Roles of Tumor Markers in Central Nervous System Germ Cell Tumors Revisited with Histopathology-Proven Cases in a Large International Cohort

Abstract

The central nervous system germ cell tumor (CNS GCT) is a rare and incompletely understood disease. A major outstanding question in the 2015 consensus document for CNS GCT management was the utility and interpretation of the tumor markers human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP) in the diagnosis of malignant non-germinomatous GCTs (hereafter NGGCTs) prior to treatment. In the current study, we assembled two geographically and ethnically different clinical cohorts from the Mayo Clinic (1988–2017) and the intracranial GCT Genome Analysis Consortium (iGCT Consortium) in Japan to address this question. Patients with both histopathological diagnosis and tumor markers available were eligible for inclusion (n = 162). Biopsy and surgical resection were performed in 85 and 77 cases, respectively. Among 77 resections, 35 demonstrated positivity for HCG, AFP, or both (45%). Seventeen of the marker-positive cases had no malignant non-germinomatous component identified on histopathology, but they were composed strictly of germinoma, teratoma, or both (49%). One embryonal carcinoma was the only marker-negative NGGCT in the study sample. Among 85 biopsies, 18 were marker positive (21%). Seven of these patients had no malignant non-germinomatous component on histopathology, suggesting the potential limitations of limited tissue sample volumes. Neither histopathological diagnosis nor tumor markers alone reliably diagnose NGGCTs due to the secretion of HCG and AFP by germinomas and teratomas. Treatment planning should incorporate integrated histopathological and laboratory-based diagnosis to optimize diagnostic and treatment strategies for this unusual and histologically heterogeneous tumor.

Impact of tumor markers on diagnosis, treatment and prognosis in CNS germ cell tumors: correlations with clinical practice and histopathology

“…The current study extends our preceding work regarding the evolving understanding of tumor markers in CNS GCTs [ 15 ]. Our previous study demonstrated that elevation of tumor marker alone cannot exclude the possibility of germinoma or teratoma within the true histopathologic profile of a given GCT.…”

“…The combined study cohort correspondingly included 161 cases: 40 from Mayo Clinic, 121 from iGCT consortium. One case was omitted from the preceding study [ 15 ], as the timing of tumor marker measurement and surgical resection was not strictly identical.…”

“…In COG and SIOP protocols, tumor marker thresholds are defined for the diagnosis of NGGCTs (with a malignant component), which in turn prompts protocol-based therapeutic assignment [ 11 ]. However, a preceding report argued that elevation of tumor markers was not limited to NGGCTs with a malignant component [ 15 ], while another study demonstrated that HCG RNA was expressed across all histological subtypes [ 16 ]. Correspondingly, establishing a GCT diagnosis and proceeding with intensive therapies on the basis of tumor markers alone remains controversial and potentially risky.…”

Clinical Outcomes and Diagnostic Consistency of Serum and CSF Tumor Markers in Pediatric Intracranial Germ Cell Tumors in Thailand: A Multicenter Study

“…11 However, mild elevations of serum β-HCG or AFP could be observed in pure germinomas. 5,22,23 Although serum and CSF AFP accounted for a higher percentage of agreement than β-HCG, the overall consistency between serum and CSF AFP and β-HCG levels was desirable with a moderate level of agreement. This could imply that assessing either serum or CSF is sufficient for diagnostic evaluation to lower the unnecessary lumbar puncture procedures among patients with ICGCTs.…”

Central nervous system mature teratoma producing carbohydrate antigen 19-9: illustrative case

“…Although many investigators have studied diagnostic criteria for tumor markers, no international consensus has been reached regarding clinical diagnostic criteria for biochemical marker levels. 21 Furthermore, no reports have clarified the clinical significance of CA19-9 in CNS GCTs.…”