Fig. 1The histological subtypes of metastatic tumor subtypes in bone marrow according to the subtypes of the primary tumors. Regardless of the primary tumor subtype, poorly differentiated or differentiating subtypes predominated at the time of diagnosis. NBU, neuroblastoma undifferentiated subtype; NBP, neuroblastoma poorly differentiated subtype; NBD, neuroblastoma differentiating subtype; GNBN, ganglioneuroblastoma nodular; GNBI, ganglioneuroblastoma intermixed; GNMI, ganglioneuroma maturing.
Fig. 2The histological features of primary and metastatic neuroblastic tumors in a representative case. (A) Primary tumor initially diagnosed as neuroblastoma (Schwannian stroma-poor), poorly differentiated subtype. (B) Primary tumor after multiple cycles of chemotherapy showing maturation evidenced by scattered differentiating neuroblasts in Schwannian stroma and fibrosis. (C) Metastatic tumor in bone marrow at initial diagnosis composed of undifferentiated neuroblasts in neuropil. (D) Metastatic tumors in bone marrow after chemotherapy showing differentiating neuroblasts or ganglion cells in Schwannian stroma.
Fig. 3Time course of histological maturation of metastatic foci in bone marrow in a single case. (A) Metastatic neuroblastic tumor (NT) in bone marrow at initial diagnosis comprised of undifferentiated neuroblasts with neuropil. (B) Metastatic NT in bone marrow after nine cycles of induction chemotherapy two months after diagnosis. Differentiating neuroblasts are seen in a background of Schwannian stroma. (C) Ganglion cells appear in a background of Schwannian stroma ten months after the initial diagnosis without additional chemotherapy.
Fig. 4Newly developed poorly differentiated neuroblastic tumor (NT) in bone marrow after multi-cycle chemotherapy in a single case. (A) Poorly differentiated neuroblasts in the background of neuropil in bone marrow at the initial diagnosis. (B, C) Metastatic NT in bone marrow after multiple cycles of chemotherapy reveal progressive differentiation of tumor cells with Schwannian stroma at three months (B) and 19 months (C) after the initial diagnosis. (D) Newly developed metastatic NTs in bone marrow composed of poorly differentiated neuroblasts approximately five years after the initial diagnosis. This patient eventually died 2.5 months after the diagnosis of recurrence.
Table 1.Clinical characteristics of the patients
Variable |
|
No. of patients (%) (n = 48) |
Age (mo) |
< 12 |
8 (16.7) |
|
12-60 |
37 (77.1) |
|
> 60 |
3 (6.3) |
Sex |
Male |
29 (60.4) |
|
Female |
19 (39.6) |
Primary tumor location |
Abdominal |
46 (95.8) |
|
Thoracic |
2 (4.2) |
INSS |
IV |
46 (95.8) |
|
IVs |
2 (4.2) |
COG risk groups |
Intermediate |
4 (8.3) |
|
High |
44 (91.7) |
MYCN amplification |
Present |
17 (35.4) |
|
Absent |
31 (64.6) |
Table 2.Histological characteristics of metastatic tumors in bone marrow (BM) before and after chemotherapy (CTx)
