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Case Report Testis-Sparing Surgery for Non-Palpable Leydig Tumors in Prepubertal Children

Vassilis Lambropoulos 1,* , Antonios Theodorakopoulos 2, Vasileios Mouravas 1, Elissavet Pazarli 3, Dimitrios Godosis 1, Chrysostomos Kepertis 1 , Kleanthis Anastasiadis 1 and Ioannis Spyridakis 1

1 2nd Paediatric Surgery Department, University of Thessaloniki, “Papageorgiou” General Hospital, 56403 Thessaloniki, Greece; [email protected] (V.M.); [email protected] (D.G.); [email protected] (C.K.); [email protected] (K.A.); [email protected] (I.S.) 2 Radiology Department, “Papageorgiou” General Hospital, 56403 Thessaloniki, Greece; [email protected] 3 Pathology Department, “Papageorgiou” General Hospital, 56403 Thessaloniki, Greece; [email protected] * Correspondence: [email protected]; Tel.: +30-6977224420

 Received: 17 January 2020; Accepted: 16 March 2020; Published: 26 October 2020 

Abstract: tumor (LCT) is an infrequent stromal of the testis with an incidence of less than 3% of all gonadal tumors in the general male population. Only 25% is found in prepubertal children, where Leydig cell tumors are always reported benign. The hospital records of two prepubertal male children, who underwent sparing surgery for testicular LCT the last five years, were retrospectively reviewed. In both of them, the lesion was incidentally found during a scrotal ultrasonography for . The diagnosis of a benign LCT was based on the pre-operative physical examination and imaging (-US, Magnetic Resonance Imaging-MRI) as well as the negative tumor markers. A -sparing procedure was decided and the pathologic examination of the surgical specimen confirmed the diagnosis. No tumor recurrence was noted on follow-up. Testis-sparing surgery provides the possibility of complete excision of such lesions and should be considered as the treatment of choice.

Keywords: Leydig cell tumor; testis; children; organ sparing surgery

1. Introduction Leydig cell tumor (LCT) is an infrequent stromal neoplasm of the testis with an incidence of less than 3% of all gonadal tumors in the general male population [1,2]. In children of prepubertal age, the incidence increases up to 9% of all primary testicular masses [3]. In the adult population, 10% exhibits malignant behavior in contrast to the childhood where Leydig cell tumors are always reported benign [4–6]. Usually it occurs in adulthood and only 25% is found in prepubertal children [7]. In most cases, it is an incidental finding during a scrotal sonographic evaluation for other reasons, since in childhood is usually presented as a small sized, non-palpable intratesticular lesion. If hormonally active, they secrete a variety of which may give an onset of endocrine signs, usually before the development of a palpable mass [8]. On (US), these lesions appear as hypoechogenic masses [9]. Contrast-enhanced Magnetic Resonance Imaging (MRI) is essential for the differential diagnosis [10]. Tumor markers such as alpha-fetoprotein (AFP), beta human chorionic (bhCG) and (LDH) are usually within normal values, in small non palpable lesions in children. Testis-sparing surgery should be considered as the treatment of choice for such cases [6].

Pediatr. Rep. 2020, 12, 86–92; doi:10.3390/pediatric12030020 www.mdpi.com/journal/pediatrrep Pediatr. Rep. 2020, 12 87 Pediatr. Rep. 2020, 12, FOR PEER REVIEW 2

