Radiation Oncology/Neuroblastoma

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[edit] Presentation

  • Has a broad spectrum of clinical presentations and paraneoplastic syndromes.
  • "Quirky natural history" from benign localized lesions to spontaneous remission of metastatic disease to aggressive widely disseminated tumors
  • May arise in any portion of the sympathetic nervous system
    • Adrenal gland 40%
    • Abdominal ganglia 25%
    • Thoracic ganglia 15%
    • Cervical ganglia 5%
    • Pelvic ganglia 5%
  • Metastatic ~60% at presentation
    • "Favorable" typically to liver, skin
    • "Unfavorable" typically to bone marrow, bones (orbits, skull)
  • Typical symptoms abdominal swelling or pain, diarrhea/constipation, bone pain, periorbital swelling
  • Paraneoplastic syndromes (rare)
    • Vasoactive intenstinal polypeptide secretion: intractable diarrhea
    • Opsoclonus-myoclonus-ataxia syndrome (1-3%): dancing eye, rhythmic jerking, ataxia
  • Spinal cord compression (7-15%) is an oncologic emergency
  • Normal sympathetic tissues secrete catecholamines, VMA/HVA noted in urine 90% of patients, but VMA or HVA screening no value

[edit] Epidemiology

  • Third most common childhood cancer (8-10%), after leukemia and brain tumors
    • Most common extracranial solid malignancy of childhood
    • Most common malignancy of infants (1/2 of all cases)
  • Incidence 9/1,000,000 -> ~650 children per year in U.S.
  • Median age at diagnosis 17 months
    • 75% <2 years
    • 90% <5 years
  • Majority is sporadic, although 1-2% appear autosomal dominant

[edit] Pathology

  • Spectrum of tumors arising from primitive sympathetic ganglion cells : neuroblastoma (~85%), ganglioneuroblastoma (~10%), and ganglioneuroma (~1%) (least to more differentiated)
  • Classification based on balance between neural-type cells (primitive neuroblasts, maturing neuroblasts, ganglion cells) and stromal Schwann-type cells (Schwannian blasts, mature Schwann cells)
  • Most undifferentiated neuroblastomas are composed entirely of neuroblasts with scant Schwannian (stromal) cells ("small, round, blue cells"
  • Positive for: neuron-specific enolase, synaptophysin, chromogranin A, neuronal filaments, S100, NB84
  • Shimada system ("favorable" vs. "unfavorable") - based on patient age, rich or poor stroma, nodularity, degree of differentiation, mitosis-karyorrhexis index (MKI)
  • International Neuroblastoma Pathology Classification System (PMID 10421273, 1999)
    • Favorable:
      • Neuroblastoma, <1.5 years old, poorly differentiated or differentiating with low/intermediate MKI tumor
      • Neuroblastoma, 1.5-5 years old, differentiating and low MKI tumor
      • Ganglioneuroblastoma, intermixed
      • Ganglioneuroma
    • Unfavorable:
      • <1.5 years old, undifferentiated or high MKI tumor
      • 1.5-5 years old, undifferentiated/poorly differentitated tumor or intermediate/high MKI tumor
      • >5 years old, any tumor
      • Ganglioneuroblastoma, nodular

[edit] Molecular biology

  • More aggressive: MYCN gene amplification (5-400x) in ~25%. MYCN is a DNA binding transcription factor known to cause malignant transformation. Infants 4S with MYCN 3-year OS <50% vs. without MYCN >90%
  • More aggressive: Chromosomal deletions 1p (in 23%) and 11q (in 35%)
  • More aggressive: Chromosomal gains 17q (in ~50%)
  • Less aggressive: DNA ploidy. 2-year EFS triploid 94% vs. diploid MYCN- 45% vs. diploid MYCN+ 11%

[edit] Workup

  • History: diarrhea/constipation, ataxia
  • Physical exam: neurologic function, skin mets (reddish-purple raised lesions), periorbital ecchimoses
  • Labs: VMA and HVA
  • Imaging: Abdominal ultrasound, CT/MRI to define extent, bone scan, meta-iodobenzyl-guanidine (MIBG, chemical analog of norepinephrine) scan
  • Bone marrow biopsy

[edit] Staging

[edit] International Neuroblastoma Risk Groups (INRG)

Staging System; 2009 (PMID 19047290)

  • Stage L1 - Localized tumor not involving vital structures as defined by the list of image-defined risk factors and confined to one body component
  • Stage L2 - Locoregional tumor with presence of one or more image-defined risk factors
  • Stage M - Distant metastatic disease (except stage MS)
  • Stage MS - Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow

[edit] International Neuroblastoma Staging System (INSS)

Revised; 1993 (PMID 8336186)

