Patient Characteristics
Demographics are summarized in Table 1 and clinical information in Table 2. A comprehensive review of the literature revealed 31 patients in 26 manuscripts from the years 1975 to 2021 [4, 8–32]. Most studies originated from East Asia (22/26). A review of tertiary institutions identified nine patients from five academic institutions in the USA (Nationwide Children’s Hospital, Columbus, OH; St. Jude Children’s Research Hospital, Memphis, TN; Rady Children’s Hospital, San Diego, CA; Children’s Hospital Los Angeles, Los Angeles, CA; Massachusetts General Hospital, Boston, MA) and one patient from Brazil (Federal University of São Paulo, Vila Clementino, São Paulo, BR). Of the 41 total patients, mean age was 9.9 years (range, newborn to 35 years). The majority (90.2%) of patients were ≤ 18 years of age. Age was unreported in one patient. A male predominance was noted (61%).
Table 1
| N | % |
Total | 41 | 100 |
Mean age, years (range) | 9.9 (newborn to 35) |
Sex | | |
Male | 25 | 61 |
Female | 16 | 39 |
Histology* | | |
Germinoma | 16 | 39 |
NGGCT | 16 | 39 |
Teratoma | 8 | 19.5 |
Mature teratoma | 1 | 2.4 |
Immature teratoma | 5 | 12.2 |
Unspecified teratoma | 2 | 4.9 |
Primary site | | |
Basal ganglia | 13 | 31.7 |
Posterior fossa | 7 | 17 |
Pineal | 3 | 7.3 |
Sellar/suprasellar | 8 | 19.5 |
Other | 4 | 9.8 |
Multiple intracranial sites | 6 | 14.6 |
Spinal metastasis | 3 | 7.3 |
Elevated markers if tested | | |
Serum bHCG | 11 | 39.3 |
Serum AFP | 14 | 58.3 |
CSF bHCG | 4 | 33.3 |
CSF AFP | 6 | 42.9 |
Response to initial therapy | | |
Complete response | 26 | 63.4 |
Partial response | 10 | 24.4 |
Progressive disease | 5 | 12.2 |
Tumor relapse | 9 | 21.2 |
Outcome | | |
Alive at last follow-up | 29 | 70.7 |
Deceased from tumor | 4 | 9.8 |
Deceased from treatment | 8 | 19.5 |
Sixteen patients had germinomas (39%), 16 had NGGCTs (39%) and eight had teratomas (19.5%); tumor histology was not reported for one patient. Of the NGGCTs, seven were YSTs (17%), two were embryonal carcinomas (4.9%), one was a STGC (2.4%), three were mixed GCTs (7.3%) and three were unspecified (7.3%). Of the teratomas, five were immature (12.2%), one was mature (2.4%) and two were unspecified (4.9%). Thirteen tumors were localized to the basal ganglia (31.7%), seven the posterior fossa (17%), three the pineal region (7.3%) and eight the sellar or suprasellar region (19.5%). Other tumors were localized to the third ventricle, fourth ventricle and cerebellopontine angle (CPA). Six patients (14.6%) presented with multiple intracranial lesions: basal ganglia/thalamus, basal ganglia/frontal lobe, pineal/suprasellar, pineal/CPA and ventral midbrain/CPA/pineal. Of these six patients, two had additional metastatic disease to the spine. One tumor was localized to the sellar region with spinal metastases.
TABLE 2 Selected clinical information for patients found in the literature (cases 1-31) and on multi-institutional review (cases 32-41).
Case
|
Age
|
Path.
