Leydig Cell Tumor in Children: a Case Report and Literature Review

Introduction

Leydig cell tumors (LCTs) are a sex cord-stromal tumor group member. It arises from Leydig cells and categorizes as one of the most common non-germ cell tumors (NGCTs) (1, 2). They presented at any age, especially in children between 5 and 9 years with precocious pseudopuberty or gynecomastia and men between 20 and 60 years (1, 2). The main clinical presentation includes unilateral testicular mass in 90 %, Isosexual precocious pseudopuberty, gynecomastia in 20 %, and elevated levels of 17-ketosteroid (3). Radical inguinal orchiectomy is considered a classical treatment. Still, young children with tumors tend to follow a benign course due to the maintenance of fertility testis-sparing surgery by tumor enucleation suggested as the treatment of choice (4, 5).

Case presentation

The patient is a 10-year-old boy admitted to the outpatient clinic with a history of left painful scrotum since last month. After signing the informed consent, his parents agreed to report the case, and reporting of his case is based on CARE guidelines. Physical examination revealed a testicular asymmetry, and the trans-illumination test showed a dark shadow in the left testis and gynecomastia but no sign of precocious puberty (Figure 1). Penis size was 2.5cm, and with severe meatus stenosis, pubic and axillary sites were hairless.  The first testicular Doppler ultrasound of the bilateral testis identified; the left testis with 22×12mm size containing a hypoechoic space-occupying lesion with a size of 8.7×8mm with multiple calcifications, and the right side of 19×11mm. The volume of the left and right testicles was 22ml and19ml, respectively. His height and weight were in the normal range of 50th percentage for sex and age.  Laboratory evaluation for teratomas tumour markers revealed alpha-fetoprotein (AFP) < 2.0 IU /mL with the references of < 7.25, and human chorionic gonadotropin (HCG) titration < 0.1 IU/mL with the references of up to 2.6 (ECL, Roche).

The patient was under observation for two weeks. The second testicular color Doppler ultrasonography (CDUS) of both testes showed the right testis with 20×9 mm size with normal echogenicity and the left testis with a size of 21×10 mm, which contained a well-defined and hypoechoic mass with the size of 8.5×7 mm and has internal coarse areas of calcification. This suggested a differential diagnosis of large cell calcifying Sertoli cell or Leydig cell tumor teratomas and revealed the normal size and echogenicity of both epididymides, no hydroceles in both scrota, and the normal parenchymal vascularity. The result of the hormonal assessment is shown in (Table 1), and all of them were in the normal range before the operation; after 2 weeks of workup, a left-testis-sparing surgery was performed.

Initial histologic reports revealed a 1-centimeter mass compatible with a Leydig cell tumor with foci of calcification, neoplastic cells with eosinophilic cytoplasm, and large cell calcifying Sertoli cell tumor in its deferential diagnosis. Still, according to immunohistochemistry (IHC) stain, tumoural cells express (inhibin, vimentin, calretinin, and melan-A), and negative for s100 and AFP, and the final diagnosis of Leydig cell tumor was confirmed (Figure 2).  Several tests like surgical pathology, immunohistochemistry (IHC), post-operative abdominal, and pelvic Computed Tomography (CT) were performed, indicating the negative retroperitoneal adenopathy, small and large bowel, and urinary bladder were unremarkable.  The result of the hormonal evaluation was performed and shown in.

Discussion

Leydig cells as interstitial cells that are found between seminiferous tubules. They are responsible for secondary sexual characteristics and the maintenance of spermatogenesis by producing testosterone (6). These tumors are the most common sex cord-stromal tumor but rare in children; they occur especially in boys aged 5 to 10 years (peak incidence around age 5 yrs) in 20 % and adults between the age of 20 to 60 (average 47 yrs). They account for 1 to 3% of all testicular tumors (7). Most of these tumors have benign behavior during this period and are characterized mainly by the secretion of androgen and sometimes estrogen (8). If it is secreting androgens, the tumor is usually asymptomatic but can cause precocious puberty in pre-pubertal boys. If the tumor secretes estrogens, it can cause feminization in young boys. In adults, this causes several problems, including gynecomastia, erectile dysfunction, infertility, genital atrophy, and a loss of libido (9) There are no proven reports of malignancy transformation of these tumors in children, whereas in up to 10% of cases of adults these tumors appear as become malignant variant (10). Due to high testosterone levels, most children present with signs of precocious puberty, such as gynecomastia (11). Besides, our case was referred to the clinic with a palpable mass in the left testicle and gynecomastia, However, his hormonal assessment revealed normal levels of androgen, and estradiol and no evidence of other signs of precocious puberty, such as early development of axillary and pubic hair, penile growth, and accelerated musculoskeletal development, was not seen which could be inferred different presentation of pediatric age LTCs versus adult ones. In all patients with testicular mass and gynecomastia, other causes, such as teratoma, Granulosa cell, and Sertoli tumors, should be considered (12). 

