Astrocytic and Oligodendroglial Tumors

Definitions and Synonyms

The infiltrative or “diffuse” forms of astrocytoma occur throughout the CNS, generally in adults, and are most frequent in the cerebral hemispheres. These lesions are composed of individual tumor cells that infiltrate widely throughout the brain parenchyma with a cellular density and degree of anaplasia that increase with tumor grade. Given the highly distinct clinical characteristics of diffuse astrocytomas based on their genetic profiles, these tumors are divided into IDH-mutant, IDH-wildtype, and H3F3 mutant subsets, the latter leading to the new WHO entity termed diffuse midline glioma, H3 K27M-mutant. There is an inherent tendency of the IDH-mutant tumors to progress to a higher grade, with GBM representing the most malignant form. Because of the inability to totally resect these tumors and their resistance to conventional therapies, these almost always recur, progress, and are universally fatal, with length of survival depending on many variables, including clinical factors, tumor grade, and molecular profile.

Incidence and Demographics

Diffuse astrocytic tumors (WHO grades II to IV) comprise roughly 60% of primary intracranial tumors, with an annual incidence of 5 to 7 per 100,000 person-years. There is a slight male predominance (1.3 to 1). These tumors can arise at any age, including childhood and the very elderly, although incidence increases substantially with advancing age and varies with molecular subtype. Older patients are also more likely to have higher grade gliomas, especially GBM.

IDH-Mutant Astrocytomas

Over 80% of grade II and III astrocytomas are IDH-mutant. Only a small percentage (5%) of primary (de novo) GBMs are IDH-mutant, yet the large majority (70% to 80%) of secondary GBMs, which progress from grade II and III diffuse astrocytomas, have IDH mutations. Combining the incidence of primary and secondary cases, IDH-mutant GBMs are estimated to represent 8% to 10% of all GBMs. While precise epidemiologic data on IDH-mutant astrocytomas are not currently available, diffuse astrocytoma, WHO grade II (including all molecular subsets and NOS categories) accounts for approximately 10% of diffuse astrocytic neoplasms, while anaplastic astrocytoma, WHO grade III, accounts for approximately 8%. The majority of patients with IDH-mutant astrocytomas present to clinical attention in their 30s and 40s (median age, 38 years) as grade II and III tumors. The age distribution of patients with grade II and III tumors is similar, while patients with IDH-mutant GBMs are slightly older, with a median age of 40 to 42 years. IDH-mutant gliomas are uncommon in the pediatric population, and when they do arise, it is usually in adolescents and older teens. Overall, patients with IDH-mutant diffuse astrocytomas are significantly younger than those with IDH-wildtype astrocytomas, grade for grade.

IDH-Wildtype Astrocytomas

The large majority (90% to 95%) of IDH-wildtype diffuse astrocytomas are primary (de novo) GBM, WHO grade IV. GBMs have an annual incidence of 3.2 cases per 100,000 population, accounting for 46% of all malignancies of the brain and for 70% of all astrocytic neoplasms. IDH-wildtype diffuse astrocytoma (WHO grade II) and anaplastic astrocytomas (WHO grade III) are uncommon, representing only 10% to 15% of astrocytomas in these classes and grades. As such, one must view such cases with some degree of skepticism and ensure that other entities (e.g., early or undersampled GBM, ganglioglioma, pilocytic astrocytoma, pleomorphic astrocytoma) are thoroughly excluded before rendering such diagnoses. IDH-wildtype GBMs are most common between the ages of 55 and 75 years, with a median age of diagnosis of 62; IDH-wildtype grade II/III astrocytomas have a median age at presentation of 50 years.

Pediatric (and Young Adult) Diffuse Astrocytomas

Diffuse astrocytomas are uncommon in the pediatric population, accounting for only 4% of all tumors in this category. The diffuse midline glioma, H3 K27M-mutant results from codon 27 mutations of the H3F3A (encoding H3.3) or HIST1H3B (encoding H3.1) genes, typically occurs in the brainstem and thalamus, and has an incidence peak between 5 and 11 years, with a mean of 7 years, but can occasionally occur in adults as well. Those originating primarily in the thalamus or spinal cord occur in somewhat older patients, with a median age of around 25 years, and display a surprisingly wide range of morphologic appearances. The H3F3A G34R/V mutant high-grade gliomas occur in the cerebral hemispheres of older children and young adults, with a mean age of 18 years; these were not officially separated into a distinct entity within the WHO 2016 scheme, although they are notable for being an IDH-wildtype high-grade glioma variant that has overlapping morphology with embryonal neoplasms in some cases (see also Chapter 12 ). Other lower grade forms of diffuse astrocytomas in childhood are rare but characterized by a different set of genetic alterations than their adult counterparts (see later discussion). Incidence rates for these molecular subtypes of astrocytomas are not available.

