Keywords
germ cell tumors (GCT) - children - gonadal - yolk sac tumor - overall survival -
event-free survival
Introduction
Pediatric germ cell tumors (GCTs) are rare tumors. GCTs originate from aberrant differentiation
of germ cells and encompass a heterogeneous collection of neoplasms, exhibiting notable
variations in histological characteristics and site of occurrence.[1]
[2] Children and adolescents can exhibit both benign and malignant GCTs, and the incidence
rates of these tumors vary depending on their age.[3]
The overall incidence of GCTs in children up to 15 years of age can be estimated at
0.9 per 100,000 children.[1]
[3] In infants, majority are benign GCTs, with the most common site being sacrococcygeal.
GCT accounts for 2 to 3% of all pediatric malignancies.[3] Out of all pediatric GCTs, approximately 60% originate from extragonadal sites,
such as the mediastinum, pineal and sacrococcygeal regions, and retroperitoneum. On
the other hand, the remaining 40% of cases are attributed to GCTs arising from the
gonadal sites, specifically the ovary and testis.[4]
[5] GCTs are the most frequently occurring tumors in the gonads among children and adolescents.[6] While GCTs may exhibit notable variations depending on their anatomical location,
they possess a significant degree of similarity and are generally regarded as a cohesive
group.[1] GCTs shows a wide range of histologic subtypes. The histologic characteristics of
each subtype are not influenced by the clinical presentation. However, the behavior
of the tumor and its biological attributes vary based on factors such as the site
of origin, stage of the tumor, and age of the patient.[7]
The International Germ Cell Cancer Cooperative Group (IGCCCG) classification is globally
employed to identify patients at high risk (HR) and provide guidance for first-line
treatment.[8] As per this classification, patients diagnosed with non-germinomatous GCTs or those
with elevated levels of tumor markers are categorized as HR individuals.
The majority of children diagnosed with GCTs achieve remarkable overall survival (OS)
rates, which has consequently resulted in a reduction in the extent of chemotherapy
administered.[9] In the past, chemotherapy was typically advised for all cases of malignant GCTs.
Nevertheless, research has demonstrated that stage I gonadal GCTs can be effectively
managed with surgical intervention and close monitoring, without the need for additional
therapy in many patients. Even in cases of relapse, chemotherapy has proven highly
successful in salvaging the patients.[10]
[11]
To gain deeper insights into the clinical features and treatment approaches for pediatric
GCTs, we conducted a comprehensive analysis of a cohort consisting of 97 patients
with GCTs who were treated at our institution over the past 4 years.
Materials and Methods
During the period spanning from January 2018 to April 2022, a group of 97 pediatric
patients (16 years old or younger) diagnosed with GCTs received surgical treatment
at the Indus Hospital & Health Network. The hospital's electronic database was utilized
to gather comprehensive information including clinical records, radiological data,
laboratory results, and pathological findings.
The diagnosis of GCTs was established by considering various factors, including clinical
manifestations, elevated levels of tumor markers (such as serum α-fetoprotein [AFP]
and β human chorionic gonadotropin [β-HCG]), imaging studies, and histological analysis.
Each patient underwent contrast-enhanced computed tomography scans of the chest, abdomen,
and pelvis. For pelvic tumors, magnetic resonance imaging of the pelvis with contrast
was performed. Additionally, bone scintigraphy was conducted for staging purposes.
The United Kingdom Children's Cancer Study Group GC 2005–04 protocol was employed
for both staging and treatment purposes. Patients were categorized into three risk
groups: low risk (LR), intermediate risk (IR), and HR, based on their stage and prognostic
factors. Patients classified as HR included those with AFP levels greater than 10,000 ng/mL,
stage IV disease (excluding testis < 5 years and all germinomas), or stage II to IV
mediastinal tumors. For stage I tumors (LR), chemotherapy was administered only if
there was disease recurrence following surgery. IR and HR patients received first-line
chemotherapy consisting of four and six cycles of JEB (carboplatin 600 mg/m2 on day 2, etoposide 120 mg/m2 for 3 days, and bleomycin 15 mg/m2 on day 3), respectively, followed by surgical intervention. Tumor markers were monitored
to assess treatment response. After completing the initial treatment, all patients
underwent long-term surveillance to detect any recurrence of the disease. In cases
where patients experienced a recurrence after JEB chemotherapy, they received four
cycles of second-line chemotherapy known as TIP (paclitaxel 175 mg/m2 on day 1, ifosfamide 1500 mg/m2 from day 2 to 6 , cisplatin 20 mg/m2 from day 2 to 6) followed by surgery.
