Clinical Features

The tumor most associated with a primary location in the midbrain is also known as the tectal glioma. Its location is prone to cause aqueductal stenosis and obstructive hydrocephalus. Magnetic resonance imaging (MRI) examination typically reveals a dorsally exophytic mass extending from the quadrigeminal plate. ¹⁶ Tectal gliomas tend to be indolent and rarely cause neurological impairment. Progression occurs in 15 to 25% of tumors. ¹⁷ Management is usually directed toward relief of hydrocephalus by shunting or endoscopic third ventriculostomy followed by observation. Biopsy and adjuvant therapy are reserved for patients with radiographic and clinical progression.

Pathology

Histological documentation, not to mention contemporary molecular profiling, is virtually nonexistent in published cases of tectal glioma. However, in keeping with their indolent clinical behavior, the majority of these tumors that have been biopsied show low-grade histology, diagnosed as World Health Organization (WHO) grade I or, more frequently, grade II astrocytomas, although other low-grade gliomas, including oligodendrogliomas and ependymomas, have been reported. ^{18 , 19}

Clinical Features

A large series conducted by Schroeder et al found that 15% of malignant primary brain tumors in children under 20 years old arise in the brainstem, with the majority being the diffuse intrinsic pontine glioma (DIPG) subtype. ²⁰ DIPG is a leading cause of brain tumor-related death in children, with a median survival of less than 1 year; more than 90% of children die within 2 years of diagnosis. ²¹ The median age of diagnosis is 6–7 years, and patients typically present with brainstem dysfunction or CSF obstruction over a period of 1 to 2 months. Additional neurological signs include cranial neuropathies, long tract disturbances, and ataxia. ²² DIPGs also account for 45 to 50% of brainstem gliomas in adults. ²³

The expansion of the pons with convex intrusion into the fourth ventricle is so characteristic of these lesions as a midsagittal radiographic finding that biopsy is usually considered unnecessary. No effective treatment has been found, despite the standard administration of radiation therapy and chemotherapy. ²⁴

Pathology

The 2016 WHO classification of brain tumors includes the DIPG as a form of diffuse midline glioma that is H3K27-mutant and classified as WHO grade IV. ²¹ The malignancy tends to produce distortion and enlargement of the pons by diffuse infiltration of the pontine parenchyma. Necrosis and hemorrhage may be seen. Microscopically, there is infiltrative growth into gray and white matter. The tumor cells vary from small and monotonous to large, pleomorphic forms ( Fig. 4.6a, b ). Nuclear morphology may be reminiscent of astrocytic differentiation, with hyper-chromatic irregular shapes, or it can show oligodendroglial morphology. Ten percent lack mitotic figures, microvascular proliferation, and necrosis, and therefore qualify only by microscopic criteria for WHO grade II status. The remainder show high-grade features with features of glioblastoma. Regardless, all forms are associated with the same dismal prognosis.

The diagnosis of a H3K27M glioma can be reliably done by immunohistochemistry; however, diagnosis is aided by concurrent immunostaining for the H3K27me3 (trimethylated) protein, which is seen in H3K27 wild-type cells ( Fig. 4.6c, d ). Among pontine gliomas with the H3K27 mutation, a recent series shows that such tumors are highly represented within the pediatric patient population, with an average age at diagnosis of 7 years and only 1 adult among 18 patients with pontine gliomas that showed the H3K27 mutation. IDH1 mutations and H3K27 mutations are believed to be es sentially mutually exclusive. ^{25 , 26} This report also underscores the particular association of H3K27 mutant gliomas with the pons; midbrain and medulla gliomas do not show the mutation. In adults, gliomas of higher grade may be seen that more closely correspond to the histology and molecular profile of supratentorial malignant gliomas. ^{23 , 27}

Clinical Features

The pilocytic astrocytoma is a WHO grade I astrocytoma. It may occur in many locations within the CNS, especially the cerebellum and optic-hypothalamic regions. A minority arise in the brainstem, which is estimated to account for 9% of all pilocytic astrocytomas, ²⁸ or involve the brainstem by infiltrative growth from the cerebellum. In either circumstance, such tumors understandably carry a worse prognosis because of the difficulty in surgical options. ²⁹

