Background
Methods
Diagnosis and diagnostic work-up
Treatment
Statistical analyses
Results
Demographic and clinical features on presentation
Feature | All patients | Treatment era |
p
| ||
---|---|---|---|---|---|
1979–1984 | 1985–1999 | 2000–2013 | |||
No. (%) | No. (%) | No. (%) | No. (%) | ||
268 (100) | 26 (9.7) | 116 (43.3) | 126 (47.0) | ||
Demographic and clinical features
| |||||
Gender | |||||
Male | 156 (58.2) | 17 (65.4) | 70 (60.3) | 69 (54.8) |
0.0501
|
Female | 112 (41.8) | 9 (34.6) | 46 (39.7) | 57 (45.2) | |
Age, days. Median (IQR) | 87 (33.5–146.5) | 75.5 (34–122) | 77 (22.5–141.5) | 97.5 (37–170) | |
Age, days | |||||
0–29 | 60 (22.4) | 6 (23.1) | 31 (26.7) | 23 (18.3) |
0.619
|
30–59 | 40 (14.9) | 4 (15.4) | 14 (12.1) | 22 (17.5) | |
60–89 | 37 (13.8) | 6 (23.1) | 15 (12.9) | 16 (12.7) | |
90–119 | 40 (14.9) | 3 (11.5) | 19 (16.4) | 18 (14.3) | |
120–365 | 91 (33.9) | 7 (26.9) | 37 (31.9) | 47 (37.3) | |
Age, days | |||||
0–29 | 60 (22.4) | 6 (23.1) | 31 (26.7) | 23 (18.3) |
0.286
|
30–365 | 208 (77.6) | 20 (76.9) | 85 (73.3) | 103 (81.7) | |
Symptoms at presentation# | |||||
None | 17 (6.3) | 0 | 4 (3.5) | 13 (10.3) |
0.039*
|
Yes, minor | 51 (19.0) | 3 (11.5) | 19 (16.4) | 29 (23.0) | |
Yes, major | 200 (74.6) | 23 (88.5) | 93 (80.2) | 84 (66.7) | |
Major symptoms | 200 (74.6) | 23 (88.5) | 93 (80.2) | 84 (66.7) | |
Hepatomegaly, yes | 186 (69.4) | 21 (80.8) | 85 (73.3) | 80 (63.5) |
0.107
|
Dyspnea, yes | 52 (19.4) | 4 (15.4) | 25 (21.5) | 23 (18.2) |
0.699
|
Organ dysfunction, yes | 34 (12.7) | 3 (11.5) | 9 (7.8) | 22 (17.5) |
0.073*
|
Combinations of major symptoms | |||||
No major symptoms or no symptom | 68 (25.4) | 3 (11.5) | 23 (19.8) | 42 (33.3) |
0.033*
|
Organ dysfunction only | 2 (0.8) | 1 (3.9) | 0 | 1 (0.8) | |
Dyspnea ± Organ dysfunction | 12 (4.5) | 1 (3.9) | 8 (6.9) | 3 (2.4) | |
Hepatomegaly ± Organ dysfunction | 146 (54.5) | 18 (69.2) | 68 (58.6) | 60 (47.6) | |
Hepatomegaly + Dyspnea (± Organ dysfunction) | 40 (14.9) | 3 (11.5) | 17 (14.7) | 20 (15.9) | |
Minor symptoms | |||||
Skin nodules, yes | 42 (15.7) | 4 (15.4) | 28 (24.1) | 10 (7.9) |
0.002*
|
Abdominal mass, yes | 34 (12.7) | 1 (3.8) | 12 (10.3) | 21 (16.7) |
0.139*
|
Cervical mass, yes | 11 (4.1) | 0 | 5 (4.3) | 6 (4.8) |
0.814*
|
Neurologic symptoms, yes | 12 (4.5) | 0 | 6 (5.2) | 6 (4.8) |
0.753*
|
Primary site | |||||
Adrenal^ | 175 (65.3) | 16 (61.5) | 77 (66.4) | 82 (65.1) |
0.272*
|
Retroperitoneal ganglia | 49 (18.3) | 4 (15.4) | 16 (13.8) | 29 (23.0) | |
Thorax | 22 (8.2) | 3 (11.5) | 11 (9.5) | 8 (6.3) | |
