Testicular Tumors in Children

27.1Introduction

•Testicular tumors are relatively rare in the pediatric age group.

•They account for only 1–2 % of all Pediatric Solid Tumors.

•Children represent only 2–5 % of all patients with testicular cancer.

•The exact incidence of testicular cancer is not known but it has been estimated at 5.5 cases per 100,000 men per year.

•Others reported an incidence of testicular cancer of 2.75–8 per 100,000 men per year.

•Testicular cancer rates are lowest in Asian and African populations, at less than 1 case per 100,000 men per year.

•Testicular cancer rates are highest in developed European countries at eight to nine cases per 100,000 men per year.

•Testicular tumors are more common in whites with a white-to-black incidence ratio of approximately 5:1.

•The highest rates of prevalence of testicular cancer is in Scandinavia, Germany, and New Zealand.

•Testicular cancers are considered the most common cancer in males aged 20–39 years.

•The median age for diagnosis of testicular cancer has been reported at 33 years.

•Testicular cancer is rarely seen before the age of 15 years.

•In the pediatric age group, the annual incidence of testicular cancer is approximately 1 in 100,000 male children per year.

•Others reported the incidence of testicular tumors in children to be only 1.6 per 1 million children-years.

•Testicular tumors are rare in children compared with testicular tumors occurring postpubertally or with other genitourinary tumors in childhood such as Wilms tumor (Figs. 27.1 and 27.2).

•The majority of testicular tumors occur in children <2 years of age.

•75 % of testicular tumors occur before age

2.5 years.

•Benign Tumors Account for 38 % of all testicular tumors.

•However, there is actually a bimodal age distribution for testicular tumors with a large peak in young adults and a much smaller peak in the first 3 years of life.

•This bimodal age distribution reflects more fundamental differences between prepubertal and postpubertal testicular tumors.

•These differences include the typical tumor histology in each group, the malignant potential of tumors at different ages, and the molecular biological differences between prepubertal and postpubertal tumors.

•The most striking difference between prepubertal and postpubertal tumors is the incidence distribution of different tumor types.

•Teratoma is considered the most common type in children.

•Undescended testes is a well-known risk of testicular cancer.

•Testicular cancer is two times to three times more common in boys undergoing prepubertal orchiopexy

•Postpubertal orchiopexy are two to six times more likely to develop testicular cancer than the general population.

•The relative risk of testicular cancer increases with age at orchiopexy.

•The relative risk of testicular cancer increases the higher the position of undescended testes.

•Others reported that 3.8 % of children with abdominal undescended testes, abnormal external genitalia, or abnormal karyotype develop testicular cancer.

•The relative risk of testicular cancer increases in those with bilateral cryptorchidism.

•74 % of malignancies in persistent cryptorchid testes, are seminoma.

•63 % of malignancies in post orchiopexy patients, are non-seminoma.

•There is no increased risk for tumors in the contralateral normally descended testis

•Other studies reported cancer in contralateral testis in 20 % of cases.

•Chromosomal Abnormalities (del(1p36)) are seen in 80 % of Yolk Sac Tumors

•Patients with Disorders of Sex Development (DSD) have increased incidence of testicular tumors.

•Hypovirilization and gonadal dysgenesis are at higher risk of developing testicular tumors.

•The presence of Y chromosome in gonadal dysgenesis increases the risk of testicular cancer to 10 % by age of 20.

•Intratubular germ cell neoplasia has been noted in 6 % of children with DSD.

•Germ cell testicular tumors are the most common solid tumors in men aged 15–35 years.

Testicular Cancer is Most Common Among Men Aged 15–40 Years, but it Has Three Peaks Depending on the Type

•Infants – 4 years of age: Teratomas and yolk sac tumors.

•25–40 years of age: Seminomas and nonseminomas.

•60 of age: Spermatocytic seminomas.

•The symptoms of testicular tumors may include one or more of the following:

–Testicular swelling which may or may not be painful

–Sharp or a dull aching pain in the lower abdomen or scrotum

–Heaviness in the scrotum

–Rarely, gynecomastia may develop from hormonal effects of β-hCG

–Low back pain from tumor spread to the lymph nodes along the back

–Shortness of breath and cough from metastatic spread to the lungs

•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.

•Adult germ-cell tumors with malignant potential, such as seminoma and embryonal carcinoma, are rarely seen in prepubertal patients.

•Testicular tumors are generally classified by the putative cell of origin.

•Testicular tumors are broadly classified into two main groups;

–Germ-cell tumors

–Stromal tumors

•In both children and adults, the vast majority of testicular tumors arise from germ cells.

