A. Epidemiology

Neuroblastoma is the most common extracranial solid tumor in children accounting for 8% to 10% of all childhood tumors. It is the most common malignant tumor in infancy and 89% of cases are diagnosed by 5 years of age.

B. Genetics

Neuroblastoma can be familial with an autosomal dominant mode of inheritance. Most cases are nonfamilial. Numerous chromosomal abnormalities occur in neuroblastoma in the form of chromosomal deletions, translocations, and cytogenetic evidence of gene amplification. Deletion of the short arm of chromosome 1 is found in 25% to 30% of cases and is an adverse prognostic factor. Amplification of the MYCN oncogene is seen in roughly 20% to 25% of primary tumors and is an adverse prognostic indicator.

C. Clinical Presentation

Most primary tumors arise within the abdomen and the majority present with abdominal pain or a palpable abdominal mass. Extrinsic compression of the bowel can produce symptoms. Metastasis is present in 70% of patients at diagnosis and can be responsible for a variety of symptoms. Some children present with rather unique paraneoplastic syndromes. Symptoms produced by catecholamine release may mimic those seen in pheochromocytoma.

D. Diagnosis

1. Increased levels of urinary metabolites of catecholamines, vanillylmandelic acid (VMA) and homovanillic acid (HVA) are found in 90% of patients.

2. Bone marrow involvement from metastatic tumor can produce anemia. Bone marrow biopsies and aspirates are performed to detect metastatic tumor.

3. Screening for metabolites of catecholamines has been employed widely in Japan. The goal is to detect disease at an earlier stage. Screening is successful in identification of neuroblastoma at a younger age, but there has been no decrease in the occurrence of neuroblastoma in older children and its subsequent mortality.

4. Plain radiographs may demonstrate a calcified abdominal or posterior mediastinal mass. Computed tomography (CT) and magnetic resonance imaging (MRI) provide more information about the local extent of the primary tumors and vascular involvement. MRI has advantages in the evaluation of intraspinal tumor extension. Imaging with both a radionuclide bone scan and metaiodobenzylguanidine (MIBG) scans are done for staging. MIBG scans use 131I-MIBG which is taken up by
the adrenergic secretory vesicles of the tumor cells in both primary and metastatic sites.

E. Pathology and Staging

1. Pathology

a. Autopsy examination in infants has found neuroblastoma in situ in 1 out of 224 infants. Most of these small tumors regress spontaneously as the incidence of neuroblastoma is lower. It has been suggested that overt neuroblastomas can regress spontaneously. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma display a histologic spectrum of maturation and differentiation. Ganglioneuroma may arise de novo or result from maturation of preexisting neuroblastoma.

b. The Shimada classification is an age-linked histopathologic classification. It is used to stratify patients according to tumor prognosis categorizing the tumor as stroma poor or stroma rich. Patients with stroma-poor tumors with unfavorable histopathologic features have a very poor prognosis (less than 10% survival).

2. Prognostic variables

a. Children aged 1 year or younger have an improved survival when compared with older children. This is attributed to more favorable biologic parameters in this age group.

b. Site of origin has been correlated with survival. Nonadrenal primary tumors have a better prognosis.

c. Stage of disease is one of the most important prognostic indicators. More advanced tumors, stages III and IV, require much more aggressive treatment.

d. A special category is stage IV-S. These tumors primarily occur in infants. They often have small primaries associated with liver, skin, and bone marrow involvement without radiographic evidence of bony metastases. These patients have a good prognosis with many tumors undergoing spontaneous regression.

e. n-myc amplification is associated with rapid tumor progression and a poor prognosis. n-myc amplification is found in 30% to 40% of advanced stage tumors. This is an adverse prognostic factor independent of the patient’s age or stage of disease.

3. Stage of the disease is a significant prognostic variable. It is used to determine postoperative adjuvant therapy. International Neuroblastoma Staging System Stage Extent of Disease

1 Localized tumor with complete gross excision, with or without microscopic residual disease.

2A Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.

2B Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor.

3 Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement.

4 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs.

4S Localized primary tumor with dissemination limited to skin, liver, and/or bone marrow (less than 10% tumor) in infants younger than 1 year of age.

F. Surgical Management

1. Low-risk disease (stages I, II, IV-S): Children with low-stage disease have an excellent survival with surgical excision alone. Chemotherapy is indicated only in the event of recurrence unless the child has MYCN amplification and unfavorable histology. Resection of the primary is not mandatory for infants with IV-S disease. The vast majority of these infants have tumors with entirely favorable markers, explaining their good prognosis. However, a small fraction have adverse markers, and these children should be considered for a more aggressive treatment with multimodal therapy.

2. High-risk disease (stages III, IV): There is some controversy regarding aggressive surgical resection at diagnosis. Many centers defer surgery until after completion of chemotherapy. The tumors are smaller and firmer, with less risk of rupture and hemorrhage following chemotherapy, resulting in a decreased rate of complications. Timing of surgery is generally 13 to 18 weeks after completion of therapy.

