although uncommon , leydig cell testicular neoplasms are the most common sex cord - stromal tumors and comprise 13% of all testicular neoplasms . the majority have been recognized in males between the ages of 20 and 60 years .
the malignant variants occur only in adults and metastasis is the major criterion of malignancy . malignancy has not been reported in leydig cell tumors in children .
it is thought that an endocrine role may contribute to the development of these tumors .
they have a tendency to cause endocrine manifestations , and testicular swelling , decreased libido ( 20% ) and gynecomastia ( 15% ) are common symptoms in adults [ 4 , 5 ] .
leydig cell tumors were once managed primarily with radical orchiectomy [ 68 ] . however , testis sparing surgery has been used increasingly in both the adult and pediatric populations . here
we report a new case with bilateral testicular leydig cell tumor in order to review the clinical , diagnostic and therapeutic aspects of this uncommon tumor .
a 30-year - old patient presented with a complaint of infertility since two years of marriage .
physical examination of the external genitalia revealed atrophic left testis and no palpable tumor mass and a solid painless mass in the upper right testicular pole in the patient .
bilateral testicular tumor was shown by scrotal doppler ultrasound examination , which originated from the bilateral mediastinum testis .
hormonal assay showed normal plasma levels of -fetoprotein ( afp ) , -human chorionic gonadotropin ( hcg ) , lactate dehydrogenase ( ldh ) , estradiol , prolactin , follicle - stimulating hormone ( fsh ) , luteinizing hormone ( lh ) and serum testosterone .
the patient underwent bilateral radical orchiectomy ; because both tumors originated from the mediastinum testis , testis sparing surgery was not performed .
a frozen section during surgery from the bilateral testis was suggestive for leydig cell tumor which was confirmed by histopathological examination showing bilateral leydig cell tumor of the testis .
the gross examination of the right testis showed a well - circumscribed , brown homogeneous solid mass with soft consistency measuring 2.5 cm in diameter .
the microscopic examination revealed a nodular pattern of large polygonal cells with round nuclei and eosinophilic cytoplasm ( fig .
tunica albuginea and spermatic cord involvement were not seen ; however , rete testis involvement was identified ( fig .
immunohistochemically , the tumor cells were positive for inhibin- , melan - a and cd56 , but negative for acth and p53 ( fig .
h&e , 200 rete testis involvement , h&e , 100 melan - a immunoreactivity in tumor cells , 200 cd 56 immunoreactivity in tumor cells , 100 inhibin- immunoreactivity within the tumor cells ( modified avidin biotin complex method / abc ) , 400 the tumor in the left testis was 2.5 cm in diameter .
histopathological features of the left testicular tumor were similar to the tumor in the right testis .
there was no disease recurrence in follow - up for 9 months and the patient is currently disease - free and under androgen supplementation for androgen insufficiency .
for example , excessive stimulation of leydig cells with luteinizing hormone due to a disorder of the hypothalamic - pituitary axis may induce their oncogenesis .
animal models have also demonstrated leydig cell tumorigenesis following long - term estrogen administration . although these tumors usually secrete testosterone , the production of estrogen , progesterone , and corticosteroids has also been shown .
estrogen excess and feminizing syndromes may occur from the peripheral aromatization of testosterone or from the direct production of oestradiol by the tumor itself . in 20% of the cases , increased oestradiol and decreased testosterone levels result in feminization in the adult and masculinization in the child .
the endocrinological manifestations may precede the palpable testicular mass , which is the most common presenting feature .
presented the largest case study of leydig cell tumor and 32% of the patients referred for a testicular mass , 8% for gynaecomastia , 8% for testicular pain , 11% for infertility and 5% for isosexual pseudo - puberty .
testicular tumor markers ( -hcg , ldh , afp ) were negative in all patients and one patient with gynecomastia showed high preoperative testosterone levels . in our case
no hormonal abnormality was present , serum tumor markers were in the normal range , and palpable testicular mass was the only manifestation of the tumor .
in pure leydig cell tumors , levels of serum tumor markers such as serum  fetoprotein ( afp ) ,  human chorionic gonadotropin ( -hcg ) , and lactate dehydrogenase ( ldh ) must be within the reference range .
but in most cases , patients present with an incidental finding of a testicular mass on scrotal ultrasonography during evaluation of hydroceles or varicoceles or during diagnostic workup for infertility , as in our case .
