Paediatric Urology

5. TESTICULAR TUMOURS IN PREPUBERTAL BOYS

5.1. Epidemiology and pathophysiology

Testicular tumours constitute approximately 1-2% of all paediatric solid tumours [153]. Testicular tumours originate from various cell types within the testis, with the specific cell of origin determining the tumour’s phenotype. This document addresses prepubertal testicular tumours. For information regarding postpubertal testicular tumours, please refer to the EAU Guidelines on Testicular Cancer [142].

In prepubertal boys, testicular tumours differ significantly from those in adolescent and adult men: they have a lower incidence (0.5 to 2 per 100,000 children, with a peak incidence between ages 0 and 4); they have a different histologic distribution; they are mostly benign (60-75%) [153-158]; and intratubular neoplasia (TIN) is practically non-existent in children [159-164]. Testicular tumours can generally be classified as germ cell tumours (GCT) or stromal tumours. Among prepubertal intra-testicular tumours, GCT account for 71-90%, of which approximately 40% to 50% are teratomas, with reports of immature teratomas in this age group [160,165]. Epidermoid cysts comprise up to 10% to 15% of all GCTs and are consistently benign [161]. Malignant GCTs, predominantly yolk-sac tumours, range from 8% to 30% in frequency.

One specific tumour type is gonadoblastoma, which contains germ cell and stromal cell tumour types and will occur almost exclusively in the setting of DSD [166].

For differential diagnosis of a scrotal mass, paratesticular tumours should be excluded, such as benign types (leiomyoma, fibroma, lipoma, hemangioma, cystic lymphangioma, and lipoblastoma), in addition to the malignant tumours such as a rhabdomyosarcoma [166-168].

5.2. Clinical presentation

Clinical presentation is a painless scrotal mass in more than 90% of the patients, detected by the caregiver, physician or the patient himself. A history of a trauma, pain or hernia is rare. A hydrocele can be found in 15-50% of patients [151,163]. In boys with early onset of puberty (e.g. early penile and prepubic hair growth) as well as high testosterone and low gonadotropin levels, a Leydig cell tumour should be excluded [164].

5.3. Evaluation

Ultrasound
To confirm the diagnosis, a high-resolution US examination (7.5-12.5MHz), preferably a Doppler US, is required. The detection rate is nearly 100% [169-172]. However, it can be challenging to differentiate between benign and malign tumours through US alone. In adults, smaller tumour size, heterogenous masses, hyperechogenicity, peripheral Doppler flow and nonenhancement on US have a significantly lower OR of malignancy, however, evidence for prepubertal males is scarce [173].

Microlithiasis
With high-resolution US, microlithiasis (hyperechoic, non-shadowing foci 1-3mm in diameter within the testicular parenchyma) is increasingly seen in prepubertal boys. The incidence of microlithiasis is significantly higher in patients who had undergone orchiopexy [174]. Routine monthly self-examination of the testes is recommended in children with microlithiasis with contributing risk factors from puberty onwards [12]. When microlithiasis is still present during transition to adulthood, a more intensive follow-up could be considered. Due to the low incidence of a contralateral tumour, even in cases of testicular microlithiasis, there is no indication for contralateral testicular biopsy in prepubertal boys [173].

Tumour markers
When tumour markers are used, age of the patient should be taken into account, since alpha-fetoprotein (AFP) has a clear limitation of its sensitivity and specificity in the first months of life [167], and sometimes takes up to 12 months before the serum concentration reaches the known standard values (<ng/mL) [158,175]. AFP is produced by > 90% of yolk sac tumours. Teratomas can also produce AFP, but not to that extent of yolk sac tumours [176]. Alpha-fetoprotein should be measured before any therapeutic intervention (tumour enucleation/orchiectomy) and should be measured five days after tumour resection/orchiectomy in those with an elevated AFP according to the half-life time of AFP. Human chorionic gonadotropin (ß-hCG) is derived from chorion carcinoma, embryonal carcinoma or seminoma. However, these tumours are extremely rare in prepubertal boys and therefore ß-hCG is not a useful tumour marker in prepubertal boys.

