Neuroblastoma

Key points

7% of childhood cancer

Derived from sympathetic neuroblasts

Can arise from:

1. Adrenal glands

2. Sympathetic chain (abdomen/pelvis, thorax, neck)

3. Ectopic adrenal tissue e.g. organ of Zuckerkandl

Thoracic lesions tend to be less aggressive + lower risk

Metastatic Sites of Neuroblastoma (in order of frequency)

Bone Marrow

• Infiltration leads to cytopenias (anaemia, thrombocytopenia, neutropenia)

• Symptoms include fatigue, bruising, and infections

Bone

• Frequently involves the skeletal system

• Causes bone pain, fractures, and limping

Lymph Nodes

• Regional and distant lymph node involvement

• Presents as enlarged, firm masses

Liver

• Hepatomegaly is common in infants

• Causes abdominal distension

Skin

• Blueberry muffin lesions (subcutaneous nodules)

• More common in infants

Lungs

• Less common site of metastasis

• May cause respiratory symptoms if involved

Central Nervous System (CNS)

• Rare, but can involve the meninges

• May present with neurological symptoms

Orbit

• May present with periorbital ecchymosis (raccoon eyes)

• Proptosis due to tumour infiltration

Opsoclonus-myoclonus-ataxia (OMA)

1-3% of children with NB, but 50% with OMA have NB

Autoimmune mechanisms involving antigen-antibody complexes that cross-react with Purkinje cells within the cerebellum. Symptoms frequently continue post-tumour excision, leading to considerable neurodevelopmental consequences

Can secrete VIP - Vasoactive intestinal peptide (VIP) - diarrhoea and hypokalaemia - generally differentiated, low risk tumours, with somatostatin receptors. Resolves after excision

Genetics

Most important is MYCN amplifcation

Found on chromosome 2

Amplification is defined as >10 copies

Indicates an aggressive tumour phenotype - will upgrade most tumours to high risk category

Most tumours express PHOX2B

Note that PHOX2B mutations are also associated with Congenital central hypoventilation syndrome and Hirschprung's disease

Histology

Favourable - stroma rich - differentiated

Unfavourable - stroma poor - immature - high mitotic karyorrhexis index (MKI)

small round blue cells arranged in rings - Homer-Wright pseudorosettes

Neuroblastoma is an example of a small round blue cell tumour (SRBCT) which have a characteristic appearance on histology. Other examples of SRBCTs include:

• Rhabdomyosarcoma

• Ewings Sarcoma

• Carcinoid tumours (Neuroendocrine carcinoma)

• Wilms tumour

• Lymphoma

• Hepatoblastoma

• Melanoma

Image Defined Risk Factors (IDRFs)

Multiple Body Compartments

• Ipsilateral tumour extension within two body compartments (neck-chest, chest-abdomen, abdomen-pelvis)

• Neck:

• Tumour encasing carotid and/or vertebral artery and/or internal jugular vein

• Tumour extending to the base of the skull

• Tumour compressing the trachea

Cervico-Thoracic Junction

• Tumour encasing brachial plexus roots

• Tumour encasing subclavian vessels and/or vertebral and/or carotid artery

• Tumour compressing the trachea

Thorax

• Tumour encasing the aorta and/or major branches

• Tumour compressing the trachea and/or principal bronchi

• Lower mediastinal tumour infiltrating the costovertebral junction between T9 and T12

• Tumour encasing the aorta and/or vena cava

Abdomen/Pelvis

• Tumour infiltrating the porta hepatis and/or hepatoduodenal ligament

• Tumour encasing branches of the superior mesenteric artery at the mesenteric root

• Tumour encasing the origin of the coeliac axis and/or superior mesenteric artery

• Tumour invading one or both renal pedicles

• Tumour encasing the aorta and/or vena cava

• Tumour encasing the iliac vessels

• Pelvic tumour crossing the sciatic notch

Intraspinal Tumour Extension

• More than one third of the spinal canal in the axial plane is invaded and/or the perimedullary leptomeningeal spaces are not visible and/or the spinal cord signal is abnormal

