1. Jennifer R. Stevane General Surgery Resident VMMC
Neuroblastoma
Jennifer R. Stevane
General Surgery Resident
VMMC

2. Patient 1 3 yo M, hx of hypotonia, gross motor delay
abdominal mass on PE
AXR  constipation
Pertinent labs:
Elevated screening urine HVA, VMA
serum HVA 828 (nl 0-45); VMA 496 (nl 0-30)
Ultrasound
17x13x11 cm calcified heterogenous mass,
Crosses midline, encases abdominal vessels
Abuts liver, spleen, displaces kidneys
Encases the portal vein and a branch of the celiac artery, abuts the liver and spleen, and displaces both kidneys inferiorly

3. Initial CT scan
CT of the chest, abdomen, and pelvis: Large heterogeneous mass in the retroperitoneum effacing the left adrenal gland and much of the right adrenal gland which may represent a bilateral adrenal neuroblastoma. There are areas of calcifications throughout and multiple abdominal vessels are encased or abutted, including the aorta, IVC, renal vessels, hepatic arteries, and aspects of the celiac plexus. No evidence of metastatic disease.

4. Obtaining a diagnosis Findings c/w neuroblastoma
General surgery consulted for:
open biopsy,
bilateral bone marrow aspirates,
double lumen catheter placement

5. -CONSIDERED FAVORABLE HISTOLOGY-
Patient K’s pathology
Mix of small round blue cells with well-differentiated ganglion cells
Low mitotic kerryorhectic index
Negative MYCN amplification by FISH
Negative for PHOX2B mutation
-CONSIDERED FAVORABLE HISTOLOGY-
Bone marrow aspirate negative for metastatic disease

6. Further work-up Bone scan: negative for metastatic disease
MIBG scan: negative for metastatic disease
Echo: wnl
Audiology: normal hearing
-Chemotherapy agents are potentially cardio-toxic (doxorubicin) and ototoxic (carboplatin.)
-mIBG is functional analog of norepinephrine and is taken up by sympathetic neurons. If test is positive, neuroblastoma is said to be “mIBG-avid.” Radioactive components such as I-131 may be added and can be used to trace response to chemotherapy or even act as targeted radiation therapy.

7. Plan INTERMEDIATE RISK: Chemotherapy Surgical resection 4 rounds
Carboplatin, etoposide, doxorubicin, cyclophosphamide
Surgical resection

8. Post chemo CT scan, preoperatively
Only ~30% tumor resectable.

9. Outcome Final Pathology: Plan: Recover from surgery
Multiple areas of treated metastatic disease
Areas of less and more differentiation
Still considered favorable histology
Plan:
Recover from surgery
Increased intensity of chemotherapy

10. Neuroblastoma Most common extracranial solid tumor of childhood
Most common abdominal malignancy of childhood
8-10% of all childhood cancers
15% cancer deaths
Incidence has remained stable in past few decades
Similar rates amongst race, female: male ratio
Ave age dx = 2 years
80% pts <4yo at time of diagnosis
Spontaneous regression in rare cases
1% familial cases, younger diagnosis

11. Presentations 65% abdominal; >50% adrenal in origin
Chest (#2), neck and pelvis as well
50% localized or regional disease at diagnosis
Abdominal symptoms
Neurological symptoms
Paraneoplastic syndromes
Abdominal: distention, constipation, palpable mass
Neurologial: Horner’s syndrome (ptosis, miosis, anhydrosis) if arising from superior cervical ganglion
Paraneoplastic: eg opsoclonus myoclonus ataxia syndrome- myoclonic jerking, random eye movement with or without cerebellar ataxia, may not resolve w/ tumor removal, neurologic degeneration

12. Work-up Thorough H&P Establish diagnosis Rule out metastatic disease
Imaging
Bone scan, mIBG, CT C/A/P
Laboratory work
LFTs, derivatives of catecholamines (HVA, VMA)
Pathological evaluation of actual tissue
Ie. Open biopsy
Hematogenous and lymphatic spreading tumor, so the path of metastasis could lead virtually anywhere but often to bone, bone marrow, and liver

13. Neuroblastoma tissue Derived from sympathetic nervous system
Sympathetic ganglia, adrenal medulla, paraganglia
“Small blue round cell”
Form nests surrounded by stromal septa
Spectrum of maturation amongst tumor cells
Undifferentiated
Poorly differentiated
Differentiating
Histology significantly impacts prognosis