Histological finding |
|
Metastatic tumors in BM before CTx (n=48) |
Metastatic tumors in BM after CTx (n=23) |
p-value |
Tumor cell differentiationa
|
Undifferentiated neuroblasts |
100 (0-100) |
50 (0-100) |
< .001 |
Differentiating neuroblasts |
0 (0-100) |
40 (0-100) |
.011 |
Ganglion cells |
0 |
0 (0-100) |
< .001 |
Schwannian stromab
|
Present |
0 (0) |
4 (17.4) |
.009 |
Absent |
48 (100) |
19 (82.6) |
|
Neuropilb
|
Present |
44 (91.7) |
17 (73.9) |
< .001 |
Absent |
1 (2.1) |
6 (12.5) |
|
N.A |
3 (6.2) |
0 (0) |
|
Necrosisb
|
Present |
8 (16.7) |
17 (73.9) |
.000 |
Absent |
35 (72.9) |
6 (26.1) |
|
N.A |
5 (10.4) |
0 (0) |
|
Table 3.Histological changes of neuroblastic tumors (NTs) in a series of bone marrow (BM) biopsies after multi-cycle chemotherapy
Case No. |
Histologic subtype of PT |
|
NT in BM initial Bx. (%) |
rNT in BM after chemotherapy (%)
|
|
1st detection |
2nd detection |
3rd detection |
4th detection |
5th detection |
1 |
NBD |
CC |
U (100) |
D (50) |
G (100) |
G (100) |
G (100) |
- |
|
|
|
- |
G (50) |
- |
- |
- |
|
|
|
SS |
Absent |
Present |
Present |
Present |
Present |
- |
|
|
TOB |
- |
15 |
34 |
41 |
44 |
- |
2 |
NBD |
CC |
U (50) |
D (50) |
G (100) |
- |
- |
- |
|
|
|
D (50) |
G (50) |
- |
|
|
|
|
|
SS |
Absent |
Absent |
Absent |
- |
- |
- |
|
|
TOB |
- |
3 |
11 |
- |
- |
- |
3 |
NBD |
CC |
U (20) |
U (20) |
D (100) |
NRT |
G (100) |
- |
|
|
|
D (80) |
D (50) |
|
|
|
|
|
|
|
|
G (30) |
|
|
|
|
|
|
SS |
Absent |
Absent |
Absent |
Present |
Absent |
- |
|
|
TOB |
- |
6 |
8 |
11 |
18 |
- |
4 |
NBP |
CC |
U (100) |
U (100) |
U (30) |
- |
- |
- |
|
|
|
|
|
D (50) |
|
|
|
|
|
|
|
|
G (20) |
|
|
|
|
|
SS |
Absent |
Absent |
Absent |
- |
- |
- |
|
|
TOB |
- |
3 |
8 |
- |
- |
- |
5 |
NBP |
CC |
U (100) |
U (50) |
U (50) |
D (100) |
G (100) |
U (100) |
|
|
|
|
D (50) |
D (50) |
|
|
|
|
|
SS |
Absent |
Absent |
Absent |
Absent |
Absent |
Absent |
|
|
TOB |
- |
3 |
5 |
13 |
21 |
31 |
6 |
NBP |
CC |
U (60) |
U (70) |
G (100) |
- |
- |
- |
|
|
|
D (40) |
D (30) |
|
|
|
|
|
|
SS |
Absent |
Absent |
Absent |
- |
- |
- |
|
|
TOB |
- |
2 |
33 |
- |
- |
- |
7 |
NBD |
CC |
U (90) |
U (60) |
U (60) |
- |
- |
- |
|
|
|
D (10) |
D (40) |
D (40) |
|
|
|
|
|
SS |
Absent |
Absent |
Absent |
- |
- |
- |
|
|
TOB |
- |
3 |
6 |
- |
- |
- |
8 |
NBD |
CC |
U (90) |
D (100) |
G (100) |
G (100) |
NRT |
- |
|
|
|
D (10) |
|
|
|
|
|
|
|
SS |
Absent |
Absent |
Present |
Present |
Present |
- |
|
|
TOB |
- |
2 |
10 |
15 |
24 |
- |
9 |
NBD |
CC |
NA |
U (30) |
D (80) |
D (60) |
D (50) |
- |
|
|
|
|
D (50) |
G (20) |
G (40) |
G (50) |
|
|
|
|
|
G (20) |
|
|
|
|
|
|
SS |
Absent |
Absent |
Absent |
Absent |
Absent |
- |
|
|
TOB |
- |
7 |
8 |
11 |
14 |
- |
10 |
GNBN |
CC |
U (100) |
U (97) |
U (100) |
- |
- |
|
|
|
|
|
D (3) |
|
|
|
|
|
|
SS |
- |
Absent |
Absent |
- |
- |
|
|
|
TOB |
Absent |
5 |
8 |
- |
- |
|