  • Stage 1 - Localized tumor. Complete gross excision, with or without microscopic residual disease. Representative ipsilateral lymph nodes negative microscopically (nodes attached and removed with the primary tumor may be positive)
  • Stage 2A - Localized tumor with incomplete gross excision. Representative ipsilateral nonadherent lymph nodes negative microscopically
  • Stage 2B - Localized tumor with or without incomplete gross excision. Positive nonadherent ipsilateral lymph nodes. Enlarged contralateral lymph nodes negative microscopically
  • Stage 3 - Unresectable tumor infiltrating across the midline with or without regional lymph node involvement. Unilateral tumor with contralateral regional lymph node involvement. Midline tumor with bilateral extension by infiltration (unresectable) or by regional lymph node involvement
  • Stage 4 - Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver, and/or other organs (except as defined for stage 4S)
  • Stage 4S - Localized primary tumor as defined for Stage 1, 2A or 2B. Dissemination limited to liver, skin and/or bone marrow (in infants <1 year of age)


Original; 1988 (PMID 8336186)

  • Stage 1 - Localized tumor confined to the area of origin. Complete gross excision, with or without microscopic residual disease. Identifiable ipsilateral and contralateral lymph nodes negative microscopically
  • Stage 2A - Unilateral tumor with incomplete gross excision. Identifiable ipsilateral and contralateral lymph nodes negative microscopically
  • Stage 2B - Unilateral tumor with incomplete gross excision. Positive ipsilateral lymph nodes. Identifiable contralateral lymph nodes negative microscopically
  • Stage 3 - Tumor infiltrating across the midline with or without regional lymph node involvement. Unilteral tumor with contralateral regional lymph nodes involvement. Midline tumor with bilateral regional lymph node involvement
  • Stage 4 - Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver, and/or other organs (except as defined in stage 4S)
  • Stage 4B - Localized primary tumor as defined for Stage 1 or 2. Dissemination limited to liver, skin and/or bone marrow


[edit] Previous staging systems

  • Children's Cancer Study Group (CCSG); 1971 - PMID 5100400. PMID 7370930 (1980)
    • Clinical staging. Stages I, II, III, IV, and IV-S. Criticized because tumor resectability did not influence staging
  • St. Jude / POG; 1983 - PMID 6848729 (1983)
    • Surgicalpathologic staging. Stages A, B, C, D, and DS
  • UICSS; 1983


[edit] Risk groups

INRG Risk Groups; 2009 (PMID 19047291)

  • Prognostic factors: INRG Stage (see above), Age, Histology, Grade, MYCN, 11q aberration, Ploidy
  • Risk groups: Very low, Low, Intermediate, High


POG Risk Groups:

Risk group INSS stage Age N-Myc amplified Histology Shimada ploidy
Low Stage 1 any any any any
Low Stage 2A/B any except as below any any any
Low Stage 4S Infant No any >1
Intermediate Stage 3 Infant No any any
Intermediate Stage 3 >1 yr No Favorable any
Intermediate Stage 4 Infant No any any
Intermediate Stage 4S Infant No Unfavorable any
Intermediate Stage 4S Infant No any =1
High Stage 2A/2B >1 yr Yes Unfavorable any
High Stage 3 Infant Yes any any
High Stage 3 >1 yr Amp or Unfavorable any
High Stage 4 Infant Yes any any
High Stage 4 >1 yr any any any
High Stage 4S Infant Yes any any
  • Stage 1-2 - always low risk
  • Stage 3 - intermediate or high risk
  • Stage 4 - intermediate or high risk
  • Stage 4S - can be low, int, or high risk

[edit] Patterns of spread

Metastasis to: lymph nodes, liver, bone marrow, subcutaneous tissue.

[edit] Studies

Risk-related therapy:

  • POG 8743 - PMID 9060959 — "Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study." Bowman LC et al. J Natl Cancer Inst. 1997 Mar 5;89(5):373-80.
    Infants. Treated with standard chemotherapy. Showed that pts who were hyperdiploid had more favorable responses compared to diploid pts. NYMC gene amplification and elevated LDH were predictive for worse outcome.
  • POG 9243 -
  • POG 8742 and POG 9244 - PMID 9516866 — "Event-free survival of children with biologically favourable neuroblastoma based on the degree of initial tumour resection: results from the Pediatric Oncology Group." Strother D et al. Eur J Cancer. 1997 Oct;33(12):2121-5.
    Pts > 1 yr old, INSS Stages 2B and 3.

[edit] Low-risk

  • POG 9641 (1998-ongoing?)
    • Purpose: supportive-care only for low risk disease
    • Pts with biologically-defined low-risk disease. Treatment with surgery followed by observation. Chemotherapy reserved for recurrence.


