Primary central nervous system germ cell tumors in children and young adults: A review of controversies in diagnostic and treatment approach

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Abstract

Primary central nervous system (CNS) germ cell tumors (GCT) are a rare heterogenous group of cancers, arising most commonly in the second decade of life. Through several clinical trials conducted around the world by various groups, the treatment approach for CNS GCT has advanced substantially with generally improved overall outcomes. In recent years, the goal of clinical trials has been focused on reduction of the radiotherapy burden and minimization of long-term toxicity. This review summarizes the current diagnostic and treatment regimens for CNS GCT, examines the controversies associated with these approaches, gaps in contemporary knowledge, and underscores the challenges we face. We also explore future directions in the management of CNS GCT with the ultimate overall aim of preserving curative outcomes, identifying novel biomarkers, and mitigating neurocognitive, endocrine, and psychological toxicity through prospective clinical studies.

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Most cited references 82

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CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014–2018

Quinn Ostrom, Gino Cioffi, Kristin Waite … (2021)

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control and Prevention (CDC) and National Cancer Institute (NCI), is the largest population-based cancer registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors available and supersedes all previous reports in terms of completeness and accuracy and is the first CBTRUS Report to provide the distribution of molecular markers for selected brain and CNS tumor histologies. All rates are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 24.25 (Malignant AAAIR=7.06, Non-malignant AAAIR=17.18). This overall rate was higher in females compared to males (26.95 versus 21.35) and non-Hispanics compared to Hispanics (24.68 versus 22.12). The most commonly occurring malignant brain and other CNS tumor was glioblastoma (14.3% of all tumors and 49.1% of malignant tumors), and the most common non-malignant tumor was meningioma (39.0% of all tumors and 54.5% of non-malignant tumors). Glioblastoma was more common in males, and meningioma was more common in females. In children and adolescents (age 0–19 years), the incidence rate of all primary brain and other CNS tumors was 6.21. An estimated 88,190 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US population in 2021 (25,690 malignant and 62,500 non-malignant). There were 83,029 deaths attributed to malignant brain and other CNS tumors between 2014 and 2018. This represents an average annual mortality rate of 4.43 per 100,000 and an average of 16,606 deaths per year. The five-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 35.6%, for a non-malignant brain and other CNS tumors the five-year relative survival rate was 91.8%.

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Intracranial germ-cell tumors: natural history and pathogenesis.

F. Hochberg, Janine M. Jennings, R Gelman (1985)

The natural history of primary intracranial germ-cell tumors (GCT's) is defined from 389 previously published cases, of which 65% were germinomas, 18% teratomas, 5% embryonal carcinomas, 7% endodermal sinus tumors, and 5% choriocarcinomas. Intracranial GCT's display specificity in site of origin. Ninety-five percent arise along the midline from the suprasellar cistern (37%) to the pineal gland (48%), and an additional 6% involve both sites. The majority of germinomas (57%) arise in the suprasellar cistern, while most nongerminomatous GCT's (68%) preferentially involve the pineal gland (p less than 0.0001). The age distribution of afflicted patients is unimodal, centering with an abrupt surge in frequency in the early pubertal years; 68% of patients are diagnosed between 10 and 21 years of age. Nongerminomatous GCT's demonstrate an earlier age of onset than do germinomas (p less than 0.0001). Prolonged symptomatic intervals prior to diagnosis are common in germinomas (p = 0.0007), in suprasellar GCT's (p = 0.001), and among females (p = 0.02). Parasellar germinomas commonly present with diabetes insipidus, visual field defects, and hypothalamic-pituitary failure. Nongerminomatous GCT's present as posterior third ventricular masses with hydrocephalus and midbrain compression. Germ-cell tumors may infiltrate the hypothalamus (11%), or disseminate to involve the third ventricle (22%) and spinal cord (10%). Among a subpopulation of 263 conventionally treated patients, two factors were of prognostic significance: 1) histological diagnosis; germinomas were associated with significantly longer survival than nongerminomatous GCT's (p less than 0.0001); and 2) staging of the extent of disease; this emphasizes the ominous character of involvement of the hypothalamus (p = 0.0002), third ventricle (p = 0.02), or spinal cord (p = 0.01). Specific recommendations regarding the necessity of histological diagnosis and staging of the extent of disease are made in light of modern chemotherapeutic advances. The pathogenesis of GCT's may be revealed by their specificity of origin within the positive (suprasellar cistern-suprachiasmatic nucleus) and negative (pineal) regulatory centers for gonadotropin secretion within the diencephalon. The abrupt rise in age distribution at 10 to 12 years suggests that the neuroendocrine events of puberty are an "activating" influence in the malignant expression of these embryonal tumors.

