels. In particular, testosterone for age ( Fig 1). Mild asymmetry of performed. The histologic report was undetectable. LH, FSH, testicular volume was noted: the demonstrated the diagnosis of well- testosterone, 17-OH-progesterone, right and left testicles measured differentiated Leydig cell tumor with androstenedione, and DHEA-S plasma

Downloaded from www.aappublications.org/news by guest on September 24, 2021 e2 MAMELI et al levels are shown in Table 1. Tumor the neoplastic cells were probably thorough work-up are crucial for markers α-fetoprotein, β-human producing locally high levels of diagnosis and treatment. chorionic gonadotropin, and inhibin androgens or substances with We suggest that every male child B were unremarkable. Bone age was androgen bioactivity. The androgen presenting with unilateral pubarche 11 years. microenvironment of the testis is should be evaluated with testicular supposed to be responsible of the Testicular ultrasound revealed a ultrasound regardless the finding of unilateral pubic hair development. hypoechoic mass measuring 0.6 systemic hyperandrogenism. This is in line with the fact that cm in diameter in the right testis. both patients had no pubic hair in a A right-testis-sparing surgery was site other than testis, normal penis performed, and diagnosis of Leydig ABBREVIATIONS growth, and bone age coincident with cell tumor was made. Surgical DHEA-S: dehydroepiandroste- chronological age. margins were negative ( Fig 1). One rone sulfate month after surgery, pubic hair in the On the basis of our findings, we infer FSH: follicle-stimulating hormone left scrotum decreased. that pediatric age LCTs may present LCT: Leydig cell tumor with different clinical and hormonal LH: profiles: (1) LCTs with systemic COMMENTS hyperandrogenism manifesting with LCTs are testicular symptoms of precocious puberty, infrequently described in children. including increased penis size, REFERENCES They may occur at any age, but most pubic hair development, accelerated skeletal and muscle growth, 1. Leonhartsberger N, Ramoner R, Aigner often in prepubertal boys between F, et al. Increased incidence of Leydig advanced bone age, and skin changes, 5 and 10 years. 7 They are benign cell tumours of the testis in the era of during childhood in most cases and (2) LCTs without systemic improved imaging techniques. BJU Int. and typically hormonally active, hyperandrogenism presenting only 2011;108(10):1603–1607 with unilateral pubarche on the secreting androgens or, more rarely, 2. Drut R, Wludarski S, Segatelli V, et al. affected testicle. In these cases, the estrogens. 7 Malignant transformation Leydig cell tumor of the testis with has not been clearly proven in effect of androgen production is histological and immunohistochemical children, whereas in adults malignant obvious at the site where the tumor features of malignancy in a 1-year-old variants occur in up to 10% of is located. boy with isosexual pseudoprecocity. Int patients. 2 Taking together these findings J Surg Pathol. 2006;14(4):344–348 suggest that LCTs in pediatric 3. Liu G, Duranteau L, Carel JC, Monroe J, Twenty-seven cases of LCTs have age patients have different Doyle DA, Shenker A. Leydig-cell tumors been described in prepubertal boys.3, 10 characteristics compared with those caused by an activating mutation Most patients presented with occurring in adults, in whom an of the gene encoding the luteinizing premature pubarche as result of the excess of steroid production is often hormone . N Engl J Med. high level of testosterone. Rarely the 1999;341(23):1731–1736 documented at diagnosis, although tumor is asymptomatic. 10 Only 1 in clinical symptoms of endocrine 4. Olivier P, Simoneau-Roy J, Francoeur 27 cases was a nonsecretory tumor disturbances may be lacking. 12 On D, et al. Leydig cell tumors in with normal testosterone level, the contrary, in children, signs of children: contrasting clinical, despite Tanner stage P2. 11 hormonal, anatomical, and molecular local hyperandrogenism could be characteristics in boys and girls. We report 2 cases of LCTs in present even in the setting of normal J Pediatr. 2012;161(6):1147–1152 prepubertal boys presenting with androgen plasmatic levels. In these advanced unilateral pubarche in the latter cases, the effect of androgens 5. Lignitz S, Partsch CJ, Wudy SA, absence of hyperandrogenism. or androgen-like substances is Hartmann MF, Pohlenz J. Clinical and metabolic fi ndings in a 6-year-old obvious and confined to the location In both patients, androgens were boy with a . Acta normal, and in particular, serum of the tumor. Paediatr. 2011;100(12):e280–e282 testosterone was undetectable Given the aspecific and remarkable 6. Santos-Silva R, Bonito-Vítor A, Campos or very low. 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Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 138 , number 5 , November 2016 e3 8. Verrotti A, Penta L, Zenzeri L, surgery for Leydig cell tumor. Clin features, follow-up and genetic Lucchetti L, Giovenali P, De Genitourin . 2013;11(3): analysis of four cases. Horm Res. Feo P. True precocious puberty 321–324 2007;67(2):89–95 following treatment of a leydig 10. Esposito C, Escolino M, Settimi A. 12. Suardi N, Strada E, Colombo R, cell tumor: two case reports and Atypical leydig cell tumor in a young et al. Leydig cell tumour of the testis: literature review. Front Pediatr. child. APSP J Case Rep. 2013;4(2):25 presentation, therapy, long-term 2015;3:93 11. Petkovic V, Salemi S, Vassella E, et al. follow-up and the role of -sparing 9. Bozzini G, Picozzi S, Gadda F, et al. Long- Leydig-cell tumour in children: variable surgery in a single-institution experience. term follow-up using testicle-sparing clinical presentation, diagnostic BJU Int. 2009;103(2):197–200

Downloaded from www.aappublications.org/news by guest on September 24, 2021 e4 MAMELI et al Atypical Leydig Cell Tumor in Children: Report of 2 Cases Chiara Mameli, Giorgio Selvaggio, Chiara Cerini, Gaetano Bulfamante, Cristina Madia, Giovanna Riccipetitoni and Gian Vincenzo Zuccotti Pediatrics 2016;138; DOI: 10.1542/peds.2016-0151 originally published online October 20, 2016;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/138/5/e20160151 References This article cites 12 articles, 0 of which you can access for free at: http://pediatrics.aappublications.org/content/138/5/e20160151#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): http://www.aappublications.org/cgi/collection/endocrinology_sub Puberty http://www.aappublications.org/cgi/collection/puberty_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 24, 2021 Atypical Leydig Cell Tumor in Children: Report of 2 Cases Chiara Mameli, Giorgio Selvaggio, Chiara Cerini, Gaetano Bulfamante, Cristina Madia, Giovanna Riccipetitoni and Gian Vincenzo Zuccotti Pediatrics 2016;138; DOI: 10.1542/peds.2016-0151 originally published online October 20, 2016;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/138/5/e20160151

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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