Neuroblastoma

Epidemiology

  • Most common extracranial childhood tumor.
  • 10% of all pediatric tumors.
  • These tumors can spontaneously regress and are less aggressive in children under 1 year old.

Pathology

  • Tumors arise from neural crest cells of the adrenal medulla and sympathetic ganglion system
  • There are 3 subtypes that increase with degree of differentiation: neuroblastoma, ganglioneuroblastoma, and ganglioneuroma.
  • It appears there are neuroblastoma-like cells in utero and there may be an aberration in the normal process to cause tumor growth.
  • NB has small round blue cells with hyperchromatic nuclei and scant cytoplasm. These cells can form pseudorosettes.
  • Neuronspecifc enolase (NSE) is a substance that has been detected in patients with certain tumors, namely: neuroblastoma, small cell lung cancer, medullary thyroid cancer, carcinoid tumors, pancreatic endocrine tumors, and melanoma.
  • Ganglioneuromas are benign and no therapy needed.
  • Ganglioneuroblastomas are less aggressive than NB but requires similar treatment.

Presentation

  • Excess catecholamines can be produced causing flushing, HTN, sweating.
  • 60% present with metastatic disease
  • Bone, bone marrow, liver lymph nodes, skin.
Mass Effects
Racoon eyes
(orbit)
Proptosis and periorbital ecchymosis occurring with retrobulbar or orbital metastases
Blueberry muffin
(skin)
Occurs with cutaneous metastases in an infant (Stage 4s).
Pepper Syndrome
(abdomen)
Massive hepatomegaly +/- respiratory distress
Hutchinson’s
(bone)
extensive skeletal metastases, particularly skull; proptosis (metastases to orbit); bone pain
Neurological Effects
Dumbbell tumors Tumors arise in paraspinal sympathetic ganglia and invade through the neural foramina possibly causing cord compression
Horner’s Ptosis, miosis, anhydrosis in the ipsilateral face
Paraneoplastic Syndromes
Opsomyoclonus Myoclonic jerking and random eye movement +/- ataxia
Kerner-Morrison Intractable secretory diarrhea due to VIP secretion

Workup

  • CT/MRI scan of area of suspicion, CXR, MIBG scan, Bone scan
  • BM aspirate
  • CBC, Chem 20, ferritin, Neuron specific enolase
  • Urine Catacholamines (homovanillic acid HVA or vanillylmandelic acid VMA) that are used for diagnosis, prognosis, and follow-up. If find increased levels in the urine + positive BM then sufficient for diagnosis of NB.
  • Either diagnosis with tissue +/- urine metabolites or BM with tumor with increased metabolites.

Staging

International staging system (INSS) 5 year OS
Stage I 90% Localized, GTR, LN\’s neg. (LN\’s attached & removed w/primary may be positive).
Stage IIa 80% Localized w/ STR, ipsilateral LN negative.
Stage IIb 70% Localized w/ STR or GTR, __ipsilateral __LN\’s positive. Contra LN\’s must be negative.
Stage III 60% # tumor crosses midline - unresectable midline tumor w/bilat extension __contra __or bilat + LN’s
Stage IV 20% Disseminated disease to LN’s, bone, BM, liver, skin and/or organs (except 4s).
Stage IVs 90% Pt <1 yo, stage I-IIb (localized) w/ BM (not bone), Skin, or Liver involvement only (BSL)

INSS risk-group

Risk 5-OS Stage 1 Stage 2 Stage 3 Stage 4 Stage 4S
Low-risk 96% any age any age MYCN- m-MYC-; FH; DI> 1
Intermediate-Risk 93% < 1 yr. < 1 yrs. and MYCN- m-MYC-; UF
> 1 yrs. w/o any other unfavorable factors
High-Risk
age < 1
28% < 1 yrs AND {mycn(+) AND unfavorable Shimada} < 1 yrs AND mycn(+) m-MYC+ OR
m-MYC- and DI = 1
age > 1 > 1 yrs AND {mycn(+) AND UH} > 1 yrs AND {mycn(+) OR UF} > 1 yrs N/A

FH = Favorable Shimada
UH = Unfavorable Shimada

Shimada

Shimada et, JNCI 73:405, 1984 evaluated the effects of histologic appearance, age @ Dx, and the MK index. Age <1.5 was better than 1.5–5 yrs, which was better than >5 yrs. Low MKI (<200 for age <1.5 yrs or <100 for age ≥1.5 yrs) was better. Looking closer at SP histology: Age <1.5 and MKI <200…or…Age 1.5-5, differentiated with MKI <100 correlated with OS \~85%. All others had OS \~5%.

