Available online 6 July 2022

Abstract

Germ cell tumors of the central nervous system (GCT-CNS) arise predominantly in midline locations of the CNS and affect young patients in their first to third decades of life. Involvement of the CNS is thought to be a sequelae of residual primordial germ cells with incomplete embryologic migration. Clinically, GCT-CNS present with symptoms of ventricular obstruction or compression of affected brain structures. Histologically, these tumors are analogous to their gonadal and extra-gonadal counterparts. Diagnosis relies heavily on morphology and immunohistochemical findings, and can be complicated by limited tumor sampling. There is currently only a limited role for molecular studies. Treatment of these lesions is made difficult by their involvement of deep and vital brain structures and accurate pathologic diagnosis is essential for appropriate therapy. Diagnosis should involve review of the clinical history, imaging studies, and assessment of serum and cerebrospinal fluid tumor markers. Current therapeutic strategies involving radiation therapy with or without chemotherapy are quite effective, in spite of the locational difficulties that often prevent gross total resection.

Introduction

Germ cell tumors of the central nervous system (CNS-GCTs) comprise a family of tumors thought to derive primarily from primitive germ cells and are CNS-based analogues of germ cell neoplasms arising in the gonads and in other extragonadal locations (EGGCT). CNS-GCTs are predominantly tumors of young patients, with incidence peaking during adolescence and a large majority of cases occurring in the first three decades of life. These lesions make up approximately 2-3% of pediatric brain tumors in the United States, and up to 10-15% of pediatric CNS tumors in east Asian countries including Japan, China, and Korea.1, 2, 3 CNS-GCTs are classified into the same subtypes as non-CNS germ cell neoplasms, with which they share morphologic, immunophenotypic, and genetic features, and have similar serum markers of differentiation (Table 1). In light of these similarities, and the excellent literature describing the various subtypes of germ cell tumors across all sites of origin, the focus of this review will be on issues that make diagnosis and treatment of CNS-GCTs challenging. In large part, this relates to the intrinsic difficulties posed by the location of these lesions deep within the intracranial cavity, involving critical brain structures in which these tumors tend to arise.

Section snippetsWhy are germ cell tumors found in the CNS?

As with non-neuraxial EGGCTs, the dominant and long-held hypothesis of the origin of CNS-GCTs relates to the embryologic migration of primordial germ cells (PGCs) from the yolk sac to the gonad. In normal development, the PGC migration pathway is lengthy and traverses the developing CNS, regulated by complex chemotactic signaling. Experimental models indicate that failure of a subset of PGCs to appropriately complete the migratory journey is a relatively common event, and mechanisms to

Conceptual categories of CNS-GCT

Germ cell neoplasms, including in the CNS, are broadly divided into germinoma and non-germinomatous GCT (NGGCT), largely due to therapeutic differences between these groups. However, from an etiologic standpoint, it may be more accurate to first make a distinction between intracranial teratomas of infancy/early childhood, and GCTs developing after early childhood. The reason for this division is that the epidemiology and the underlying genetics of these two groups of tumors appears largely

Updates in the 2021 5th edition of the CNS WHO

The WHO Classification of Central Nervous System Tumors (CNS WHO) 5th edition was recently released, updating many of the definitions of tumors in this classification system.6 A major theme of this update was the incorporation of molecular diagnostic techniques, including both molecular definitions of existing diagnostic categories and the recognition of new molecularly-defined tumor types. The chapter on germ cell tumors, however, remains largely unchanged, with only a minimal role for

Clinical presentation and preoperative workup

CNS-GCTs typically present with symptoms related to compromise of adjacent CNS structures. Pineal region masses can impinge upon the cerebral aqueduct and restrict flow of cerebrospinal fluid (CSF), leading to symptoms of obstructive hydrocephalus with elevated intracranial pressure. Presenting symptoms include persistent/progressive headaches and cranial neuropathies such as oculomotor dysfunction/visual disturbance. Severe cases can present with nausea/vomiting and loss of consciousness

Surgical approaches at diagnosis – biopsy versus resection

If AFP and/or beta-hCG levels are elevated in the setting of neuroradiologic findings consistent with CNS-GCT, obtaining tissue for diagnosis is not required, and surgery may be reserved for residual mass lesions following chemoradiation therapy.17 In other cases, obtaining tissue for diagnosis is beneficial in order to guide therapeutic decision-making, and should be pursued if not clinically contraindicated. Gross total resection (GTR) at the time of diagnosis is indicated only for pure

Histopathologic diagnosis and challenges

All subtypes of germ cell tumors, including mixed tumors, can involve the CNS; these share the histologic and immunophenotypic characteristics of their extra-cranial GCT counterparts (summarized in table 1, Figure 1, and Figure 2). Diagnostic challenges in CNS-GCTs are therefore primarily due to the limited nature of many biopsy specimens, in which adequacy of the tissue for diagnosis is balanced by the desire to avoid procedure-related damage to important CNS structures.

Immunohistochemistry

Treatment and prognosis

Accurate diagnosis, including integration with CSF and serum tumor markers, is clinically important, as the appropriate therapeutic regimen for CNS-GCT depends heavily on the specific subtype that is diagnosed. Optimizing therapeutic protocols to maximize disease control while minimizing unwanted side effects continues to be an active area of clinical research. While recommendation of specific treatment regimens is beyond the scope of this review, the general strategies currently in use are

Conclusions

The histopathologic evaluation of CNS-GCTs has remained largely unchanged in recent years. Despite advances in molecular neuropathology, there is thus far a minimal role for molecular studies in the diagnostic workup of these tumors.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declarat of Competing Interest

The authors have no competing interests to declare

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