Staging
In patients with a malignant tumour (yolk sac tumour, immature teratoma), staging should be performed, including either a CT scan or MRI of the abdomen and a CT scan of the chest. If there is any suspicion of a non-organ-confined tumour, the patient should be referred to a paediatric oncologist. In patients with the rare diagnosis of a Granulosa cell tumour, imaging of the abdomen to exclude enlarged lymph nodes is reasonable, as this may be a potentially malignant tumour. In those with Sertoli or a Leydig cell tumour, an MRI is recommended, because 10% are malignant and the metastases do not respond very well to chemotherapy or radiation in the adult literature [177,178]. For information about staging of testicular tumours, we refer to the EAU Guidelines on Testicular Cancer [142]. In benign tumours (mature teratoma, epidermoid cysts), no further staging is required.

5.4. Treatment/management

If a testicular tumour is suspected, surgery with the option of intraoperative frozen section should be performed. It is not necessary to do this as an emergency procedure. However, to confirm the diagnosis and to avoid familial anxiety, the operation should be scheduled as soon as possible, preferably within the next few days. Whenever possible, testis-sparing surgery (TSS) should be performed. In a systematic review, the recurrence rate after surgery was found to be 5.8% (95% CI: 2.3-14.1%) in cohorts, including a benign rate of 70.9% [179]. Testis-sparing surgery was performed in 36.2% of these patients.

When performing TSS, frozen sections during surgery can be performed to confirm the diagnosis (benign vs. malignant tumour) and to confirm whether a microscopically margin-negative resection is performed, in which no gross or microscopic tumour remains in the primary tumour bed (R0 resection). In cases of an R0 resection, the tunica is closed and the testis is replaced in the scrotum. In case of R1 resection (removal of all macroscopic disease, but microscopic margins are positive for tumour) confirmed by frozen section in a malignant or potential malignant tumour, an orchiectomy should be performed at the same time of surgery. If the final pathology later demonstrates an R1 resection in a malignant tumour despite intraoperative negative margins on frozen section, an inguinal orchiectomy can be safely performed. Similarly, in a multicentre retrospective study, intraoperative biopsy followed by tumorectomy to preserve healthy testicular tissue in benign testicular tumours was recommended [180].

Orchiectomy could be considered only if normal testicular parenchyma is no longer detectable in the preoperatively high-resolution US and/or if the AFP is > 100ng/mL in a > 12-month-old boy, which is highly suspicious of a yolk sac tumour.

For surgical technique, the Panel is in favour of an inguinal approach. Moreover, clamping of the vessels has the advantage of offering a better view when organ sparing surgery is performed. However, there is no evidence in the literature that tumour-spread is prevented by clamping the vessels. In addition, a retrospective multicentre study suggested that a scrotal approach may be applied for selected cases [181].

As most paratesticular tumours are benign, intraoperative frozen section should be available during surgery and organ-sparing surgical approach is preferred in benign tumours. If a paratesticular rhabdomyosarcoma is suspected, radical inguinal orchiectomy should be performed if tumour size allows it. Otherwise, it is better to extend the inguinal incision down to the scrotum or use a combined inguinal and scrotal approach to facilitate a complete gross total tumour resection [182].

5.5. Tumour entities in prepubertal boys

5.5.1. Germ cell tumours

Teratomas are usually benign in prepubertal children and represent the greatest proportion of intratesticular tumours (approximately 40%) [153,183]. Teratomas present at a median age of 13 months (0-18 months).They should only be considered malignant tumours in adolescents and adults. Histologically, they can consist of a combination of the three primitive embryological germ-cell layers (ectoderm, mesoderm and endoderm). Most of these elements show microscopically mature elements [184], however, some immature teratomas in this age group have also been reported [185]. Upon US examination, a heterogenous picture with some calcification is seen [186] and AFP should be less than 100ng/mL in an infant. After organ-sparing surgery, only one recurrence was reported in the literature [187].

Epidermoid cysts are of ectodermal origin and seem to be related to well-differentiated teratomas. They are always benign [184]. Keratin-producing epithelium is responsible for the keratinised-squamous-epithelial deposits, which appear hyperechogenic in a US [186]. Organ-sparing surgery should be performed and, if confirmed by histology, there is no need for surveillance despite the fact that one ‘recurrence’ has been reported thirteen years after diagnosis [188].

