Neuroblastoma

2. • Most common
• Extracranial solid tumor in children
• Malignancy in infants <1 year old.
• The median age at diagnosis is 17 months.
• Males>Females
• Abdomen is most common primary site (50%–80%)
• Other common sites
• Adrenal gland (35%)
• Low-thoracic or abdominal paraspinal ganglia (30%–35%)
• Posterior mediastinum (20%)
• Pelvis (2%), cervical spine (1%), and other sites (12%)

3. • Neuroblastoma, a small round blue cell tumor
Others: Lymphoma, all other “blastomas,” small cell
carcinoma of the lung, PNET and Ewing’s sarcoma,
and rhabdomyosarcoma
• Benign ganglioneuroma (well-differentiated,
favorable prognosis)
• Ganglioneuroblastoma (moderately differentiated,
unfavorable prognosis)
• Neuroblastoma (poorly differentiated, favorable to
poor prognosis)

4. • Arises from primitive
neural crest cells of the
sympathetic nervous
system
• Spinal ganglion
• Dorsal spinal nerve roots,
and
• Adrenal medulla.
• Homer-Wright
pseudorosettes are found
in 15–50% of cases.

6. Immunohistochemistry (IHC)
•Positive for
• Neuron-specific enolase
• Chromogranin A
• Neurofilament protein
• S100, and
• Synaptophysin
• Negative for
• Leukocyte common antigen
• Vimentin
• Myosin and Actin
• Desmin

7. Genetics:
• N-myc protein amplification - short arm of chromosome 2 (20-25%)
• Cytogenetic abnormalities associated with poorer prognosis:
• LOH 1p, 11q, or isolated 17p; gain of 1q or 17q
• Diploid tumors (DNA index 1)
• Increased telomerase activity through TERT promoter rearrangement
• ALK copy number gain and gene amplification.
• Favorable factors
• Hyperdiploidy or
• TRK-A amplification.

8. Biochemistry
• In 90% of cases, elevated levels of catecholamines or
their metabolites are found in the urine or blood.
• Catecholamines and their metabolites
• Dopamine
• Homovanillic acid (HVA), and/or
• Vanillylmandelic acid (VMA)

9. Screening
• Screening Urine catecholamines in asymptomatic infants at three
weeks, six months, and one year has been performed in Japan,
Canada, Austria and Germany since the 1980s.
• Screening was halted in Japan in 2004 after studies in Canada and
Germany showed no reduction in deaths due to neuroblastoma.
• The high spontaneous regression rate led to overdiagnosis of clinically
insignificant disease.
• Screening does not change the mortality rate of neuroblastoma, as
confirmed in international trials.

10. www.acco.org/blog/neuroblastoma-childhood-cancer-signs-and-symptoms

11. • Abdominal mass, abdominal pain, fever, malaise, weight loss, micturition, dyspnea,
and dysphagia.
• 1/3 experience fatigue, anorexia, irritability, and pallor.
• Bone pain frequent in pts with skeletal mets (Skull/Posterior orbit).
• Excess catecholamines can produce flushing, sweating, and HTN (rare).
• 70% of patients present with metastatic disease with bone marrow mets seen in
80% to 90% & LN+ in 35%.
• Spontaneous regression may occur, especially in infants with 4S disease.
• 5-yr OS is 71% in modern era
• Mainly to increased cure rates in pts with less aggressive disease.

12. Other Signs:

14. Work-up
• H&P, Labs include urine catecholamines, vanillylmandelic acid, and homovanillic acid, CBC,
BUN/Cr, and LFTs.
Imaging: CT/MRI of primary, MIBG scan, and CXR.
• CXR/CT chest for metastases.
• Primary tumor is calcified on X-ray in 80–90% of cases (vs. 5–10% in Wilms’).
• MIBG Scan:
• Meta-iodobenzylguanidine scan uptake in 90 to 95% of all neuroblastomas (MIBG-avid) [Sensitivity 97% &
Specificity 92%]
• The mechanism is that MIBG is taken up by sympathetic neurons, and is a functioning analog of the
neurotransmitter norepinephrine.
• When it is radio-iodinated with I-131 or I-123, it is a very good radiopharmaceutical for diagnosis and
monitoring of response to treatment for this disease.
• Bone scan if primary tumor is not MIBG Avid.
• Biopsy the primary or involved nodes.
• All patients should have a bilateral bone marrow biopsy and aspirate.

