NEUROBLASTOMALYNDON WOYTUCKMBBS4 PROGRAMME AT ST GEORGE’S UNIVERSITY OF LONDON DELIVERED BY THE UNIVERSITY OF NICOSIASHEBA MEDICAL CENTER AT TEL HASHOMER

CELLULAR

• Neuroblasts are pluripotent stem cells of the nervous system

• These cells migrate along the neuraxis to populate various sites, with tumours presenting in adrenal medulla (40%), paraspinal ganglia (25%), thoracic (15%), pelvic (5%), cervical (3%), and miscellaneous (12%)

• Neural crest tumours can be classified as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, depending on the degree of maturation and differentiation of the tumour.

Histology: Top right - neuroblastoma: A monotonous population of hyperchromatic cells with scant cytoplasm. Bottom left - ganglioneuroblastoma: Increased schwannian stroma. Bottom right - ganglioneuroma: Mature ganglion cell with schwannian stroma.

GENETIC

• MYCN oncogene is overexpressed via amplification of the distal arm of chromosome 2 in approximately 25% of de novo cases and is more common in patients with advanced-stage disease, with rapid tumor progression and poor prognosis• Short arm deletions of chromosome 1 are the most common chromosomal

abnormality present in neuroblastoma and confer a poor prognosis. The 1p chromosome region likely harbours tumor suppressor genes or genes that control neuroblast differentiation• hyperdiploidy (DNA index >1) has a good therapeutic response to

cyclophosphamide and doxorubicin, with better prognosis

PROGNOSIS AT PRESENTATION• Infants more commonly present with thoracic and cervical tumors, whereas older children more

frequently have abdominal tumors.• ~70-80% of patients >18 months present with metastatic disease

• lymph nodes, liver, bone, and bone marrow

• Patients with localized tumours have an 80-90% 3-year event-free survival [EFS] rate • <50% with metastasis are cured, even with the use of high-dose therapy followed by autologous

bone marrow or stem cell rescue.• Generally, >50% of patients present with metastatic disease at the time of diagnosis, 20-25%

have localized disease, 15% have regional extension, and approximately 7% present during infancy with disseminated disease limited to the skin, liver, and bone marrow (stage 4S).

• The 3-year EFS for high-risk patients, those with disseminated disease, treated with conventional chemotherapy, radiation therapy, and surgery is less than 20%. • Differentiating agents and dose intensification of active drugs, followed by autologous bone marrow transplant,

have been reported to improve the outcome for these patients, contributing to an EFS of 38%. A single-arm study of tandem stem cell transplantation: 3-year EFS of 58%, with other ongoing randomized studies

EPIDEMIOLOGY

• 7.8% of childhood cancers in the United States• Incidence ~9.5 cases per million children (highest among high income countries)• Incidence white>black children• Sex: male-to-female ratio 1.2:1.• Age: Incidence decreases every consecutive year up to age 10 years, after which the

disease is rare• The survival rate 5 years from diagnosis is approximately 83% for infants, 55% for children

aged 1-5 years, and 40% for children older than 5 years• 40% of patients are at <1year, 35% at 1-2 years, and 25% >2 years old when diagnosed.

PRESENTATION• Pain or palpable mass• May present with abdominal distension• Other symptoms dependent on local mass effect• emesis, weight loss, anorexia, fatigue, and bone pain. Hypertension is an uncommon sign of the disease and is generally caused by

renal artery compression, not catecholamine excess. Chronic diarrhea is a rare presenting symptom secondary to tumor secretion of vasoactive intestinal peptide secretion. bone pain and a limp. However, patients may also present with unexplained fever, weight loss, irritability, and periorbital ecchymosis secondary to metastatic disease to the orbits. The presence of bone metastases can lead to pathologic fractures. neurologic symptoms, including weakness, limping, paralysis, and even bladder and bowel dysfunction. mild airway obstruction or chronic cough Horner syndrome metastatic disease confined to the liver, skin, and bone marrow (stage 4S). If this type of tumor develops in neonates, skin lesions may be confused with congenital rubella, and, if the patient has severe skin involvement, the term "blueberry muffin baby" may be used.

• Approximately 2% of patients present with opsoclonus and myoclonus a paraneoplastic syndrome characterized by the presence of myoclonic jerking and random eye movements. These patients often have localized disease and a good long-term prognosis. Unfortunately, the neurologic abnormalities can persist or progress and can be devastating.

• Finally, intractable diarrhea is a rare paraneoplastic symptom and is associated with more differentiated tumors and a good prognosis.