2. Case Case Reports Reports The hospital records of two prepubertal male children who underwent organ sparing surgery forfor testicular LCT the last five five years were retrospectively reviewed. Their Their age age was was 10 10 and 11 years old, respectively, and both of them underwent a scrotal US exam due to testicular pain, which could not be be related related to to any any pathology pathology on on clinical clinical examination, examination, as the as thefirst first child child was wascomplaining complaining about about pain onpain the on ipsilateral the ipsilateral side of side the of lesion the lesion and the and latter the latterto the tocontralateral the contralateral side. Physical side. Physical examination examination of the externalof the external genitalia genitalia in both in patients both patients revealed revealed normal normal testis testisin position, in position, size and size consistency. and consistency. No palpableNo palpable masses masses were were noted. noted. The testicular The testicular sonographic sonographic findings findings revealed revealed a hypoechoic a hypoechoic mass with mass a diameterwith a diameter of 3 and of 33.4 and mm, 3.4 mm,respectively. respectively. In both In both cases, cases, there there was was a aclear clear demarcation demarcation from from the surrounding normal normal testicular testicular tissue, tissue, and and on on Color Color Doppler Doppler evaluation evaluation they they both both presented presented a rim a rim of marginalof marginal blood blood flow. flow. No Nointratesticular intratesticular calcifications calcifications were were noted noted (Figure (Figure 1). Due1). to Due the to nodule’s the nodule’s small dimensions,small dimensions, the position the position coordinates coordinates of the lesion of the were lesion determined were determined in three inaxes, three transverse, axes, transverse, sagittal andsagittal coronal and coronalso that the so that surgeon the surgeon could have could a have dissection a dissection plane planecorresponding corresponding to the toUS the findings. US findings. Our patientsOur patients underwent underwent a scrotal a scrotal MRI in MRI order in orderto evaluate to evaluate the intratesticular the intratesticular mass and mass contribute and contribute to the surgicalto the surgical treatment. treatment. The lesions The were lesions well were circumscribed well circumscribed isointense isointense on T1‐WI, onhypointense T1-WI, hypointense on T2‐W1 and on demonstratedT2-W1 and demonstrated intense enhancement intense enhancement after intravenous after administration intravenous administration of contrast material of contrast (Figure material 2). A preoperative(Figure2). A preoperative diagnostic orientation diagnostic orientationtowards LCT towards was LCTmade. was Both made. males Both were males evaluated were evaluated by a pediatricby a pediatric endocrinologist endocrinologist and andno nohormonal hormonal or ordevelopmental developmental abnormalities abnormalities were were found. found. Tumor Tumor markers were within normal range. No No intra intra-abdominal‐abdominal or or inguinal inguinal lymph nodes nodes were were found on US exam and chest chest X X-rays‐rays were were normal. normal. The The surgeon’s surgeon’s choice choice of of testicle testicle sparing sparing surgery surgery had had the the parents’ parents’ consent in both cases.

Figure 1. 1. UltrasoundUltrasound (US) (US) images, images, in in B B ( (AA)) and and color color Doppler Doppler mode mode ( (BB),), depicting depicting a a hypoechoic hypoechoic lesion lesion with intense vascularization due to a prominent peripheral arterial vessel.

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Figure 2. (A(A) )Magnetic Magnetic resonance resonance imaging imaging (MRI) (MRI) depicting depicting the the lesion lesion as isointense as isointense on T1 on‐WI, T1-WI, (B) hypointense(B) hypointense on onT2‐ T2-WI,WI, (C) ( Cand) and with with intense intense enhancement enhancement after after administration administration of of endovenous contrast material.

Through a standardstandard inguinalinguinal incision, incision, the the spermatic cord was was isolated isolated and and clamped clamped at at the the level level of ofthe the internal internal inguinal inguinal ring, ring, using using a soft a soft vascular vascular clamp. clamp. The The affected affected testis testis was was then then delivered delivered into into the woundthe wound and placedand placed into a separateinto a separate operative operative field in order field to in avoid order tumor to avoid spillage. tumor The gubernaculumspillage. The gubernaculumtestis was sectioned, testis andwas the sectioned, and the tunica was opened albuginea longitudinally, was opened having longitudinally, in mind a dissectionhaving in planemind a corresponding dissection plane to thecorresponding US findings. to Thethe US lesion findings. was easily The lesion recognized was easily due to recognized its characteristic due to itsmacroscopic characteristic appearance macroscopic as a yellow appearance to soft as brown a yellow mass, to well soft demarcated brown mass, from well the demarcated surrounding from normal the surroundingtesticular tissue. normal The noduletesticular as welltissue. as aThe 2–5 nodule mm rim as of well normal as a tissue 2–5 mm around rim wereof normal excised tissue and around sent for pathologicwere excised examination. and sent for The pathologic tunica albuginea examination. was repaired The tunica using albuginea a 6.0 absorbable was repaired running using suture a and 6.0 absorbablethe vascular running clamp was suture removed and the (Figure vascular3). The clamp ischemia was timeremoved was recorded (Figure 3). and The did ischemia not exceed time 30 minwas (28recorded and 22 and min, did respectively). not exceed 30 The min organ (28 and was 22 re-inserted min, respectively). into the . The organ On was discharge, re‐inserted both patientsinto the werescrotum. evaluated On discharge, with a US both of the patients testis which were confirmedevaluated with the complete a US of excisionthe testis of which the lesion confirmed (Figure 4the). complete excision of the lesion (Figure 4).