14. Genetics PHOX2B 3 exons, codes for transcription factor
PCR amplification used for evaluation
Associated with congenital central hypoventilation syndrome, Hirschsprung’s disease
Familial neuroblastoma
2.3% sporadic neuroblastoma cases
Multiple genetic investigations for neuroblastoma, would briefly review the two evaluated for this patient.
PHOX2B:
Congenital central hypoventilation syndrome, hirschsprung’s are also neural crest tumors.
A distant relative on mother’s side had neuroblastoma

15. Genetics MYCN Leads to p53 inhibition
Amplified in 25-35% of neuroblastomas
>10 copies
FISH analysis
Mechanism of amplification unknown
Indicates more aggressive tumor
Less favorable outcome
Therefore…included in COG risk stratification

16. INSS (Staging: 1986, 1993)
Stage 1: localized tumor confined to area of origin
Stage 2: Unilateral tumor
2A: incomplete gross dissection, no LNs
2B: ipsilateral LNs positive for metastatic disease
Stage 3: Tumor extends across the midline, +/-LNs
Unilateral tumor w/ contralateral LNs
Midline tumor w/ bilateral LNs
Stage 4: Dissemination to distant LNs, bone marrow, liver
Stage 4s: <1yo with localized primary tumor as in stages 1-2, with limited spread to liver, skin, marrow
International neuroblastoma staging system
Stage 1: Localized tumor confined to the area of origin.Stage 2A: Unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor.Stage 2B: Unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor.Stage 3: Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement.Stage 4: Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S.Stage 4S: Age <1 year old with localized primary tumor as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors).

17. Risk Assessment

18. Prospective cohort analysis, 1990-2002
The International Neuroblastoma Risk Group (INRG) classification system: An INRG Task Force report (J Clin Oncol 2009)
Prospective cohort analysis,
8800 children w/ neuroblastoma, worldwide
Inclusion: diagnosis confirmed b/t , <21yo, informed consent
evaluate prognostic factors
Primary end-point: Event free survival
7 most significant prognostic factors identified
prognostic factors:
age > or < than 12 months and 18 months, year of enrollment in study, Initial treatment, INSS stage, Evans stage, serum ferritin, LDH, histologic classification, stromal content, grade of NB cell differentiation, mitosis-karyorrhexis index, genetics such as MYCN amplification

19. International Neuroblastoma Risk Group (INRG)
Being validated, may replace INSS, used internationally
Stage L1: Localized disease without image-defined risk factors.Stage L2: Localized disease with image-defined risk factors.Stage M: Metastatic disease.Stage MS: Metastatic disease "special" where MS is equivalent to stage 4S.
Very low risk: 85% EFS
Low risk: 75-85%
Intermediate risk: 50-75%
High risk: <50% EFS

20. Our pt, revisited 3yo Differentiating Low MKI Favorable histology
No comment on tumor ploidy
Neuroblastoma diagnosis
If L2, then low risk
If M, then high risk

21. Treatment Low risk: Intermediate risk: High risk: No treatment
Surgery alone
Intermediate risk:
Chemotherapy, surgery
High risk:
Intensive chemotherapy, surgery, radiation, stem cell transplant, biologic tx w/ accutane or mAB tx (GM-CSF, IL-2) \

22. Prospective treatment cohort study 262 patients, enrolled 1992-1996
Outcomes of children with intermediate-risk neuroblastoma after treatment stratified by MYCN status and tumor cell ploidy (J Clin Oncol 2005)
Prospective treatment cohort study
262 patients, enrolled
Treatment assignments based on:
Age, MYCN status, tumor cell ploidy.
Age 12 mos
MYCN>10 copies classified as “amplified”
Ploidy- diploid, hyperdiploid

23. Arm A: Arm B: Inclusion criteria
Outcomes of children with intermediate-risk neuroblastoma after treatment stratified by MYCN status and tumor cell ploidy
Arm A:
Inclusion criteria
5 cycles cyclophosphamide/doxorubicin, surgery
214 patients, 178 (83%) received only Arm A
If poor response, then cross over to Arm B
6yr event free survival 86%
Arm B:
Inclusion criteria ***MYCN amplification, cell ploidy
6 cycles carboplatin, etoposide, ifosfamide, surgery
48 pts, 46/48 <1yo,
6yr event free survival 46%, 26/48 deaths
Arm A infants w/ stages B-D and DS w/o MYCN amplification and hyperdiploid OR children >12mos w/ stage B MYCN nonamplified tumors of any ploidy.
Arm B infantsyounger than 12 mos with stages B-D or DS disease w/ MYCN amplification

24. Significance of both MYCN amplification and ploidy in risk assessment
Outcomes of children with intermediate-risk neuroblastoma after treatment stratified by MYCN status and tumor cell ploidy
Excellent response rates for intermediate-risk pts w/ favorable biology on pathology
Significance of both MYCN amplification and ploidy in risk assessment
Arm A regimen chemotherapy was less toxic than Arm B chemotherapy
???Benefit of reducing therapy in patients with favorable tumors?