|
10 site(s)
|
Surgery
|
RT field: dose Gy (boost)
|
Chemotherapy
|
Response
|
Outcome
|
OS (months)
|
COD
|
11
|
13y
|
NG
|
BG
|
Bx
|
WBI: 30
|
Ifos, Carbo, Etop
|
CR
|
Alive
|
21
|
NA
|
22
|
2y
|
T
|
CB
|
Bx
|
No
|
No
|
PD
|
Dead
|
2
|
Tumor
|
33
|
7y
|
T
|
V
|
Bx
|
Yes: NR
|
No
|
PD
|
Dead
|
2
|
Tumor
|
44
|
4m
|
T
|
BG
|
Bx
|
No
|
No
|
PD
|
Dead
|
7
|
Tumor
|
55
|
9y
|
G
|
BG
|
STR
|
Yes: NR
|
No
|
CR
|
Alive
|
36
|
NA
|
66
|
12y
|
NG
|
BG
|
STR
|
Yes: NR
|
Cisplatin, Etop
|
PR
|
Alive
|
NR
|
NA
|
77
|
6y
|
NG
|
CB
|
STR
|
No
|
Cisplatin, Bleomycin, VBL, Cyclo
|
CR
|
Dead
|
NR
|
Sepsis
|
88
|
12y
|
NG
|
BG
|
GTR
|
WBI: 21
|
Cisplatin, Etop
|
PR
|
Dead
|
21
|
Pneumonia
|
99
|
11y
|
NR
|
BG
|
None
|
Yes: NR
|
No
|
PD
|
Dead
|
NR
|
NR
|
1010
|
10y
|
G
|
BG
|
STR
|
Focal: 30
|
Cisplatin, Etop
|
CR
|
Alive
|
NR
|
NA
|
1111
|
10y
|
G
|
BG/T
|
STR
|
No
|
No
|
PR
|
Dead
|
1
|
CP failure
|
1211
|
20y
|
G
|
P
|
STR
|
Focal: 40
|
Paraplatin, Etop
|
PR
|
Alive
|
NR
|
NA
|
1312
|
9y
|
G
|
BG
|
STR
|
No
|
Cisplatin, Etop, Bleomycin
|
CR
|
Dead
|
11
|
Sepsis
|
1412
|
3y
|
NG
|
CB
|
GTR
|
No
|
Cisplatin, Etop, Bleomycin
|
CR
|
Alive
|
36
|
NA
|
1513
|
22y
|
NG
|
S
|
Bx
|
No
|
No
|
PR
|
Dead
|
1.5
|
Infection
|
1614
|
35y
|
G
|
P/CB; Mets
|
Bx
|
Local: 42
|
Carbo, Etop
|
CR
|
Dead
|
35
|
Tumor
|
1715
|
17y
|
NG
|
BG
|
Bx
|
Yes: NR
|
Ifos, Cisplatin, Etop
|
PR
|
Alive
|
NR
|
NA
|
1816
|
2m
|
T
|
CB
|
GTR
|
No
|
Cisplatin, Etop
|
CR
|
Alive
|
46
|
NA
|
1917
|
Newborn
|
T
|
P
|
GTR
|
No
|
No
|
CR
|
Alive
|
3
|
NA
|
2018
|
12y
|
G
|
BG
|
STR
|
WBI: 40; Spine: 26
|
No
|
CR
|
Alive
|
60
|
NA
|
2119
|
14y
|
G
|
BG
|
Bx
|
WBI: 24
|
Ifos, Cisplatin, Etop
|
CR
|
Alive
|
16
|
NA
|
2220
|
1.5y
|
NG
|
PF
|
GTR
|
No
|
Cisplatin, Etop, Bleomycin
|
CR
|
Alive
|
23
|
NA
|
2321
|
17y
|
NG
|
S
|
STR
|
No
|
Carbo, Etop, cisplatin, bentuximab-vendotin
|
CR
|
Alive
|
24
|
NA
|
2422
|
18y
|
G
|
CB/P/MB; Mets
|
Bx
|
CSI: 23.4
|
Carbo, Etop
|
PR
|
Alive
|
21
|
NA
|
2523
|
15y
|
G
|
BG
|
Bx
|
WVI: 30
|
Ifos, Cisplatin, Etop
|
PR
|
Dead
|
11
|
Sepsis
|
2624
|
1y
|
NG
|
V
|
STR
|
Local: 41.4
|
Ifos, Cisplatin, Etop
|
CR
|
Alive
|
154
|
NA
|
2725
|
8y
|
NR
|
BG
|
Bx
|
WBI: 24; Local: 24
|
Carboplatin, Etop, Ifos
|
PR
|
Alive
|
60
|
NA
|
2826
|
6m
|
NG
|
P/S
|
None
|
CSI: 18
|
Carboplatin, Etop, Ifos, Thiotepa
|
CR
|
Alive
|
96
|
NA
|
2926
|
7m
|
G
|
S
|
STR
|
WVI: NR
|
No
|
CR
|
Dead
|
48
