Neuroblastoma -Investigation, Staging and Treatment

Neuroblastoma -most common intra-abdominal tumor in children. Most common malignancy in the first year of life. It can occur in neonates and fetus. Most common extracranial solid tumor in children. 98% are sporadic, and 2% familial.  90% are vasoactive and produce catecholamine and its derivatives, such as VMA and HVA. The most common age group  -0-5 years. The origin of cells for neuroblastoma are primitive neural crest cells. 

RISK FACTORS OF NEUROBLASTOMA

• Risk factors and associations of neuroblastoma are as follows. Neurofibromatosis-1, Hirschsprung disease, Heterochromia iridis, Fetal hydantoin syndrome, Fetal alcohol syndrome, Friedrich ataxia

FAMILIAL NEUROBLASTOMA 

• Most familial neuroblastomas have mutations in the ALK(anaplastic lymphoma kinase) gene, PHOX2B, and BARD1 genes. Deletion of chromosome 1p or rearrangement seen in 80% of cases. Associated with N-myc oncogene amplification in about 20% of cases and causes aggressive diseases. 

PATHOLOGY OF NEUROBLASTOMA

• Grossly, soft, rounded, heterogeneous masses that tan to pale grey with hemorrhage, cyst formation, punctate calcification, and necrosis.  A fibrous pseudo-capsule may be seen.

HISTOPATHOLOGY OF NEUROBLASTOMA

Histology - Solid sheets of small round blue cells. The cells may show mitotic activity, karyorrhexis, and pleomorphism.  The background has faintly eosinophilic material composed of neuritic processes of primitive neuroblasts called neuropil.  Homer-Wright pseudo rosettes- tumor cells arrange as a rosette with a neuropil in the center. Immunohistochemistry is positive for neuron-specific enolase.  Electron microscopy shows cytoplasmic granules filled with catecholamine called dense core granules.  Neuroblastoma showing hemorrhage, necrosis, and whitish calcification. 

Also Read: KAWASAKI DISEASE : History, Symptoms, Causes and Treatment

CLINICAL FEATURES OF NEUROBLASTOMA

• Constitutional features: Low-grade fever, malaise, loss of appetite, weight loss, and night sweats. Abdominal mass-It is predominant in neuroblastomas arising from the adrenal medulla, painless. Features due to the release of vasoactive peptides. The release of catecholamines causes episodes or outbreaks of hypertension, excessive sweating, diarrhea (vasoactive intestinal peptide), and autonomic dysfunction. 
• Features related to metastasis: The most common site of metastasis -bone, including the skull, long bones, and spine. The clinical features include. Bony pain and irritability, limping, Proptosis, Raccoon eyes, Vertebral collapse. The involvement of bone marrow causes cytopenia in the late stages. Due to associated syndrome or paraneoplastic syndrome.

SYNDROMES ASSOCIATED WITH NEUROBLASTOMA

Syndromes	Features
Pepper syndrome	Massive hepatic involvement with or without respiratory involvement
Horner syndrome	Ptosis, miosis, and anhidrosis Common in neuroblastoma arising from superior cervical ganglia. Symptoms do not resolve with resection in many cases
Hutchinson disease	Limping and irritability due to bony metastasis
Kerner-Morison syndrome	Intractable diarrhea due to VIP secretion Biologically favorable histology  Treatment – Octreotide, loperamide
Opsoclonus-myoclonus-ataxia syndrome Or Dancing eyes-dancing feet syndrome	Conjugate spontaneous eye movements. Myoclonic jerks of hands and feet  Cerebellar ataxia  likely immune-mediated and may not resolve upon tumor resection.  Biologically favorable and well-differentiated. May show neuropsychological sequelae.
Neurocristopathy syndrome	Associated with other neural crest disorders, including.  Hirschsprung disease Congenital hypoventilation syndrome  Neurofibromatosis-1
ROHHAD	RO -Rapid onset Obesity H-Hypothalamic dysfunction H-Hypoventilation  AD-Autonomic Dysfunction Approximately 40% have neural crest-derived tumors, including neuroblastoma.