15. NEUROBLASTOMA STAGING SYSTEMS

18. • Shimada classification: Favorable (FH)/Unfavorable (UH)
• Age
• Amount of Schwann cell stroma (Stromal pattern)
• Nodular vs. diffuse pattern
• Degree of neuroblastic differentiation
• Mitosis karyorrhexis index (MKI- Fragmentation of the nucleus)
• Favorable Shimada:
• Young age
• Rich stroma with non-nodular pattern
• Mature neuroblast differentiation
• Low MKI

19. • The International Neuroblastoma Staging System (INSS) used to stage
neuroblastomas and it attempts to combine the previously used Evans and
Pediatric Oncology Group (POG) staging systems.
• This was initially developed in 1986 and revised in 1993 and takes into account
the results of surgery to remove the tumor.
• The INSS staging system was further classified into low, intermediate, and
high-risk groups by the Children’s Oncology Group (COG).
• The International Neuroblastoma Staging System (INSS) is based on
surgicopathologic findings.

20. International Neuroblastoma Staging System (INSS)

22. • 60% of patients <1 year present with localized disease.
• 70% of patients >1 year present with metastases.
• London (JCO 2005):
• Retrospective analysis of 3666 patients on POG and CCG
studies from 1986 to 2001 demonstrated prognostic
contribution of age to outcome is continuous.
• 460-day cutoff selected to maximize the outcome difference
between younger and older patients.

23. • INRG developed a staging system (INRGSS) based on
preoperative evaluation and extent of disease as determined
by imaging defined risk factors (IDRFs).
• INRGSS simplifies staging into localized (L1/L2) versus
metastatic disease (M/MS).
• The International Neuroblastoma Risk Group (INRG)
classification system is used to develop pretreatment risk
stratification to help standardize patients enrolled on trial.
International Neuroblastoma Risk Group Staging System(INRGSS)

24. International Neuroblastoma Risk Group
(INRGSS)
• L1: Localized tumor not involving vital structures as defined by the list
of imagedefined risk factors and confined to one body compartment
• L2: Locoregional tumor with presence of one or more image-defined
factors
• M Distant: metastatic disease (except stage MS)
• MS: Metastatic disease in children younger than 18 months with
metastasis confined to the skin, liver, and/or bone marrow

25. INRGSS image-defined risk factors
Ipsilateral tumor extension
within two body compartments
Neck-chest, chest-abdomen, or abdomen-pelvis
Neck Encasing carotid and/or vertebral artery and/or internal jugular vein.
Extending to the base of skull.
Compressing the trachea.
Cervicothoracic junction Encasing brachial plexus roots.
Encasing subclavian vessels and/or vertebral and/or carotid artery.
Compressing the trachea
Thorax Encasing the aorta and/or major branches.
Compressing the trachea and/or principal bronchi.
Lower mediastinal tumor, infiltrating the costovertebral junction between T9 and T12.
Thoracoabdominal Encasing the aorta and/or vena cava.
Abdomen/pelvis Infiltrating porta hepatis and/or the hepatoduodenal ligament.
Encasing branches of the SMA at the mesenteric root.
Encasing the origin of the celiac axis and/or the SMA.
Invading one or both renal pedicles.
Encasing aorta and/or vena cava.
Encasing iliac vessels.
Pelvic tumor crossing the sciatic notch.
Intraspinal tumor 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 tumors
Pleural effusion, with or without malignant cells
Ascites, with or without malignant cells

27. 5year EFS cutpoints for the INRG pretreatment risk groups:
• Very low: >85%
• Low: 75–85%
• Intermediate: 50–75%
• High: <50%

28. Treatment Recommendations

29. • Treatment is determined by risk stratification
• Low
• Intermediate
• High risk
• COG risk grouping:
• Stage
• Age
• N-myc
• DNA ploidy
• Shimada histology.
• Pts with amplified N-myc are either low or high risk
• Pts with 11q aberration are intermediate to high risk
• Pts with stage I disease are low risk

31. • POG 8104 (Nitschke, JCO 1988):
• 101 patients with POG A (INSS 1) disease.
• Gross total resection → observation
• 2-year DFS 89%.
• CCG 3881 (Perez, JCO 2000):374 patients treated with Evans I–II
(INSS 1–2B)
• Surgery alone (plus RT for spinal cord compression).
• Recurrences managed with surgery or multimodality therapy.
At 4-years EFS OS
stage I 93% 99%
stage II 81% 98%
Low Risk