•Seminoma, the most common germ cell tumor is considered a postpubertal tumor, although it

has been reported in patients as young as 8 years.

Germ Cell Tumors Account for 95 % of Testicular Tumors in Adult but Only 60–77 % in Children and Include

•Seminomas

•Teratomas

•Embryonal carcinoma

•Choriocarcinomas

•Yolk sac tumors

•Mixed tumors.

•Seminomas comprise approximately 50 % of all germ cell tumors.

•Seminomas are generally believed to arise from the germinal epithelium of the seminiferous tubules because “seminoma cells” are morphologically similar to spermatogonia and also because seminomas are frequently found within the seminiferous tubules in early stages.

•Seminoma is confined to the testis in 85 % of patients at presentation.

•Unlike the nonseminomatous germ cell tumors, pure seminoma tends to remain localized or tends to involve only lymph nodes.

•It initially spreads to draining lymph nodes in the retroperitoneum and then spreads proximally to involve the lymphatics in the mediastinum and supraclavicular lymph nodes.

•Only rarely does pure seminoma spread hematogenously to involve lung parenchyma, bone, liver, or brain.

•Epidermoid cysts are generally considered a monodermal form of teratoma.

•Gonadoblastomas, which occur almost exclusively in the setting of disorders of sexual development, contain both germ cell and stromal elements.

•Mixed germ cell tumors which contain two or more histological types are particularly common in adolescents and adults whereas prepubertal germ cell tumors are virtually always of a single histological type.

Stromal Tumors

•Leydig cell tumor

•Sertoli cell tumor

•Juvenile granulosa cell tumor

•Testicular tumors may also be classified based on their clinical behavior as benign or malignant.

•Seminoma, embryonal carcinoma, choriocarcinoma and yolk sac tumors are malignant.

•Teratomas, which are uniformly benign in children, are often malignant in adults.

•Histologically, teratoma is often pure with diploid DNA content containing all three embryological germ layers (ectoderm, mesoderm, and endoderm).

•The most common germ-cell tumors are teratomas and yolk-sac tumors, which account for about 62 % and 26 % of testicular tumors, respectively.

•Some series report that teratomas, which most believe are vastly underreported because of their benign nature, may account for almost 50 % of prepubertal testicular tumors.

•However, in tumor registries, yolk-sac tumors are more common than teratomas, perhaps reflecting a reporting bias.

•Prepubertal teratomas account for less than 30 % of testicular germ-cell tumors in children and are uniformly benign.

•Most stromal tumors are benign, though occasionally malignant behavior is seen, particularly in older patients.

•The large majority of testicular tumors in adolescents and adults are malignant germ cell tumors – most commonly mixed germ cell tumors with pure seminomas occurring in older men.

•In contrast, the most common germ cell tumor in children is a benign teratoma.

•The most common malignant tumor in children is a yolk sac tumor, which is very rare in its pure form in post-pubertal patients.

•Overall, approximately 75 % of testis tumors in prepubertal patients are benign.

•Molecular biological and histological studies further support the distinct nature of prepubertal and postpubertal testis tumors.

•For example, chromosome 12 abnormalities are seen in nearly all adult malignant germ cell tumors, but are not seen in prepubertal yolk sac tumors which display abnormalities in other chromosomes.

•Intratubular germ cell neoplasia (ITGCN) which is frequently seen in the testicles of men with malignant germ cell tumors, does not occur in the setting of prepubertal yolk sac tumor.

•ITGCN is also generally absent in prepubertal testicles harboring a teratoma, while 88 % of testes removed for adult teratoma contain areas of ITGCN.

•These differences in histological distribution and clinical behavior have led to a divergence in the management strategies for prepubertal and postpubertal tumors.

•In children, a testis-sparing approach is becoming more common given the high incidence of benign tumors in this population.

•When a malignant tumor is identified, orchiectomy and observation with very selective use of chemotherapy has become the standard approach; retroperitoneal lymph node dissection (RPLND) and radiation therapy play a very limited role.

•Gonadal stromal tumors are significantly less common than germ-cell tumors (i.e. tumors of non–germ-cell origin) and primarily include juvenile granulosa-cell tumors, Leydig-cell tumors, and Sertoli-cell tumors.

•The vast majority (85 %) of yolk-sac tumors in children present as clinical stage I disease, compared with only 35 % in adults.

•An intratesticular lesion should be considered a malignancy unless proven otherwise.

•Scrotal sonography localizes the lesion and distinguishes a solid from a cystic mass.

•It can be extremely helpful in detecting small lesions within the testis, but its findings are not specific and by itself cannot exclude malignancy.