Brainstem pilocytic astrocytomas present similarly to cerebellar examples, as circumscribed cystic or lobulated lesions with bright contrast enhancement, but solid types may arise as dorsally exophytic lesions of the brainstem, often from the pontomedullary region. Thus, radiographic localization and characterization are important in distinguishing brainstem pilocytic astrocytomas from diffuse astrocytomas. Brainstem pilocytic astrocytomas are particularly associated with NF1 as part of a spectrum of radiographically detected focal regions of brainstem enlargement, which can be seen with or without contrast enhancement. A series of 125 patients with NF1 and brainstem abnormalities included one biopsied patient with proven pilocytic astrocytoma. The other lesions were mostly indolent and many remained stable or even regressed. ³⁰

Pathology

Pilocytic astrocytomas display a tan-pink color with a distinctly mucoid texture, often recognizable even in the smallest specimens. The most classic microscopic appearance of pilocytic astrocytomas is that of a microcystic tumor with a rich fibrillary background that shows a biphasic pattern, alternating between dense eosinophilic vasocentric regions and looser intervening areas ( Fig. 4.7a ). Either of the two patterns may dominate the microscopic appearance of the specimen; therefore, the dense or compact differentiation when unaccompanied by looser areas is especially prone to misdiagnosis as a diffuse fibrillary astrocytoma. This may prove especially challenging with small brainstem biopsies.

At the cytological level, astrocytes in these tumors have elongated profiles (“piloid” or hair-like) with benign ovoid nuclei. Multinucleated cells may be prominent. Clear cell differentiation may be extensive, sometimes indistinguishable from that of oligodendrogliomas ( Fig. 4.7b ). Considering the distinct rarity of oligodendrogliomas in the brainstem, a clear cell glioma in the posterior fossa is in fact more likely to be a pilocytic astrocytoma. Vascular proliferation is characteristic and may be one of the most essential features, along with contrast enhancement, in distinguishing the pilocytic astrocytoma from a WHO grade II diffuse astrocytoma. Mitotic activity is very unusual, and when division figures are identified, they are often within vascular endothelial cells.

Rosenthal fibers are eosinophilic elongate or beaded structures, usually within the compact perivascular compartments; these fibers are also quite useful in securing the diagnosis of pilocytic astrocytoma ( Fig. 4.7c ). Eosinophilic granular bodies (EGBs) are more frequent in loose regions, whereas Rosenthal fibers are found in denser, compact, typically perivascular areas. Both EGBs and Rosenthal fibers share immunoreactivity for glial fibrillary acidic protein (GFAP), ubiquitin, and αB crystallin, ³¹ and EGBs may express α1-antichymotrypsin, α1-antitrypsin, and lysozyme. ³²

Pilocytic astrocytomas are quintessential WHO grade I gliomas. However, “malignant” forms exist, marked by numerous mitotic figures (at least 4 mitoses/10 high-power fields at 400X), robust vascular proliferation, hypercellularity, and moderate-to-severe cytologic atypia, with or without necrosis, which may even be of the pseudopalisading type. A report of 34 cases did not appear to suggest that the brainstem is more vulnerable to this tumor type than it is to conventional pilocytic astrocytomas without anaplasia. ³³ The tumors may have had a WHO grade I pilocytic astrocytoma precursor, coexistent pilocytic astrocytoma, pilocytic astrocytoma documented by previous biopsy, or exhibited characteristic pilocytic features in an otherwise anaplastic astrocytoma. A clinical history of neurofibromatosis type I or radiation therapy may be present. P53 abnormalities may highlight the anaplastic portions of these tumors. High mitotic rates and necrosis appear to be the best predictors of a poor prognosis. Notwithstanding these disconcerting features, which might otherwise equate with a diagnosis of glioblastoma, such lesions should be designated “anaplastic” or WHO grade III.