G. Postoperative Treatment

1. Chemotherapy: A variety of multi-agent treatments have been developed to treat high-risk patients. Despite marked treatment intensification, relapse continues to be a problem. The use of marrow ablative chemoradiotherapy followed by autologous marrow transplant has resulted in higher survival rates. Other modalities are being developed to target the tumor using biologic therapy.

2. Radiation therapy: Radiation therapy is primarily used for treatment for unresectable disease. Doses of external beam irradiation used have ranged between 15 Gy and 30 Gy, depending on the patient’s age, location of the tumor, and extent of residual disease.

A. Epidemiology

Rhabdomyosarcoma (RMS) accounts for 10% to 15% of all pediatric solid tumors with 20% of RMS arising in the genitourinary (GU) tract. The most common GU sites are prostate, bladder, and paratesticular. There is a bimodal age distribution with a peak incidence in the first 2 years of life and again at adolescence.

B. Genetics

The Li-Fraumeni syndrome results from germline mutations of the p53 tumor suppressor gene. Soft tissue sarcomas account for up to 20% of the tumors seen in these patients. Neurofibromatosis is an autosomal dominant disorder. The incidence of RMS is estimated to be 10% in affected individuals. Other disorders with an increased risk for RMS are multiple endocrine neoplasia type 2A and Costello, Noonan, and basal cell nevus syndromes.

C. Clinical Presentation

Presentation will vary by tumor site. Bladder and prostate tumors often have a clinical presentation of urinary obstruction. This can be stranguria or urinary retention. Hematuria is common. Physical examination will often reveal a palpable abdominal mass.

Paratesticular rhabdomyosarcoma presents as a painless scrotal mass. It is usually detected at an earlier stage due to the superficial location.

Vaginal and vulvar rhabdomyosarcoma present with a vaginal mass and/or bleeding. Prolapse of the mass from the vaginal introitus can be quite striking. This is a typical finding with the sarcoma botryoides variant.

D. Diagnosis

CT or MRI is used to stage the extent of disease. It can be difficult to determine the site of origin of pelvic tumors. This is particularly true for distinguishing bladder and prostate tumors. In paratesticular rhabdomyosarcoma it is important to assess the lymph node status. Lymph nodes are the primary site of initial extension.

E. Pathology and Staging

1. Pathology: There are three main pathologic variants of rhabdomyosarcoma. Embryonal RMS is the most common subtype and accounts for most genitourinary tumors. This type can present as sarcoma botryoides, a polypoid variety that occurs in hollow organs or body cavities such as the bladder or vagina. The botryoides variants have excellent survival. The second most common type is alveolar and has a worse prognosis. Alveolar tumors can be categorized by the presence or absence of oncogenic fusion proteins produced by chromosomal translocations. The majority of alveolar tumors are fusion-positive and have an inferior prognosis compared to fusion-negative alveolar tumors and embryonal RMS.

2. Staging: The Intergroup Rhabdomyosarcoma Study (IRS) Clinical Staging Classification is given below.

Stage 1: Favorable site^*, nonmetastatic

Stage 2: Unfavorable site, small tumor, negative nodes, nonmetastatic

Stage 3: Unfavorable site, big or positive nodes, nonmetastatic

Stage 4: Any site, metastatic.

In the genitourinary tract the testes, vagina, and uterus are more favorable than the prostate and bladder.

F. Surgical Treatment

The role or surgery will vary by site.

1. Paratesticular tumor: Initial intervention is radical orchiectomy. The tumor arises in the distal spermatic cord and may invade the testis or surrounding tissues. Retroperitoneal sampling is not recommended in children younger than 10 years of age. Children’s Oncology Group (COG) recommends that children older than 10 years of age undergo ipsilateral retroperitoneal lymph node dissection prior to chemotherapy.

2. Bladder prostate: Surgical management of a bladder/prostate primary has become more conservative. Most patients receive chemotherapy and/or radiation prior to surgery. The goal is to shrink the tumor to allow bladder preservation. With intensification of treatment, 60% of the patients now retain a functional bladder with an overall survival of 85%. Tumors that are in the periphery of the bladder can be managed with partial cystectomy. If chemotherapy does not result in adequate shrinkage to allow partial resection, a radical cystectomy may be necessary.

G. Postoperative Treatment

Multimodality therapy is used in the treatment of rhabdomyosarcoma. The primary chemotherapy is vincristine, dactinomycin, and cyclophosphamide (VAC). For higher-risk tumors, more intensive regimens have been utilized. Radiation therapy is given if the tumor fails to regress on chemotherapy. Survival rates vary by site.

1. Paratesticular: Survival of paratesticular RMS is excellent. This is due to several factors. Most of the tumors are stage I at diagnosis. More than 90% have embryonal histology. Overall 3-year survival in COG studies exceeds 90%.