|
Moyamoya
|
3026
|
4m
|
T
|
PF
|
GTR
|
No
|
Etop, Carboplatin, Bleomycin
|
CR
|
Alive
|
216
|
NA
|
3126
|
NR
|
G
|
S
|
None
|
WVI: NR
|
Etop, Carboplatin, Bleomycin
|
CR
|
Alive
|
72
|
NA
|
32
|
15.8y
|
G
|
S; Mets
|
Bx
|
CSI: 24 (40)
|
No
|
PR
|
Alive
|
6
|
NA
|
33
|
8.8y
|
NG
|
P
|
Bx
|
CSI: 36
|
Carboplatin, Etop, Cyclo
|
CR
|
Alive
|
NR
|
NA
|
34
|
2m
|
T
|
PF
|
GTR
|
No
|
No
|
CR
|
Alive
|
NR
|
NA
|
35
|
17.2y
|
NG
|
S
|
STR
|
No
|
Carboplatin, Etop, Thiotepa
|
CR
|
Alive
|
NR
|
NA
|
36
|
8y
|
G
|
S
|
Bx
|
WVI: 24 (36)
|
Carboplatin, Etop, Ifos
|
CR
|
Alive
|
70
|
NA
|
37
|
12.7y
|
NG
|
S
|
None
|
WVI: NR
|
Carboplatin, Etop, Ifos, Cyclo, Thiotepa
|
CR
|
Alive
|
14.5
|
NA
|
38
|
6.7y
|
NG
|
S/P/V
|
None
|
CSI: 18 (27)
|
Carbo, Etop, Ifos, Thiotepa
|
CR
|
Alive
|
18
|
NA
|
39
|
4m
|
T
|
PF
|
GTR
|
No
|
Carboplatin, Etop, Bleomycin
|
CR
|
Alive
|
255
|
NA
|
40
|
6.7y
|
G
|
S/P/V
|
None
|
CSI: 18 (27)
|
Carboplatin, Cyclo, Etop, VCR, Thiotepa
|
CR
|
Alive
|
115
|
NA
|
41
|
34.7y
|
G
|
S
|
Bx
|
Local: 36
|
No
|
PD
|
Alive
|
10
|
NA
|
Abbreviations: 10, primary; BG, basal ganglia; Bx, biopsy; Carbo, carboplatin; CB, cerebellum; CSI, craniospinal irradiation; COD, cause of death; CP, cardiopulmonary; CR, complete response; Cyclo, cyclophosphamide; Etop, etoposide; GTR, gross total resection; Ifos, ifosfamide; mets, metastatic; m, months; NA, not applicable; NR, not reported; Path., pathology; PR, partial response; P, pineal; PF, posterior fossa; RT, radiotherapy; S, sellar/suprasellar; STR, subtotal resection; T, thalamus; Tx, treatment; VCR, vincristine; V, ventricle; WBI, whole brain irradiation; WVI, whole ventricular irradiation; y, years; #, number.
Clinical Presentation and Tumor Markers
Presenting symptoms were reported for 33 patients (80.5%). Duration of symptoms was available for 18 patients (43.9%) and ranged from one week to 2.5 years (mean 6.9 months). Six of these patients (20%) had symptoms for greater than 6 months. Of the 33 patients whose presenting symptoms were reported, hemiparesis (24.4%) was the most common symptom, followed by visual disturbance (19.5%), nausea/vomiting (17%), lethargy (14.6%), headache (14.6%), polyuria (12.2%), ataxia (9.8%), motor impairment (9.8%), polydipsia (9.8%), head enlargement (7.3%), seizures (2.4%), amenorrhea (2.4%) and facial nerve palsy (2.4%); one tumor was identified on prenatal ultrasound.
