Testicular tumours in children: a single-centre experience

Abstract

Introduction:

Testicular tumours in childhood have diverse characteristics for different age ranges. This study aimed to describe the pattern, presentation and outcomes of primary testicular tumours in a paediatric population.

Methods:

A retrospective study was conducted from January 2010 to December 2020 on children (≤18 years) with a diagnosis of primary testicular tumour. Baseline demographics, clinical characteristics, pathology, treatment and outcomes of these patients were analysed. The data were entered into IBM SPSS Statistics version 20.0. Chi-square test and Fisher’s exact test were applied to find the statistical significance, which was set at P value ≤ 0.05.

Results:

The study included 115 males, with 85 (73.9%) patients in the prepubertal age range with a mean age of 2.53 ± 2.06 years and 30 (26.1%) patients in the postpubertal group with a mean age of 15.73 ± 1.25 years. Yolk sac tumour was the most common (62.6%) histological subtype. Majority (46.1%) of patients had stage I disease on presentation, while 29.6% had stage IV disease. All patients underwent upfront high inguinal radical orchiectomy, which was followed by platinum-based adjuvant chemotherapy in 67% of the patients. The five-year event-free survival and overall survival for all patients were 75% and 91%, respectively.

Conclusion:

Primary testicular tumours follow a bimodal age distribution pattern. Majority of patients can be cured with platinum-based chemotherapy despite having advanced disease at presentation.

INTRODUCTION

Testicular tumours are uncommon in children and constitute a heterogeneous group of tumours in terms of age distribution, distinct biological behaviour, histopathology and variable prognosis.[1] Testicular tumour accounts for 2%–4% of all childhood tumours; however, its incidence has increased globally over the past decades and testicular cancer is the most common malignancy in young males in many populations.[2,3] Most prepubertal testicular tumours are germ cell tumours (GCTs) that comprise various histological subtypes, with yolk sac tumour and teratoma being the most common, while mixed GCT and seminoma are most frequently reported in postpubertal males.[4] Paediatric sex cord-stromal tumours (SCSTs) of the testis are very rare and account for about 6%–8% of all testicular neoplasms in children and adolescents.[5]

Clinical presentation varies with the age and stage of tumour and ranges from from simple scrotal swelling to painful abdominal mass and respiratory symptoms due to visceral metastasis. Various risk factors, such as cryptorchidism, gonadal dysgenesis, testicular microlithiasis, tumour in opposite testis and family history of testicular cancer, have proven association with testicular tumour.[3] Serum tumour markers, such as alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (β-hCG), and ultrasonography are important tools in the diagnosis and surveillance of testicular tumours. If malignancy is suspected, computed tomography (CT) of the chest, abdomen and pelvis is necessary to search for pulmonary and retroperitoneal metastases.

There are a few publications on epidemiological differences, clinical presentation and histological subtypes of testicular tumours in children and adolescents.[6,7] However, there are few studies on prepubertal testicular tumours with histological divisions according to age, and they have mainly described the correlation of preoperative serum AFP levels with histological confirmation of malignancy postoperatively in different age groups.[8] Morover, some studies have described the management and outcome of paediatric testicular tumours according to age distribution of pre- and postpubertal groups with short-term follow-up.[9] Data regarding the current management of testicular tumour with age, staging, distant metastasis, relapse and survival outcome are lacking.

To the best of our knowledge, there are few studies found worldwide and none from our country on the management of paediatric testicular tumour. Herein, we share our comprehensive experience of the oncological management of paediatric testicular tumours from the biggest cancer hospital in Pakistan. The purpose of this study was to determine the pattern of testicular tumours in children, including their relative frequencies, age distribution, clinicopathological characteristics, tumour markers, site of metastasis, treatment provided, relapse and the disease outcome.

METHODS

This is a retrospective study conducted at the Department of Surgical Oncology from January 2010 to December 2020 after approval was obtained from the Institutional Review Board (IRB). We included all male patients up to the age of 18 years with primary testicular tumour. Metastatic nonprimary testicular tumours and lymphoproliferative neoplasms like leukaemia and lymphoma were excluded.

Cases were identified with a keyword search of ‘testicular mass or malignancy’ in our electronic health records of the hospital information system. Variables that were assessed included age at diagnosis, clinical presentation, time of disease onset, baseline ultrasound and CT findings for diagnosis and staging, preoperative and postoperative tumour markers, site of metastasis, pathological staging, type of treatment provided and disease course. All findings were entered into a predesigned proforma.