32. • If GTR: Surgery → observation.
• If STR/unresectable, or recurrence after GTR → Chemo for 6–12 weeks.
• Chemotherapy regimens: Carboplatin, VP-16, CY, ADR, and/or Topotecan and
Cyclophosphamide.
• If patient has severe symptoms from spinal cord compression, respiratory
compromise, or GI/GU obstruction
• Start chemotherapy immediately (Early radiation in symptomatic/ progressive cases) →
Surgery
• RT (1.5/21 Gy) is used for symptoms that do not respond to chemotherapy or for
massive hepatomegaly causing respiratory distress (1.5/4.5 Gy).
• For clinically stable stage 4S low-risk patients, observe after biopsy unless massive
hepatomegaly causes respiratory distress (then treat with chemotherapy ± RT).

33. • Castleberry, POG (Castleberry, JCO 1991):
• 62 patients >1 year old with POG C (INSS 2B-3)
• Randomized to post-op chemotherapy ± concurrent RT → second-look
surgery → chemotherapy.
• RT was to the primary and regional nodes(1.5/24 Gy for <2 years old or 1.5/30
Gy for >2 years old).
• Chemo-RT improved DFS (31 → 58%) and CR rate (45 → 67%).
• POG 8742 & 9244 (Eur J Cancer 1997): 49 patients >1 year old with
INSS 2B-3
• Surgery → chemotherapy × 5c → second-look surgery → RT for viable residual
tumor → chemotherapy.
• RT was 1.5/24 Gy for age 1–2 years, 1.5/30 Gy for age >2 years.
• Two-year EFS
• 85% after GTR vs. 70% after STR
• 92% for FH vs. 58% for UH
INTERMEDIATE RISK

34. • RT was shown to increase both EFS and OS when added to
adjuvant CHT in the Castleberry study of POG C pts.
• The current intermediate-risk pts, are not the same pts as
those in the Castleberry study.
• RT is not a standard component of first-line therapy.
• As in low-risk pts, RT is typically reserved for pts with
residual disease refractory to CHT, recurrent disease, or
those who remain symptomatic.

35. • Maximal safe resection with lymphadenectomy →
chemotherapy for 12–24 weeks depending on biology.
• Chemotherapy regimens consist of carboplatin, VP-16, CY, ADR,
and/or topotecan and cyclophosphamide.
• Unresectable tumors may require preoperative
chemotherapy to convert them to resectable status.
• Radiation controversial in intermediate-risk disease
• If PR to chemotherapy → second-look surgery. If viable
residual disease present → RT to primary (1.5/24 Gy)
• If stage 4S with respiratory distress → RT to liver (1.5/4.5 Gy)

36. CCG 3891 (NEJM 1999; IJROBP 2003; JCO 2009):
539 high-risk patients
• After induction CHT, pts without progression underwent delayed primary surgery with nodal assessment followed by RT to
gross residual disease.
• Induction CHT consisted of cisplatin, doxorubicin, etoposide, and cyclophosphamide x five cycles.
• RT dose was 20 Gy/10 fx to extra-abdominal disease and 10 Gy/5 fx to mediastinal and intra-abdominal tumors.
• Pts were subsequently randomized to receive consolidation CHT or myeloablative CHT + TBI with SCT.
• Consolidation CHT consisted of three cycles of cisplatin, etoposide, doxorubicin, ifosfamide.
• Myeloablative CHT was carboplatin and etoposide.
• TBI was 10 Gy/3 fx daily.
• Following SCT or consolidation CHT, pts without disease progression were randomized to six cycles of 13-cis-retinoic acid
(isotretinoin) or no further therapy.
• 2009 update:
• ABMT + TBI improved 5-year EFS (19 → 30%)
• Cis-retinoic acid improved 5-year EFS (31 → 42%)
• Trend toward improved OS for both.
HIGH RISK

37. • ANBL0532 (Park, ASCO 2016): 652 patients with high-risk NB
• Induction chemotherapy and surgery with randomization to single
vs. tandem ASCT
• Tandem SCT improved 3-yr EFS from 48.8% to 61.8% (p = .008)
with a nonsignificant improvement in OS (69.0%–73.8%, p = .256).
• 249 pts received postconsolidation immunotherapy, which also
improved both EFS and OS
• Immunotherapy: anti-GD2 antibody with isotretinoin vs. isotretinoin alone
• EFS 55.4% vs. 73.7%, p < .001
• OS 75.7% vs. 86.3%, p = .016).