Serum AFP and bHCG was tested in 25 and 28 patients, respectively. Of these patients, 14 (58.3%) had elevated serum AFP and 11 (39.3%) had elevated serum bHCG. Cerebrospinal fluid AFP and bHCG was tested in 14 and 12 patients, respectively. Of these patients, six (42.9%) had elevated CSF AFP and four (33.3%) had elevated CSF bHCG. In those with both serum and CSF testing, serum AFP matched CSF AFP in 11 of 12 patients (91.7%) while serum bHCG matched CSF bHCG in 9 of 10 patients (90%). Overall, 17 of 31 patients (54.8%) had elevated AFP, while 12 of 35 patients (34.3%) had elevated bHCG at initial diagnosis.
Treatment and Response
Treatment approaches are summarized in Table 3. Of the patients with germinomas (n = 16), nine (56.3%) underwent surgical biopsy and seven (46.7%) underwent subtotal resection (STR). Ten patients (62.5%) received chemotherapy. All chemotherapies were platinum-based. Only one patient received chemotherapy alone. Of the patients who underwent combined chemotherapy/RT, all patients received chemotherapy prior to RT. Fourteen patients (87.5%) received RT; two patients (12.5%) received craniospinal irradiation (CSI) (mean 2370c Gy), three (18.8%) received whole brain radiotherapy (WBRT) (mean 29.3 Gy), four (25%) received whole ventricle irradiation (WVI) (mean 27 Gy), four (25%) received focal RT (mean 30 Gy) and one (6.3%) received an unspecified regimen. Four patients (25%) received primary site boost (mean total dose 43.3 Gy; three WVI, one CSI). Complete response (CR) was achieved in nine patients (56.3%) following therapy.
Table 3
Treatment | Total | Histologic Type |
Germinoma | NGGCT | Teratoma |
N | % | N | % | N | % | N | % |
Radiation | 27 | 65.9 | 14 | 87.5 | 11 | 68.8 | 1 | 12.5 |
Chemotherapy | 26 | 63.4 | 10 | 62.5 | 15 | 93.8 | 3 | 37.5 |
Surgery | 34 | 82.9 | 15 | 93.8 | 12 | 75 | 8 | 100 |
Treatment Comparison | | | | | | | | |
RT only* | 1 | 2.4 | 0 | 0 | 0 | 0 | 0 | 0 |
RT + biopsy | 3 | 7.3 | 2 | 12.5 | 0 | 0 | 1 | 12.5 |
RT + STR | 3 | 7.3 | 3 | 18.8 | 0 | 0 | 0 | 0 |
RT + chemotherapy | 5 | 12.2 | 1 | 6.3 | 4 | 25 | 0 | 0 |
RT + biopsy + chemo | 9 | 21.2 | 6 | 37.5 | 3 | 18.8 | 0 | 0 |
RT + STR + chemo | 4 | 9.8 | 2 | 12.5 | 2 | 12.5 | 0 | 0 |
RT + GTR + chemo | 2 | 4.9 | 0 | 0 | 2 | 12.5 | 0 | 0 |
Chemo + Biopsy | 1 | 2.4 | 0 | 0 | 1 | 6.3 | 0 | 0 |
Chemo + STR | 3 | 7.3 | 1 | 6.3 | 2 | 12.5 | 0 | 0 |
Chemo + GTR | 4 | 9.8 | 0 | 0 | 1 | 6.3 | 3 | 37.5 |
Biopsy only | 3 | 7.3 | 0 | 0 | 1 | 6.3 | 2 | 25 |
STR only | 1 | 2.4 | 1 | 6.3 | 0 | 0 | 0 | 0 |
GTR only | 2 | 4.9 | 0 | 0 | 0 | 0 | 2 | 25 |
*Histology was unspecified for one patient who was treated with RT only. |
Abbreviations: Chemo, chemotherapy; NGGCT, non-germinomatous germ cell tumor; RT, radiotherapy; STR, subtotal resection; GTR, gross total resection. |
Of the patients with NGGCTs (n = 16), five (31.3%) underwent surgical biopsy (three YSTs, one mixed GCT, one embryonal carcinoma), three (18.8%) underwent gross total resection (GTR) (two YSTs, one STGC) and four (25%) underwent STR (two YSTs, one embryonal carcinomas, one mixed GCT). Fifteen patients (93.4%) received chemotherapy; 10 (62.5%) received combined chemotherapy/RT (three YSTs, three mixed GCTs, one STGC, three unspecified) and four (25%) received chemotherapy-only (two YSTs, two embryonal carcinomas). All chemotherapies were platinum-based. One patient received no adjuvant therapy (one YST). Ten patients (62.5%) received RT; four (25%) received CSI (mean 22.5 Gy), two (12.5%) received WBRT (mean 25.5 Gy), one (6.3%) received WVI (dose unreported), two (12.5%) received focal RT (mean 45.6 Gy) and one (6.3%) received an unspecified regimen. Three patients (18.8%) received primary site boost (mean total dose 27 Gy). Complete response was achieved in 12 patients (75%) following therapy.
