This document was drafted August 2023. This document will continue to be periodically updated to reflect the growing body of literature related to this topic.

KEYWORDS: Children, Adolescents, Germ Cell Tumor, Pediatric, Oncology, Rhabdomyosarcoma, Renal Tumor, Testicular Tumor, Wilms Tumor, Bladder Tumor, Late Effects

Learning Objectives:

At the end of medical school, the medical student will be able to…

1. Describe the epidemiological features of the most common pediatric genitourinary cancers
2. Discuss the basics of evaluations and treatments for the different tumors types

Introduction

Diagnosing and managing genitourinary cancer in children and adolescents requires a distinct knowledge base compared to cancers in adults. In this review, we summarize the information relevant to medical students on the topic of pediatric genitourinary cancers.

Wilms tumor

Wilms tumor (nephroblastoma) is the most common renal tumor in children, occurring typically in ages 3 to 4 years old. It is most commonly noted when a large abdominal mass is palpated or when the child has gross hematuria. About 5% of Wilms tumors are bilateral. In children with predisposition syndromes, tumors may occur earlier and in both kidneys. Syndromes associated with Wilms tumor development include isolated hemihypertrophy, Beckwith-Wiedemann syndrome (BWS), Denys-Drash syndrome (associated with differences in sexual differentiation), WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and developmental delay), Perlman syndrome, Sotos syndrome, and Simpson-Golabi-Behmel syndrome.

Diagnosis and Staging: Diagnosis begins with a thorough medical history, physical examination, and imaging studies such as ultrasound, computed tomography (CT) scan of the chest/abdomen/pelvis, and magnetic resonance imaging (MRI). Once a suspected Wilms tumor is identified, a biopsy is usually not recommended before surgery due to the risk of tumor spillage and because of the high likelihood that Wilms tumor is the diagnosis. In children with less typical presentations, biopsy may be considered. In the United States, the collaborative working group NWTS (National Wilms Tumor Study) hosted large-scale, multicenter studies that improved the overall 5-year survival for Wilms tumor patients with favorable histology to over 90%, and helped establish current Children’s Oncology Group (COG) guidelines. COG guidelines endorse the upfront surgical removal of the tumor, usually through complete nephrectomy. The use of nephron-sparing surgery (partial nephrectomy) for unilateral Wilms tumor remains hotly debated but can be considered in some patients. Children with Stage V (bilateral) disease typically receive upfront chemotherapy followed by bilateral nephron-sparing surgery (though unilateral nephrectomy is necessary in some cases). The surgical approach for Wilms Tumor is transperitoneal, typically through a midline or hemichevron/chevron incision, and lymph nodes must be sampled for proper staging. A full lymph node dissection is not currently mandated, though research is ongoing to determine the number and extent of lymph node resection. Palpation of the contralateral (uninvolved) kidney is no longer necessary given the uniquity of high-quality, thin-slice CT scans. Extreme care should be taken intraoperatively to avoid spill (intraoperative tumor rupture), as this requires an escalation in postoperative therapy.

Staging is crucial to determine the extent of disease spread and to guide treatment decisions. Wilms tumor staging involves assessing the tumor's size, location, presence of lymph node involvement, and distant metastasis. Recently, loss of heterozygosity of chromosomes 1p or 16q, and 1q gain, have also emerged as prognostic factors for favorable histology Wilms tumors.

Table 1: Children’s Oncology Group Staging and Risk Stratification for Wilms Tumor

Adapted from the NCCN Guidelines (nccn.org).

N.B.: Tumor in the adrenal gland is considered Stage III if the adrenal gland is separately resected, but when the adrenal gland is resected en bloc with the involved kidney, staging depends on the other criteria.

Treatment: The NCCN guidelines (see REFERENCES) outline treatment approaches based on risk stratification.

Low-Risk: For tumors with favorable histology and limited disease spread, surgery alone is often sufficient. Chemotherapy may be considered after surgery to reduce the risk of recurrence.

Intermediate-Risk: Surgery is still the primary treatment, but chemotherapy before surgery (upfront chemotherapy) may be recommended to shrink the tumor and facilitate surgery. Postoperative chemotherapy is also given to decrease the risk of recurrence.

High-Risk: This category includes tumors with anaplastic histology or extensive disease spread. Treatment usually involves neoadjuvant chemotherapy followed by surgery and intensive postoperative chemotherapy. Radiation therapy may also be considered in specific cases.

Follow-Up: After completing treatment, regular follow-up visits are essential to monitor for potential recurrence and long-term effects of treatment. These visits include physical examinations, imaging studies, and laboratory tests. The frequency of follow-up visits decreases over time if no signs of recurrence are observed. Survivors of Wilms tumors require lifelong monitoring due to the risk of late effects from treatment, such as kidney and heart problems. Long-term survivorship care focuses on addressing potential medical, emotional, and social challenges.