Our institute’s protocol for the diagnosis of testicular tumour is based on clinical features, levels of tumour markers (AFP and β-hCG), imaging (ultrasound and CT scan) and histopathology. Testicular tumour is staged according to the Children’s Oncology Group (COG). Upfront high inguinal radical orchiectomy was performed for all the patients, and further treatment was planned according to the stage after discussion at the multispeciality tumour board meeting. Cisplatin-based chemotherapy regimen for four to six cycles was used post surgery based on the stage of the tumour, status of tumour markers and presence of metastatic or residual disease. The decision to resect metastatic or residual retroperitoneal lymph node (RPLN) disease after adjuvant chemotherapy was individualised after discussion with the multispeciality board. Metastatectomy and retroperitoneal lymph node dissection (RPLND) are usually performed in patients who have residual disease more than 2 cm post chemotherapy and have a rising pattern of serum AFP/β-hCG. After completion of treatment, all the patients were followed up with measurement of tumour markers (serum AFP and β-hCG levels), an X-ray of chest and ultrasound of scrotum and abdomen at 3 months, 6 months, then yearly up to 5 years according to the hospital policy.

IBM SPSS Statistics version 20.0 (IBM Corp, Armonk, NY, USA) was used for data analysis. The data were further divided into prepubertal (0.5–12 years) and postpubertal (12–18 years) age groups (because of the bimodal age distribution of the disease) and analysed. Mean and standard deviations were used to describe categorical data, while frequencies and proportions were used to describe quantitative data. Univariate analysis was performed to look at the factors associated with morbidity and mortality. A multivariate analysis was performed using a logistic regression model to identify the risk factors for all variables that were found to be significant in univariate analysis. Survival analysis was done in terms of overall survival (OS) and event-free survival (EFS). Event was defined as disease relapse or death. Event-free survival was defined from the date of completion of treatment to the date of disease relapse, progression or death, and OS was the time from the initial diagnosis to the date of last follow-up or death due to any cause. EFS and OS were analysed by the Kaplan–Meier method. P values < 0.05 were considered significant.

RESULTS

There were a total of 115 patients with primary testicular tumour. Mean age at diagnosis was 5.97 ± 6.28 years (median and interquartile range [IQR]: 2 [1–13] years). Eighty-five (73.9%) patients belonged to the prepubertal age group, while 30 (26.1%) patients were in the postpubertal age group at diagnosis. Ninety-three (80.8%) patients presented with localised scrotal symptoms only, while 22 (19.1%) patients presented with distant symptoms along with scrotal mass; however, upon investigation, 56 (48.7%) patients were found to have distant metastases as detailed in Table 1. Regarding associated factors, three (2.6%) patients in this study had a history of cryptorchidism, two (1.7%) patients had precocious puberty and one (0.9%) patient had multiple haemangioma. Only three (2.6%) patients had positive family history of testicular malignancy. Tumour marker AFP was raised in 99 (86.08%) patients. A summary of the patients’ demographics and tumour characteristics is presented in Table 1.

Table 1.

Demographics and tumour characteristics of patients with paediatric testicular tumours.

Characteristic	n (%)
Duration of symptoms (mth)
<1	4 (3.5)
1–3	43 (37.4)
3–6	36 (31.3)
>6	32 (27.8)
Age (yr)
0.5–12	85 (73.9)
12–18	30 (26.1)
Clinical presentation
Testicular swelling	81 (70.4)
Testicular swelling + pain in swelling	12 (10.4)
Testicular swelling + distant symptoms	22 (19.1)
Tumour laterality
Right testis	62 (54)
Left testis	52 (45)
Bilateral	1 (0.9)
Histological type
Yolk sac tumour	72 (62.6)
Mature teratoma	3 (2.6)
Immature teratoma	1 (0.9)
Mixed germ cell tumour	26 (22.6)
Embryonal carcinoma	4 (3.5)
Seminoma	6 (5.2)
Sex cordstromal tumours	2 (1.7)
Choriocarcinoma	1 (0.9)
Stage at diagnosis
I	53 (46.1)
II	11 (9.6)
III	17 (14.8)
IV	34 (29.6)
Site of metastasis (n=56)
Lung	7 (6.1)
Lung + retroperitoneum	21 (18.3)
Lung + inguinal lymph nodes	1 (0.9)
Retroperitoneum	21 (18.3)
Retroperitoneum + inguinal lymph node	1 (0.9)
Liver	1 (0.9)
Inguinal lymph node	4 (3.5)
Size of retroperitoneal lymph nodes (cm) (n=43)
<2	6 (5.2)
2–5	13 (11.3)
5–10	9 (7.8)
>10	15 (13.0)