Shimada good prognostic factors.

  • young age (less than 1 to 1.5 year)
  • low MKI (mitotic index)
  • differentiated histology

Favorable factors

  • N-myc = 1
  • DNA Index (DI) > 1 (hyperdiploid, triploid, ect.)
  • age < 1

Poor prognosis

  • Deletion at chromosome 1 at 1p36 locus,
  • N-myc amplification (N-myc > 1)

Treatment overview

Low-risk (Surgery alone)

  • Chemotherapy is reserved for patients who are symptomatic, such as from spinal cord compression or, in stage 4S, respiratory compromise secondary to hepatic infiltration. The chemotherapy consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide.

Intermediate-risk (Surgery and chemo)

  • Patients categorized as intermediate risk are treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described above.

High-risk (add RT)

  • Multiagent chemotherapy consisting of very high doses of the drugs listed above
  • Then resection of the primary tumor
  • followed by myeloablative chemotherapy or sometimes TBI, and autologous stem cell transplantation.
  • Radiation of residual tumor and original sites of metastases is often performed before, during, or after myeloablative therapy.
  • Both myeloablative therapy and retinoic acid improve outcome in patients categorized as high risk.** **
  • Stage 4S (observation)
  • Often undergo spontaneous regression with survival of 75-90%
  • Small infants may need low dose RT (150QD x 3)or chemotherapy to decrease the size of the mass so alleviates symptoms.
  • Evans-D\’Angio (Nickerson JCO 2000:18477)
  • Observation, chemo, RT or CRT. 5 year OS 100% for observation and 81% for patients who needed chemo for progression on symptoms. 5 of 6 deaths in patients who are < 2 mo old.

Radiation Treatment

  • Radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy, or for intermediate-risk patients whose tumor has responded incompletely to both chemotherapy and attempted resection and also has unfavorable biologic characteristics.

High-risk patients

  • 20-27 Gy RT to primary site and to areas of residual

POG study by Castleberry, et al JCO 9(5):789,1991 reported on 62 pts (age > 12 mos) w/ POG C disease. After best resection, pts randomized to receive AC x 5 ± RT (1.5 Gy/fx QD. Age 12 – 24 mos: total dose = 18 – 24 Gy; age ≥ 24 mos: total dose = 24 – 30 Gy, with lower doses reserved for abdominal or thoracic paravertebral 10 and supraclav nodes). 2nd look surgery and consolidation chemo (AC & P/VM if CR or P/VM alone if no CR). **Conclusion: **Response, DFS, and OS for patients > 12 mos is improved with the addition of post-op primary tumor bed RT.

Arm % CR DFS OS
AC x 5 46% 32% 41%
AC x 5 & RT 76% 59% 73%
p value 0.013 0.009 0.008

CCG: Haas-Kogan, IJROBP 56(1):28, 2003. 539 pts. CCG-3891. Chemo, primary surgery, and 10 EBRT to gross residual disease randomized to continuation chemo vs 10 Gy TBI and auto BMT. 22 vs 52% local recurrence rates repectively (p = 0.2).Conclusion: 20 Gy improved local control compared to 10 Gy.

Marcus "34 DAT" showed 97% local control rate at 3 years with 52 stage 4 or high-risk stage 3: 5 cycles of induction chemotherapy, surgical resection of the primary tumor when feasible, local radiotherapy (10.5-18 Gy), and then consolidation with tandem myeloablative cycles with autologous peripheral blood stem cell rescue (the second of the myeloablative regimens included 12 Gy of total body irradiation). Conclusion local control rate is excellent with current RT regiment (ie. No need for higher doses).

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