Yolk sac tumours are the predominant prepubertal malignant germ cell tumours and represent approximately 15% of the prepubertal tumours in boys [153]. Yolk sac tumours usually occur within the first two years of life [189]. Histologically, they are mostly solid, yellow-grey tumours, and up to 80-85% of the tumours are organ-confined (Stage I) [190]. Yolk sac tumours are associated with elevated AFP levels, which is seen in more than 90% of cases [191]. The tumour usually spreads haematogenously, and 20 percent of those presenting initially with Stage I disease (no metastatic disease in the MRI-abdomen and CT scan of the chest, as well as normal age-adapted AFP values) may develop visible metastases within the next two years. Therefore, close follow-up together with the paediatric oncologists including AFP every two to three months and MRI of the abdomen is recommended, at least for the first two to three years [167]. This is especially recommended in those patients with invasions of the lymphatic vessels, because this has been shown to be a prognostic factor [189]. In cases of recurrence, chemotherapy should be performed by paediatric oncologists according to national study protocols [192]. The overall three-year and five-year survival rates of patients with a yolk sac tumour were 96.1% and 95.3%, respectively [193].

5.5.2. Gonadal stromal tumours

Juvenile granulosa cell tumours typically occur within the first six months of life They are well circumscribed and have a typical yellow-tan appearance; two-thirds have cystic elements and one-third are solid. A systematic review in which all case series were pooled showed that in all 166 patients described the disease was benign [194].

Sertoli cell tumours usually occur within the first year of life [195]. In the paediatric age group, the large-cell calcifying Sertoli cell tumours (LCCSCT) is the most common tumour variant [196,197]. They can occur in patients with complex dysplastic syndromes, such as the Carney or Peutz-Jeghers syndrome [197-199]. With the exception of one case report with the histological diagnosis of a malignant LCCSCT [196], all other reported tumours are benign. Therefore, organ-sparing surgery should be performed.

Leydig cell tumours arising from the testosterone producing Leydig cells should be suspected in boys with early onset of puberty with high testosterone and low gonadotropin levels [168]. Patients are usually between six and ten years of age, and the tumours are well-circumscribed with yellow-brown nodules. There are no reports of malignant Leydig cell tumours in children, and after organ-sparing surgery, there are no reported recurrences [200,201]. The adult literature reports a malignancy rate of 10%, and primary retroperitoneal lymphadenectomy should be discussed in cases with enlarged lymph nodes, because these metastases do not respond very well to chemotherapy or radiation [202].

5.5.3. Other tumours

Testicular adrenal rest tumours (TARTs) can occur in boys with a congenital adrenal hyperplasia (CAH). Up to one-third of the TARTs occurs prepubertally, and the proportion increases with age. A significant correlation exists with poor hormonal control [203-205]. In a comparative study, factors found to correlate with TARTs volume included ACTH levels (coefficient 0.004; p = 0.009) and the three-year average of serum testosterone levels (coefficient 9.64; p = 0.003) [206]. A delayed CAH diagnosis of over one year was associated with a 2.6x higher risk of TART [207]. While TARTs have no malignant potential, they can have a lasting impact on fertility by displacing the normal testicular parenchyma [208,209]. These patients should be offered US screening and advice on fertility with the option of cryopreservation [209]. A cross-sectional clinical study found that the size of the TART affects the volume of residual spermatogenic testicular tissue, while current CAH control impacts adrenal androgen hypersecretion [210].

5.6. Follow-up

Regular US examination is recommended in the follow-up period to detect any recurrence and/or other abnormalities. As there are only a few studies with recurrence after testicular-sparing surgery or orchiectomy, no clear recommendation can be made concerning the interval and the duration of follow-up. However, performing a US examination every three to six months within the first year seems reasonable, because few recurrences have been detected at this time and the rate of atrophy is extremely low after organ-sparing surgery [211]. Only in patients with a malignant tumour, regular follow-up examination after the first year of surgery seems reasonable (see above). The follow-up in patients with a Leydig cell tumour should include endocrinological examinations.