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FigureFigure 3. (A(A) )Vascular Vascular clamp clamp (blue (blue arrow), arrow), Leydig Leydig cell tumor (LCT,(LCT, blackblack arrow).arrow). ( (BB)) Testis Testis reconstruction,reconstruction, ( C) Surgical specimens.

Figure 4. (A,B) No evidence of the lesion in B‐mode and in color Doppler mode, immediately after Figure 4. ((AA,,BB)) No evidence of the the lesion in B B-mode‐mode and in color Doppler mode, immediately after surgery, (C,D) and in late follow up. surgery,surgery, (C,,D) and inin latelate followfollow up.

TheThe pathologic examination examination of of the the surgical surgical specimens specimens confirmed confirmed the the pre pre-operative‐operative diagnosis. diagnosis. MacroscopicallyMacroscopically the the tumor tumor was was well well-‐ circumscribed, within within the testicle. Microscopically, Microscopically, the the tumor was composed composed of of large large polygonal polygonal cells cells with with eosinophilic eosinophilic glanular glanular cytoplasm and andround round nuclei. nuclei. The histologicalThe histological diagnosis diagnosis of benign of benign LCT LCT was was made made based based on the on thetypical typical morphological morphological characteristics characteristics of theof the tumor tumor cells cells (proposed (proposed by Kim by Kim et al.) et al.)[5] and [5] and included included the thesmall small size size of the of tumor the tumor (~3 mm), (~3 mm), the intratesticularthe intratesticular localization localization of the of tumor the tumor with non with‐ infiltrating non- infiltrating margins, margins, the absence the absenceof atypia, of necrosis atypia, and/ornecrosis angioinvasion, and/or angioinvasion, and the andlow themitotic low mitoticindex. index.Immunohistochemically, Immunohistochemically, the tumor the tumorcells were cells positivewere positive for inhibin for inhibin-‐α andα vimentinand vimentin (Figure (Figure 5). 5).

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Figure 5. ((A)) Hematoxylin–eosin (H/E), (H/E), magnificationmagnification 1010×.. Well Well circumscribed circumscribed nodule nodule with solid × architecture. ( (BB)) Hematoxylin–eosin (H/E), (H/E), magnificationmagnification 200200×.. Neoplasm Neoplasm characterized characterized by by solid × growth of polygonal cells with eosinophiliceosinophilic granulargranular cytoplasm.cytoplasm. No No evidence of mitosis, nuclear atypia andand/or/or necrosis. necrosis. (C ) Magnification(C) Magnification 200 . Neoplastic200×. Neoplastic cells are positivecells are for positive a-inhibin for immunostain. a‐inhibin × immunostain.(D) Magnification (D) Magnification 200 . Neoplastic 200×. cells Neoplastic are positive cells for are vimentin positive immunostain. for vimentin immunostain. × The follow follow-up‐up of these these patients—24 patients—24 and and 84 84 months months post post-op,‐op, respectively—with respectively—with clinical clinical examination, examination, ultrasonography (Figure(Figure4) and4) and measurement measurement of tumor of tumor markers, markers, as well as as endocrinological well as endocrinological evaluation, evaluation,revealed no revealed LCT relapse no LCT and relapse normal and testicular normal growth. testicular growth.