Other Considerations: Guidelines emphasize individualized treatment plans, considering factors such as age, tumor biology, and patient response to treatment. Multidisciplinary collaboration between pediatric oncologists, surgeons, pathologists, and radiologists is crucial to providing optimal care.

Other renal tumors

Pediatric renal tumors beyond Wilms tumors encompass a diverse group of malignancies. Renal cell carcinoma (RCC) is the second most common renal tumor in pediatric patients. In patients >12 years old, RCC associated with a genetic predisposition should be suspected (Table 2). Other rare renal tumor include rhabdoid tumors, which often present at a late stage and spread quickly. Congenital mesoblastic nephromas are often diagnosed early in life or in utero. These are usually curable with complete resection. Multilocular cystic nephromas are benign tumors made of cysts that can occur at any age. These are usually associated with an inherited predisposition and chest imaging should be obtain due to the frequent coexistence of pleuropulmonary blastoma.

Table 2: Genetic Alterations Associated with Renal Cell Carcinoma

Adapted from the open access article: Testa U, Pelosi E, Castelli G. Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets. Medicines (Basel). 2020 Jul 29;7(8):44. doi: 10.3390/medicines7080044. PMID: 32751108; PMCID: PMC7459851.

Genitourinary Rhabdomyosarcoma

Pediatric genitourinary rhabdomyosarcoma (RMS) is a rare and aggressive cancer that can arise anywhere in the soft tissues of the genitourinary system, including unfavorable sites (bladder and prostate) and favorable sites (paratesticular region, vagina, and uterus).

Epidemiology and risk factors: Genitourinary RMS accounts for about 5-8% of all childhood rhabdomyosarcomas occurring most often in children aged 2 to 5 years, although it can affect individuals of all ages. There is no clear gender predilection. Certain genetic syndromes, such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and DICER1 mutations, may increase the risk of genitourinary RMS.

Clinical presentation and evaluation: Depending on the affected organ and tumor size, the presentation might vary. Hematuria, increased frequency of urination, and pelvic or abdominal pain are typical symptoms. A palpable mass may occasionally be found during a physical examination. Since these symptoms can match those of other benign disorders, an early diagnosis can often be difficult, and a high index of suspicion must be maintained.

Diagnostic evaluation: Imaging tests such as ultrasound, MRI, or CT scans are frequently used as the first step in the diagnosis followed by possible biopsy. Rhabdomyosarcoma cells, identified by their spindle-shaped form and expression of certain molecular markers (specifically, the extent of FOXO1 fusion positivity), confirm the diagnosis.

Treatment and prognosis: The conventional method for treating genitourinary RMS is multimodal therapy, which combines chemotherapy, radiation therapy, and surgery. The exact treatment regimen is determined by the staging and clinical grouping (Table 3). Upfront radical orchiectomy is the initial treatment for paratesticular RMS (retroperitoneal lymph node dissections are reserved for children over the age of 10 years), while tumors in the bladder, prostate, vagina, and uterus are typically treated via a multimodal approach. Radiation therapy is frequently combined with surgery, though the exact therapeutic regimen is typically tailored to an individual patient’s tumor and treatment goals. Vincristine, actinomycin-D, and cyclophosphamide are the most common chemotherapy agents. The prognosis for pediatric genitourinary RMS varies depending on the location, size, and response to treatment of the tumor. Multimodal therapeutic advancements have considerably increased the overall survival rate. Long-term monitoring is necessary, though, as survivors may face side effects of the treatment such as infertility problems and secondary malignancies.

Table 3: Rhabdomyosarcoma Staging and Clinical Grouping

Adapted from the open access article: Deel MD. Advances in the management of pediatric genitourinary rhabdomyosarcoma. Transl Androl Urol. 2020 Oct;9(5):2441-2454. doi: 10.21037/tau-20-480. PMID: 33209718; PMCID: PMC7658124.

Testis tumors

Testis tumors are relatively rare (1-2% of all pediatric solid tumors) and typically occur at two timepoints – between ages 2-4 years and again around puberty. Primary tumors are divided into two types based on the cell of origin: germ cell tumors and non-germ cell tumors, the former comprising the majority (~95%). Risk factors for germ cell tumors include undescended testicles (cryptorchidism; Figure 1), family history, personal history of germ cell tumors, and a precancerous lesion called germ cell neoplasia in situ. Early (pre-puberty) correction of undescended testicles with a surgery called orchiopexy might reduce the future risk of germ cell tumors. More than half of these tumors in children and adolescents are benign, with pre-pubertal mature teratoma being the most common benign tumor.

Figure 1: Undescended testicle

Diagnosis and staging: The most common presentation is a painless mass in the testicle itself. There might be other systemic symptoms depending on the type of non-germ cell tumor (see below) and if the germ cell tumor has spread beyond the testicle (metastasis). Initial evaluation typically consists of a physical exam, tumor markers, and a scrotal ultrasound. Tumor markers include AFP, β-hCG, and LDH which might be elevated for some germ cell tumor. Some markers are specific to certain tumor histologies (Table 4). Their decline after surgery indicates potential cure with tumor removal alone. LDH is the most non-specific of these markers. Hormones might also be assessed for some non-germ cell tumors. If the scrotal ultrasound suggests a malignant tumor, patients will undergo staging imaging with CT of the chest, abdomen, and pelvis. The most common site of metastatic spread for germ cell tumors would be the lymph nodes in the retroperitoneum (Figure 2). A general description of staging is noted in Table 5.