•A biopsy should not be performed, as it raises the risk of spreading cancer cells into the scrotum.

•Inguinal orchiectomy is the preferred method to treat testicular cancer.

•The lymphatic system of the scrotum is linked to the lower extremities, while the testicle lymphatics drain to the retroperitoneum.

•A transscrotal biopsy or orchiectomy will potentially lead to spread of cancer cells in the scrotum and subsequent spread to the inguinal nodes and further, while in an inguinal orchiectomy only the retroperitoneal route of spread exists.

•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.

•Retroperitoneal lymph node dissection is reserved for children with persistent retroperitoneal lymphadenopathy or increased serum tumor markers after orchiectomy and chemotherapy.

•Testis-sparing surgery with frozen section is a reasonable consideration for this and other benign prepubertal tumors. No follow-up is recommended for prepubertal teratomas, whereas postpubertal patients should be monitored into adulthood.

•Tumor excision without orchiectomy is particularly attractive in prepubertal patients because most tumors are benign in this population.

•An elevated AFP level in a child over 1 year of age virtually always reflects the presence of a yolk sac tumor and precludes a testis-sparing approach.

•For a testis-sparing approach, the testis is delivered into the inguinal incision (the cord having been occluded with a non-crushing clamp or vessel loop), the field is draped off with towels and the tunica vaginalis is opened. The tumor is excised or enucleated and sent for frozen section. If a benign histology is confirmed, then the testicular defect is closed with absorbable suture and the testis is returned to the scrotum. If a malignancy is detected, or the frozen section is nondiagnostic, then an orchiectomy is performed. Reports from small series suggest that this approach is safe and is effective in preserving testicular tissue.

•The lesions successfully treated with tumor enucleation (Testis-sparing surgery) included teratomas, epidermoid cysts, Sertoli cell tumors, and Leydig cell tumors.

•Adjuvant therapy:

–Following excision of the primary tumor, universally benign tumors require no further evaluation or treatment.

–Treatment options for potentially malignant tumors include surveillance, chemotherapy, retroperitoneal lymph node dissection (RPLND), and radiation therapy.

–Virtually all germ cell tumors are sensitive to platinum-based multiagent chemotherapy which plays a major role in their management.

–RPLND plays an important staging and therapeutic role for mixed germ cell tumors in adolescents, but is rarely employed in cases of prepubertal yolk sac tumor.

–Radiation therapy is primarily used in treating seminoma – a very rare tumor in the pediatric population. The specific adjuvant therapy for a given patient is dependent on tumor histology and stage.

•Testicular cancer has one of the highest cure rates of all cancers:

–If the cancer did not spread outside the testicle, the 5-year survival rate is 99 %.

–If the cancer has grown into nearby structures or has spread to nearby lymph nodes, the 5-year survival rate is 96 %.

–If the tumor has spread to organs or lymph nodes away from the tumor, the 5-year survival rate is around 74 %.

27.2Classification of Testicular Tumors

•The most striking difference between prepubertal and postpubertal tumors is the incidence distribution of different tumor types.

•Testicular tumors are generally classified according to the cells of origin.

•Germ cell tumors include:

–Seminoma

–Embryonal carcinoma

–Choriocarcinoma

–Yolk sac tumor

–Teratoma. Epidermoid cysts are generally considered a monodermal form of teratoma.

•Stromal tumors include:

–Leydig cell tumor

–Sertoli cell tumor

–Juvenile granulosa cell tumor.

•Gonadoblastomas, which occur almost exclusively in those with disorders of sexual development, contain both germ cell and stromal elements.

•Mixed germ cell tumors which contain two or more histological types are particularly common in adolescents and adults whereas prepubertal germ cell tumors are virtually always of a single histological type.

•Testicular tumors may also be classified based on their clinical behavior as benign or malignant.

•Malignant testicular tumors include:

–Seminoma

–Embryonal carcinoma

–Choriocarcinoma

–Yolk sac tumors

–Teratomas are universally benign in prepubertal patients, but may behave in a malignant fashion in adolescents and adults.

•Benign testicular tumors include:

–Most stromal tumors are benign, though occasionally malignant behavior is seen, particularly in older patients.

–The large majority of testicular tumors in adolescents and adults are malignant germ cell tumors – most commonly mixed germ cell tumors with pure seminomas occurring in older men.

–In contrast, the most common germ cell tumor in children is a benign teratoma.

–The most common malignant tumor in children is a yolk sac tumor, which is very rare in its pure form in post-pubertal patients.

–Overall, approximately 75 % of testicular tumors in prepubertal patients are benign.