Clinical Manifestations and Localization

Like other CNS diseases, the clinical presentation of the diffuse astrocytomas varies according to the sites of involvement and the rate of growth. The most common site is within the cerebral hemispheres, with a slight predilection for the frontal and parietal lobes and a lower frequency in the occipital lobes. These lesions are most often centered in the subcortical white matter, but have a tendency to infiltrate widely and include the cerebral cortex, deep gray structures, and even the contralateral hemisphere. In children, and less commonly in adults, the diffuse forms of astrocytoma can arise in the brainstem, thalamus, and basal ganglia. These tumors may also occur in the spinal cord, but the cerebellum is a highly unusual site. As mentioned, a significant subset of tumors in these last five sites represents the diagnostic entity of diffuse midline glioma, H3 K27M-mutant.

The most common clinical symptoms are new onset seizures, change in behavior, motor deficits, and signs/symptoms of increased intracranial pressure (e.g., headaches, nausea/vomiting, papilledema). IDH-wildtype astrocytomas are usually high grade (WHO grade III to IV) at clinical presentation and have short histories with rapid progression, whereas IDH-mutant astrocytomas present most often as grade II or III and are more indolent, often with insidious onset and a longer, protracted clinical course, with seizures being particularly common. Pediatric high-grade gliomas nearly always arise de novo and rarely are the result of progression from a lower grade precursor. When they arise in the brainstem, they are associated with progressive cranial nerve palsies.

Radiologic Features and Gross Pathology

Diffuse astrocytomas (WHO grade II) are most commonly seen on MR images as ill-defined, deep-seated, or predominantly subcortical cerebral hemispheric masses. They are typically nonenhancing lesions, best appreciated on T2-weighted or fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) sequences, where the signal hyperintensity reflects vasogenic edema generated in response to diffuse infiltration by individual tumor cells ( Fig. 6.1 ). Due to their infiltrative nature, microscopic disease is almost always present beyond the tumor margins defined by MR imaging ( Fig. 6.2 ). Secondary signs of mass effect include midline shift, ventricular compression, and sulcal effacement. Anaplastic astrocytomas (grade III) may be radiographically identical or may show faint, punctate, or irregular foci of contrast enhancement ( Fig. 6.3A ). Glioblastomas show a “ring-enhancing” or “rim-enhancing” pattern with a central low-density region of necrosis surrounded by an irregular, variable-thickness rim of contrast enhancement ( Fig. 6.4A ). Importantly, this rim-enhancing component is always surrounded by T2-weighted or FLAIR signal hyperintensity that represents an associated diffusely infiltrating neoplasm. Those GBMs that cross the corpus callosum are often referred to as “butterfly lesions” due to involvement of the white matter in the centrum semiovale bilaterally. Occasionally, diffusely infiltrative astrocytomas will have multiple, small separate foci of contrast enhancement and may be considered as a “multifocal glioma.” In fact, these do not usually represent multiple distinct tumors, but are rather multiple foci of high-grade progression to GBM within a single widely disseminated tumor.

By traditional MRI studies, the neuroimaging features and locations of IDH-mutant and IDH-wildtype diffuse astrocytomas are not substantially different, grade for grade. However, MR spectroscopy is capable of identifying 2-hydroxyglutarate (2-HG), which is the oncometabolite generated by tumors with IDH mutations, providing a potential means to characterize the IDH status of diffuse gliomas by neuroimaging. H3 K27-mutant diffuse gliomas are characterized by their locations in the midline, often affecting the pons, thalamus, and/or spinal cord, while the G34R/V mutants are most often noted in the cerebral hemispheres ( Fig. 6.5 ).

In treated gliomas, foci of radiation necrosis are radiologically and grossly similar to GBM and may produce considerable neurologic worsening due to mass effect ( Fig. 6.6A ). Therefore, the differential of tumor recurrence/progression versus radiation necrosis is a common clinical dilemma (see Chapters 4 and 21 for greater detail). Special techniques, such as positron emission tomography (PET), single-photon emission computerized tomography (SPECT), diffusion weighted imaging (DWI), and perfusion studies may be useful for further distinguishing these two diagnostic considerations, yet each has its shortcomings and a biopsy may ultimately be necessary.

Grossly, the diffuse astrocytomas are ill defined and subtly discolored with secondary mass effects identical to those seen radiologically. As described, there are typically foci of microscopic disease beyond the grossly suspected borders that are invisible to the naked eye. GBMs are classically variegated, with foci of necrosis and hemorrhage.