giannarini et al . in a series with 17 patients with no bilateral lesions found that 5 patients ( 29.4% ) presented with primary infertility , 4 ( 23.5% ) with gynecomastia and 2 ( 11.8% ) after selfpalpation of a scrotal mass . in the remaining 6 patients ( 35.3% )
boys with estrogen - secreting tumors may present with feminizing symptoms such as gynecomastia or breast tenderness .
adults with androgen - secreting tumors are generally asymptomatic . but in adults with estrogen - secreting tumors , loss of libido , erectile dysfunction , and infertility have been observed .
scrotal ultrasonography is performed to confirm the diagnosis and most of the tumors are hypoechoic and show hypervascularization [ 9 , 10 ] .
mri may be an alternative diagnostic tool for small nonpalpable leydig cell tumors not otherwise visible on sonograms . if malignancy is suspected ct scanning of the abdomen and chest radiography are indicated .
as in all intrascrotal tumors , the final diagnosis is based on the histopathological findings after removal of the tumor .
macroscopically , leydig cell tumors present as well - circumscribed , yellow to brown masses within the testicle .
microscopically , these tumors are composed of large , closely packed cells with eosinophilic cytoplasm , bland nuclei , and small nucleoli .
reinke crystals are pale staining , cylindrical , rectangular , or rhomboid inclusions that are pathognomonic for leydig cell tumors and are found in up to 30% of patients with such tumors .
all definitive diagnoses interpreted the neoplasia as benign lct using the criteria originally proposed by kim et al . , which included dimensions ( maximum neoplasia diameter ) , the presence of infiltrating margins and extratesticular extension , atypias , the presence of necrosis and of angioinvasion , and high mitotic index .
leydig cell tumors have been primarily managed with radical inguinal orchiectomy [ 6 , 9 , 12 ] .
however , conservative management with testis sparing surgery in younger adults and children were reported in the literature [ 8 , 10 ] .
inguinal orchiectomy should be performed with early control of the spermatic cord and without violation of the scrotal skin .
testis sparing surgery with enucleation of the mass has been reported in children and younger adults in order to maintain fertility [ 1315 ] .
bilateral radical orchiectomy was performed in our case ; because both tumors originated from the mediastinum testis , testis sparing surgery could not be performed .
chemotherapy with the bleomycin - etoposide - platinum regimen used for germ cell malignancies has limited efficacy in managing malignant leydig cell tumors .
the tyrosine kinase inhibitor imatinib has shown some chemotherapeutic activity in animal models , although this was not demonstrated in human trials .
observation is sufficient in patients in whom a benign leydig cell tumor is treated with radical inguinal orchiectomy .
patients with malignant tumors require regular follow - up imaging , including ct scanning of the chest and abdomen .
metastatic sites include the liver ( 45% ) , lungs ( 40% ) , and bone ( 25% ) . in the review of the literature
, there is no proven treatment of choice in case of progressive disease making any one superior to the others ( surgery , radiotherapy and chemotherapy ) . on the other hand , when there are no metastases and
there is no evidence of malignancy , a regular follow - up is preferred by clinical examination , ct scan or ultrasound of the abdomen and by measuring the testosterone and estradiol levels because of the risk of metastases many years after orchiectomy even in a histologically bland tumor .
late onset of metastasis , up to 8 years after orchiectomy , has been reported , which supports the recommendation of long - term tumor surveillance for 10 - 15 years after surgery .
the mean survival in patients with a malignant variant is 23 years [ 2 , 3 , 18 ] .
 leydig cell tumors are rare testicular tumors of the male gonadal interstitium . 
 although uncommon , leydig cell testicular neoplasms are the most common sex cord - stromal tumors and comprise 13% of all testicular neoplasms . 
 this tumor is always benign in children and approximately 90% are benign in adults . in most cases , patients present with an incidental finding of a testicular mass on scrotal ultrasonography during evaluation of hydroceles or varicoceles or during diagnostic workup for infertility . 
 leydig cell tumors have been primarily managed with radical inguinal orchiectomy . 
 however , conservative management with testis - sparing surgery in younger adults and children were reported in the literature . here 
 we report a case of bilateral leydig cell tumor of the testis treated with radical orchiectomy who presented with the complaint of infertilityand no disease recurrence in followup for 9 months . 
 the patient is currently disease - free and under androgen supplemantation for androgen insufficiency . 
 we recommend complete exam and diagnostic workup in patients with infertility and azoospermia . 
Introduction
Case report
Discussion