3. Discussion Discussion The interstitial cells of Leydig are situated adjacent to the seminiferous seminiferous in the testicle and produce under the influence influence of luteinizing (LH). (LH) [ [8]8]. Testicular Testicular tumors tumors comprise comprise only 1% of solid tumorstumors duringduring childhood childhood and and LCTs LCTs are are even even rarer, rarer, since since they they present present only only 4–9% 4–9% of allof allprimary primary testicular testicular tumors tumors in this in this age age group group. [3,11 Ref.,12]. [3,11,12] The affected The boysaffected usually boys present usually with present isosexual with isosexualprecocious precocious pseudopuberty pseudopuberty due to the heightened due to secretionthe heightened of , secretion mostly of testosterone.androgens, Evenmostly in testosterone.these symptomatic Even in cases these the symptomatic course of LCTs cases is considered the course benign of LCTs in is childhood considered [4– benign6]. The in amplified childhood. use [4of− scrotal6] The amplified US has contributed use of scrotal to the US early has detectioncontributed of non-palpableto the early detection indolent of masses non‐palpable in asymptomatic indolent massesprepubertal in asymptomatic boys. prepubertal boys. Sonographic findingsfindings of of the the a ffaffectedected testicle testicle usually usually demonstrate demonstrate a small a small hypoechoic hypoechoic nodule, nodule, well welldefined, defined, relatively relatively homogeneous, homogeneous, which which can contain can contain faint internalfaint internal echoes echoes corresponding corresponding to small to small areas areasof hemorrhage of hemorrhage or fibrosis, or fibrosis, with intense with intense peripheral peripheral rim of vascularizationrim of vascularization due to adue hypertrophic to a hypertrophic arterial arterialvessel originating vessel originating from a capsular from a arterycapsular [13 –.15]. US Ref. sensitivity [13–15] and US specificitysensitivity of and the specificity examined lesionsof the examinedis 96% and lesions 44%, respectively is 96% and [ 44%,15]. The respectively. pre-operative Ref. di[15]fferential The pre diagnosis‐operative can differential be clarified diagnosis by the use can of becontrast-enhanced clarified by the use MRI of [10 contrast,13]. Its‐enhanced major disadvantages MRI. Ref. [10,13] are the Its high major cost disadvantages and the need are for sedation.the high costA US and examination the need for could sedation. be the onlyA US diagnostic examination tool. could However, be the due only to diagnostic the low incidence tool. However, of these tumors due to thein every low incidence single institution, of these tumors surgeons in usuallyevery single demand institution, a complete surgeons preoperative usually diagnostic demand a approach,complete preoperativeespecially for diagnostic uncertain approach, cases. Characteristic especially for findings uncertain include cases. iso- Characteristic or intermediate findings signal include intensity iso‐ oron intermediate T1-WI, low signal signal intensity intensity in on T2-WI, T1‐WI, intense low signal and homogeneousintensity in T2 enhancement‐WI, intense and after homogeneous intravenous enhancementadministration after of contrast. intravenous administration of contrast. Tumor markers AFP, bhCG and LDH, should always be measured not only in order to exclude malignancy, but also for the post‐operative follow‐up of the patients. In case of hormone‐active

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Tumor markers AFP, bhCG and LDH, should always be measured not only in order to exclude malignancy, but also for the post-operative follow-up of the patients. In case of hormone-active lesions, an endocrinological evaluation should be carried out in order to exclude other hormone secreting diseases that may cause secondary Leydig cell hyperplasia. Since we had to treat asymptomatic patients with unilateral, incidentally found on US examination testicular LCT lesion, which was non-palpable, testicle-sparing surgery (TSS) was the best option. It provides the possibility of complete excision of the lesion and has no impact on the child’s psychological encumbrance, since there are good functional and cosmetic results. We consider radical orchidectomy as an overtreatment. Parents should be aware of the possibility of synchronous or metachronous bilaterality of these lesions and give their consent on TSS [14]. Intra-operative use of US, which is unfortunately not available in our hospital, could probably further reduce the ischemia time which should always be kept less than 30 min duration. The surgical specimen was not sent for frozen section analysis due to the pre-operative favorable physical examination and imaging (US, MRI), the negative tumor markers, the very small lesion’s size (less than 4 mm) and the characteristic macroscopic intra-operative image of the nodule. The permanent histology for benign LCT is based on the criteria suggested by Kim et al., which include the dimensions of the nodule, the margins of the mass (whether or not free), the extra-testicular extension, the presence of angioinvasion or necrosis, atypias and the high mitotic index [5]. These criteria are further completed by Cheville et al., including ploidy and proliferation rate [4]. Despite the fact that these lesions have shown a favorable outcome, a follow-up is essential for a long period with physical and imaging (US) examination. Until now, there is only one case of malignant LCT in a 9-year-old child, but with bilateral testicular involvement and with mass dimensions on one side greater than 6 cm [16]. A multidisciplinary approach including pediatric surgeons, endocrinologists, radiologists and pathologists leads to a precise diagnosis which is essential for choosing the right way of surgical treatment. Testis-sparing surgery should always be performed in such benign cases. There is no impact on the child’s psychological encumbrance since there are good functional and cosmetic results, and the prepubertal patient has a better chance of fathering children.

Author Contributions: V.L.: data collecting, analyzing, manuscript writing, final revision; A.T.: data analyzing, final revision; V.M.: references search, final revision; E.P.: data analyzing, final revision; D.G.: data analyzing, manuscript writing, final revision; C.K.: references search, final revision; K.A.: references search, final revision; I.S.: references search, final revision. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.

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