All of the patients underwent upfront orchiectomy, which was followed by adjuvant chemotherapy in 77 (67%) patients. The PEB combination (cisplatin, etoposide and bleomycin) was used as the most common first-line chemotherapy regimen. Nineteen (16.6%) patients had distant metastases that persisted and needed metastatectomy after chemotherapy. Of these, nine patients underwent RPLND, six patients underwent inguinal lymph node excision, while four patients underwent video-assisted thoracoscopy and wedge excision of nodules (three in lung lobules and one in pleural base). The patient with bilateral testicular tumour underwent unilateral orchiectomy followed by chemotherapy, which resulted in resolution of tumour in the opposite testis.

Of the 115 patients, 79 (68.7%) patients had complete remission, 14 (12.2%) patients had partial response, nine (7.8%) patients were lost to follow-up and four (3.5%) patients were under treatment at the time of writing. Nine (7.8%) patients died — two from respiratory failure, two from chemotherapy-related complications and five from rapid progression of disease.

Twenty-six (22.6%) patients out of 115 patients experienced relapse or died. Of the 17 patients who relapsed, six and 11 patients had stage III and stage IV disease at relapse, respectively. Site of relapse included lungs (n=3), RPLN (n=7), inguinal lymph nodes (n=1), multiple sites (n=6) Sixteen patients received second-line chemotherapy VIP (etoposide or vinblastine, ifosfamide and cisplatin), while one patient received chemoradiotherapy. Fifteen patients recovered, while two patients had a second relapse; one of them received further chemotherapy (four cycles of gamitabine/oxaliplatin) and recovered, while the second patient was on palliative chemotherapy at the time of writing. Occurrence of event in different histological subtypes is shown in Figure 1.

Figure 1.

Chart shows the outcome according to tumour histological subtype.

There were 85 patients in the prepubertal age group (mean age 2.53 ± 2.06 years) and 30 patients in the postpubertal age group (mean age 15.73 ± 1.25 years). Most common histological subtype in the prepubertal group was yolk sac tumour, while mixed GCT was more common in the postpubertal age group. Proportion of different histological subtypes in both age groups is shown in Table 2.

Table 2.

Comparison of prepubertal and postpubertal groups.

Parameters	Prepubertal (n=85)	Postpubertal (n=30)	P
Family history
Positive	1	2	0.16
Negative	84	28
Histology
Yolk sac tumour	70	2	0.001*
Mature teratoma	2	1
Immature teratoma	1	0
Mixed germ cell tumour	6	20
Embryonal carcinoma	1	3
Seminoma	3	3
Sex cordstromal tumours	2	0
Choriocarcinoma	0	1
Stage at diagnosis
I	46	7	0.012*
II	9	2
III	10	7
IV	20	14
Event
No	68	21	0.19
Yes	17	9
Additional surgery	13	6
RPLND	5	4	0.24
Metastatectomy (other sites)	8	2

*Statistically significant. RPLND: retroperitoneal lymph node dissection.

Majority (46/85, 54%) of patients presented at stage I disease in the prepubertal age group, while most (14/30, 46.6%) of the patients in the postpubertal age group had stage IV disease at the initial diagnosis. In the prepubertal group, 13 out of 85 patients needed metastatectomy in addition to orchiectomy, whereas in the postpubertal group, six out of 30 patients underwent additional surgery. Detailed comparison of some of the parameters is shown in Table 2.

Median duration of follow-up of the patients was 42 months. Five-year EFS and OS were estimated for patients with testicular tumour according to age and stage of disease. Five-year EFS for all patients were 75%, with 78% for the prepubertal group and 62% for the postpubertal group, and the EFS for stages I, II, III and IV disease was 75%, 62%, 82% and 74%, respectively. Five-year OS for all patients was 91%, with 95% for the prepubertal group and 76% for the postpubertal group, and the OS for stages I, II, III and IV disease was 100%, 82%, 89% and 78%, respectively [Figure 2].

Figure 2.

Kaplan–Meier survival curve shows cumulative overall survival in patients with primary testicular tumours according to disease stage.