Infiltration of Adjacent Organs/Structures

• Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery

Conditions to be Recorded but Not Considered IDRFs

• Multifocal primary tumours

• Pleural effusion, with or without malignant cells

• Ascites, with or without malignant cells

Encasement refers to tumour in contact with >50% of the circumference of a vessel

Summary of IDRFs: A tumour crossing into other body compartments and/or significant involvement of vital structures has IDRFs

INRG staging system (INRGSS)

INRG Risk stratification

• Very low

• Low

• Intermediate

• High

The following factors are charted when calculating risk (summary)

MYCN amplification will make most tumours high risk

Examples of tumours in risk groups:

Very Low Risk

• INRG Stage: L1/L2

• Histology: GN maturing, GNB intermixed

• MYCN: Any

OR

• INRG Stage: MS

• Age (months): < 18

• MYCN: Not amplified

• 11q Aberration: No

  
  

Low Risk

• INRG Stage: L2

• Age (months): < 18

• Histology: Any except GN maturing or GNB intermixed

• MYCN: Not amplified

• 11q Aberration: No

OR

• INRG Stage: M

• Age (months): < 18

• MYCN: Not amplified

• DNA Ploidy: Hyperdiploid

Intermediate Risk

• INRG Stage: L2

• Age (months): > 18

• Histology: GNB nodular, neuroblastoma

• Differentiation: Differentiating

• MYCN: Not amplified

• 11q Aberration: Yes

• DNA Ploidy: Not specified

  
  

High Risk

• INRG Stage: L1

• Age (months): Any

• Histology: Any except GN maturing or GNB intermixed

• MYCN: Amplified

OR

• INRG Stage: M

• Age (months): > 18

OR

• INRG Stage: MS

• Age (months): < 18

• MYCN: Amplified

  
  

10% not MIBG avid - so Technetium 99 needed for bony involvement or PET CT

Management

Chemotherapy for all but very low risk (L1, <18m, MYCN -ve)

Surgery for primary mass is often all that is needed - except in neonates (see scenario below)

Observation is all that is usually needed for younger patients with Stage MS with favourable biology

Low + intermediate risk chemotherapy (CCLG)

Etoposide/Carboplatin +/- CADO (cyclophosphamide, doxorubicin, and vincristine)

Add Radiotherapy + cis Retinoic acid for: L1 & MCYN +ve, L2 & age >18 months

High risk management (CCLG + SIOPEN NBL 1)

Rapid COJEC (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]) induction

If complete/partial response - Surgery + High dose chemo (Bisulfan/Mephalan)

If poor response - recruit to trial e.g VERITAS. Consider 131I-MIBG

Then use the following adjuvant treatments:

Autologous stem cell transplant

Radiotherapy

Anti GD2

Operation

Excision of primary mass is not recommended for:

1. L2 tumours + <18 months old at presentation, where the IDRF remain positive following chemotherapy or natural involution, unless there are segmental alterations

2. Metastatic (MS) tumours age < 12 months at presentation, with no segmental chromosomal alterations irrespective of IDRF status

3. M tumours age <12 months at presentation + persistent metastatic disease (not counting liver mets) after chemotherapy

   
   

Summary: Younger patients with metastases or L2 tumour (risky resection) after chemotherapy unless other high risk features should not undergo excision of primary mass

Other principles:

Hepatomegaly with stage MS may be so severe that it causes abdominal compartment syndrome - a laparostomy may be needed

Nephrectomy should be avoided if possible

Trap door incision for upper thoracic tumours

Standard scenario

Infant with abdominal mass suggestive of neuroblastoma

Differentials:

1. Neuroblastoma

2. Wilms

3. Rhabdomyosarcoma

4. Retroperitoneal germ cell tumour

Ensure resuscitated

History

Onset of symptoms

Examination

Blood pressure

Abdominal masses

Liver edge (May suggest liver mets)

Skin mets (blueberry muffin spots)

Spinal curvature from mass effect

Investigations

Calcium, LDH

Tumour markers to distinguish from GCT

Urine catecholamines

USS if not already done

MRI/CT abdomen

CT chest

Oncology MDT 1st discussion

Likely outcome -

MIBG

Hickman line + percutaneous tumour biopsy + bone marrow aspirate

2nd MDT discussion for staging and risk stratification

Comment on likely stage and risk group

Treatment based on risk group

Special scenario - Neonatal adrenal mass

Differentials

1. Neuroblastoma

2. Sequestration

3. Adrenal haemorrhage

4. Benign tumours

History

Antenatal scan features, was MRI done?