Neck | 9 (3.4) | 0 | 5 (4.3) | 4 (3.2) | |
Not identified | 13 (4.9) | 3 (11.5) | 7 (6.0) | 3 (2.4) | |
Liver infiltration, yes | |||||
yes | 230 (85.8) | 22 (84.6) | 102 (87.9) | 106 (84.1) |
0.689*
|
Positive bone marrow cytology, yes | |||||
yes | 111 (41.4) | 8 (30.8) | 42 (36.2) | 61 (48.4) |
0.082*
|
Biochemical, biologic and histologic features
| |||||
Urine VMA (222 tested) | |||||
Normal | 59 (26.6) | 2 (8.3) | 22 (22.9) | 35 (34.3) | 0.019 |
Elevated | 163 (73.4) | 22 (91.7) | 74 (77.1) | 67 (65.7) | |
Urine HVA (112 tested) | |||||
Normal | 18 (16.1) | 0 | 2 (6.1) | 16 (21.0) | 0.149* |
Elevated | 94 (83.9) | 3 (100) | 31 (93.9) | 60 (79.0) | |
Serum LDH (227 tested) | |||||
Normal | 131 (57.7) | 7 (87.5) | 78 (75.7) | 46 (39.7) | < 0.001* |
Elevated | 96 (42.3) | 1 (12.5) | 25 (24.3) | 70 (60.3) | |
Serum ferritin (193 tested) | |||||
Normal | 116 (60.1) | 5 (100) | 55 (61.1) | 56 (57.1) | 0.176* |
Elevated | 77 (39.9) | 0 | 35 (38.9) | 42 (42.9) | |
MYCN gene (183 tested) | |||||
Normal | 168 (91.8) | 0 | 61 (91.0) | 107 (92.2) | 0.776 |
Amplified | 15 (8.2) | 0 | 6 (9.0) | 9 (7.8) | |
1p chromosome (138 tested) | |||||
Normal | 110 (79.7) | 1 (100) | 32 (76.2) | 77 (81.1) | 0.603* |
Deleted | 28 (20.3) | 0 | 10 (23.8) | 18 (18.9) | |
DNA index (121 tested) | |||||
Aneuploid | 80 (66.1) | 0 | 24 (60.0) | 56 (69.1) | 0.318 |
Di-tetraploid | 41 (33.9) | 0 | 16 (40.0) | 25 (30.9) | |
Histology by INPC (75 tested) | |||||
Favorable | 69 (92.0) | 0 | 0 | 69 (92.0) | – |
Unfavorable | 6 (8.0) | 0 | 0 | 6 (8.0) |
Biochemical, biologic and histopathologic data
Treatment, clinical course and outcome
First treatment era (1979–1984)
Second treatment era (1985–1999)
Third treatment era (2000–2013)
Patient outcome and prognostic factors
Entire cohort | Progressions | 10-yrs PFS |
p
| Deaths | 10-year OS |
p
| |
---|---|---|---|---|---|---|---|
No. (%) | No. (%) | % (95% CI) | No. (%) | % (95% CI) | |||
268 (100) | 83 (31) | 68.2 (62.1–73.5) | 46 (17.2) | 82.7 (77.4–86.8) | |||
Treatment era | |||||||
1979–1984 | 26 (9.7) | 8 (30.8) | 69.2 (47.8–83.3) | 0.217# | 6 (23.1) | 76.9 (55.7–88.9) | 0.041# |
1985–1999 | 116 (43.3) | 43 (37.1) | 62.3 (52.7–70.5) | 26 (22.4) | 77.2 (68.3–83.9) | ||
2000–2013 | 126 (47) | 32 (25.4) | 72.4 (62.4–80.1) | 14 (11.1) | 89.7 (82.9–93.9) | ||
Gender | |||||||
Male | 156 (58.2) | 52 (33.3) | 65.4 (57.1–72.5) | 0.24 | 34 (21.8) | 78.5 (71.1–84.2) | 0.018 |
Female | 112 (41.8) | 31 (27.7) | 72.1 (62.7–79.5) | 12 (10.7) | 88.5 (80.3–93.4) | ||
Age, days | |||||||
0–29 | 60 (22.4) | 23 (38.3) | 59.8 (45.7–71.4) | 0.033# | 17 (28.3) | 73.0 (59.7–82.5) | 0.067# |
