Neuroblastoma

Topic overview

Drs Erika Newman, Dan von Allmen and Tony Sandler join Dr. Todd Ponsky in a discussion covering the latest in neuroblastoma.

Contributing editor: Rachel (Rae) Hanke, MD

Case 1: Mother who presents with 26 week fetus with a prenatal diagnosis of a left sided supra-renal mass. Work up was otherwise normal.

• Adrenal hemorrhage, neuroblastoma, pulmonary sequestration, misdiagnosed renal anomaly, etc.

Family counseling?

• Reassurance and focus on healthy pregnancy

• Be sure to assess familial history of neuroblastoma

• No further testing needed

• Plan for further evaluation after birth.

Case 1 continued: Uneventful birth at 38 weeks.

• Post-natal evaluation:
• Physical exam—ensure they’re otherwise healthy
• Labs:
• Urine catecholamines
• Imaging:
• Abdominal ultrasound
• Potentially MIBG (if catecholamines are high)
• No need for CT scan at this point
• Bone marrow biopsy (if MIBG shows bone metastasis)
• MIBG scan:
• Characterize primary lesion (MIBG avid or not)
• Evaluate for metastasis
• Perinatal phase: most often in liver, bone, skin and lymph nodes

Case 1 continued: Urine catecholamines are positive but MIBG is only positive for suprarenal mass.

• Observe?
• Conversation and decision made with family
• Be sure family knows we don’t have a tissue diagnosis until the mass is removed—may be something else!
• Can safely observe neonates with close surveillance via urine catecholamines and serial abdominal ultrasounds
• Avoid surgery and chemotherapy
• Even if mass increases in size and is later removed, low risk of being high risk tumor
• Surveillance:
• Frequency varies, but generally for the first year:
• Assess ultrasound and catecholamines: at Birth, 3 weeks, 6 weeks, 12 weeks, then 1 year (if stable)
• At 1 year increase interval to every 6 months; followed by oncologists beyond that
• Reference: A Prospective Study of Expectant Observation as Primary Therapy for Neuroblastoma in Young Infants, a Children’s Oncology Group Study by Jed Nuchtern et al. http://bit.ly/34ToHV7
• Operate?
• Indications:
• Overall size: 5cm
• Increasing in volume by ≥ 50%
• Increase in VMA or HVA (urine catecholamines) by ≥50%
• Laparoscopic vs open?
• Newman/von Allmen:
• If <6cm, try laparoscopic
• No need for lymph node sampling (not like Wilms tumor)

Case 1 variation: The child has skin lesions and liver metastasis.

• Changes the stage to M (old staging = 4S)
• Biology tends to be "good”
• Risks:
• Local compression or abdominal compartment syndrome
• Can result in respiratory compromise
• Treatment
• No distress: aggressive observation
• Some compromise:
• Biopsy and verify staging
• Chemotherapy or radiation
• Acute decompensation:
• Decompressive laparotomy
• Do you biopsy skin lesions or metastasis?
• Classic findings: blue blebs skin lesions, liver metastasis, adrenal mass, elevated urine metanephrines—no need to biopsy
• If you’re performing emergent laparotomy, then biopsy the easiest lesion
• Avoid sampling the liver as it bleeds easily
• Consider biopsy to determine N-Myc amplification level

Case 2: Otherwise healthy 3-year-old with incidentally found centralized abdominal mass.

• Initial evaluation:
• History and physical:
• Any other illnesses, family history, past medical history (including diarrhea—VIP excretion)
• Labs: CBC, CMP, amylase, lipase, LDH, urine catecholamines
• Imaging:
• Ultrasound (solid vs cystic)
• If solid mass also get a CT scan

Case 2 continued: CT scan shows 10cm mass with microcalcifications, more solid than cystic, that encases aorta and celiac axis.