The patients were closely monitored to assess their event-free survival (EFS) and
OS rates. An “event” was defined as disease relapse/progression or death from any
cause. EFS was determined by calculating the time from the start of treatment to the
occurrence of the event, while OS was calculated from the start of treatment to the
date of the last follow-up or date of death. In survival analysis, all patients were
considered until the date of the last follow-up or until April 30, 2022, whichever
came earlier.
Primary Outcome
In this study, EFS and OS were the primary outcomes.
Secondary Outcome
Most of the tumor recurrences occurred in the HR group of GCT and was found as an
additional information.
Inclusion Criteria
-
Patients with biopsy-proven extracranial GCTs within the age range of 0 to 16 years.
-
Patients who received surgical treatment outside of our hospital were also included.
Exclusion Criteria
-
Patients older than 16 years were excluded.
-
Patients with intracranial GCTs.
-
Patients with refractory or progressive extracranial GCT treated outside of our institution.
Statistical Analysis
The data analysis was performed using the Statistical Package for Social Sciences
(SPSS; IBM, version 24.0, Armonk, New York, United States). For age, AFP, HCG, and
lactate dehydrogenase (LDH) variables, the median (interquartile range) was calculated
as the data did not follow a normal distribution. Frequencies and percentages were
calculated for sex, histology, stage of the disease, presence of metastatic disease,
initial treatment characteristics, recurrence, and outcomes. The frequency distributions
along with corresponding percentages were also calculated for the categories of age,
AFP, β-HCG, and LDH. A chi-square test/Fisher's exact test was run to check the association
of outcome and recurrence of disease with demographic, laboratory, and clinical parameters.
The Mann–Whitney test was employed to assess the median difference in AFP, β-HCG,
and LDH values. The Kaplan–Meier method was utilized to estimate the OS and EFS rates.
Univariate and multivariate analyses were conducted using Cox's proportional hazard
model. The significant parameters identified in the univariate analyses were subjected
to multivariate analysis, and their association with recurrence/outcome was expressed
as hazard ratios (HRs) with a 95% confidence interval. A significance level of < 0.05
was set to determine a significant association between recurrence/outcome and the
factors under investigation.
Ethical Approval
This analysis was conducted under an ethical exemption granted by the institutional
ethical review board with the reference IHHN_IRB_2022_07_020 on August 3, 2022. All
procedures performed in the study involving human participants adhered to the ethical
principles outlined by the institutional and/or national research committee. The study
also complied with the guidelines set forth in the 1964 Helsinki Declaration and its
subsequent amendments or equivalent ethical standards.
Results
This retrospective study included a cohort of 97 patients, with a median age of 4
years (1.9–10) at the time of diagnosis. The male-to-female ratio was approximately
1:1.7, with males having a median age of 2 years (1.5–3.5) and females having a median
age of 8.4 years (2.5–11).
According to the histopathology, the majority were the yolk sac tumor (YST) (50.5%),
followed by dysgerminoma (17.5%). The study included a total of 97 patients, with
33 (34%) classified as HR, 35 (36.1%) classified as IR, and 29 (29.9%) classified
as LR. The disease was metastasized in 28 (29%) patients, 17 (60.7%) had pulmonary
metastatic diseases while 11 (39.3%) had nonpulmonary metastatic diseases at the time
of diagnosis. The surgical excision was done in 84 (86.6%) patients, in which 55 (65%)
had residual disease treated with adjuvant first-line chemotherapy and 29 (35%) were
LR with complete surgical excision. The tumor was nonresectable in 13 (13.4%) patients,
and neoadjuvant chemotherapy was given.
The first-line chemotherapy (JEB) was given to 68 (70%) patients. The recurrence has
occurred in 16 patients in which 6 (38%) were from the LR group (chemo-naive) patients,
1 (6%) patient from IR, and 9 (56%) were from the HR group. The IR and HR patients
were offered the second-line chemotherapy (TIP).