DISCUSSION

Paediatric testicular tumours are rare and can occur in all age groups; however, they have bimodal age distribution. There are only few reports regarding the epidemiological features of testicular tumours, especially their age distribution, management and survival analysis, and data is even scarcer from the developing world. Our cohort of 115 patients is one of the largest from Pakistan and may be larger than that of any other single-centre study from the South Asian region in the published literature reports. With 73.9% patients in the prepubertal age group and a median age of 2, our data conforms to the present literature of high prevalence in this age group.[7,8]

The approach on approach towards the paediatric testicular tumours is based on clinical findings, ultrasound of the scrotum, raised tumour markers like AFP and β-hCG, and lactate dehydrogenase levels. Final histology on excisional biopsy (orchiectomy) confirms the type and extent of tumour and further dictates the adjuvant therapy.[10,11] Fine-needle aspiration cytology of testicular tumours is generally not recommended, as exact histological typing is not reliable and fails to develop into a routine investigation, possibly due to needle tract implantation and recurrence. Furthermore, fine-needle aspiration cytology is valuable in metastatic diseases like synchronous presence of disease in cervical and retroperitoneal nodes.[12,13,14]

All patients in our series presented with testicular swelling, with 10.4% having pain in the swelling as a presenting symptom; this is comparable to other studies on scrotal swelling/mass.[15,16] Various risk factors are associated with testicular malignancy. A meta-analysis by Banks et al.[17] showed that history of cryptorchidism is associated with a four-fold increased risk of testicular GCT. However, it is worth noting that only three patients in our study had a history of cryptorchidism.

In our study population, the most common histological subtype in the prepubertal age group was yolk sac tumour (82.3%), while mixed GCT (66.6%) was the most common in the postpubertal age group. Nogueira et al.[18] had similar findings in a Brazilian population, showing 77.3% endodermal sinus tumour and 70% mixed GCT among children and adolescents, respectively. On the contrary, Metcalfe et al.[19] found mature teratoma to be the most common histological subtype in their study. In our prepubertal group, 48.57% and 27.14% of the patients with yolk sac tumour had stage I and stage IV disease, respectively, at diagnosis. In a Korean study,[8] 92% of patients with yolk sac tumours had stage I disease at the time of diagnosis, while an Indian study[20] reported that the majority (57.1%) of patients presented with stage IV disease.

In other studies, testicular preserving surgeries have been attempted.[19,20] In our study, we performed upfront orchiectomy in all patients with primary testicular tumours as part of our protocol. In our cohort, 56 out of 115 patients had metastases while only 19 patients needed metastatectomy as an additional surgery following adjuvant chemotherapy, highlighting the role of chemotherapy in disease remission and favouring the adjuvant approach against upfront metastatectomy, thus reducing the morbidity related to surgery. A study from India[20] showed RPLN involvement in 16 out of 28 cases, and 50% of these cases underwent RPLND. In addition, two patients had lung metastatectomy, one had hepatic metastatectomy, and one had neck, liver and lung metastatectomy after completion of chemotherapy. Another study by O’Shea et al. showed 18% metastatic disease at presentation, out of which 5.8% needed additional surgery.[21]

Moreover, a high inguinal radical orchiectomy is the standard initial treatment of suspicious testicular tumours and provides histological diagnosis. Surgical approaches, including scrotal orchiectomy, open testicular biopsy and fine-needle aspiration, have historically been condemned. Scrotal violation further enhances morbidity and leads to disfiguring local therapies. Also, statistically significant differences were seen in the local recurrence rate between the inguinal approach and scrotal violation studies.[22] However, some authors have favoured a scrotal approach in low-grade testicular tumours due to a low risk of contamination.[23]

Kumar et al.[20] reported a median follow-up of 46.3 months in patients with testicular tumours who had a four-year EFS of 73.3% and OS of 87.9%, and this is comparable to our results of five-year EFS and OS of 75% and 91%, respectively, with a median follow-up of 42 months. The same study further reported a four-year EFS rate of 74.5% and 71.4% for testicular tumours in the pre- and postpubertal groups, respectively, which is also comparable to the findings in our cohort (five-year EFS of 78% and 62% in the pre- and postpubertal groups, respectively).

This study is one of the largest cohorts from a developing country on paediatric testicular tumours and has a detailed analysis of variables and prognostic factors with age distribution, showing an OS rate of 91%. This is also one of the first few studies in recent times to address the pattern and outcomes of primary testicular tumours in male children. We strongly advocate radical orchiectomy for all stages of tumours, and further treatment stratification should be according to residual disease and recommendations from a multidisciplinary team. Future collaborative studies will be valuable to add more knowledge and nationwide outcome data for the betterment of patient management and family counselling.

In conclusion, testicular tumours follow a bimodal age distribution with different histological patterns and are more advanced at advancing age. The majority of testicular tumours can be cured with platinum-based chemotherapy, with a good OS rate.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.