30–59 | 40 (14.9) | 14 (35.0) | 65.0 (48.2–77.6) | 8 (20.0) | 80.0 (64.0–89.5) | ||
60–89 | 37 (13.8) | 9 (24.3) | 75.0 (57.5–86.1) | 6 (16.2) | 83.8 (67.4–92.4) | ||
90–119 | 40 (14.9) | 15 (18.1) | 61.6 (44.6–74.8) | 7 (17.5) | 81.0 (63.5–90.6) | ||
≥ 120 | 91 (33.9) | 22 (26.5) | 75.5 (65.2–83.1) | 8 (8.8) | 91.0 (82.7–95.4) | ||
Age, days | |||||||
0–29 | 60 (22.4) | 23 (38.3) | 59.8 (45.7–71.4) | 0.058 | 17 (28.3) | 73.0 (59.7–82.5) | 0.006 |
30–365 | 208 (77.6) | 60 (28.8) | 70.7 (64.0–76.4) | 29 (19.9) | 85.5 (79.6–89.7) | ||
Symptoms at presentation | |||||||
None | 17 (6.3) | 1 (5.9) | 94.1 (65.0–99.2) | < 0.001# | 0 | 100 | < 0.001# |
Yes, minor | 51 (19.0) | 9 (17.7) | 82.4 (68.8–90.4) | 2 (3.9) | 96.0 (84.9–99.0) | ||
Yes, major | 200 (74.6) | 73 (36.5) | 62.4 (55.1–68.8) | 44 (22.0) | 77.9 (71.3–83.2) | ||
Hepatomegaly | |||||||
None | 82 (30.6) | 15 (18.3) | 81.7 (71.5–88.5) | 0.004 | 4 (4.9) | 94.7 (86.5–98.0) | < 0.001 |
Yes | 186 (69.4) | 68 (36.6) | 62.2 (54.6–68.9) | 42 (22.6) | 77.4 (70.6–82.9) | ||
Dyspnea | |||||||
None | 216 (80.6) | 57 (26.4) | 73.4 (66.9–78.8) | < 0.001 | 24 (11.1) | 88.4 (83.1–92.2) | < 0.001 |
Yes | 52 (19.4) | 26 (50) | 47.1 (32.5–60.3) | 22 (42.3) | 59.5 (44.9–71.4) | ||
Organ dysfunctions | |||||||
None | 234 (87.3) | 72 (30.8) | 68.8 (62.4–74.4) | 0.714 | 36 (15.4) | 84.0 (78.4–88.2) | 0.032 |
Yes | 34 (12.7) | 11 (32.4) | 64.5 (44.3–78.9) | 10 (29.4) | 73.5 (55.3–85.3) | ||
Combinations of major symptoms | |||||||
No major symptoms | 68 (25.4) | 10 (14.7) | 85.3 (74.4–91.8) | < 0.001 | 2 (2.9) | 97.0 (88.6–99.2) | < 0.001 |
Hepatomegaly ± Organ dysfunction | 146 (54.5) | 47 (32.2) | 67.4 (59.0–74.4) | 22 (15.1) | 84.4 (77.2–89.5) | ||
Dyspnea ± Organ dysfunction | 12 (4.5) | 5 (41.7) | 58.3 (27.0–80.1) | 2 (16.7) | 83.3 (48.2–95.6) | ||
Hepatomegaly + Dyspnea (±Organ dysfunction) | 40 (14.9) | 21 (52.5) | 43.0 (26.3–58.7) | 20 (50) | 52.4 (36.0–66.4) | ||
Organ dysfunction only | 2 (0.8) | 0 | 100 | 0 | 100 | ||
Abdominal mass | |||||||
None | 234 (87.3) | 77 (32.9) | 66.1 (59.5–71.9) | 0.078 | 45 (19.2) | 80.6 (74.7–85.2) | 0.023 |
Yes | 34 (12.7) | 6 (17.6) | 82.4 (64.9–91.7) | 1 (2.9) | 97.1 (80.9–99.6) | ||
Cervical mass | |||||||
None | 257 (95.9) | 80 (31.1) | 68.0 (61.8–73.4) | 0.797 | 44 (17.1) | 82.8 (77.5–87.0) | 0.896 |
Yes | 11 (4.1) | 3 (27.3) | 72.7 (37.1–90.3) | 2 (18.2) | 77.9 (35.4–94.2) | ||
Skin nodules | |||||||
No | 226 (84.3) | 64 (28.3) | 70.7 (64.1–76.3) | 0.029 | 36 (15.9) | 83.9 (78.2–88.3) | 0.255 |
