NEUROBLASTOMA INFANCY CHILDHOOD TUMOR

Neuroblastoma is the most common solid tumor of infancy and childhood. Most appear during the first five years of life; over half occur in children under 2 years of age. Two-thirds of children over 2 years of age have disseminated disease at presentation. Neuroblastomas can occur at any site where neural crest tissue is found in the embryo and are derived from primordial neural crest cells and neuroblasts migrating from the mantle layer of the developing spinal cord into the sympathetic ganglion chain and the adrenal medulla. The etiology is unknown. About three-fourths of neuroblastomas arise in the abdomen; half of these originate in the adrenal gland. About 20% occur in the posterior mediastinum. Other uncommon sites include the pelvis (4%), and the neck (4%). It's a solid, highly vascular tumor with a friable pseudocapsule.

Staging:
Stage I- tumor limited to organ of origin.
Stage II- regional spread that does not cross the midline.
Stage III- tumor extending across the midline.
Stage IV- distant metastasis.
Stage IV-S patients with a small primary and metastases limited to liver, skin, or bone marrow without radiographic evidence of bone metastases.

The clinical presentation is an abdominal mass (50-75%), hypertension (25%), weight loss, diarrhea,fever, bone pain. Rare: "opso-myoclonus" (dancing eye syndrome), Horner's syndrome, Panda's eyes, VIP syndromes.

Diagnostic work-up includes: IVP, ultrasound, chest films, KUB (fine stipple calcifications 50%), skull x-rays, urinalysis, CBC, Urine VMA, HVA, and bone marrow aspirate. Other markers: cystathione, homoserine, neuron-specific enolase and ferritin.

The surgical goal is complete removal of the tumor when possible. Unfortunately, metastases are present in 60-90% of patients at diagnosis. Even in these patients attempts to reduce the bulk of tumor is important. Further treatment with radiation and chemotherapy depends on stage and extent of metastases.

There is a 100% survival for stage I, although this stage is extremely rare. Survival for stage II is 75%, stage III is 35%, stage IV 10-20%, and stage IV-S is about 80%. Age is an important prognostic factor, with 75% survival in children less than one year; 50% in children 1-2 years of age; 25% in children 2-3 years of age, and 15% in children over 3 years. Other prognostic factors are related to stage, nutritional status, site of primary, maturity state of tumor, VIP tumor (+), positive lymph nodes (-), high ferritin, NSE, and Diploid DNA levels(-).

Routine use of prenatal sonography will increase the incidental diagnosis of fetal neuroblastoma. Most are detected during the third trimester of pregnancy as cystic/solid suprarenal mass. The tumor does not cross the placenta but can metastasize in utero to the fetal liver or placenta. After birth 50% of babies have elevated HMA/VMA levels. Most enjoy improved survival due to: lower stage of disease, cystic variety (in-situ), and higher stage IV-S (which has been associated with spontaneous immuno-regression. Adverse biologic features are: diploid tumor karyotype (cytometry) and amplify N-myc oncogene. They can be very difficult to differentiate from neonatal adrenal hemorrhage; T2 of MRI can be of help. Are they neuroblastoma in-situ, and will they regress spontaneously without treatment are question waiting answer in the near future.

Neuroblastoma (NB) in early stages of development (stage I & II) benefits from surgical excision. The role of surgery in the management of neuroblastoma stage III tumor (tumor infiltrating across the midline with or without lymph node involvement) is controversial. Many variables enter the formula of determining risk of disease, i.e., age, site, stage, N-myc status, DNA diploidy and Shimada classification to mention a few of the most important. Some reports have independently found that stage III managed initially with chemotherapy and radiotherapy and is responding benefits from eventual complete tumor excision despite site, age or histology.

Complete surgical excision as determine by free margin of tissue has a significant survival advantage overall. Preop chemotx converts a friable tumor into a firmer, more mature and easily resectable tumor. Surgical complications in advance stages are higher (bleeding, nephrectomy, adjacent organ removal, infection). Some have found that complete resection is not needed in biologically favorable children with NB less than one year of age. Biologically unfavorable patients one year of age or greater who undergo gross surgical resections has improved survival. Defining subgroups of patient with poor prognostic biologic markers and histology to decide whether surgery or bone marrow transplant is the next best option is pending trial randomization and study.

Stage IV Neuroblastoma (metastatic NB) refers to high risk group of children with the primary tumor in the adrenal gland, mediastinum or pelvis associated with disease progression in other sites (bone marrow, cortical bone, liver, lymph node). Role of surgery in stage IV NB is controversial. Cure will require control of the primary tumor and elimination of metastatic disease. For infants with metastatic NB a more than 95% resection has been found adequate surgical treatment either initially or after effective chemotherapy. Adding ipsilateral lymph node dissection does not appear to affect survival. Delayed surgery after several courses of chemotherapy may be as effective as initial resection and is associated with fewer complications statistically.

Resection without induction chemotx results in significant blood loss. High risk NB usually invades blood vessels and surrounding structures precluding resection. Intensive preop chemotherapy reduces tumor size and invasiveness allowing surgical removal. A fibrotic capsule forms with less blood supply to the tumor. Stage IV NB is best managed with initial chemotx until distant metastasis are controlled followed by primary gross tumor removal (even in the face of significant tumor reduction) and completion chemotx. Gross complete resection is best accomplished when a good partial response is obtained. Radiotx is added to unresectable lesions. Even when chemotx changes the tumor histology (Shimada) from unfavorable to favorable this does not improve overall outcome. Resection is not confounded by biology of the tumor (n-myc status). Survival is improved with kidney preservation during surgery. Local control of disease is a prerequisite for successful bone marrow transplantation.