Clinical, Histopathologic, Radiographic and Molecular Classification of Medulloblastoma

Medulloblastoma, a malignant neoplasm of the posterior fossa with a high propensity for metastatic spread, is one of the most common central nervous system tumors in children. Despite the long-term survival of many patients, definitive therapy is associated with significant morbidity. Adjuvant craniospinal irradiation and chemotherapy leaves many survivors debilitated from treatment-associated side effects including endocrine dysfunction, growth defects, and intellectual impairment. Although classically staged by clinical features, medulloblastoma has been the subject of extensive histopathologic, radiographic, and molecular studies aimed at defining prognosis and identifying novel therapeutic targets. These analyses have revealed specific tumor characteristics that are predictive of outcome independent of clinical stage, as well as biologic pathways that drive tumorigenesis. Despite these scientific discoveries that carry a potential for targeted therapy, there have been few recent innovations in the clinical management of medulloblastoma. Here we summarize the clinical, histopathologic, radiographic, and molecular characteristics of both pediatric and adult medulloblastoma. Although these features are employed in clinical practice to counsel patients and predict clinical course, they have yet to be translated into therapeutic advances. Ultimately, the precise classification of medulloblastoma is likely to facilitate modification of therapy with reduced toxicity in some cases, while improving clinical outcome with targeted therapies in others. However, additional data concerning the molecular pathways that facilitate medulloblastoma development and progression are necessary before therapeutic innovations are likely to be realized. Central Haas-Kogan et al. (2014) Email: JSM Clin Oncol Res 2(4): 1025 (2014) 2/10 Treatment consists of maximal safe surgical resection followed by adjuvant craniospinal irradiation and chemotherapy for most patients. Although this multi-modal approach results in long-term survival for approximately 75 percent of patients, most survivors suffer from an impaired quality of life due to treatment-associated side effects. Chief among these is cognitive dysfunction, including slowed processing speed, and deficits in working memory and attention [3]. Many patients also develop hearing deficits, endocrine dysfunction, and growth defects, and are at an increased risk for secondary malignancies following the presently non-specific, highly toxic treatment regimen [47]. Given the relative morbidity of definitive therapy, significant effort has been dedicated to stratifying medulloblastoma patients based on presentation, tumor characteristics, and survival with the overall goal of de-escalating therapy in appropriate cases and intensifying treatment in others. In this regard, clinical and histopathological features are being combined with radiographic findings and molecular studies in increasingly complicated risk stratification schemes. This review aims to summarize the utility and limitations of the clinical, histopathological, radiographic, and molecular characteristics of medulloblastoma that are used to classify patients and guide therapeutic decisions. CLINICAL RISK STRATIFICATION Pediatric medulloblastoma Controversy exists concerning the most meaningful prognostic factors for clinical stratification of medulloblastoma patients. Based on primary tumor size and the extent of metastases, the Chang Criteria have served as the primary staging system for medulloblastoma since their inception in 1969 (Table 1) [8]. Spread to the leptomeninges is particularly critical, and 5-year progression-free survival in patients with microscopic or gross disease in the neuraxis or systemically is approximately half that of individuals with tumor confined to the posterior fossa [9]. With respect to surgical technique, five-year actuarial survival increases from approximately 40 percent following biopsy alone, to nearly 75 percent for those who undergo gross or even subtotal resection [10,11]. Despite the increase in overall survival following introduction of postoperative craniospinal radiation and chemotherapy in the 1970s, patients diagnosed before age 3 continue to have a markedly lower survival than older individuals [9,12]. Consequently, medulloblastoma is often viewed in terms of averageand high-risk features, which are defined by (i) age at presentation, (ii) extent of residual tumor on the most involved computed tomography (CT) axial image following resection, and (iii) the presence or absence of metastases (Table 2). Following surgery, average risk medulloblastoma patients typically receive 2340 cGy of craniospinal irradiation in 180 cGy fractions, followed by a selective posterior fossa boost to a total dose of 5400 cGy. In contrast, high-risk patients are generally treated with 3600 cGy of craniospinal radiation, again followed by a posterior fossa boost to a total dose of 5580 cGy. The particular emphasis placed on posterior fossa control through maximal safe resection and radiotherapy is derived from the finding that 50-70 percent of recurrences occur in the tumor bed, and are often associated with leptomeningeal spread [13]. Following radiation, chemotherapy is employed to decrease the risk of recurrence, and minimize the dose of craniospinal extent of tumor T1 primary tumor <3 cm in diameter T2 primary tumor >3 cm in diameter T3 primary tumor >3 cm in diameter with radiographic or operative extension beyond the posterior fossa T3a extension into the aqueduct of Sylvius and/or foramen of Luschka T3b extension into the brainstem T4 primary tumor >3 cm in diameter with extension past the aqueduct of Sylvius and/or the foramen magnum extent of metastasis M0 no evidence of gross or microscopic subarachnoid or hematogenous metastases M1 microscopic tumor cells present in the cerebrospinal fluid M2 gross nodular metastases in the 3 rd or 4th ventricles, or within the subarachnoid spaces of the cerebellum and/or cerebrum M3 gross nodular metastases in the spinal canal M4 systemic metastases outside the cerebrospinal axis Table 1: Clinical Staging of Medulloblastoma. average risk high risk age at diagnosis ≥3 years ≤3 years extent of residual tumor ≤1.5 cm2 ≥1.5 cm2 metastatic/disseminated disease absent present Table 2: Clinical Risk Stratification of Medulloblastoma. radiation required for disease control in average risk patients post hoc. Patients younger than 3 to 5 years of age similarly benefit from chemotherapy as a temporizing measure to delay radiation and allow for brain and spinal cord development. Nevertheless, consensus is lacking concerning the appropriate timing of radiotherapy for pediatric medulloblastoma patients who have yet to complete neurocognitive development. Although radiation unequivocally improves local control and survival, intellectual impairment from ionizing radiation is well-known to be inversely related to patient age at the time of treatment [3,14]. More so than any other side effect of treatment, neurocognitive dysfunction following craniospinal irradiation has driven the histopathological, radiographic and biologic investigations aimed at re-defining the staging system of medulloblastoma with the overall goal of de-escalating definitive therapy in appropriate cases. Adult medulloblastoma Although approximately 20 percent of medulloblastomas occur in patients above the age of 16, there are no prospective randomized trials upon which to base treatment recommendations for adults [15]. Consensus is particularly vague with respect to role of chemotherapy in adult medulloblastoma patients, where toxicity is generally greater and there is less urgency to reduce the dose of craniospinal radiation. Irrespective of treatment, late relapses are more common in adults, as are systemic metastases [16]. Regardless, long-term survival for adults with medulloblastoma ranges from 58 to 84 percent, similar to pediatric patients [17]. Also similar to childhood medulloblastoma cases, adults who undergo gross total resection or who were diagnosed in the era of multi-modal therapy have a better prognosis than historic controls. Despite these similarities, Central Haas-Kogan et al. (2014) Email: JSM Clin Oncol Res 2(4): 1025 (2014) 3/10 clinical prognostic factors for adult medulloblastoma are controversial, and contrasting studies have variably supported and invalidated the classic pediatric predictive elements in adult tumors [15]. Molecular profiling has similarly demonstrated both overlapping and disparate features between pediatric and adult medulloblastomas, although these characteristics will be discussed in further detail below.