25. Prospective, nonrandomized, Stage 3 trial
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
Prospective, nonrandomized, Stage 3 trial
Purpose: achieve a 3yr estimate of >90% overall survival utilizing outpt chemotherapy in children w/ intermediate risk neuroblastoma
Inclusion, :
Infants (<1yo) and children w/ newly diagnosed intermediate risk neuroblastoma w/o MYCN amplification
Standard treatments have rates of survival in this population of approximately 90% at 3 years, the study was hoping to exceed that.
Intermediate risk = stage 3 or 4 disease, stage 3 w/ favorable histology, infants with 4S disease.

26. MYCN determined by FISH
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
MYCN determined by FISH
DNA index for ploidy performed w/ flow cytometry
Favorable = favorable histology, DNA index>1
Unfavorable = unfavorable histology, DNA index <1, or both

27. Treatment Favorable: Unfavorable: 4 cycles
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
Treatment
Favorable:
4 cycles
Carboplatin, etoposide, cyclphosphamide, doxorubicin combinations
Surgical excision after chemotherapy
Unfavorable:
8 cycles of the above chemotherapy agents
3 week intervals
Those who did not respond to the reduced treatment were then given an additional 4 cycles as in the unfavorable group.
Monitored for toxicities

28. Primary end point: overall survival at 3 yrs
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
Intention to treat
Event free survival
Overall survival
Primary end point: overall survival at 3 yrs
Expected overall survival 90% at 3 yrs
Considered cured
Expected treatment failure 10%

29. 31 infants with stage 4s disease 323 favorable pathology (reduced tx)
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
270 stage 3 disease
178 stage 4 disease
31 infants with stage 4s disease
323 favorable pathology (reduced tx)
141 unfavorable pathology (extended tx)
138/323 in reduced tx arm received 4 additional cycles of chemotherapy
Patient characteristics

30. Surgical resection data for 235/479 pts
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
Surgical resection data for 235/479 pts
99.6% definitive excision attempted
89 total resection
51 near total (>90% tumor)
26 major resection (>50%)
54 limited resection (<50%)
14 unknown
No significant difference in overall survival b/t groups
Patient characteristics

31. Complications included: Surgical Chemotherapy related
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
Complications included:
Surgical
Eg. Hemorrhage, loss of organ, anatomical injury
Chemotherapy related
Eg. Myelosuppression, organotoxic effects, infxn
Patient characteristics

32. 3 yr overall survival: 3 yr EFS: Stage 3= 98% Stage 3= 92%
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
3 yr overall survival:
3 yr EFS:
Stage 3= 98%
Stage 3= 92%
Stage 4= 93%
Stage 4= 81%
Stage 4s= 97%
Stage 4s= 90%
Stage 3 and 4s vs 4 significant in both categories (p<0.002 and p<0.001 respectively)
Ploidy and favorable biologic features had significance in survival prognosis
Histopathological features did not
Patient characteristics

33. 59 first events documented:
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
59 first events documented:
Disease progression, n=42
Death, n= 14
Secondary leukemia, n= 3
10% for pts w/ favorable biological features
17% for pts w/ unfavorable biological features

34. -overall survival in 3 years 96% -importance of ploidy in prognosis
Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma (NEJM 9/30/2010)
Discussion-
-overall survival in 3 years 96%
-importance of ploidy in prognosis
-those w/ advanced neuroblastoma without MYCN amplification can be cured with reduced toxicity regimens
-high surgical complication rate
**SUCCESSFUL SURVIVAL RATES W/ LOWER DOSE AND DURATION CHEMOTHERAPY REGIMENS**

35. Bibliography
Bagatell et al. Outcomes of children with intermediate-risk neuroblastoma after treatment stratified by MYCN status and tumor cell ploidy. J Clin Oncol 2005;23:
Baker et al. Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 2010;363:
Cohn et al. The international neuroblastoma risk group (INRG) classification system: An INRG task force report. J Clin Oncol 2009;27:
Matthay. Neuroblastoma: Biology and Therapy. Oncology 11(12) 1997
Park et al. Neuroblastoma: Biology, Prognosis, and Treatment. Hematol Oncol Clin N Am 24 (2010) 65-86