Posterior Fossa and Brainstem Tumors in Children

Histology

CAs may be composed of histologically diverse tumor types such as pilocytic astrocytomas ( Fig. 11.1 ), fibrillary astrocytomas, high-grade astrocytomas, and pilomyxoid astrocytomas. The majority (75%) are World Health Organization (WHO) grade 1 pilocytic astrocytomas.

Macroscopically these tumors are soft, pink-gray, and discrete. The typical appearance is a well-circumscribed solid component known as a mural nodule with a cyst formation in the wall. The wall may contain tumor or may consist mainly of nonneoplastic gliotic tissue. The cyst contains xanthochromic fluid; however, calcium or hemosiderin deposits may be seen. Pilocytic astrocytomas classically show biphasic architecture with compact and loose areas. Loose areas contain protoplasmic astrocytes, microcysts, and eosinophilic granular bodies. Compact areas are composed of bipolar cells with the presence of Rosenthal fibers. In classic PA, infiltration of the adjacent brain can be seen. Cellular atypia, vascular endothelial proliferation, and a high mitotic index may be present but have no impact on event-free survival. However, histopathologic factors that do predict a poorer clinical outcome include a lack of degenerative-type nuclear atypia, vascular hyalinization, necrosis, calcification, the presence of >25% oligodendroglial morphology, and leptomeningeal invasion.

Molecular Biology

Mutations, duplications, and fusions of the BRAF gene locus have been found to be elevated in pilocytic astrocytomas. BRAF is a downstream effector within the ERK/MAPK signaling pathway, which in turn is one of the most prominent pathways in the regulations of cell growth, proliferation, differentiation, and apoptosis in all cells. Dysregulation of this pathway is apparent in one-third of all cancers. The most common disruption of the BRAF gene is a fusion with the gene KIAA1549 due to a segmental duplication at chromosome band 7q34. The most frequently identified point mutation is that of BRAF ^v600E , which describes the replacement of valine with glutamic acid at codon 600. The presence of the BRAF ^v600E offers an opportunity to consider targeted chemotherapy with specific BRAF ^v600E pharmacologic inhibitors.

Management

The first-line treatment of choice for CAs is surgical extirpation, with the goal of GTR without neurologic deficit. The key in the surgical resection of cystic lesions is removal of the mural nodule. Surgeons have debated the importance of cyst wall excision; however, no statistical difference in survival between patients with cyst wall removal and those without has been found. GTR is achieved in 50% to 89% of patients.

The most important prognostic factors for progression-free survival (PFS) are extent of resection and tumor location. Overall mortality is very low with rates of 0% to 4% in large series. Subtotal resection is associated with increased rate of recurrence (7% vs. 27%) but not overall survival. Leptomeningeal spread is not common and is mostly seen in partially resected tumors and tumors of the very young. Long-term stability or spontaneous regression of the residual tumor after partial resection can be observed, so a strategy of observation could be recommended until residual tumor growth is confirmed. Hydrocephalus is shown to resolve without any additional treatment in up to 60% of patients after the posterior fossa mass has been removed.

For the lesions that are progressive or unresectable, chemotherapy has become the preferred therapy. Regimens of carboplatin and vincristine have been effective since the 1990s. This combination has been shown to improve 5-year event-free survival to 39% in sporadic and to 69% in neurofibromatosis type 1 (NF1) associated gliomas. However, 40% of children experience hypersensitivity reactions, thrombocytopenia, and myelosupression. Alternatively, combination therapy in the form of procarbazine, 6-thioguanine, Lomustine (CCNU), vincristine with dibromodulcitol, or CCNU with vinblastine has also been shown to improve outcomes.

Although radiotherapy is still used for the treatment of CAs, it is generally avoided in young children due to neurocognitive side effects. Furthermore, malignant transformation and radiation-induced side effects have been reported. Some reports show better progression-free survival in comparison with chemotherapy; however, others show no evidence of increased overall survival. Studies have also suggested that conformal proton radiotherapy and stereotactic radiosurgery may be safe and effective treatment strategies for recurrent, progressive, and inaccessible tumors.