Out of the total patient population, 90 (92.8%) were reported as alive, while 7 patients
(7.2%) had unfortunately passed away; the nonsignificant association of recurrence
and outcomes with demographic, clinical, and laboratory parameters are depicted in
[Table 1].
Table 1
Demographic, clinical, and laboratory parameters in study patients
|
Characteristics
|
Recurrence
|
p-Value
|
Outcomes
|
p-Value
|
|
Yes (n = 16)
|
No (n = 81)
|
Alive (n = 90)
|
Expired (n = 7)
|
|
Age (y) (n) (%)
|
|
< 10
> 10
|
13 (81.3)
03 (18.8)
|
56 (69.1)
25 (30.9)
|
0.385[a]
|
63 (70)
27 (30)
|
06 (85.7)
01 (14.3)
|
0.669[a]
|
|
Sex (n) (%)
|
|
Male
Female
|
04 (25)
12 (75)
|
31 (38.3)
50 (61.7)
|
0.312[b]
|
32 (35.6)
58 (64.4)
|
03 (42.9)
04 (57.1)
|
1.000[a]
|
|
Histology (n) (%)
|
|
Mature teratoma
|
01 (6.3)
|
10 (12.3)
|
0.685[a]
|
11 (12.2)
|
0
|
1.000[a]
|
|
Immature components
(teratoma)
|
01 (6.3)
|
04 (4.9)
|
1.000[a]
|
05 (5.6)
|
0
|
1.000[a]
|
|
Dysgerminoma
|
02 (12.5)
|
15 (18.5)
|
0.730[a]
|
16 (17.8)
|
01 (14.3)
|
1.000[a]
|
|
Mixed GCT
|
03 (18.8)
|
09 (11.1)
|
0.412[a]
|
11 (12.2)
|
01 (14.3)
|
1.000[a]
|
|
Yolk sac tumor
|
09 (56.3)
|
40 (49.4)
|
0.616[b]
|
44 (48.9)
|
05 (71.4)
|
0.436[a]
|
|
Embryonal carcinoma
|
0
|
03 (3.7)
|
1.000[a]
|
03 (3.3)
|
0
|
1.000[a]
|
|
Risk (n) (%)
|
|
Low risk
Intermediate risk
High risk
|
06 (37.5)
01 (6.3)
09 (56.3)
|
23 (28.4)
34 (42)
24 (29.6)
|
0.019[b]
|
29 (32.2)
31 (34.4)
30 (33.3)
|
0
04 (57.1)
03 (42.9)
|
0.191[a]
|
|
Metastatic disease (n) (%)
|
|
Yes
No
|
05 (31.3)
11 (68.8)
|
23 (28.4)
58 (71.6)
|
0.772[a]
|
27 (30)
63 (70)
|
01 (14.3)
06 (85.7)
|
0.669[a]
|
|
AFP (ng/mL) (n) (%)
|
|
< 10,000
> 10,000
Normal
|
03 (18.8)
10 (62.5)
03 (18.8)
|
28 (34.6)
30 (37)
23 (28.4)
|
0.164[b]
|
29 (32.2)
35 (38.9)
26 (28.9)
|
02 (28.6)
05 (71.4)
0
|
0.169[a]
|
|
HCG (IU/L) (n) (%)
|
|
< 5,000
> 5,000
|
14 (87.5)
02 (12.5)
|
73 (94.8)
04 (5.2)
|
0.274[a]
|
80 (92.9)
06 (7.1)
|
07 (100)
0
|
1.000[a]
|
Abbreviations: AFP, α-fetoprotein; GCT, germ cell tumor; HCG, human chorionic gonadotropin.
* Significant value.
a Fisher's exact test.
b Pearson's chi-square test.
There were 59 (60.8%) gonadal and 38 (39.2%) extragonadal GCTs. The anatomical distribution
is shown in [Fig. 1A], in which the common site of extragonadal was the abdomen, 14 (36.8%), followed
by the sacrococcygeal, 13 (34.2%), while other 11 (29%) were the mediastinum and retroperitoneum
sites. In the 13 sacrococcygeal region, 5 (38%) showed mature teratoma (MT), the age
of these 5 patients were: 1 (20%) was < 1 year, 3 (60%) were < 5 years, and 1 (20%)
patient was of 11 years.