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Pediatric central nervous system germ cell tumors: a review.

Stewart Goldman, Juan E Echevarría, Jason Fangusaro (2008)

Central nervous system (CNS) germ cell tumors (GCTs) represent approximately 3% of primary pediatric brain tumors and encompass a wide pathologic spectrum. CNS GCTs are most commonly located in the pineal and suprasellar regions of the brain and can be divided into major groups including germinomas and nongerminomatous GCTs (NGGCTs), with teratomas often considered a separate category. The clinical presentation varies by location and size, and it frequently includes endocrine abnormalities, visual changes, and signs of increased intracranial pressure. Neuroimaging studies cannot differentiate GCTs from other tumors, and therefore, the diagnosis usually requires histologic confirmation. The rare exceptions are the cases where characteristic elevations of tumor markers, including alpha-fetoprotein and/or beta-human chorionic gonadotropin are documented in the serum and/or cerebrospinal fluid. In these cases, the imaging findings along with the tumor marker elevation may be diagnostic in themselves without the need for tissue confirmation. Treatment and prognosis differ greatly between groups. Germinomas have a superior prognosis than NGGCTs. Five-year overall survival rates >90% were reported initially with the use of craniospinal irradiation. More recently, the use of chemotherapy in addition to radiation therapy has afforded the ability to decrease the dose and volume of radiation therapy without affecting survival rates. NGGCTs are less radiosensitive than germinomas, but the use of adjuvant chemotherapy has improved survival rates in this group as well. The standard management for CNS GCTs remains controversial. Treatment regimens aimed to improve progression-free and overall survival times are ongoing.

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Author and article information

Contributors

Girish Dhall

Mohamed S. Abdelbaki

Journal

Journal ID (nlm-ta): Neoplasia

Journal ID (iso-abbrev): Neoplasia

Title: Neoplasia (New York, N.Y.)

Publisher: Neoplasia Press

ISSN (Print): 1522-8002

ISSN (Electronic): 1476-5586

Publication date PMC-release: 13 December 2022

Publication date Collection: February 2023

Publication date (Electronic): 13 December 2022

Volume: 36

Electronic Location Identifier: 100860

Affiliations

[a ]Dana-Farber / Boston Children's Cancer and Blood Disorder Center, USA

[b ]Department of Pediatrics, Harvard Medical School, Boston, USA

[c ]Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia

[d ]University of New South Wales, Randwick, New South Wales, Australia

[e ]The Alabama Center for Childhood Cancer and Blood Disorders at Children's of Alabama, Birmingham, USA

[f ]University of Alabama, Birmingham, USA

[g ]The Division of Hematology and Oncology, St. Louis Children's Hospital, Washington University, School of Medicine in St. Louis, Washington University, St. Louis, Missouri, USA

Author notes

[* ]Corresponding author at: The Alabama Center for Childhood Cancer and Blood Disorders at Children's of Alabama, 1600 7th Avenue S, Lowder 512, Birmingham, AL 35233, USA. Gdhall@ 123456uabmc.edu

[** ]Co-corresponding author at: Washington University School of Medicine in St. Louis, 660 South Euclid Avenue – Campus Box 8116, St. Louis, MO 63110, USA. MohamedA@ 123456wustl.edu

[1]

These authors contributed equally to this manuscript.

[2]

These authors contributed equally to the supervision of this manuscript.

Article

Publisher Item ID: S1476-5586(22)00085-9 Publisher ID: 100860

DOI: 10.1016/j.neo.2022.100860

PMC ID: 9772847

PubMed ID: 36521378

SO-VID: e0d55645-6261-496c-a28a-0bda8d022334

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 29 August 2022

Date revision received : 18 November 2022

Date accepted : 28 November 2022

Primary central nervous system germ cell tumors in children and young adults: A review of controversies in diagnostic and treatment approach

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Karger: Oncology

Most cited references 82

CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014–2018

Intracranial germ-cell tumors: natural history and pathogenesis.

Pediatric central nervous system germ cell tumors: a review.

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