  • GPOH NB95-S and NB97 (Germany)(1995-2004)
    • Prospective. 340 infants, age <1 year, with Stage 1-3, and MYCN-. Surgery if risk of operation was low (56%); chemotherapy only if threatening symptoms (17%). 93 patients (27%) observed with U/S q6 weeks and MRI q3 months.
    • 2008 PMID 18349403 -- "Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97." (Hero B, J Clin Oncol. 2008 Mar 20;26(9):1504-10.)
      • Subset analysis of 93 patients who were observed only.
      • Outcome: spontaneous regression 47%, no change 11%, local progression/stage 4S progression 38%, stage 4 progression 4%. Time-to-regression variable, 1-18 months after diagnosis, in 34% patients >1 year. Median OS, 3-year OS and MDFS not different from patients treated with surgery or chemotherapy
      • Conclusion: Spontaneous regression seen regularly in infants with localized neuroblastoma, and not limited to first year of life. Wait-and-see strategy justified

[edit] Stage 1-2

Surgery alone:

  • POG 8104 / POG 8441 (1981-86)
    • Prospective. 101 pts with POG / St Jude Stage A (same as INSS 1 but allows for lymph nodes adherent to tumor but removed in resection). Protocol allowed all stages, but this report focuses on Stage A.
      • Treatment: Surgical excision alone.
    • PMID 3411339, 1988 — "Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study." Nitschke R et al. J Clin Oncol. 1988 Aug;6(8):1271-9.
      • 2-yr DFS 89%
    • Conclusion: surgery is sufficient treatment for Stage A (equivalent to Stage 1).

[edit] Stage 3-4

High risk:

  • CCG 3891 (1991-96)
    • Randomized. 539 pts. High-risk, Evans Stage IV, or Stage III with MYCN amplification, elevated ferritin, or unfavorable histology.
      • Initial chemotherapy: 5 cycles of cisplatin, doxorubicin, etoposide, and cyclophosphamide. Surgery and RT: given between cycles 4+5 for gross residual disease.
      • Randomized to: 1) Myeloablative therapy and ABMT with TBI vs. 2) intensive nonmyeloablative chemo (cisplatin, etoposide, doxorubicin, ifosfamide x 3 cycles)
      • 2nd randomization: +/- 6 cycles of 13-cis-retinoic acid (isotretinoin)
    • PMID 10519894, 1999 — "Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group." Matthay KK et al. N Engl J Med. 1999 Oct 14;341(16):1165-73.
      • 3-yr EFS 34% (ABMT) vs 22%, 46% (retinoic acid) vs 29%.
    • Conclusion: survival benefit for ABMT and 13-cis-retinoic acid in high risk pts.

[edit] Stage 4S

  • CCG 3881 (1989-95)
    • Prospective. 80 pts. Evans Stage IV-S (concordant with INSS 4S). Surgical staging in 49. Trial enrolled good, intermediate, and selected poor-risk neuroblastoma, but report focuses on Stage IV-S pts only.
      • Treatment: supportive care only. 31 pts had resection. Chemo +/- RT was given for rapid tumor growth and compromise of vital organs.
    • PMID 10653863, 2000 — "Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study." Nickerson HJ et al. J Clin Oncol. 2000 Feb;18(3):477-86.
      • Median f/u 43 mos. 5-yr EFS was 86%, OS 92%. Supportive care alone was possible in 57% of pts. EFS worse for infants < 2 months age. Favorable histology in 96%, no pts had MYCN amplification.
    • Conclusion: many pts with Stage 4S have excellent survival with no therapy.

[edit] Abdominal neuroblastoma

  • Emory; 2005 PMID 16302219 -- "Comparison of conventional to intensity modulated radiation therapy for abdominal neuroblastoma." (Paulino AC, Pediatr Blood Cancer. 2005 Nov 21; [Epub ahead of print])
    • Retrospective. 6 children, 3 different RT techniques compared
      • Technique A: parallel-opposed AP/PA fields to midline
      • Technique B: IMRT, CTV = tumor after chemo + 1.5 cm margin; PTV = CTV + 0.5 cm margin
      • Technique C: as B + vertebral bodies included in PTV
    • Conclusion: "Dose to the PTV and CTV were not significantly different using the three techniques. Although Technique C was the best method of RT delivery in midline tumors with respect to kidney doses, this was at a cost of a higher mean dose to the liver, stomach, and spleen. This, together with the theoretical increase in secondary malignancies, should be considered when treating a child with IMRT techniques. IMRT was not found to be better than the conventional AP/PA field for lateralized tumors."

[edit] Treatment guidelines

  • Low-risk: Surgery alone. Chemotherapy for persistence or recurrence (carbo/etoposide or carbo/cyclophosphamide/doxorubicin)
  • Intermediate-risk: Surgery then chemotherapy. Short course of chemotherapy (4 courses) if favorable histology. Longer course (8 courses) if unfavorable histology. Radiation therapy (18 to 30 Gy) for local persistence or recurrence of disease.
  • High-risk: Initial resection or biopsy. Aggressive course of chemotherapy. Maximal surgical resection to achieve a complete response or debulk tumor. RT to primary and metastatic sites dependent on response. Myeloablative therapy and ABMT.


[edit] Radiation technique

Fields should cover primary site and draining lymphatics.

  • Children < 18 months: 15 Gy + 5-10 Gy boost
  • Older children: 15-20 Gy + 5-10 Gy boost
  • Stage 4S: 450 cGy in 3 fractions (150 cGy/fx) for liver.

[edit] External links

  • [1] - Good resource with staging, etc.
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