Age-Dependent Presentation and Clinical Course of 1465 Patients Aged 0 to Less than 18 Years with Ovarian or Testicular Germ Cell Tumors; Data of the MAKEI 96 Protocol Revisited in the Light of Prenatal Germ Cell Biology

Abstract

Objective: To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT).

Methods: Patients <18 years with ovarian and testicular GCT (respectively OGCT and TGCT) were prospectively registered according to the guidelines of MAKEI 96. After resection of the primary tumor, patients staged ≥II received risk-stratified cisplatin-based combination chemotherapy. Patients were analyzed in respect to age (six age groups divided into 3-year intervals), histology, stage, and therapy. The primary end point was overall survival.

Results: Between January 1996 and March 2016, the following patients were registered: 1047 OGCT, of those, 630 had ovarian teratoma (OTER) and 417 had malignant OGCT (MOGCT); and 418 TGCT, of those, 106 had testicular teratoma (TTER) and 312 had malignant TGCT (MTGCT). Only in MTGCT, older age correlated with a higher proportion of advanced tumors. All 736 teratomas and 240/415 stage I malignant gonadal GCT underwent surgery and close observation alone. In case of watchful waiting, the progression rate of OGCT was higher than that of TGCT. However, death from disease was reported in 8/417 (1.9%) MOGCT and 8/312 (2.6%) MTGCT irrespective of adjuvant chemotherapy and repeated surgery.

Conclusions: The different pathogenesis and histogenesis of gonadal GCT reflects sex- and age-specific patterns that define clinically relevant risk groups. Therefore, gender and age should be considered in further research on the biology and clinical practice of pediatric gonadal GCT.

Keywords: age; children and adolescents; germ cell tumors; histology; ovary; sex; testis.

Figure 1

Occurrence of gonadal teratoma and malignant germ cell tumor with respect to sex and age. (A) Age distribution of 1047 patients with an ovarian germ cell tumor (OGCT) according to the histology groups: the green line represents the 630 teratomas (TER) and the red line represents the 417 malignant ovarian germ cell tumors (MOGCT) OGCT showed a continuously increasing incidence with a peak at approximately 12 years; (B) Age distribution of 418 patients with a testicular germ cell tumor (TGCT) according to the histology groups: the green line represents the 106 teratomas (TER) and the red line represents the 312 malignant testicular germ cell tumors (MTGCT). TGCT showed a bimodal age distribution.

Figure 2

Occurrence of gonadal histology subentities with respect to sex and age. The green lines represent the benign teratomas (TER) according the grade of Gonzales-Crussi divided into grade 1 to 3 (light green) teratoma and teratoma grade 0 (dark green line). The other coloured lines represent the several malignant histological subentities: the yellow line are yolk sac tumor within teratoma components (YST+TER), the violet line represent pure yolk sac tumor, the blue line mixed malignant germ cell tumors (MGCT) and the green line pure dysgerminoma (DYS)/seminoma (SEM). (A) Timely occurrence of the benign subentities in ovarian germ cell tumors (OGCT). The occurrence of both benign subentites in the age groups are similar but teratomas grade 0 are occurring more often; (B) Timely occurrence of the benign subentities in testicular germ cell tumors (TGCT) The first peak of both teratoma grade 0 and teratomas grade 1-3 appears from birth to 3 years, whereas only teratomas grade 1-3 are seen in the other age groups; (C) Timely occurrence of the malignant subentities in ovarian germ cell tumors (OGCT) All malignant subentities occurred during infancy and early childhood with predominant YST histology and presented a slower rise starting at 6 years of age with a peak during adolescence for all malignant GCT subentities; (D) Timely occurrence of the malignant subentities in testicular germ cell tumors (TGCT). The first peak consisting of YST occurred from birth to 3 years, whereas the second peak exclusively including MTGCT started at 12 years and reached its highest point at 15 to <18 years. Between the two peaks, there is an almost complete lack of all malignant subentities over a period of 9 years

Figure 3

Outcome in stage I patients undergoing w&w strategy, Events (red column) are presented in respect to age and the histologic subentities. (A) Events in 137 FIGO stage I patients undergoing w&w strategy with malignant ovarian germ cell tumors (MOGCT): 46 Events are presented in respect to age and the histologic subentities. In MOGCT, higher age correlates with a higher progression rate, this difference is significant. Furthermore pure YST histology was associated with a high risk of progression; (B) Events in 103 Lugano stage I patients undergoing w&w strategy with malignant testicular germ cell tumors (MTGCT): 12 Events are presented in respect to age and the histologic subentities. In MTGCT, no age and histology specific trends were observed.

Figure 3

Outcome in stage I patients undergoing w&w strategy, Events (red column) are presented in respect to age and the histologic subentities. (A) Events in 137 FIGO stage I patients undergoing w&w strategy with malignant ovarian germ cell tumors (MOGCT): 46 Events are presented in respect to age and the histologic subentities. In MOGCT, higher age correlates with a higher progression rate, this difference is significant. Furthermore pure YST histology was associated with a high risk of progression; (B) Events in 103 Lugano stage I patients undergoing w&w strategy with malignant testicular germ cell tumors (MTGCT): 12 Events are presented in respect to age and the histologic subentities. In MTGCT, no age and histology specific trends were observed.