Maternal hypertension (due to catecholamine secretion)

Difficult delivery/foetal distress - suggests differential is adrenal haemorrhage

Examination

Blood pressure

Abdominal masses

Skin lesions (blueberry muffin spots)

Investigations

Urine catecholamines

Post natal USS

Oncology MDT

Management

CCLG guidelines- Adrenal mass <5cm + <3 months age

Serial USS + HVA/VMA

MIBG + BM aspirates at 3 months of age

If increase in size or HVA/VMA - do MIBG/BM aspirates if not already done so then resect/biopsy immediately

If stable - Resect at 12-18 months (or biopsy if L2) if still persistent

Procedures with senior oncology surgeon

Example surveillance schedule (COG)

HVA and VMA + abdominal USS on week 3, 6, 12, 18, 30, 42, 66, 90

Evidence - COG series 2012 - 80% of children were spared a surgical procedure with an excellent three year event free survival

Special scenario - Spinal cord compression

Concerns

1. Irreversible neurological damage

2. Control of tumour - probable neuroblastoma

Resuscitation

History

Duration of symptoms, pain

Bowel/bladder involvement

Feeding, Weight loss

Opsoclonus

Exam

Abdomen and spine for mass/deformity

Neurological exam (ASIA template)

Emergency MRI spine

Oncology team:

IV Dexamethasone TDS

Tunnelled central line - Carboplatin + etoposide - do not delay chemo to obtain biopsy

Reassess with MRI after chemo

If symptoms persist - laminotomy +/- resection of intraspinal component

Proceed to discuss neuroblastoma management + involvement of spinal surgeons for resection

References

Berdon WE, Stylianos S, Ruzal-Shapiro C, Hoffer F, Cohen M. Neuroblastoma arising from the organ of Zuckerkandl: an unusual site with a favorable biologic outcome. Pediatr Radiol. 1999 Jul;29(7):497-502. doi: 10.1007/s002470050629. PMID: 10398782.

Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, Faldum A, Hero B, Iehara T, Machin D, Mosseri V, Simon T, Garaventa A, Castel V, Matthay KK; INRG Task Force. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009 Jan 10;27(2):289-97. doi: 10.1200/JCO.2008.16.6785. Epub 2008 Dec 1. PMID: 19047291; PMCID: PMC2650388.

Surgical Management of Head and Neck Pathologies 2021; Pediatric Head and Neck Malignancies, Dustin A. Silverman

Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon T, Cohn SL, Pearson AD; INRG Task Force. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. 2009 Jan 10;27(2):298-303. doi: 10.1200/JCO.2008.16.6876. Epub 2008 Dec 1. PMID: 19047290; PMCID: PMC2650389.

Irwin MS, Naranjo A, Zhang FF, Cohn SL, London WB, Gastier-Foster JM, Ramirez NC, Pfau R, Reshmi S, Wagner E, Nuchtern J, Asgharzadeh S, Shimada H, Maris JM, Bagatell R, Park JR, Hogarty MD. Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group. J Clin Oncol. 2021 Oct 10;39(29):3229-3241. doi: 10.1200/JCO.21.00278. Epub 2021 Jul 28. PMID: 34319759; PMCID: PMC8500606.

Nuchtern JG, London WB, Barnewolt CE, et al. A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children's Oncology Group study. Ann Surg. 2012;256(4):573-80

80% of children were spared a surgical procedure with an excellent three year event free survival

CCLG guidelines: Low & Intermediate risk NB, High risk NB, Relapsed NB