Fig. 1 (A) Anatomical distribution of gonadal and extragonadal germ cell tumors. (B) Distribution according to histopathology.
In gonadal GCT, in testis, the most common was YST, 21 (80.8%), followed by mixed
GCT (MGCT) 3 (11.5%) and each of one case of mature and immature teratoma (IMT). In
ovarian tumor, dysgerminoma, 14 (42.4%), was the most common, followed by YST 8 (24.2%),
MGCT 6 (18.2%), 1 (3%) MT, and two of each case of embryonal carcinoma (EC) and IMT.
Total 49 cases of YST were reported in our study, the AFP level was high ≥ 10,000
(ng/mL) in 34 (69.4%), < 10,000 (ng/mL) were 13 (26.5%), and 2 (4.1%) were in normal
range.
The histopathological distribution is shown in [Fig. 1B], YST and dysgerminoma were commonly found in 49 and 17 patients, respectively. MT
and IMT were in 11 and 5 patients, respectively, however, 3 were EC.
MGCT was found in 12 patients; we have reported 3 patients in each MGCT with EC + YST
and IMT + EC + YST. Two patients in each MGCT with YST + dysgerminoma, YST + IMT,
and YST + MT. One in each MGCT with IMT + dysgerminoma ([Fig. 1B]).
Survival Analysis
The study followed all patients for a median duration of 17.2 months (8.2–25.3). Seven
patients died, 03 were related to progressive disease, 01 had secondary malignancy
(brain tumor), 02 had bacterial and fungal infections, and 01patient had a recurrence
of the disease.
Recurrence has occurred in 16 patients in which 10 (62.5%) were off treatment after
first-line chemotherapy and 06 (37.5%) were LR chemo-naive patients. In these 6 patients,
1 had lymphovascular invasion and 2 patients had mixed histology, while 3 had dysgerminoma
and 1 YST.
For the entire patient cohort (n = 97), the 5-year EFS rate was determined to be 83.5%, while the 5-year OS rate was
calculated as 92.8% ([Fig. 2A]).
Fig. 2 (A) The 5-year event-free survival (EFS) and overall survival (OS). (B–E) The 5-year EFS according to the risk factors (IR = intermediate risk; LR = low-risk;
HR = high-risk; AFP = α-fetoprotein.).
[Fig. 2B] shows the 5-year EFS rates among different risk groups (LR, IR, and HR), demonstrating
a statistically significant difference. Owing to female predominance and primary nononcological
surgeries outside the tertiary care center, we found lower EFS in the LR group as
compared with the IR group.
Furthermore, [Fig. 2C] illustrates the EFS rates for children without metastases (84.1%) and those with
metastases (82.1%), showing no statistically significant difference. In [Fig. 2D], patients with AFP < 10,000 ng/mL exhibited a higher EFS compared with those with
elevated AFP ≥ 10,000 ng/mL, although the difference was not statistically significant.
The EFS of patients after the first-line treatment with the small residual disease
was 42.1% as compared with patients with complete remission, 93.6%, which was statistically
significant ([Fig. 2E]). Through multivariable analysis, it was determined that the presence of residual
disease emerged as the sole independent prognostic factor, with a HRs of 7.42. The
residual disease was small in size and was not amenable for surgery without mutilation.
We did not encounter condition like growing teratoma syndrome. Also, patients in the
HR group and AFP level > 10,000 ng/mL were found to have 2.4 and 1.3 times higher
HRs, respectively, which was statistically nonsignificant. There were 36% higher chances
of patients with metastatic disease to have disease recurrence, but it was statistically
nonsignificant ([Table 2]).