Of the patients with teratomas (n = 8), three (37.5%) underwent surgical biopsy-only (one immature teratoma, two unspecified teratomas) and five (62.5%) underwent GTR (four immature teratomas, one mature teratoma). Adjuvant therapy was chemotherapy-only (three immature teratomas) or RT-only (one unspecified teratoma). All chemotherapy regimens were platinum-based. Five patients (62.5%) achieved CR following therapy.
Treatment-Related Adverse Events
Treatment-related adverse events are summarized in Table 4. Sixteen patients (39%) experienced Grade 3–5 treatment-related complications. Grade 3–4 myelosuppression occurred in five patients. Nine patients experienced Grade 3–5 infections, which included four episodes of sepsis, three episodes of pneumonia, one episode of mucositis and one post-surgical infection of unknown origin. One patient experienced post-surgical cardiopulmonary failure and one experienced moyamoya following RT. Of the 16 patients, nine received combined chemotherapy/RT, four received chemotherapy only, one received RT only and two underwent surgery without adjuvant therapy. Of the 16 patients who experienced adverse events, eight (50%) died of their complications.
Table 4
Grade 3–5 treatment-related complications
Treatment-related complications | N (%) |
Myelosuppression | 5 (12) |
Sepsis | 4 (9.8) |
Pneumonia | 3 (7.3) |
Mucositis | 1 (2.4) |
Infection of unknown origin | 1 (2.4) |
Post-surgical cardiopulmonary failure | 1 (2.4) |
Moyamoya | 1 (2.4) |
Outcomes
Time to follow-up was available for 32 patients (mean 3.9 years; range, one month to 21.2 years). Overall, nine patients (21.2%) experienced disease relapse or progression; four patients experienced local relapse after CR (one germinoma, one teratoma, two NGGCTs) and five patients experienced disease progression despite therapy. Of the four patients who experienced local relapse, salvage regimens included platinum-based chemotherapy (n = 3), repeat surgery (n = 2) and radiotherapy (n = 1). Three patients who experienced disease relapse were successfully salvaged and had no evidence of disease (NED) at last follow-up, whereas one died from treatment-related pneumonia. Four patients who had progressive disease died, while one remained alive with residual tumor at last follow-up.
Overall, four patients (9.8%) died from tumor progression (three teratomas, one unspecified histology), while the remaining eight patients (19.5%) died from treatment-related adverse events. Of the germinoma patients, two died from chemotherapy-related sepsis, one from pneumonia, one from post-surgery cardiopulmonary failure and one from Moyamoya following RT only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection and one from pneumonia following surgery/chemotherapy/RT.
At last follow-up, 28 patients (68.3%) were alive with NED and one patient (2.4%) was alive with residual tumor. The 3-year OS for all histological types was 66% (95% CI 45.7%-81.5%). Three-year OS was 62% for germinomas (95% CI 30.5%-85.5%), 79% for NGGCTs (95% CI 38%-94.3%) and 53% for teratomas (95% CI 13.2%-82.5%) (Fig. 1a). There was no significant difference in 3-year OS based on histology (p = 0.74). Three-year OS was 74.7% (95% CI 47.4%-89.9%) for those who received RT, 76.7% (95% CI 48.2%-90.8%) for chemotherapy and 72.4% (95% CI 44.7%-90.5%) for combined chemotherapy/RT (Fig. 1b). There was no significant difference in 3-year OS based on treatment (p = 0.87).