Mysterious,enigmatic and evanescent,the Neuroblastoma(NBL) is the 3rd most common paediatric tumour.It constitutes 10% of all childhood carcinomas and the survival rate is <30%.
The peak incidence is at 2 years.Arising from the neural crest cells ,it shows different levels of differentiation:-
1.Adrenal glands
2.Posterior mediastinum
3.Neck
4.Pelvis
5.Any sympathetic ganglion
75% of the times,it presents as an abdominal/pelvic mass out of which half arise from the adrenal medulla.
It occurs only occasionally in adults,around 80% cases are below 10years of age.
Pathological picture:Found more on the left than right side,NBL may be bilateral in a few cases.
Macroscopically,the tumour is soft in consistancy (gray brain -like tissue);may range from minute nodules (in-situ lesions)to large masses >1kg in weight.
Microscopically,masses of undifferentiated small,round cells (neuroblasts)are seen.Fibrils form longitudinal bundles or round whorls around cell masses giving a pseudorosette appearance (Homer Wright).
Better differentiated lesions contain more large cells with vesicular nuclei and prominent nucleoli-designated as ganglioneuromas.Large tumours show wide-spread necrosis and calcification.
Spread:
Hematogenous spread is common.
Bone(30%)
liver (20%)
Skull or brain (11%)
Lungs (9%)
Special predeliction exists for mets in the orbit causing proptosis with peripheral haemorrhage.
IN A CASE OF PROPTOSIS IN A YOUNG CHILD,THE CLINICIAN MUST EXAMINE ABDOMEN TO EXCLUDE NEUROBLASTOMA.
Mets in skull from adrenals occur through vertebral system of veins.
Lymphatic spread is late and involves regional nodes(25%) and cervical nodes(5%).
Clinical features:
Abdominal mass (asymptomatic in 2/3 rd patients)is commonest symptom .There may be weight loss,fever,vomitting and abdominal pain.
Pallor and pancytopenia may be present due to bone marrow involvement.
liver enlargement may be due to mets.Mets in skull may lead to swelling of head,proptosis with or without ecchymosis of the lids (Raccoon eyes).Occasional blindness and bone pain may be seen.
As NBL also originate in paraspinal ganglia,they may invade through the neural foramina and compress the spinal cord causing muscle weakness and sensory symptoms.
Due to paraneoplastic syndrome there may be cerebellar ataxia,involuntary movements and nystagmus-DANCING EYES AND FEET SYNDROME.
Rarely severe watery diarrhoea due to secreation of VIP maybe seen.
Posterior mediastinal mass and lung mets may lead to Horner's syndrome,dyspnoea or pneumonia.
SKIN has a typical BLUEBERRY MUFFIN appearance due to mets.
Opsoclonus/Myoclonus may be seen with pervasive and permanent neuro and cognitive deficits and psychomotor retardation.(immuological injury)
Cervical tumours may be palpable or actually visible.They may cause stridor or dysphagia
Criteria for diagnosis:(one out of the two)
1.Unequivocal pathologic diagnosis made from tumour by Light microscopy(with or without immunohistochemistry,electron microscopy or increased serum catecholamines)
2.Combination of Bone marrow aspirate/biopsy containing unequivocal tumour cells and increased level of serum/urinary catecholamines.
International NBL staging system:
Stage I Localised tumour with complete gross excision with or without microscopic residual disease,representative ipsilateral lymph nodes -ve for tumour microscopy.(nodes attached to or removed with primary tumour may be +ve)
Stage 2a Localised tumour with incomplete gross excision,representative ipsilat. non-adherant l.nodes -ve for tumour microscopically
Stage 2b Localised tumour with or without complete gross excision with ipsilat. non-adherant l.nodes +ve for tumour;enlarged contralateral l.nodes must be -ve microscopy.
Stage 3 Unresectable U/L tumour with C/L regional lymph node involvement or midline tumour with B/L extension by infiltration(unresectable) or by l.node involvement.
Stage 4 Any primary with dissemination to distant l.nodes,bone,bone marrow,liver ,SKIN or other organs.
Stage 4s Localised primary tumours(as in stage 1,2a,2b) with dissemination to SKIN ,liver and /or bone marrow (limited to infant epinephrine or NE is produced.
Therefore HVA (Homo vanillic acid) is raised and more specific than the increase in VMA.
LFT is not of much value though even in hepatic mets.
Also important markers are:
LDH>1500 IU/ml
Serum Ferritin>142ng/ml
Neuron specific enolase>100ng/ml
(to be correlated with advanced disease and decreased survival)
Staging work-up:
Chest X-ray
Bone marrow biopsy
radionucleotide scans to search for mets.
(Any abnormality on chest X-ray to be followed up with CT)
MIBG scan is the single best method to document presence of Metastasis.
Abdomen CT -may show occasional obstruction of ureter and displacement of intact kidney .
Open biopsy.
Treatment:
The treatment depends on the stage of the tumour.
Stage I Total excision alone.
Stage II Total excision +/- Post-operative radiotherapy and /or chemotherapy
Stage III Resectable tumours:Excision +multidrug chemotherapy+radiotherapy
Unresectable: Cytoreduction with chemotherapy and radiotherapy,followed by excision of the shrunken tumour.
Stage IV Combination chemotherapy.Attempted excision of residual tumours may be done in those responding to chemotherapy.
Stage IVs Excision of the primary tumour.
Occasionally the patient develops resp.distree due to rapidly enlarging tumour.Rx is low dose irradiation.Alternatively,the abdominal cavity is enlarged using sialastic patch in abdomen wall (as in gastroschisis/giant exomphalos).
Standard chemotherapeutic agents used:Cyclophosphamide,Vincristine.
Other recently tried drugs:Adriamycin,Cisplatin,Melphalan and Ditriazoimidazole carboximide.
However the results of chemo and radiotherapy are disappointing.
New approaches are 1.High dose chemotherapy
2.Total Body Irradiation
3.Allogeneic or autologous bone marrow transplantation.
Before re-infusion, autologous bone marrow may be 'cleaned' of tumour cells by treatment with cytotoxic agents couples to monoclonal antibodies directed against neuroblastoma cells.
Tumour cells may be extracted from the marrow by magnetic separation after application of magnetic beads coupled to monoclonal antibodies by COUNTERFLOW CENTRIFUGAL ELUTRIATION technique.
'Intracellular 'radiotherapy is based on affinity of radioactive I131 MIGB to tumour tissue.
Prognosis:
3 year survival for all stages is 30-50%
Patients 1year,low n-myc
>1 year,amplification of n-myc,
favourable biology
IVs favourable biology
Intermediate III 1 year,favourable biology
IVs low n-myc
High II > 1year,all unfavourable
biology
III 1year,unfav.biology
IV 1 year
IVs amp n-myc
Poor prognostic factors:-
Unfavourable biology
Primary abdominal lesion
High neuron specific enolase
High serum ferritin
Low ratio of VMA to HVA
n-myc amplification
Gain of genetic materialfrom chromosome arm 17q associated with chr.1p deletion
Multi-drug resistant protein
Expression of TRK is inversely associated with n-myc and carries good prognosis.
Diploid tumour carries unfavourable while hyperploid carries favourable prognosis.
Classification By Shimada et all deals with prognostication based on degree of differentiation,mitotic karyorrhexis index,presence/absence of stroma.
Epilogue:As we come to the end of unravelling most of the secrets of Neuroblastoma ,we must understand that this is still a mystery tumor .We are still not totally in a position to battle this neoplasm.Thus this is a challenge to the future generation of surgeons and researchers to come up with a cure.
Happy reading!
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