Table 2
Multivariate analysis for hazard ratio
|
HRs
|
95% CI
|
p-Value
|
|
High-risk group
|
2.416
|
0.656–8.895
|
0.185
|
|
Metastatic disease
|
0.361
|
0.098–1.331
|
0.126
|
|
AFP > 10,000 (ng/mL)
|
1.370
|
0.424–4.422
|
0.598
|
|
Residual diseases
|
7.426
|
2.455–22.46
|
< 0.001[a]
|
Abbreviations: AFP, α-fetoprotein; CI, confidence intervals; GCT, germ cell tumor;
HRs, hazard ratio.
a Significant value < 0.05.
Discussion
GCTs are uncommon neoplasms characterized by diverse histological subtypes, encompassing
both benign and malignant forms. Due to their rarity, a retrospective study was conducted
to evaluate the treatment outcomes of pediatric GCTs at our medical facility. Consistent
with established international guidelines, all patients received chemotherapy as part
of their treatment regimen.[12] In our study, girls were more frequently affected than boys, which is consistent
with the literature.[13]
[14]
Malignant testicular tumors are less frequently reported compared with extragonadal
GCTs and mature teratomas.[15] In our study, the majority of cases (60.8%) exhibited gonadal involvement, while
39.2% showed extragonadal involvement. Among the histological subtypes, YST was the
most frequently observed, which aligns with findings from previous studies.[14]
[15] However, our study revealed that ovarian GCTs accounted for a larger proportion
(56%) of the cases.
In our study, we also identified MGCTs, with the most prevalent combination being
YST and EC. This finding is consistent with previous studies that have reported similar
results, indicating the recurrent occurrence of this specific combination in MGCTs.[16] Tumor markers play a crucial role in the diagnosis, detection of relapse, and follow-up
of GCTs. In our study, we found that serum AFP elevation, which is commonly associated
with the presence of a YST component, was observed in 87.5% of patients with GCTs.
These findings align with the results reported by Kumar et al, indicating a high concurrence
in the incidence of elevated AFP levels among patients with GCTs.[16] Among the cases of YST in our study, 35 individuals (71.4%) exhibited an AFP level
exceeding 10,000 ng/mL. Interestingly, our study did not identify elevated AFP as
a significant prognostic factor, which aligns with the findings of a study conducted
by Marina et al. This suggests that AFP levels may not independently predict the prognosis
of YSTs in pediatric patients, consistent with the previous research.[17]
In our study, patients with β-HCG levels below 5,000 IU/L experienced a recurrence
rate of 87.5%, with 92.9% of these patients still alive. In contrast, those with β-HCG
levels above 5,000 IU/L had a recurrence rate of 12.5%, with only 7.1% alive. These
findings are consistent with previous research that identifies β-HCG as a significant
prognostic marker in GCTs. For example, Lorch et al[18] demonstrated that elevated β-HCG levels in patients with metastatic GCTs were associated
with poorer survival outcomes and a higher likelihood of recurrence.
The management approach for GCTs is influenced by various factors such as tumor location,
disease extent, patient age, and coexisting medical conditions. Typically, the management
strategy involves surgical resection for localized disease, chemotherapy for cases
with residual or metastatic disease, and a combination of neoadjuvant chemotherapy
and delayed surgical excision for unresectable lesions. These treatment modalities
are implemented based on individual patient considerations to optimize outcomes in
GCT management.[19]
[20] Localized GCTs are primarily treated through surgical resection. The primary objective
of the surgical procedure is to achieve complete removal of the tumor while ensuring
the preservation of normal tissue and organ function. The surgical approach aims to
maximize tumor removal while minimizing potential damage to surrounding healthy tissues
and organs. In some cases, a radical orchiectomy (removal of the testicle) may be
necessary for testicular GCTs. In ovarian GCTs, surgical resection may involve removal
of the affected ovary or ovaries.[19]
[20] Chemotherapy is the primary treatment for residual or metastatic disease. Platinum-based
chemotherapy, which includes drugs such as cisplatin, carboplatin, and oxaliplatin,
has been shown to be highly effective in treating GCTs. Chemotherapy is typically
given in cycles, with a period of rest between each cycle to allow the body to recover.[19]
[20] Unresectable lesions in GCTs may be managed through a combination of neoadjuvant
chemotherapy and delayed surgical excision. Neoadjuvant chemotherapy refers to the
administration of chemotherapy before surgery, with the goal of reducing the size
of the tumor and increasing the feasibility of surgical removal. This approach allows
for tumor shrinkage, facilitating subsequent surgical intervention by improving the
chances of achieving complete resection while preserving normal tissue function. Neoadjuvant
chemotherapy followed by delayed surgical excision is employed to optimize the management
of GCTs in cases where immediate surgical resection is not feasible. Delayed surgical
excision involves waiting until the tumor has responded to chemotherapy before removing
it surgically.