Histopathology

The recognized genetic subsets of diffuse astrocytomas, including those that are IDH-mutant, IDH-wildtype, and H3F3-mutant, have overlapping morphologic features and patterns of infiltration that cannot be distinguished with certainty by routine histology. These tumors may have a wide spectrum of cell types in pure or mixed forms (see upcoming discussion), though the fibrillary pattern is the prototype, composed of elongate, irregular hyperchromatic nuclei, often with no discernible cytoplasm (“naked nuclei”), but embedded in a dense fibrillary matrix (see Fig. 6.2 ). Alternatively, these cells may have eosinophilic cytoplasmic processes that variably blend in with the surrounding neuropil. In establishing the diagnosis of a diffuse astrocytoma, critical attention must be given to defining an astrocytoma as infiltrative before applying grading criteria to a biopsy or resection specimen in which an astrocytic neoplasm is present. Non-infiltrative (or combined solid and infiltrative) forms of astrocytomas such as pilocytic astrocytoma, subependymal giant cell astrocytoma, and pleomorphic xanthoastrocytoma (see Chapter 7 ) are relatively compact and discrete on imaging and gross pathology compared to diffusely infiltrative astrocytomas, yet they cause diagnostic challenges because of overlapping morphologic features. Infiltration of CNS parenchyma by astrocytic tumor cells is readily identified when neoplastic cellularity is low and entrapped normal elements of the brain (i.e., neuronal cell bodies or axons) are seen in the background. Recognition of a low- to high-cell density gradient of astrocytoma cells from regions of non-neoplastic brain into central regions of the tumor mass is also helpful in documenting infiltration. In instances where biopsy material consists of only a high tumor cell density that obscures background CNS microarchitecture, infiltration can be difficult to appreciate on hematoxylin-eosin (H & E) sections. In these instances, identification of entrapped axons can be highlighted either by silver stains or immunohistochemistry for neurofilament protein, thus establishing infiltration (see Fig. 6.2E ).

The lowest grade infiltrative or diffuse astrocytomas (WHO grade II) are characterized by a modestly increased cellularity as a result of the presence of neoplastic cells percolating through CNS parenchyma. Smear preparations can be helpful in demonstrating the highly fibrillar processes that extend from neoplastic cell bodies, which defines their glial differentiation (see Fig. 6.2A ). Nuclei are enlarged, hyperchromatic, and have irregular contours when compared to non-neoplastic astrocytes ( Fig. 6.2A–D ). Their slightly oblong shape and irregular contours contrast with the round regular nuclei of classic oligodendroglioma. Architectural distortion of involved CNS parenchyma in the form of edematous splaying of neuropil or microcyst formation often accompanies low-grade infiltrative astrocytomas ( Fig. 6.2D ). Microcalcifications are also occasionally noted. In other cases, histologic findings can be subtle, with only minimal hypercellularity and disturbance of normal microarchitecture; molecular surrogate immunostains (e.g., IHD1 R132H and H3 K27M) may be required for diagnosis in such cases (see Fig. 6.5F and G ). Secondary structures of Scherer are nearly as common in astrocytomas as they are oligodendrogliomas, including subpial condensation, perineuronal satellitosis, and perivascular aggregation (see Figs. 6.2B–C ; also Major Patterns in the Front Matter).

Anaplastic astrocytoma (AA, WHO grade III) is distinguished from grade II infiltrating astrocytoma by the presence of mitotic activity; additionally, there is generally increased cellularity and a higher degree of nuclear pleomorphism and atypia (see Fig. 6.3B ). Conceptually, it represents the transition from grade II infiltrative tumors to GBM. Correlation of histopathologic findings with the neuroimaging finding is always recommended, because the biopsy may contain a nonrepresentative portion of a larger and more aggressive lesion (i.e., GBM). Histologic differences between a grade II and grade III astrocytoma can be subtle and the minimal number of mitoses needed for an anaplastic designation is still not established, especially in terms of the IDH-mutant examples (see Histologic Variants and Grading section).

Glioblastoma is the highest grade form of infiltrating astrocytoma (see Fig. 6.4 ). In addition to the histopathologic findings of AA, either microvascular proliferation (also called microvascular hyperplasia, endothelial proliferation, or endothelial hyperplasia) or necrosis (often both) is seen ( Fig. 6.4 ). Necrosis can be in the form of palisading, with a dense packing of neoplastic cells around a necrotic center, generally with their long axis perpendicular to necrosis ( Fig. 6.4G ), or it can be broad, infarct-like areas ( Fig. 6.4H ). Within short proximity to the nuclear palisades, there is usually evidence of microvascular proliferation in a pattern that often mirrors the margins of the palisading cells. Microvascular proliferation can also be seen at the infiltrating edge of GBMs and consists predominantly of rapidly dividing, plump endothelial cells that form tufted microaggregates. Occasionally, these aggregates form multiple lumens similar to renal glomeruli and are referred to as “glomeruloid” ( Fig. 6.4C–F ). Some mistakenly use the term microvascular proliferation to refer only to an increased number of blood vessels. Although increased numbers of vessels may indeed be present in high-grade astrocytomas, for the purpose of grading astrocytic neoplasms, the term refers to the morphologic finding of proliferating endothelial and perivascular cells that create a multilayered appearance or form tufted aggregates that emerge from parent vessels.

Histologic Variants and Grading

Although the majority of diffuse astrocytomas, including GBMs, have “fibrillary” morphology and are composed of tumor cells with elongated processes on cytologic and histologic preparations, there is a great deal of histomorphologic diversity (see Figs. 6.7–6.14 ; Box 6.1 ). Descriptors such as gemistocytic, small cell, sarcomatous, adenoid, epithelioid, granular cell, giant cell, and primitive neuronal have been applied to specific tissue patterns or variants of the infiltrative astrocytomas. Whether each morphologic category of neoplasm behaves in a distinct manner, either in terms of biologic aggressiveness or response to therapy, is not clear in all cases, but some have genetic alterations that are relatively specific.