Yes | 42 (15.7) | 19 (45.2) | 54.8 (38.7–68.3) | 10 (23.8) | 75.9 (59.7–86.2) | ||
Neurologic symptoms | |||||||
None | 256 (95.5) | 77 (30.1) | 69.1 (62.9–74.5) | 0.148 | 45 (17.6) | 82.6 (77.3–86.8) | 0.404 |
Yes | 12 (4.5) | 6 (50) | 50.0 (20.9–73.6) | 1 (8.3) | 75.0 (12.8–96.1) | ||
Primary site | |||||||
Adrenal | 175 (65.3) | 59 (33.7) | 65.8 (58.2–72.3) | 0.609 | 33 (18.8) | 80.4 (73.5–85.8) | 0.489 |
Abdomen | 49 (18.3) | 11 (22.5) | 75.0 (58.7–85.6) | 7 (14.3) | 87.8 (74.8–94.3) | ||
Thorax | 22 (8.2) | 7 (31.8) | 68.2 (44.6–83.4) | 1 (4.5) | 95.5 (71.9–99.4) | ||
Neck | 9 (3.4) | 3 (33.3) | 66.7 (28.2–87.8) | 2 (22.2) | 71.1 (23.3–92.3) | ||
Not detected | 13 (4.9) | 3 (23.1) | 76.9 (44.2–91.9) | 3 (23.1) | 76.9 (44.2–91.9) | ||
Primary site thorax | |||||||
No | 246 (91.8) | 76 (30.9) | 68.9 (62.7–74.4) | 0.944 | 45 (18.3) | 81.5 (75.8–85.9) | 0.112 |
Yes | 22 (8.2) | 7 (31.8) | 68.2 (44.6–83.4) | 1 (4.5) | 95.5 (71.9–99.4) | ||
Liver infiltration | |||||||
No | 38 (14.2) | 7 (18.4) | 81.6 (65.2–90.8) | 0.084 | 0 | 100 | 0.004 |
Yes | 230 (85.8) | 76 (33) | 65.9 (59.3–71.8) | 46 (20) | 79.8 (73.7–84.5) | ||
Positive bone marrow cytology | |||||||
No | 157 (58.6) | 49 (31.2) | 68.3 (60.3–75.0) | 0.753 | 28 (17.8) | 81.9 (74.9–87.2) | 0.643 |
Yes | 111 (41.4) | 34 (30.6) | 68.1 (58.2–76.2) | 18 (16.2) | 83.6 (74.6–89.6) | ||
Urine VMA (222 tested) | |||||||
Normal | 59 (26.6) | 16 (27.1) | 72.4 (59.0–82.1) | 0.381 | 5 (8.5) | 91.5 (80.8–96.4) | 0.13 |
Elevated | 163 (73.4) | 53 (32.5) | 66.7 (58.7–73.5) | 27 (16.6) | 83.9 (77.2–88.7) | ||
Urine HVA (112 tested) | |||||||
Normal | 18 (16.1) | 4 (22.2) | 77.8 (51.1–91.0) | 0.253 | 2 (11.1) | 88.9 (62.4–97.1) | 0.846 |
Elevated | 94 (83.9) | 33 (35.1) | 64.0 (53.0–73.0) | 12 (12.8) | 88.3 (79.9–93.3) | ||
Serum LDH (227 tested) | |||||||
Normal | 131 (57.7) | 33 (25.2) | 74.6 (66.2–81.2) | 0.055 | 14 (10.7) | 89.1 (82.3–93.4) | 0.031 |
Elevated | 96 (42.3) | 35 (36.5) | 60.9 (49.6–70.4) | 20 (20.8) | 78.8 (68.1–86.2) | ||
Serum Ferritin (193 tested) | |||||||
Normal | 116 (60.1) | 34 (29.3) | 70.5 (61.2–77.9) | 0.859 | 15 (12.9) | 87.0 (79.4–92.0) | 0.425 |
Elevated | 77 (39.9) | 22 (28.6) | 70.0 (58.1–79.1) | 13 (16.9) | 82.8 (72.1–89.6) | ||
MYCN gene (183 tested) | |||||||
Normal | 168 (91.8) | 53 (31.5) | 67.1 (59.1–73.9) | 0.673 | 21 (12.5) | 86.8 (79.9–91.5) | 0.021 |
Amplified | 15 (8.2) | 6 (40) | 60.0 (31.8–79.7) | 5 (33.3) | 66.7 (37.5–84.6) | ||
1p chromosome (138 tested) | |||||||
Normal | 110 (79.7) | 31 (28.2) | 71.3 (61.7–78.8) | 0.141 | 10 (9.1) | 89.1 (79.2–94.4) | < 0.001 |
