Work-up & Staging

Question 1

Outline the workup for pts with suspected NB.

Answer 1

Suspected NB workup:

1. H&P
2. Labs: CBC, BUN/Cr, LFTs, serum markers, UA, urine catecholamines
3. Imaging of primary: CT C/A/P, abdominal US, or MRI abdomen/liver/spine
4. Workup of mets: bone scan, I-131 metaiodobenzylguanidine [MIBG] scan, bilat BM Bx, CT/MRI as needed

5, Pathology: DNA content, N-myc amplification, and cytogenetics

Question 2

Why is a BM Bx important in the workup of NB?

Answer 2

BM Bx may obviate the need for primary site Sg if the testing is positive and the clinical picture is clear.

Question 3

What % of NB pts have uptake on an I-131 MIBG scan?

Answer 3

∼90% of NB pts have uptake on an I-131 MIBG scan.

Question 4

What are the currently used NB staging systems?

Answer 4

As of 2010, most cooperative group trials use the International Neuroblastoma Staging System (INSS), which involves the extent of surgical resection. However, a new staging system that uses only pre-Tx factors has been developed: the International Neuroblastoma Risk Group (INRG). These 2 staging systems will likely be used concurrently to allow for comparisons b/t trials. (Monclair T et al., JCO 2009)

Question 5

Summarize the INSS staging system.

Answer 5

Stage 1: unilat localized tumor s/p GTR +/– microscopic residual Dz; ipsi LN–, though LNs attached and removed with the primary may be involved

Stage 2A: unilat localized tumor s/p STR only; ipsi LN–, though LNs attached and removed with the primary may be involved

Stage 2B: unilat localized tumor s/p GTR or STR with involved nonadherent ipsi LNs; enlarged contralat LN– microscopically

Stage 3: unresectable localized tumor extending across the midline +/– regional LN involvement; unilat localized tumor with contralat regional LN involvement; midline tumor with bilat involvement via LN or direct extension

Stage 4: distant Dz except as defined by stage 4S

Stage 4S: localized unilat primary as defined by stage 1, 2A, or 2B; distant Dz limited to the liver, skin, and/or <10% of BM in infants <1 yo

Question 6

What are the prognostic factors in NB per INRG?

Answer 6

Age, stage, histologic category, grade, N-myc amplification, 11p or 11q aberration, DNA ploidy

Question 7

Summarize the INRG staging system.

Answer 7

In the INRG system, locoregional tumors are staged L1 or L2 based on the absence or presence of 1 or more of 20 image-defined radiographic findings (IDRFs). These IDRFs generally affect whether or not a tumor is surgically resectable and to what degree, although resectability is ultimately surgeon-dependent. Metastatic tumors are defined as stage M, except for stage Ms, in which mets are confined to the skin, liver, and/or BM in pts <18 mos old. (Monclair T et al., JCO 2009)

Question 8

What is the INRG stage of an 8-mo-old pt with metastatic Dz to bone only?

Answer 8

An 8-mo-old pt with metastatic Dz to bone only is INRG stage M (only BM, liver, and skin mets qualify for stage MS).

Question 9

What is the INSS stage of a 14-mo-old pt with metastatic Dz to BM only?

Answer 9

A 14-mo-old pt with metastatic Dz to BM only is INSS stage 4 (only pts <12 mos old qualify for stage 4S).

Question 10

What 2 clinical factors are most predictive of cure in NB?

Answer 10

The 2 clinical factors most predictive of cure are age and stage at Dx.

Question 11

In children with metastatic Dz, what is the most important prognostic factor?

Answer 11

In children with metastatic Dz, age (<1 yo best) is the strongest prognostic factor, even more so than N-myc.

Question 12

The Shimada classification system divides NB into what 2 categories? What 5 features are used to classify pts in this system?

Answer 12

The Shimada classification system divides NB into favorable histology (FH) and unfavorable histology (UH). Favorable factors:

Stroma-rich

Age

Differentiation

Mitotic/karyorrhectic index

Nodularity

(Mnemonic: Dr. Shimada has a SAD MiNd)

Favorable tumors:

1. Age <1.5 yr: Poorly differentiated or differentiating NB, low/intermediate mitosis/karyorrhexis index
2. Age b/t 1.5–5 yr: Differentiating NB and low mitosis/karyorrhexis index
3. Ganglioneuroblastoma, intermixed (Schwannian stroma-rich) & ganglioneuroma histologies

Question 13

What 5 factors are used to classify NB pts into low-, intermediate-, and high-risk groups per the COG?

Answer 13

5 factors used to classify NB in COG low-, intermediate-, and high-risk groups:

1. Stage, INSS
2. Age
3. N-myc status
4. DNA ploidy
5. Shimada classification

(Mnemonic: SANDS, see Table 4-1)

Question 14

An NB pt with stage I Dz and N-myc amplification is in what risk group?

Answer 14

All stage I NB pts are low risk.

Question 15

Can a pt with N-myc amplification be classified as intermediate risk?

Answer 15

No. All NB pts with N-myc are either low risk or high risk.

Question 16

Summarize COG Risk Groups.

Answer 16

Question 17

What makes a stage 2 or stage 3 pt high risk?

Answer 17

Stage 2 pts are high risk if they have all 3 risk factors: (1) N-myc amplification, (2) UH, and (3) ≥1 yo.

Stage 3: either (1) N-myc amplification at any age, or (2) ≥1 yo & UH.

Question 18

What feature makes NB pts with stage 4S Dz high risk?

Answer 18

NB stage 4S pts are high risk if tumors are N-myc amplified.

Question 19

What features make NB pts with stage 4S Dz intermediate risk?

Answer 19

NB stage 4S pts are intermediate risk if tumors are not N-myc amplified and are either Shimada UH or have diploid DNA.

Question 20

In which COG risk group do NB pts most commonly present?

Answer 20

NB pts are most commonly high risk (55%). 30% are low risk.

Question 21

Estimate the 3-yr OS for low-, intermediate-, and high-risk NB.

Answer 21

NB 3-yr OS by risk group:

Low risk: 95%–100%

Intermediate risk: 75%–98%

High risk: <30%

Question 22

What % of stage 4S pts experience spontaneous regression?

Answer 22

Up to 85% of pts with stage 4S NB experience spontaneous regression. Thus, low-risk stage 4S pts can be observed.

Question 23

What is the appropriate staging work up for a patient with neuroblastoma?

Answer 23

Approximately 60% of patients present with metastatic disease and 80% to 90% of these patients have bone marrow involvement. Staging work up includes a CT or MRI of the primary site; bilateral iliac bone marrow aspirates and core biopsies; CT of the chest, abdomen, and pelvis; MIBG scintigraphy (bone scan if primary is not MIBG avid), and urinary catecholamines (vanillylmandelic acid and homovanillic acid).

Brisse, HJ, McCarville, MB, Granata, C, et al. Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project. Radiology. 2011;261(1):243-257.