Prepubertal Testicular and Paratesticular Tumors 

Updated: Mar 03, 2020
Author: Christopher S Cooper, MD, FACS, FAAP; Chief Editor: Marc Cendron, MD 

Overview

Practice Essentials

Testicular tumors account for 1-2% of all pediatric tumors, with an incidence of 0.05-2 per 100,000 children.[1]  A bimodal age distribution is observed; one peak occurs in the first 2 years of life, and the second occurs in young adulthood.

Pediatric prepubertal testicular tumors are dramatically different from adult neoplasms. Germ-cell tumors account for only 60-77% of testicular tumors in children but account for 95% of testicular tumors in adults.[2]  Adult germ-cell tumors with malignant potential, such as seminoma and embryonal carcinoma, are not present in prepubertal patients. Teratomas, which are uniformly benign in children, are often malignant in adults.

The 2016 update of the World Health Organization (WHO) classification of testicular germ-cell tumors divided them into two broad categories on the basis of whether they are derived from a precursor lesion: germ-cell neoplasia in situ (GCNIS).[3]  Prepubertal tumors are non-GCNIS-derived,[4] whereas postpubertal tumors are GCNIS-derived, though benign prepubertal-type teratomas may rarely develop in the postpubertal testis.

The most common germ-cell tumors are yolk-sac tumors and teratomas, which were reported by Ross to account for about 62% and 26% of testis tumors, respectively.[5, 6]  Nistal et al reported frequencies of 49% for yolk-sac tumors, 13% for teratomas, 9% for seminomas and mixed germ-cell tumors, and 29% for sex-cord stromal tumors.[7]

Some series have suggested that teratomas, which most believe are vastly underreported because of their benign nature, may account for almost 50% of prepubertal testicular tumors.[8]  A descriptive analysis of prepubertal testicular germ-cell tumors from a large Chinese center cited frequencies of 50.9% for teratomas, 29.2% for yolk-sac tumors, 19.3% for epidermoid cysts, and 0.6% for mixed germ-cell tumors.[9] However, in tumor registries, yolk-sac tumors have been more common than teratomas, though it is possible that this may reflect a reporting bias.[5, 10, 11]

Gonadal stromal tumors are generally considered significantly less common than germ-cell tumors and primarily include juvenile granulosa-cell tumors, Leydig-cell tumors, and Sertoli-cell tumors.

Pathophysiology

The vast majority (85%) of yolk-sac tumors in children present as clinical stage I disease, compared with only 35% in adults.[12]  Alpha-fetoprotein (AFP) can be used as a reliable tumor marker because levels are increased in more than 90% of yolk-sac tumors. Therefore, patients can be safely managed with observation after orchiectomy followed by chemotherapy for recurrent tumors.[13]  Retroperitoneal lymph node dissection is reserved for children with persistent retroperitoneal lymphadenopathy or increased serum tumor markers after orchiectomy and chemotherapy.

Prepubertal teratomas account for fewer than 30% of testicular germ-cell tumors in children and are uniformly benign.[5]  Histology is often pure with diploid DNA content containing all three embryologic germ layers (ectoderm, mesoderm, and endoderm). Testis-sparing surgery with frozen section is a reasonable consideration for this and other benign prepubertal tumors.[14, 15] No follow-up is recommended for prepubertal teratomas, whereas postpubertal patients should be monitored into adulthood.

Epidermoid cysts are benign tumors of epithelial origin and account for 10-15% of cases.[1, 16]  They are often firm and well defined, with a central hypoechoic region or mixed internal echogenicity surrounded by an echogenic rim on ultrasonography (US). After tumor enucleation, these tumors do not require follow-up.

Seminomas and mixed germ-cell tumors are extremely rare in prepubertal children. Most authorities believe that seminomas should be managed as in adults and mixed germ-cell tumors should be treated according to the most malignant subtype present.

Sertoli-cell tumors are the most common gonadal stromal tumors in prepubertal children. They tend to appear as painless masses in boys younger than 6 months and produce no endocrinologic effects; however, 14% of patients present with gynecomastia.[12]  All reported lesions in children younger than 5 years have been benign. Therefore, children younger than 5 years are adequately treated with orchiectomy and do not require metastatic evaluation. Older children should undergo chest radiography and abdominal computed tomography (CT) to rule out metastases. Metastases are treated with a combination of radiotherapy, chemotherapy, and retroperitoneal lymph node dissection.