The functional outcomes and patients' quality of life are determined by the pathology of the tumor itself, the duration of symptoms, hydrocephalus, the extent of surgical resection and postoperative morbidity, and the side effects of any adjuvant treatments. Permanent neurologic deficits have been reported to range from 15% to 50%. Cerebellar mutism or cerebellar symptoms may be seen depending on the location and size of the tumor in up to 8%. Regarding postoperative surveillance, studies have revealed that one-third of recurrences arose in the interval between years 2 and 5. Therefore scans conducted in this interval have greater value in detection of recurrence.

The future of low-grade glioma treatment appears to be moving into the realm of molecules targeted at the MAPK pathway. Current phase I and II trials include that of AZD6244, an inhibitor of MAPK activator kinases MEK1 and MEK2. However, the downstream effect of such inhibitors is not always predictable with sorafenib (a multikinase inhibitor) resulting in paradoxical pathway activation and subsequent early tumor progression.

Cancer vaccines are also exciting therapies, designed to trigger systemic immunity against antigens overexpressed by tumor cells. Clinical trials have demonstrated the safe and potent efficacy with vaccinations for adult malignant gliomas. Vaccine-based approaches are hypothesized to be more effective during childhood or young adulthood when immunity is intact. A trial of a peptide-based vaccination using glioma-associated antigen-derived epitopes in recurrent low grade glioma (LGG) has been shown to be safe with a promising level of activity.

Diagnosis

The majority of patients present with symptoms approximately 1 to 3 months prior to diagnosis. The characteristic appearance of MB on CT and MRI is a well-circumscribed, hyperattenuating posterior fossa mass arising in the middle and lower vermis filling the fourth ventricle and causing hydrocephalus in a high percentage of cases ( Fig. 11.2A and B ). Desmoplastic-excessive nodularity MB is usually multinodular and located peripherally in the cerebellum. Large cell-anaplastic MB typically presents as a small tumor in the fourth ventricle, without hydrocephalus but with early leptomeningeal dissemination ( Fig. 11.2C ).

Histology

Bailey and Cushing first introduced the term medulloblastoma in 1925 because of its similarity with the embryonal medullary velum. Based on histopathology, MBs were thought to be a subtype of an infratentorial primitive neuroectodermal tumor (PNET). However, microarray studies later revealed that they are a molecularly distinct entity from supratentorial PNET. In fact, a strong link has been shown to exist between cerebellar stem cells and MB cells.

According to the 2007 WHO classification, MB is a grade IV tumor consisting of five variants: classic, desmoplastic/nodular, medulloblastoma with extreme nodularity, anaplastic, and large cell. Macroscopically the tumor generally appears as a soft, fleshy, pink-gray mass. Cyst calcifications can be detected in up to 20% of cases, and a spontaneous tumor hemorrhage can be found in 3% to 5% of MBs. The classic histology, representing about two-thirds of all cases, consists of a highly cellular neoplasm, composed of undifferentiated, small, round- or oval-shaped blue cells with a high nuclear-to-cytoplasmic ratio and hyperchromatic nuclei. Homer Wright (neuroblastic) rosettes are present in less than 40% of cases. The mitotic index is usually in the range of 0.5% to 2%, and the Ki67 proliferation index is generally higher than 20%. The desmoplastic-nodular variant comprises 7% to 16% of cases, with a higher prevalence in adults and infants. It is characterized by a biphasic architecture that consists of regions with dense intercellular reticulin and nodular reticulin-free zones (pale islands), in which tumor cells show a neurocytic phenotype. The large cell and anaplastic subtypes account for 10% of MBs. Large cell MB is composed of sheets of large round cells with large nuclei and prominent nucleoli and a low nuclear-to-cytoplasmic ratio. Nuclear molding, cell-to-cell wrapping, and nuclear pleomorphism are the characteristics of the anaplastic MB. MB with extensive nodularity (MBEN) is the most differentiated form of desmoplastic MB, accounting for 3% of cases.

A modern genomic approach has demonstrated that MB has four distinct molecular variants. Major molecular subgroups of MB are wingless (WNT), sonic hedgehog (SHH), group 3, and group 4, with each group showing different demographics, genetics, recurrence patterns, and outcome ( Table 11.3 ).