38. • High-dose induction chemotherapy (ifosfamide and cisplatin)
+/- 131 I-MIBG → attempt maximal safe resection.
• After surgery → high-dose chemotherapy and tandem
transplant.
• All patients then
→ RT (1.8/21.6 Gy) to the postchemotherapy,
presurgical extent of tumor
→ +/− 1.8/14.4 Gy boost to gross residual disease
→ cis-retinoic acid +/− antibody therapy for 6 months.

39. Radiation
• Indications:
• Highrisk: RT is delivered to the primary tumor and persistent metastatic sites.
• Intermediate-risk: RT is delivered to recurrent or gross residual disease.
• Adjuvant RT: Not indicated for low- or intermediate-risk disease
• Urgent symptomatic (life/organ threatening) concerns without
significant response to CHT
• Eg: Liver mets with respiratory compromise or cord compression.

40. Simulation and Field Design
• CT and/or MRI used for planning 3DCRT or IMRT plans.
• Treat the postchemotherapy, presurgical tumor extent with
a 1–1.5 cm margin, adjusted for pushing borders.
• If lymph node involvement is suspected or proven, cover
involved LN.
• Do not give elective nodal RT because of morbidity and lack of
benefit.
• Always cover full width of vertebrae to avoid scoliosis.

41. DOSE PRESCRIPTIONS
• Intermediate risk = 24 Gy/1.5 Gy/# (controversial)
• High risk = 21.6 Gy/12# plus 14.4 Gy/8# @1.8 Gy/# (boost to gross residual
disease)
• 4S liver involvement = 4.5 Gy/ 3# @ 1.5 Gy/# (Hepatic metastasis causing
respiratory compromise)
DOSE LIMITATIONS
• Ipsilateral kidney: D25% <18 Gy, D100% <14.4 Gy
• Contralateral kidney: D75% <18 Gy
• Liver: mean <15 Gy, D85% <30 Gy
• Lung: ipsilateral D70% <20 Gy, contralateral D10% <20 Gy
• Vertebral bodies: min 18 Gy if overlaps with PTV
• Spine: 36 Gy after induction with bleomycin and mitomycin

42. COMPLICATIONS:
• Acute: Diarrhea, nausea, vomiting, erythema, fatigue, myelosuppression.
• Late: Site irradiated and the total dose of both radiation and chemotherapy
agents used.
• Age at the time of treatment may influence the risk and severity of skeletal anomalies, which
may include spinal deformities such as kyphosis, scoliosis, or limb shortening.
• Younger children are more prone to late radiation injury than older children. (<6months)
• Both laminectomy and RT dose >17.5 Gy were risk factors for development of scoliosis in
children with abdominal neuroblastoma.
• A report from the Childhood Cancer Survivor Study showed the 20-year cumulative
incidences of neurologic, sensory, endocrine, and musculoskeletal toxicities were 29.8%,
8.6%, 8.3%, and 7.8%.
• The cumulative incidence of secondary malignancies was 3.5% at 25 years after diagnosis.

43. • For cord compression, CHT is preferred followed by surgical
decompression.
• For widespread disease, 131I-MIBG scan, chemotherapy, or bone
marrow transplantation could be considered.
• Iobenguane I-131 (COG ANBL1531) is essentially therapeutic MIBG
including I-131 (diagnostic MIBG includes I-123) and has shown
dramatic responses in relapsed/refractory cases.
• Crizotinib is active against ALK mutated tumors.

44. • Targeted radionuclides:
• I-131 MIBG therapy, response rates of 30-40% pts
• Being investigated before resection or in combination with SCT for
consolidation.
• Differentiation therapy:
• Neuroblastoma cell lines can be induced to terminally differentiate with
retinoids.
• Risk of relapse is reduced in pts who receive isotretinoin.
• Immunotherapy:
• Neuroblastoma cells express disialoganglioside GD2 on their surface.
• Dinutuximab, a chimeric anti-GD2 antibody (ch14.18) is FDA-approved for
adjuvant first-line therapy
• Significant acute toxicity - capillary leak syndrome and pain.
Other modalities

45. THANK YOU