Large-cell calcifying Sertoli-cell tumor is a variant with large amounts of cytoplasm and calcification. One third of patients with this tumor have associated genetic abnormalities; however, these tumors are universally benign.

Leydig-cell tumors are the second most common gonadal stromal tumors in children and are also benign. These tumors most often occur in boys aged 5-10 years, and the synthesis of testosterone may produce precocious puberty, gynecomastia, and elevated levels of 17-ketosteroids. Leydig-cell tumors must be differentiated from hyperplastic nodules that develop in boys with poorly controlled congenital adrenal hyperplasia (CAH).

Juvenile granulosa-cell tumors account for approximately 3% of all neonatal testicular tumors and commonly appear as cystic, painless testicular masses.[13, 17, 18]  They almost always appear in the first year of life, and most appear by age 6 months. They can be associated with anomalies of the Y chromosome, mosaicism, and ambiguous genitalia. These tumors are hormonally inactive and benign.

Gonadoblastoma occurs in association with disorders of sex development (DSDs). About 80% of cases involve phenotypic females with intra-abdominal testes or streak gonads.[19]  The putative gonadoblastoma gene is on the Y chromosome, and the tumor almost always develops in a child with a Y chromosome. The streak gonads in patients with mixed gonadal dysgenesis often develop gonadoblastomas. Incidence peaks at puberty, and early gonadectomy is recommended in patients at risk for gonadoblastoma. Metastatic spread occurs in 10% of patients.[20]  These tumors may elevate serum levels of beta human chorionic gonadotropin (β-HCG).

Cystic dysplasia of the testis is a benign lesion that is often associated with ipsilateral renal agenesis or dysplasia. This association, along with a characteristic appearance on US (ie, hypoechoic lesions), permits preoperative diagnosis and possible treatment with testicular-sparing surgery.[5]

Leukemia and lymphoma are the most common secondary malignancies to affect the testis.[21]  These tumors can present bilaterally, and because the blood-testis barrier protects the intratesticular cells, the testis may be the site of residual tumor in children after chemotherapy. Metastatic disease to the testes should be considered in a child presenting with bilateral testicular tumors.

Paratesticular structures can give rise to various benign (lipoma, leiomyoma, hemangioma, or fibroma) and malignant tumors; however, these are extremely rare. Rhabdomyosarcoma is the most common malignant tumor (17%) and may arise from the distal spermatic cord and appear as a scrotal mass or hydrocele.[12]  These tumors have a bimodal distribution and occur in boys aged 3-4 months and in teenagers. As many as 70% of cases involve the retroperitoneal lymph nodes at presentation.

These tumors are highly aggressive and spread via the blood or lymphatics or through direct extension to the lungs, cortical bone, or bone marrow in 20% of patients at the time of diagnosis. Radical inguinal orchiectomy followed by retroperitoneal lymph node dissection is recommended for all children older than 10 years and for those younger than 10 years with retroperitoneal disease. Patients with positive lymph nodes are treated with multimodal therapy (chemotherapy and radiation).

Etiology

The cause of pediatric testicular tumors is unknown. An association with antenatal exposure to diethylstilbestrol (DES) has been postulated but not demonstrated.

Epidemiology

United States statistics

Testicular tumors account for approximately 1-2% of all pediatric solid tumors.[1] The incidence is 0.05-2 per 100,000 children. Although benign tumors are more common in prepubertal patients than in postpubertal patients, yolk-sac tumors have been more commonly reported in some series and tumor registries. The true incidence of benign tumors, such as teratomas, may be less than what is reported because of reporting bias.

International statistics

The worldwide incidence of prepubertal testicular and paratesticular tumors is similar to that in the United States.

Age-, sex-, and race-related demographics

The incidence of pediatric testicular tumors peaks in children aged 2-4 years. Most yolk-sac tumors occur in children younger than 2 years.

Testicular tumors occur in boys and men.

Testicular gem cell tumors appear to have a 1.4-fold greater incidence in Asian/Pacific Islanders than in white or black children. There seems to be no discernible difference in the incidence of testicular tumors between black and white boys aged 0-14 years.[22]

Prognosis

The prognosis for patients with benign testicular lesions is excellent. Even for patients with metastatic yolk-sac tumor, survival with chemotherapy is approximately 90%.[18]

Patients with rhabdomyosarcoma have an overall survival rate of more than 70% when treated with multimodal therapy. Poor prognostic indicators include alveolar histology, age older than 7 years, unresectable retroperitoneal disease, and distant metastatic disease.