Management

The present clinical approach to MB requires multimodal therapy with maximal safe surgical resection as the first therapeutic step, followed by chemotherapy and craniospinal irradiation. Patients younger than 3 years, with dissemination beyond the primary site and postoperative residual tumor over 1.5 cm ² , are assigned to have high-risk disease.

The goals of surgery are to treat associated hydrocephalus, provide tissue for diagnosis, and remove as much tumor as feasible. One study showed that there is no prognostic difference between gross total resection and near-total resection; therefore gross total resection should not be pursued at the risk of postsurgical neurologic morbidity. The incidence of posterior fossa syndrome (cerebellar mutism) varies widely (range 2%–29%) and might increase after GTR. Most patients with postoperative cerebellar mutism syndrome have mild to severe cognitive deficits, speech deficits, and ataxia.

Management of hydrocephalus is crucial, because in about one-third of patients hydrocephalus persists after tumor removal. Studies have shown a rate of CSF diversion surgery for the SHH, group 3, and group 4 subgroup patients to be around 22% to 33% and none for the WNT subgroup.

MB subgroups show different clinical behaviors and may benefit from subgroup-specific treatments. The protein phosphatase inhibitor norcantharidin has been shown to alter WNT signaling and impair MB growth by promoting loss of nuclear β-catenin. Therapies to modulate SHH signaling mostly focus on smoothened (SMO) inhibitors such as vismodegib and sonidegib. To overcome tumor resistance, combining SMO antagonists with PI3K blocker or glioma-associated oncogene homolog (GLI) inhibitors may be a strategy. Studies on group 3 and group 4 MBs mostly investigate agents to suppress MYC-related pathway activity.

Conformal radiation therapy requires the administration of high-dose irradiation to the craniospinal axis, with a boost to the posterior fossa or tumor bed for local control and to sites of metastasis if present. Interestingly, irradiation of the tumor bed alone leads to a significant improvement in neurocognitive outcomes, but overall effects on survival still need to be examined. Overall survival rates have shown significant associations with molecular subgroup, metastatic status, craniospinal radiation, and geographic location.

Diagnosis

Ependymomas are categorized into three variants based on MRI: (1) midfloor type: the tumor is strictly exophytic, develops from the obex, localized to the floor of the fourth ventricle ( Fig. 11.3 ); (2) lateral type: the tumor develops from the lateral recess, and it extends into and fills the CPA cistern, involving the brainstem and cranial nerves; and (3) roof type: the tumor develops from the inferior medullary velum and localizes to the roof. Leptomeningeal dissemination occurs in 8% to 12% of patients most commonly in the lumbosacral region (spinal thecal sac), typically appearing as nodular or diffuse enhancement along the surfaces.

Histology

According to the WHO classification, ependymoma includes types designated as grade I (myxopapillary or subependymoma), grade II (ependymoma with designations as cellular, papillary, clear cell, or tanycytic), and grade III (anaplastic ependymoma). Previously they were thought to originate from the lining of cerebral ventricles or the central canal of the spinal cord; however, studies suggest that radial glial stem cells may be the cell of origin. Key histologic features of ependymoma are perivascular pseudorosettes (ependymal cell cytoplasmic processes radially converging to blood vessels) and ependymal rosettes (tumor cells arranged as single layers to form a lumen). They are well circumscribed and do not infiltrate diffusely surrounding brain tissue. There is a debate in the literature about the precise definition of anaplastic criteria and the prognostic value of it.

Molecular Biology

Based on genome-wide DNA methylation patterns, studies have identified nine distinct molecular subgroups of ependymal tumors across all age groups in different regions of the nervous system and two distinct subgroups of posterior fossa ependymomas. Group A posterior fossa tumors are aggressive tumors classically occurring in infants and young children. Group B tumors are phenotypically more benign and mostly seen in adolescents and young adults. These tumors display divergent transcriptomic aberrations, chromosome 1q25 gain being the most common one. Activation of PI3K/Akt and epidermal growth factor receptor (EGFR) pathways and overexpression of human telomerase reverse transcriptase (hTERT) are associated with worse outcome.