Figure 2: Testicular Cancer Spread and Staging

Table 4: Serum Tumor Markers and Associated Germ Cell Tumors

Table 5: Children’s Oncology Group Germ Cell Tumor Staging System

Germ cell tumors: Germ cell tumors are divided into seminoma and non-seminoma tumors. Management typically includes partial or radical orchiectomy depending on the histology. Treatment for metastatic disease follows National Comprehensive Cancer Network guidelines including potential radiation, chemotherapy, or surgical removal of metastatic disease. Follow-up for malignant tumors would consist of regular self-exams, history and physical examinations, and periodic abdominal and chest imaging.

Seminoma is uncommon in pediatric patients except for rare patients with differences of sexual development. These would commonly treated with radical orchiectomy and serial monitoring. Pure seminoma tumors might be accompanied by a rise in β-hCG, but a rise in AFP would indicate the presence of another tumor type.

Teratoma is the most common pediatric testicular tumor and is usually benign in pre-pubertal children. Tumor markers are negative and in pre-pubertal children with small masses, partial orchiectomy can be considered if the benign pathology can be confirmed by pathology.

Of the other malignant germ cell tumors, yolk sac tumors are the most common and these commonly occur in boys less than 2 years of age. Another potential tumor type includes epidermoid cysts which are cyst-like on ultrasound and can be removed with partial orchiectomy.

Non-germ cell tumors: Non-germ cell tumors, also known as gonadal stromal tumors are usually benign and might associate with various symptoms (e.g., deep voice, precocious puberty, genital hair growth) depending on if they secrete hormones. These tumors are usually treated with removal alone (complete or partial orchiectomy) and monitoring hormone levels to assure after surgery to ensure complete resection. Leydig cell tumors produce testosterone and thus patients might present with early puberty features. These are typically benign. Sertoli cells are related to sperm production in males and tumors of this cell type are less common than Leydig cell tumors.. Leukemias and lymphomas might also manifest in the testis and should be considered in patients with a history of these neoplasms as the testis is considered a “sanctuary site” for tumor cells after chemotherapy. Finally, testicular microlithiasis is a common finding of calcifications on scrotal ultrasound and does not portend an increased risk of future germ cell tumors; while many testicular tumors are associated with microlithiasis, the converse was not found to be true in a large-scale study.

Bladder Tumors

Bladder tumors are quite rare in the pediatric population but should be considered when a mass is seen sonographically or with gross hematuria. Bladder tumors in children are often low-grade and are typically treated with transurethral resection. The need for additional therapies and the timing of periodic surveillance is determined by histologic evaluation.

Late Effects and Survivorship

As survival has improved for pediatric cancers, there has been an increased emphasis on survivorship, or optimizing a survivor’s health after completion of treatment for cancer. Late effects after pediatric cancer treatment fall into three broad categories: chronic health conditions that develop secondary to the treatment itself, new that arise due to cancer treatment, and alterations in fertility owing to the primary disease or the treatment. Oncofertility offers children with cancer options to optimize their fertility. A detailed discussion of oncologic late effects is beyond the scope of this section, but late effects can be observed in nearly every organ system. Common late effects include renal insufficiency, hypertension, cardiac issues, pulmonary issues, dental issues, musculoskeletal issues, and mental health concerns.

Conclusions

The body of information on the topic of pediatric genitourinary oncology is distinct from that of adult oncology. General familiarity with these tumors types, clinical presentations and general management will aid the entire medical community in improving care for these patients.

References

Guideline Statement Executive Summary Introduction Initial Management Staging Management Additional Survivorship Future Directions Abbreviations References Diagnosis and Treatment of Early Stage Testicular Cancer: AUA Guideline (2019)
https://www.auanet.org/guidelines-and-quality/guidelines/testicular-cancer-guideline

Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow Up (2021)
https://www.auanet.org/guidelines-and-quality/guidelines/renal-mass-and-localized-renal-cancer-evaluation-management-and-follow-up

NCCN Guidelines: Wilms Tumor (Nephroblastoma) Version 1.2023
https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1500

NCCN Guidelines: Kidney Cancer Version 1.2024
https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440

NCCN Guidelines: Testicular Cancer Version 1.2023
https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1468

NCCN Guidelines: Soft Tissue Sarcoma Version 2.2023
https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1464

Authors

2023
Adam B. Weiner, MD
Los Angeles, CA
Disclosures: Nothing to disclose

Kathleen Keiran, MD
Seattle, WA
Disclosures: Nothing to disclose

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