Deleted | 28 (20.3) | 13 (46.4) | 50.8 (29.7–68.5) | 10 (35.7) | 67.9 (47.3–81.8) | ||
DNA index (121 tested) | |||||||
Aneuploid | 80 (66.1) | 24 (30) | 70.0 (58.7–78.8) | 0.734 | 3 (3.8) | 96.3 (88.8–98.8) | < 0.001 |
Di-tetraploid | 41 (33.9) | 14 (34.2) | 65.8 (49.1–78.1) | 10 (24.4) | 70.8 (49.2–84.5) | ||
Histology INPC (75 tested) | |||||||
Favourable | 69 (92) | 16 (23.2) | 73.9 (59.3–83.9) | 0.78 | 5 (7.3) | 94.2 (85.3–97.8) | 0.147 |
Unfavourable | 6 (8) | 2 (33.3) | 66.7 (19.5–90.4) | 2 (33.3) | 66.7 (19.5–90.4) | ||
Upfront treatment | |||||||
Observation | 69 (25.8) | 31 (44.9) | 55.1 (42.6–65.9) | 0.015 | 13 (18.8) | 81.1 (69.7–88.6) | < 0.001 |
Chemotherapy | 90 (33.6) | 29 (32.2) | 66.8 (55.8–75.6) | 23 (25.6) | 73.2 (62.2–81.5) | ||
Resection of primary | 76 (28.4) | 14 (18.4) | 81.1 (70.2–88.3) | 4 (5.3) | 94.3 (85.4–97.9) | ||
Chemotherapy + Resection of primary | 19 (7.1) | 4 (21.1) | 76.6 (48.0–90.7) | 2 (10.5) | 94.7 (68.1–99.2) | ||
Radiotherapy + Other | 14 (5.2) | 5 (35.7) | 64.3 (34.3–83.3) | 4 (28.6) | 71.4 (40.6–88.2) |
No. (%) 266 | PFS |
p
| OS | ||||||
---|---|---|---|---|---|---|---|---|---|
Univariate |
p
| Multivariate | Univariate | Multivariate | |||||
HR (95% CI) | HR (95% CI) | HR (95% CI) |
p
| HR (95% CI) |
p
| ||||
Major symptoms | |||||||||
None | 68 (25.4) | 1 | < 0.001 | 1 | < 0.001 | 1 | < 0.001 | 1 | < 0.001 |
Dyspnea ± Organ dysfunction | 12 (4.5) | 3.5 (1.2–10.2) | 3.1 (1.1–9.3) | 5.9 (0.8–41.6) | 4.6 (0.6–33.2) | ||||
Hepatomegaly ± Organ dysfunction | 146 (54.5) | 2.4 (1.2–4.7) | 2.2 (1.1–4.3) | 5.3 (1.2–22.6) | 4.6 (1.1–19.8) | ||||
Hepatomegaly + Dyspnea (± Organ dysfunction) | 40 (14.9) | 5.5 (2.6–11.7) | 5.5 (2.6–11.8) | 24.4 (5.7–104.4) | 24.1 (5.6–103.4) | ||||
Treatment era | |||||||||
1979–1984 | 25 (9.4) | 1 | 0.202# | 1 | 0.355# | 1 | 0.041# | 1 | 0.049# |
1985–1999 | 116 (43.6) | 1.3 (0.6–2.7) | 1.4 (0.7–3.0) | 1 (0.4–2.4) | 1.2 (0.5–2.8) | ||||
2000–2013 | 125 (47.0) | 0.8 (0.4–1.8) | 0.9 (0.4–2.0) | 0.5 (0.2–1.3) | 0.5 (0.2–1.3) | ||||
Gender | |||||||||
Male | 154 (57.9) | 1 | 0.209 | 1 | 0.707 | 1 | 0.013 | 1 | 0.091 |
Female | 112 (42.1) | 0.8 (0.5–1.2) | 0.8 (0.5–1.3) | 0.5 (0.2–0.9) | 0.6 (0.3–1.1) | ||||
Age, days | |||||||||
0–29 | 60 (22.6) | 1 | 0.077 | 1 | 0.637 | 1 | 0.011 | 1 | 0.639 |
30–365 | 206 (77.4) | 0.6 (0.4–1.0) | 0.9 (0.5–1.5) | 0.4 (0.2–0.8) | 0.9 (0.4–1.6) | ||||
Abdominal mass | |||||||||
None | 232 (87.2) | 1 | 0.052 | 1 | 0.751 | 1 | 0.006 | 1 | 0.813 |
Yes | 34 (12.8) | 0.5 (0.2–1.1) | 1.2 (0.4–3.6) | 0.1 (0.0–1.0) | 0.7 (0.1–8.4) |