EXAMINATION

• Children are usually referred to a pediatric oncologist by primary care providers who have identified a persistent unexplained symptom or sign, either upon physical examination or based on screening test findings.

• In patients with suspected neuroblastoma, performing a thorough examination with careful attention to vital signs (eg, blood pressure), neck, chest, abdomen, skin, and nervous system is essential.

• Metastatic lesions of the skin are common in infants younger than 6 months and may represent stage 4S disease.

• Examination of the abdomen may reveal an abdominal mass, leading to the appropriate workup.• Neurologic examination may reveal Horner syndrome. In the case of dumbbell tumors, compression of

the spinal cord may produce lower extremity weakness or paraplegia. Patients with neurologic involvement by tumor should be treated emergently, secondary to the risk of permanent neurologic sequelae.

DIFFERENTIAL

• For an intra-thoracic neuroblastoma consider:• intrathoracic lymphoma• extra lobar pulmonary sequestration• round pneumonia• ganglioneuroma• ganglioneuroblastoma• For an intra-abdominal neuroblastoma consider:• ganglioneuroma• ganglioneuroblastoma• rhabdomyosarcoma• Wilms tumour

INVESTIGATION

• CBC count and differential (Anemia or other cytopenias suggest bone marrow involvement.)• Urine collection for catecholamines (VMA/HVA) and UAA single sample or collected urine test for VMA/HVA is

highly accurate in CLIA approved laboratories. Centers usually send samples to a specialty laboratory and/or perform a timed collection of urine.

• A urinary catecholamine level is considered to be elevated if it is 3 standard deviations higher than the age-related reference range levels.

• Serum creatinine• Liver function tests• Electrolytes• Calcium, Magnesium, Phosphorus, Uric acid; • Serum lactate dehydrogenase (LDH); Ferritin; Thyroid-stimulating hormone (TSH), T4; Immunoglobulin (Ig)G

levels

INVESTIGATION

• Xray: typically demonstrating an intrathoracic or intraabdominal soft-tissue mass. Pressure on adjacent bones may cause remodelling of ribs, vertebral bodies or pedicle thinning. Up to 30% may have evidence of calcification on the plain film. Skeletal metastases usually ill-defined and lucent, with periosteal reaction or metaphyseal lucency.

• Ultrasound: Neuroblastoma on ultrasound demonstrates a heterogeneous mass with internal vascularity. Often there are areas of necrosis that appear as regions of low echogenicity. Calcification may or may not be evident on ultrasound

• CT:tumour typically is heterogeneous with calcifications seen in 80-90% of cases2. Areas of necrosis are of low attenuation. May usually displace tissues or invade. Commonly lymph node enlargement

• MRI: superior to all other modalities in assessing the organ of origin, intracranial or intraspinal disease and bone marrow disease

• MIBG (metaiodobenzylguanidine labeled to Iodine123) 95% of neuroblastomas secrete catecholamines, however, 30% of neuroblastomas are negative on MIBG: sensitivity: 88%, specificity: 99% (for sympathetic tissue)

MANAGEMENT• Medical: Cooperative Group Treatment Strategies – Low, intermediate and high risk stratification: Vincristine, cyclophosphamide, and doxorubicin

• Carboplatin and etoposide• Cisplatin and etoposide• Ifosfamide and etoposide• Cyclophosphamide and topotecan

• Consolidation regimens used in neuroblastoma include the following:• Carboplatin and etoposide with melphalan or cyclophosphamide• Thiotepa and cyclophosphamide• Melphalan and total body irradiation

• In Europe, several studies have used busulfan with melphalan or cyclophosphamide. One commonly used salvage or relapse therapy regimen is the combination of topotecan and cyclophosphamide. The use or retinoids have been incorporated in maintenance regimens in the posttransplant setting. Irinotecan is also under investigation.

• Surgical: Surgical resection plays an important role in the treatment of patients with neuroblastoma. For patients with localized disease, surgical resection is curative. For patients with regional or metastatic disease, surgery to establish a diagnosis and obtain adequate samples for biologic studies is essential. Typically, second-look surgery postchemotherapy is used to attempt a complete resection. The emphasis in the second-look procedure is as complete a debulking as possible without sacrificing major organ function. Patients with residual disease postchemotherapy and surgery may benefit from the use of radiotherapy.

FOLLOW UP CARE

REFERENCES

• Radiopaedia. Neuroblastoma. Accessed from: http://radiopaedia.org/articles/neuroblastoma • Medscape. Pediatric Neuroblastoma. Accessed from: http://

emedicine.medscape.com/article/988284-overview