10 Radiation-Induced and Multiple Meningiomas
Introduction
Meningiomas are largely benign sporadic tumors occurring as solitary lesions whose management complexity is usually provided by the troublesome locations of their arachnoidal origins throughout the cranial vault and by their capacity to recur if a Simpson grade I resection is not achieved. More rarely, meningiomas may arise as multiple distinct or contiguous tumors. In some cases, multiple tumors arise in the context of prior cranial irradiation, begetting “radiation-induced meningiomas” (RIMs). In other cases, multiple tumors may arise in the setting of neurofibromatosis 2 (NF2) or, as with their solitary counterparts, as sporadic cases of multiple tumors with no clear inheritance pattern. Multiplicity of tumors is a shared feature of patients with radiation-induced tumors and nonirradiated patients harboring multiple meningiomas as part of, or distinct from, NF2.
Radiation-Induced Meningiomas
Accumulating evidence over the last 50 years has convincingly linked radiation exposure to the development of cancer in humans. Indeed, radiation-induced meningiomas are the most common form of such neoplasms reported in the literature,1 and specific criteria have been developed to appropriately define them ( Table 10.1 ).2 Large cohorts of patients treated with cranial irradiation or who survived the catastrophic atomic bombings of the last world war have, in particular, provided devastating evidence of the role of radiation in meningioma tumorigenesis. In contemporary neuro-surgery, the expanding role of therapeutic stereotactic radiation, while greatly reducing the exposure of non-target tissues to radiation, provides an appropriate context to review the concept of meningiomas wrought by cranial irradiation.
Biology and Pathology
Tumors arise from the accumulation of mutations in genes that program the neoplastic phenotype. Indeed, nearly all tumors show evidence of activation of mutant versions of protooncogenes and the inactivation of tumor suppressor genes. Ionizing radiation is capable of inciting the diverse genetic events that occur in tumor formation through direct mutagenesis of participating oncogenes and tumor suppressors; widespread genomic instability, which is perpetuated in surviving dividing cells; and the direct compromise of DNA repair mechanisms.3 Recent genetic studies have illuminated the karyotypic chaos found in radiation-induced tumors, in stark contrast to the majority of nonradiation-induced meningiomas, whose hallmark is loss of part or all of chromosome 22 (harboring the NF2 gene). These studies have reported several genetic alterations, including loss of genetic material on chromosome 1, 6, and 22, among others2,4,5; selected data from our center are shown in Table 10.2 .2 In particular, structural abnormalities of chromosomes 1 and 6 may portend more aggressive meningioma behavior.6 Interestingly, only 56% of cases in our series showed loss or deletion of chromosome 22, an abnormality characteristic of nonradiation-induced meningiomas.
Although the specific genetic events underpinning the genesis of RIMs have not been fully clarified, it is likely that this markedly aberrant genetic landscape governs the abnormally aggressive behavior of these tumors when compared with their nonradiation-induced counterparts: they tend to possess atypical histological features ( Fig. 10.1 ), display more rapid growth, and show higher rates of multiplicity and recurrence.2
Dose Effect
The risk of developing solid cancers varies directly with lifetime exposure to radiation. Historically, RIMs have been categorized by the level of prior radiation given to patients in whom these tumors later arise.7 Low dose is defined as doses of less than 10 Gy, intermediate refers to doses between 10 and 20 Gy, and high dose is characterized by doses of greater than 20 Gy. Overall, tumor formation appears to be accelerated by radiation exposure early in life and higher dosages of radiation, and dose of radiation appears to correlate with earlier development of tumors in patients. Because meningiomas may be incited by even low doses of radiation, several authors have presaged an inevitable increase in the incidence of RIMs induced at any dosage in the setting of expanding use of radiotherapy and diagnostic radiological studies.1,8–11
High Dose
The overwhelming majority of patients who develop high-dose RIMs have undergone cranial irradiation early in life, with reported doses ranging from 22 to 87 Gy.12 The average latency from radiotherapy to meningioma diagnosis is ~19 years,8,9 which is consistent with our series in which the latency period in high-dose RIMs was 24.6 years.2 More recently, a multicenter case-control study as part of the Childhood Cancer Survivor Study investigated the development of new primary brain tumors in more than 14,000 survivors of cancer in childhood.13 Meningiomas were diagnosed with a median latency of 17 years after radiation, exposure to which was the most important risk factor for meningioma development in these patients (odds ratio [OR] = 9.94; 95% confidence interval [CI]: 2.17 to 45.6).
Low and Intermediate Dose
Meningiomas also occur in patients exposed to doses of radiation less than 20 Gy. The development of meningiomas in patients who had undergone scalp irradiation for tinea capitis in the first half of the twentieth century provided the first large-scale evidence of radiation-induced meningioma. The treatment paradigm, known as the Adamson-Kienbock method, involved radiating the entire scalp, with the surface receiving 5 to 8 Gy and the skull base ~0.7 Gy. In their landmark paper, Modan et al reported an increased risk of meningioma in more than 10,000 adults who had undergone scalp irradiation for tinea capitis as children.14 More recent follow-up studies have reported that a mean of 1.5 Gy conferred a 10-fold increased risk of meningioma development,15 with risk correlated with dose and rising to 18.8-fold when exposure was greater than 2.6 Gy.16 Multiple meningiomas were also more common in patients who had undergone prior irradation.17
Compelling evidence demonstrating the tumor-inducing effects of low-dose radiation has also been provided by large studies of survivors of the atomic bombings of Hiroshima and Nagasaki. Beginning in 1994, an increasing number of reports have documented an increased incidence of meningiomas among survivors from both catastrophic events, with incidence correlated with distance from bomb epicenter and age at time of exposure.18–20 A more recent analysis of a cohort of more than 85,000 survivors over the two atomic bombings in the Life Span Study21 reports that RIMs in this cohort more closely resemble the epidemiological characteristics of “spontaneous” meningiomas.
Diagnostic irradiation has historically been linked to meningioma development, with Preston-Martin and White reporting a higher incidence of meningioma in patients who had undergone full-mouth dental x-rays.22 Current applicability of these data are unclear because dosages administered today are drastically lower.23 The use of computed tomographic (CT) scanning has escalated dramatically in the last decade, and, although the radiation dose per scan is low, their common use has caused significant concern for their potential roles in delayed carcinogenesis.24
Other contemporary uses of radiation in the low- and intermediate-dose range include stereotactic radiosurgery. Given the long latency periods between cranial irradiation and meningioma formation as already outlined, studies reporting no increased risk of tumor formation after radiosurgery with mean follow-up periods of 6 years25 may be ill equipped to address the phenomenon of radiosurgery-induced meningioma. Isolated reports describing the development of meningiomas in patients after radiosurgery exist, but a true incidence of this clinical entity will only be ascertained through careful long-term radiologic follow-up.26
We have observed an average latency period of 30 years from time of irradiation to tumor detection, which is largely consistent with other published reports of latency after low- to moderate-dose radiation.2
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