• Evaluation?
• Oncology consult
• Bone marrow biopsy
• Abdominal CT scan (already done)—MRI is an option
• MIBG
• Chest CT (evaluate for metastasis)
• Head CT (if there are symptoms)
• Biopsy for pathology and biology
• Do you need a PET scan?
• If MIBG-avid, it’s not really needed in initial work up
• 10% of neuroblastomas are not MIBG-avid, and may be picked up on PET scan
• Laparoscopic vs percutaneous vs open biopsy
• Sandler: Open biopsy
• Retroperitoneal approach through most lateral part of incision (posterior-lateral approach)
• Notes concern for increased difficulty controlling bleeding with a peritoneal approach
• Uses pledgeted sutures and packs with Surgicel® to control bleeding
• N-myc, Alk mutation, biology for pathology, diploid status of tumor
• Newman: Percutaneous (most of the time)
• Working to standard approach with interventional radiology, pathology and surgery
• 80% of biopsies at C.S. Mott are percutaneous, most often retroperitoneal
• Approximately 50% of children’s hospitals use percutaneous biopsy for masses suspicious for neuroblastoma
• Evidence: percutaneous biopsies are equally as good at getting a diagnosis, determining high vs low risk, and evaluating N-Myc amplification
• It cannot determine loss of heterozygosity (for 11q)
• Ways to optimize percutaneous biopsy:
• Immediate evaluation by pathologists (frozen section)
• Get 10-12 core biopsies
• Standardizing highergauge needle
• Open biopsies increase risk for blood transfusions, need for narcotics and need for hospital admission
• Von Allmen: Percutaneous (most of the time)
• If tumor is amenable, interventional radiology performs percutaneous biopsy
• Embolize tract on the way out to minimize risk of bleeding

Case 2 continued: Biopsy shows no N-Myc amplification

Staging from the International Neuroblastoma Risk Group:

• Pre-treatment risk group based on several factors:
• Patient age, histologic category, tumor differentiation, N-Myc status, presence of ploidy, and aberration of 11q
• Will categorize them into very low, low, intermediate or high risk
• Think of it like imperforate anus:
• Generalize into low and high imperforate anus
• Low generally does well and high generally doesn’t
• Most important factors:
• N-Myc status
• If amplified its automatically high risk disease
• Non-amplified is more likely to be low or intermediate risk disease
• Loss of heterozygosity (LOH) at 11q
•  Can also automatically make intermediate or high risk disease
• Age is important, but not as important as N-Myc or LOH status
• < 18 months = better outcomes
• >18 months = worse outcomes
• Most important in determining risk of child with metastatic disease
• Outcomes:
• Generally, low or intermediate risk = good outcomes, high risk = poor outcomes
• Reference: http://bit.ly/2RtEk1M and http://bit.ly/2PgNRq8

Case 2 continued: Biopsy shows N-Myc amplification.

• Treatment:
• Need central access
• von Allmen:
• Often obtain biopsy, bone marrow sample and place line under same anesthesia exposure
• Consider double lumen central line for bone marrow transplant based on presumed high risk of patient
• Timing of surgery in relation to chemotherapy cycle:
• COG protocols call for OR after cycle 5
• von Allmen: operate before cycle 4 or 3 if possible
• Newman: operate between cycle 3 and 4
• Operation more challenging after 5 or 6 cycles as tumor becomes more fibrotic
• Sandler: Resect around 4th or 5thcycle
• Reference: Kinetics of primary tumor regression with chemotherapy: implications for the timing of surgery. MP LaQuaglia.  http://bit.ly/2YpoWoi

Surgical Approach:

• Data somewhat conflicting on high risk neuroblastoma disease regarding extent of resection (e.g. remove ≥90% of disease)
• All agree we should resect as much as possible without risking bad outcomes
• Leave behind vasculature and nerves
• No need to cause disability
• Radiation and aggressive surgery can result in great local control of disease
• Metastasis, not local recurrence, is what kills patients in neuroblastoma
• Operative tips:
• Start away from tumor and follow healthy blood vessels to the tumor, and remove what you think is safe
• If it comes off easily, keep going; if it doesn’t, then stop
• There is no correlation between the findings on post-operative imaging and findings reported in the operative note
• We don’t know what we are leaving behind

Immunotherapy:

• Monoclonal antibody against Gangliocyte GD2 for high risk disease
• Improved survival from 46% to 60% in 2 years
• Ultimate survival not evaluated
• Neuroblastoma is not an immunogenic tumor
• The difference will be making neuroblastoma an immunogenic tumor

Intro and outro tracks are adapted from "I dunno" by grapes, featuring J Lang, Morusque. Artist URL: http://bit.ly/38oiDGq

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