Changes in tumor size (>5 centimeters), tumor hemorrhage, and tumor necrosis may suggest malignant changes, especially in 5 to 10 percent of prepubertal adults between the ages of 30 and 60 (8). The common microscopic pathology is characterized by medium to large polygonal cells with round to oval nuclei and prominent nucleoli with rich eosinophilic cytoplasm separated by fibrovascular septa and resembling normal Leydig cells. In 30 to 40 % of cases, pale-staining, plump rod-shaped or rhomboid structures in the cytoplasm intranuclear structures (Reinke crystals) can be seen. (13, 14) Immunohistochemistry (IHC) staining shows positivity for inhibin, calretinin, vimentin, and Melan-A and negativity for S100, AFP, and EMA, and our IHC stain showed the cells of tumor positive for ( inhibin, vimentin, calretinin, and melan-A) but negative for s100 and AFP (8, 15, 16).

Testis-sparing as tumor enucleation seems to be a rationale for LCTs with benign behavior ( the mass is less than 2.5 cm and the tumor markers are normal before surgery), and negative intraoperative frozen section for malignancy is mandatory (4) and in children to keep the fertility can be the method of choice and observation is sufficient for this group in long term monitoring. Radical inguinal orchidectomy is a classical treatment, especially in malignant cases, and it can be accompanied by retroperitoneal lymphadenectomy (RPLND) in metastatic cases. These LCTs rarely respond to chemoradiotherapy (11, 17).

Due to the possibility of Tumor recurrence in the malignant group during the first two years after surgery, so patient monitoring at regular intervals is needed. These monitoring should include thorough clinical exam, check of hormonal profile (luteinizing hormone [LH], follicle-stimulating hormone [FSH], testosterone, estrogen, and estradiol), tumor markers (beta-HCG, LDH, AFP), and follow-up imaging (chest and abdominal computed tomography scan) at 4 months during the first year, followed by similar imaging two-yearly during the second year and yearly examinations thereafter (18). Metastases most frequently occur in the retroperitoneal lymph nodes, liver (45%), lung (40%), and bone (25%) (19).

Figure 1. A ten-year-old boy with left testicular swelling and 

Figure 2. A: Hematoxylin and eosin staining (H&E-4X) in tumor cells with abundant eosinophilic cytoplasm. B: Neoplastic cell with well-distinguished cell border (H&E-40X)

Table 1. The result of serology testing targeted hormonal assessment

Beta-hCG: Beta human Chorionic Gonadotropin; FSH: Follicle Stimulating Hormone; LH: Luteinizing Hormone; DHEA: Dehydroepiandrosterone; ACTH: Adrenocorticotropic Hormone; TSH: Thyroid Stimulating Hormone

Conclusions

Due to the highly variable clinical presentation of tumors, especially in children, and the importance of maintaining fertility in this group and increased incidence of malignancy, especially in adolescence, early detection and timely treatment are crucial. A testicular ultrasound should be done as an extension of the physical exam for any children with Painless swelling, sudden hydrocele, or any symptoms related to the scrotum of the unknown cause, even in the absence of signs of precocious puberty, and referred all these patients to a pediatric urologist for further workup.

Authors’  contributions

All authors contributed equally. All authors reviewed and approved the final version of the manuscript.

Acknowledgments

Special thanks to the Department of Pediatric Surgery, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran

Conflict of interest

All authors declare that there are no conflicts of interest regarding the publication of this manuscript.

Funding 

The authors received no financial support for this research. 

Ethical statement

This manuscript is based on the CARE guidelines, and informed consent was signed by the case’s parent in this study. 

Data availability

Data will be provided by the corresponding author upon request. 

Abbreviations

ACTH         Adrenocorticotropic Hormone

Beta-hCG    Beta human Chorionic Gonadotropin

CLIA           Chemiluminescence Immunoassay

DHEA         Dehydroepiandrosterone

ECLIA         Electrochemiluminescence Immunoassay Analyzer

ECL            Electro Chemi Luminescence

FSH            Follicle Stimulating Hormone

LH              Luteinizing Hormone

TSH            Thyroid Stimulating Hormone