Malignant gliomas account for 60% of all primary brain tumors in adults. Glioblastoma Multiforme (GBM) is the most common primary glial tumor with a dismal prognosis and a median survival of approximately 14 months. Extra-neural metastases from primary brain tumors are unusual with an incidence rate of less than 2%. This has been attributed to factors such as short survival, lack of true lymphatics in the CNS, and physical barriers provided by the dura, extracellular matrix, and basement membrane. Although most GBMs occur sporadically, there is a known association with therapeutic radiation exposure and with work in nuclear disaster cleanup. To our knowledge, no case of GBM with metastasis occurring in a patient with occupational radiation exposure currently exists in the literature. In this article, we present a case of GBM with lung metastasis occurring in a 51-year-old Caucasian male, whose history is significant for occupational exposure to ionizing radiation, and review the literature on GBM risk factors and potential mechanisms of metastasis.
Glioblastomas (GBMs) are the most common and yet the most aggressive primary intraparenchymal brain tumors in adults [
A 50-year-old Caucasian man nuclear power plant worker with an unremarkable medical history presented with complaints of recurrent headaches, nausea, and vomiting with left sided facial droop and personality changes, all occurring for 3-4 weeks. A computerized tomography (CT) scan of the brain showed a right frontal mass. Subsequently a pre- and postcontrast magnetic resonance imaging (MRI) was performed that showed a right frontal mass [Figures
(a) and (b): pre- and postcontrast MRI demonstrating large right frontal ring-enhancing mass, October 2008. (c) Chest CT with mass in the left lung, May 2009.
Histologically, the initial resection specimen of the right frontal lobe mass was a high-grade glioma that infiltrated the adjacent brain tissue [Figure
Brain tumor. (a) The tumor is composed of large and small cells (LFB/H&E, 100x). (b) The tumor contains many multinucleated giant cells (LFB/H&E, 400x). (c) The tumor displaying necrosis with palisade (H&E, 100x).
The resection of the recurrent brain tumor yielded a high-grade infiltrating glioma with predominantly astrocytic features in that the predominant cell population had elongated bipolar processes. The tumor again had vascular hyperplasia. There was also extensive radiation induced necrosis.
The left lower lobe lung tumor was a metastatic glioma characterized by nests and sheets of cells with moderate to abundant amounts of eosinophilic to pale cytoplasm [Figure
Lung tumor. (a) The tumor forms a solid mass (left side) with bordering alveoli (right side) (H&E, 100x). (b) Necrosis in the lung tumor (H&E, 100x). (c) GFAP immunostain demonstrating immunopositive tumor cells in the lung with immunonegative pulmonary cells (right side) (GFAP immunostain, 100x).
Historically, the glial origin of GBMs was first recognized by Virchow in 1863. The erstwhile term “glioblastoma multiforme” was coined by Mallory in 1914 [
Incidence rates of gliomas vary significantly by histologic type, age at diagnosis, sex, race, and country [
Several epidemiologic risk factors have also been examined as potential contributors to glioma risk. Amongst these factors, those which seem to have a significant association include a decrease in risk by history of allergies or atopic disease(s) and an increase in risk by exposure to IR [
Certain forms and doses of IR are generally accepted as having the potential to cause brain tumors. Atomic bomb studies, nuclear test fall-out data, studies of survivors of therapeutic radiation for cancer and for benign conditions, and occupational and environmental studies have connected IR to glioma genesis [
The data showing the association between radiation and gliomas is limited but data in adults show heightened greater risk in certain groups exposed to radiation. Two cohorts from Latvia and Estonia that consisted of approximately 10,000 individuals exposed to nuclear radiation showed a statistically significant increase in brain cancers [
Morphologically GBMs are composed of cells that resemble astrocytes with irregular, ovoid, or elongated but mostly round nuclei that tend to lie toward one side or edge of the cell body. The
Metastatic spread of GBM outside the CNS is unusual, reported to occur in less than 2% of all GBMs [
The most common sites of metastatic spread are the lungs and pleurae followed by lymph nodes, bone, and liver [
Several theories have been proposed as possible routes and mechanisms of such metastatic spread but, despite all the theories and evidence, such metastasis by gliomas is still a poorly understood process. Historically, it has been postulated that the lack of lymphatic vessels in the CNS constitutes a barrier to tumor spread [
Functional lymphatic vessels lining the dural sinuses have been demonstrated. These structures express all the molecular hallmarks of lymphatic endothelial cells (LYVE1, PROX1, and vascular endothelial growth factor receptor 3 (VEGFR3)) and are able to carry both fluid and immune cells from the CSF and drain to the deep cervical lymph nodes [
In 2014, a study done by Muller
Patients with GBM typically respond initially to therapy but ultimately relapse within the high-dose irradiation field, suggesting the presence of a subpopulation of resistant cells. While heterogeneity of tumors in different patients can in part explain varied patient responses to therapy,
In 2000, Park
The standard therapy for newly diagnosed GBM is the “Stupp regimen” that uses Temozolomide and radiation. Our patient failed this regimen and in fact developed a metastatic lesion that we have described in this case report [
While gliomas occurring in the setting of occupational IR exposure may not represent a distinct clinical entity, it has been shown that certain forms of IR exposure do impart an increased risk of GBM development. The occurrence of a metastatic glioma in our patient with a history of occupational radiation exposure is both unique and intriguing as to what role might have been played by his occupational IR exposure. If the dose and duration of exposure were known in our patient it would have contributed to a better understanding of the association between low dose and high dose IR with primary brain tumors such as gliomas. This perhaps warrants more focused studies exploring the effects of IR on specific tumor subtypes and their relationship to specific dosage and duration of exposure. As innovative therapeutic interventions such as targeted therapies become increasingly available, longer GBM survival rates and subsequently more cases of dissemination of GBMs outside the CNS can be expected. For this reason, it is essential that physicians be cognizant of the potential for such metastatic disease in patients with GBMs.
All the authors have no financial disclosures to declare.
All the authors have no conflicts of interest to declare.