One death occurs per every 10 million cases per year.

A large series by Maizlin et al evaluated 479 prepubertal patients (≤12 years; median age at diagnosis, 3 years) with testicular tumors from the National Cancer Data Base (1998-2012).[11]  Yolk-sac tumors were the most common histology. Of the 479 patients, 465 underwent resection (radical orchiecomy in 75%); chemotherapy was used in 28% of cases and radiotherapy in 7%. Mortality was 3% at a mean follow-up of 5.6 years, and it was not significantly affected by tumor histology or extent of surgical resection.

Patient Education

For any child with history of testicular malignancy, self-testicular examination is recommended at start of puberty and should be performed monthly thereafter.

For patient education resources, see the Men's Health Center and the Cancer Center, as well as Testicular Cancer and Testicular Self-Exam.

 

Presentation

History

About 85% of children with testicular tumors present with painless scrotal swelling. A few present with a hydrocele, scrotal pain, or a history of trauma, any of which probably alerts the child to the presence of a painless and enlarged testicle.

About 10-25% of patients with a malignant tumors present with a hydrocele.

Physical Examination

Physical examination usually reveals a painless scrotal swelling with a hard mass or associated hydrocele. However, normal physical findings are not sufficient to exclude a tumor.

Some hormonally active tumors may appear in association with precocious puberty or gynecomastia.

 

DDx

 

Workup

Laboratory Studies

It is important to obtain a serum alpha-fetoprotein (AFP) level before treating a testicular mass. AFP levels are elevated in 80% of patients with yolk-sac carcinomas and serve as a tumor marker. The half-life of AFP is about 5 days, and levels should return to normal (< 20 ng/mL) within 1 month after complete removal of the tumor.

AFP levels are usually elevated in neonates (~50,000 ng/mL) and drop to 10,000 ng/mL by age 2 weeks and to 300 ng/mL by age 2 months; therefore, age-specific values should be used. Persistently elevated AFP levels after surgery suggest tumor metastases or recurrence. Liver dysfunction can also cause false-positive elevations of AFP levels.

Serum testosterone levels may be elevated in Leydig-cell tumors.

Gonadoblastoma may elevate levels of beta human chorionic gonadotropin (β-HCG).

Imaging Studies

Ultrasonography (US) is helpful in evaluating the testicle and in distinguishing an extratesticular mass from an intratesticular mass (see the images below).[23]

Ultrasonogram revealing cystic dysplasia of testic Ultrasonogram revealing cystic dysplasia of testicle.
Ultrasonogram in infant revealing heterogeneous in Ultrasonogram in infant revealing heterogeneous intratesticular mass that proved to be juvenile granulosa-cell tumor.

Chest radiography should be performed; 20% of yolk-sac tumors occur with metastases to the lung.

Patients with rhabdomyosarcomas require chest radiography, abdominopelvic computed tomography (CT), bone scanning, and bone-marrow aspiration.

Procedures

The type of testicular tumor is diagnosed after inguinal orchiectomy or after an inguinal approach to testicular-sparing surgery is used.

When preoperative AFP levels are normal and the level of suspicion for a benign lesion (eg, cystic dysplasia, teratoma) is high, the tumor is excised from the testis via an inguinal approach. Intraoperative histologic confirmation of a benign lesion by frozen section permits testicular-sparing surgery.

Histologic Findings

Histologic evaluation of the yolk-sac tumor demonstrates eosinophilic periodic acid-Schiff (PAS)-positive inclusions in the cytoplasm of clear cells that consist of AFP and Schiller-Duval bodies.

Teratomas and teratocarcinomas contain elements derived from more than one of the three germ tissues (ie, endoderm, mesoderm, and ectoderm). These tumors are often cystic, and tissues such as skin, hair, bone, and even teeth may be present. Although they contain areas of poorly differentiated cells with a malignant appearance, teratomas are consistently benign in children younger than 2 years.

About 90% of paratesticular rhabdomyosarcomas demonstrate a favorable embryonal pattern on histology.