Q. Name the syndrome that increases Will’s tumor and neuroblastoma risk.

A. Beckwith-Weideman syndrome.

It poses a 30-75% risk of Will’s tumor and 5-10% neuroblastoma in children.

Q. What are the sites of metastasis of neuroblastoma?

A. Site of metastasis- lymph nodes, bones, bone marrow, and liver.

 Pulmonary metastasis is rare in neuroblastoma. 

Also Read: The Genetics of Down Syndrome

INVESTIGATIONS OF NEUROBLASTOMA

• Gold standard tests - biopsy and immunohistochemistry.  CT scan shows supra-renal calcification. MRI shows paraspinal tumors.- Iodine-123 or 131 MIBG and PET scan for the diagnosis of metastasis. About 95% of patients show elevated tumor markers, urinary VMA and HVA.
• Old staging of neuroblastoma according to the INSS classification system. Criteria for staging are as follows. Stage 1 – localized and completely resectable tumors. Stage 2 – incompletely resectable. Stage 3 – cross the midline. Stage 4 – disseminated or metastatic.

STAGING OF NEUROBLASTOMA

• The international neuroblastoma risk-group staging system recently revised the grading criteria as follows. L1 tumors (previously classified as INSS stage 1) are localized and confined to one body compartment without any Image Defined Risk Factors (IDRF). L2 tumors (previously classified as INSS stage 2 and 3) are localized tumors with the presence IDRF. M tumors are disseminated metastasized tumors to bones, bone marrow, liver, distant lymph nodes and other organs. (Previously classified as INSS stage 4). Stage MS (previously stage 4S) is neuroblastoma in children younger than 18 months and showing spontaneous regression.

STAGE MS

• Stage MS is also called stage 4S. Mainly seen in age group <18 months. The earlier the age of incidence, the better the outcomes. The clinical features include-Widespread subcutaneous nodules, massive hepatic involvement, a small primary tumor, the involvement of bones and bone marrow is minimal, Show autoregression, excellent prognosis -survival rate >= 85%

 Also Read: Pigmentary Disorders in Children

TREATMENT FOR NEUROBLASTOMA 

• Treatment is well-defined for each stage. Low-risk - include L1, L2, and MS, and their treatment s include. Primary surgery for L1. Surgery with or without chemotherapy for L2. Observation in most; chemotherapy for severely symptomatic stage MS patients
• Intermediate risk:- stages L2 and M with favorable prognostic factors- Surgery with chemotherapy, Radiotherapy in patients with aggressive and residual disease. The high-risk group - stage M cases with unfavorable prognostic factors. Palliative surgery has scope when the tumor is large. Chemotherapy with radiotherapy. Bone marrow transplantation. Isotretinoin or 13-cis-retinoic acid. Dinutuximab: Antiganglioside GD2 monoclonal antibody has been recenlty FDA approved.

Also Read: Progeria- Pathogenesis, Clinical Features and Treatment

PROGNOSTIC FACTORS OF NEUROBLASTOMA 

Factors	Favorable	Unfavorable
Stage	1, 2A, 2B, and 4S	3 and 4
Age	Below 18 months	Above 18 months
Schwannian stroma	Present	absent
Gangliocytic differentiation	Present	Absent
Mitotic karyorrhectic index (increased proliferation and death rate)	<200 per 5000 cells	> 200 per 5000 cells
Ploidy	Hyper ploidy	Nearly diploid
Loss or deletion of 1p	Absent	Present
Loss or deletion of 11q	Absent	Present
Loss or deletion of 14q	Absent	Present
Gain of 17q	Absent	Present
N-myc	Not amplified	Amplified
Expression of TRKA	Present	Absent
Expression of TRKB	Absent	Present
Neuritogenic genes mutation (ATRX and PTPRD)	Absent	Present

If you are preparing for NEET-SS 2024 and ahead, check out SS ELITE Plan (Version 3.0) and what makes it the perfect study resource for your super speciality preparation.