•Although testicular cancer can be derived from any cell type found in the testicles, more than 95 % of testicular cancers are germ cell tumors.

•Most of the remaining 5 % are sex cordgonadal stromal tumors derived from Leydig cells or Sertoli cells.

•Correct diagnosis is necessary to ensure the most effective and appropriate treatment.

Classification of Testicular Tumors

•Testicular tumors are divided into two types:

–Primary testicular tumors

–Secondary testicular tumors

•Primary testicular tumors:

–Germ cell tumors (95 %)

•Seminomas (45 %)

•Nonseminomas (50 %)

–Mixed germ cell tumors (40 %)

–Teratoma and teratocarcinomas (30 %)

–Embryonal cell tumor (20 %)

–Choriocarcinoma (1 %)

–Yolk sac tumors (endodermal sinus tumors)

–Non-germ cell tumors (5 %)

•Stromal Leydig cell tumors

•Sertoli cell tumors

•Gonadoblastoma

•Mixed Germ cell tumors

•Secondary testicular tumors:

–Lymphoma, leukemia, and melanoma are the most common malignancies that metastasize to the testicle.

•Testicular tumors are also classified into:

–Primary testicular tumors

–Secondary or metastatic tumors

•The World Health Organization classification system for testicular tumors:

•Germ cell tumors

–Precursor lesions

• Intratubular germ cell neoplasia

–Unclassified type (carcinoma in situ)

–Specified types

–Tumors of one histologic type (pure forms)

• Seminoma

–Variant – Seminoma with syncytiotrophoblastic cells

•Spermatocytic seminoma

–Variant – spermatocytic seminoma with sarcoma

•Embryonal carcinoma

•Yolk sac tumor

•Trophoblastic tumors

–Choriocarcinoma

•Variant – monophasic choriocarcinoma

–Placental site trophoblastic tumor

–Cystic trophoblastic tumor

•Teratoma

–Variant – Dermoid cyst

–Variant – Epidermoid cyst

–Variant – Monodermal teratoma (Carcinoid, Primitive neuroectodermal tumor (PNET), Nephroblastomalike tumor, others).

–Variant – Teratomic with somatic-type malignancy

–Tumors of more than one histologic type (mixed forms)

•Embryonal carcinoma and teratoma

•Teratoma and seminoma

•Choriocarcinoma and teratoma and embryonal carcinoma

•Others

•Sex cord/Gonadal stromal tumors

–Leydig cell tumor

–Sertoli cell tumor

•Lipid rich variant

•Scleriosing variant

•Large cell calcifying variant

•Intratubular sertoli cell neoplasia in Peutz-Jeghers syndrome

–Granulosa cell tumour

•Adult type

•Juvenile type

–Thecoma Fibroma Group

–Sex cord/gonadal stromal tumor – incompletely differentiated

–Sex cord/gonadal stromal tumour – mixed types

•Thecoma

•Fibroma

•Mixed Germ Cell and Sex Cord/Gonadal Stromal Tumors

–Gonadoblastoma

–Germ cell-sex cord/gonadal stromal tumour, unclassified

•Miscellaneous tumors of the testis

–Carcinoid

–Tumors of ovarian epithelial types

•Serous tumour of borderline malignancy

•Serous carcinoma

•Well differentiated endometrioid tumour

•Mucinous cystadenoma

•Mucinous cystadenocarcinoma

•Brenner tumour

–Nephroblastoma

–Paraganglioma

•Haematopoietic tumors

•Tumors of collecting ducts and rete

–Adenoma

–Carcinoma

•Tumors of the paratesticular structures

–Adenomatoid tumour

–Malignant and Benign Mesothelioma

–Adenocarcinoma of the epididymis

–Papillary cystadenoma of the epididymis

–Melanotic neuroectodermal tumour

–Desmoplastic small round cell tumour

•Mesenchymal tumors of the spermatic cord and testicular adnexae

–Lipoma

–Liposarcoma

–Rhabdomyosarcoma

–Aggressive angiomyxoma

–Angiomyofibroblastoma-like tumour (see Myxoma)

–Fibromatosis

–Fibroma

–Solitary fibrous tumour

–Others

•Secondary tumors of the testis

•The most common type of testicular tumor in children is the germ cell tumors.

•Endodermal sinus tumor (yolk sac tumor) and teratomas are the most common germ cell tumors among all testis tumors in children.

•These tumors present with a malignant behavior sometimes. These tumors spread to the lung, retroperitoneal lymph nodes, bone, or the central nervous system.

•The most common malignant tumor is usually the endodermal sinus tumor in children.