The introduction of platinum-based chemotherapy has led to a remarkable improvement
in the chances of survival for children diagnosed with GCTs. Currently, approximately
90% of children with GCTs can expect to survive for at least 5 years, a substantial
increase compared with the less than 50% survival rate in the period before platinum-based
treatments were available. Nevertheless, the outlook for each child is influenced
by various factors such as the specific type and location of the tumor, the stage
of the disease at diagnosis, as well as the age and overall health of the patient.[19]
[20]
Our study revealed consistent findings with regard to the cure rates of ovarian and
testicular GCTs at different stages. Specifically, stage I GCTs exhibited a 100% cure
rate, indicating successful treatment for all patients in this stage. For stage III
GCTs originating from any primary site, the cure rate was determined to be 82%, while
for stage IV GCTs from any primary site, the cure rate stood at 75%. Furthermore,
we observed that the histology, or tumor type, played a significant role in prognosticating
immature malignant teratoma ovarian tumors. Among these ovarian tumors, those of the
neural type with grades II and III demonstrated the least favorable prognosis.[21]
[22] Two cases of ovarian tumors with progressive disease were identified in our report.
Unfortunately, these patients were lost to follow-up after undergoing second-line
chemotherapy.
A study conducted by Akyüz et al[23] from Turkey reported the OS and EFS rates in ovarian tumors as 68 and 57%, respectively,
but in our study, we reported 97% OS and 84.8% EFS in ovarian tumors. We have 96.6%
OS for gonadal tumors and 86.8% for extragonadal tumors; however, in a study conducted
by Feltbower et al,[24] the 5-year survival rates for gonadal GCT were reported to be 93 to 95%, while the
rates for extragonadal GCT were 70 to 75%. Mann et al[25] also reported similar findings, with 5-year survival rates of 90.9 and 87.8%, which
aligned with our study. Furthermore, a more recent extensive population-based study
from Germany indicated a 5-year survival rate of 92% for both gonadal and extragonadal
GCTs.[26]
Risk of recurrence is more in patients with HR disease as we reported in our study,
27.3% in HR. Actual recurrence occurred more in patients with residual disease after
first-line chemotherapy, that is, 55.6%, rather than patients with no residual.
Pediatric and adult GCTs have many differences in terms of histology, different staging
systems, and survival. In adult gonadal GCT, testicular GCT is staged as per the American
Joint Committee on Cancer and ovarian as per the International Federation of Gynecology
and Obstetrics, while pediatric GCT as per the IGCCCG.[27] MGCTs are more common in adolescent and young adults. Children with testicular non-seminomatous
GCT have improved survival compared with adults.[28]
The study provides confirmation that positive outcomes can be attained for children
diagnosed with pediatric GCTs. It highlights the significant impact of a multidisciplinary
approach to pediatric oncology care, which has substantially enhanced survival rates
for children with GCTs in Pakistan. The recent advancements in health care services
within the country have played a crucial role in raising life expectancy and achieving
better outcomes for children with cancer.
Study Limitations
We have presented in this study the in-depth analysis of GCTs but our data has some
limitations. We were not able to do follow-up of this large cohort for short duration,
so far. We aim to follow this cohort with longer duration and add assessment of long-term
toxicities of chemotherapy.
Conclusion
In conclusion, a comprehensive approach involving collaboration among surgeons, histopathologists,
oncologists, and radiation therapists is crucial for effectively managing GCTs in
children. The combination of surgical interventions and chemotherapy has played a
vital role in enhancing the overall outcomes for pediatric GCT patients. However,
it is essential to develop personalized treatment plans to maximize the effectiveness
of interventions. With the continuous advancements in pediatric oncology care, there
has been a notable improvement in the prognosis for children with GCTs in Pakistan,
instilling optimism for even better outcomes in the future.