Staging

The intergroup staging system for testicular germ cell tumors is as follows:

  • Stage I - Limited to the testis and completely resected [24] (85% of children < 4 years present with stage I disease, compared with only 35% of adults)
  • Stage II - Removed by transscrotal orchiectomy, involvement of scrotum or spermatic cord, persistently elevated markers
  • Stage III - Retroperitoneal lymph node involvement (≤ 2 cm, no visceral or extra-abdominal involvement)
  • Stage IV - Distant metastases
 

Treatment

Medical Care

Current chemotherapeutic regimens for yolk-sac tumors are platinum-based protocols. Common agents include etoposide, bleomycin, and cisplatin. Most often, a pediatric oncologist enrolls patients who require chemotherapy into a multigroup research protocol. The protocols vary, depending on the particular trial.

Surgical Care

The treatment for yolk-sac tumors is inguinal orchiectomy and close surveillance.[25] The tumor usually spreads to the lungs.

Follow-up should include monthly tests of serum alpha fetoprotein (AFP) levels, chest radiography every 2 months for 2 years, and computed tomography (CT) or magnetic resonance imaging (MRI) of the retroperitoneum every 3 months for the first year and then biannually.

Because spread to the retroperitoneal lymph nodes is uncommon, routine prophylactic dissection of the nodes is not performed.

Chemotherapy is administered in patients with radiographic evidence of metastatic disease or persistently elevated serum AFP levels. The use of combination chemotherapy with cisplatin, etoposide, and bleomycin has been an effective treatment for metastatic disease, with a survival rate approaching 90%.

More than 99% of all patients with yolk-sac tumors are expected to survive.

Chemotherapy is recommended in all patients with yolk-sac tumors and stage II disease. In boys with persistently elevated levels of tumor markers after chemotherapy, dissection of the retroperitoneal lymph node may be required. Boys with stage III or IV germ-cell tumors are treated with chemotherapy. If elevated marker levels or retroperitoneal disease persists, biopsy or resection of residual tumor is performed.

Prepubertal testicular teratomas, Leydig-cell tumors, and Sertoli-cell tumors are benign, and orchiectomy or testis-sparing surgery[26] with complete excision is curative.

Stage II or higher teratocarcinomas require treatment with cisplatin, bleomycin, and vinblastine.

Treatment of gonadoblastoma involves removal of the gonad. Streak gonads are routinely removed because of the risk of malignant degeneration.

Seminoma is rare before puberty and is managed in a manner similar to that in the adult population.

Juvenile granulosa-cell tumor is managed with inguinal orchiectomy and follow-up chest radiography for 1 year. Juvenile granulosa-cell tumors rarely metastasize. Testis-sparing surgery has not been routinely recommended, though there is growing evidence that this approach is reliable and safe in selected patients.[27, 17, 28, 29, 18]

Perform radical inguinal orchiectomy to treat paratesticular rhabdomyosarcoma. If the scrotum is involved, hemiscrotectomy should be performed, with adjuvant chemotherapy.

All children with rhabdomyosarcoma require vincristine, doxorubicin (Adriamycin), and dactinomycin (VAC) chemotherapy or treatment with a combination of these drugs. Patients with evidence of metastatic disease may require radiation therapy.

Routine dissection of the retroperitoneal lymph nodes is recommended in all patients aged 10 years or older (regardless of the imaging results) and in patients younger than 10 years whose images show retroperitoneal disease.

Children younger than 10 years have a survival rate of nearly 95%. Children older than 10 years have a worse prognosis and an increased risk for involvement of the retroperitoneal lymph nodes; therefore, an aggressive approach with dissection of the retroperitoneal lymph nodes is recommended.

Routine dissection of the retroperitoneal lymph nodes is not performed to manage prepubertal testicular tumors. The incidence of metastases to the retroperitoneal lymph nodes is lower for these tumors than for postpubertal testicular tumors. However, the prognosis of children older than 10 years who have rhabdomyosarcoma is poor; modified retroperitoneal lymph node dissection is now recommended for these patients.

Complications

Treatment-related complications include known short- and long-term effects of surgery, chemotherapy, and external-beam irradiation. The effects include risk of infertility, hemorrhagic cystitis, and subsequent development of secondary malignancy.

Children should be counseled regarding these risks before treatment.

Long-term follow-up care is required.

Consultations

Consult a pediatric oncologist if chemotherapy is to be administered; consult radiation oncologists for external-beam irradiation, as indicated.

 

Medication

Medication Summary

Consult with a pediatric oncologist regarding chemotherapy for most current regimen and dosing (see Treatment).