Case. A 54-year-old female has a history of right frontal grade II oligodendroglioma, IDH1-mutated, 1p19q co-deleted that was treated 11 years ago with radiation with procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy. After a long history of well-controlled seizures, she presented with refractory breakthrough focal seizures despite escalating levetiracetam to 2000 mg twice daily and lacosamide to 300 mg twice daily. A contrast-enhanced brain MRI revealed an enlarging T2/fluid attenuated inversion recovery (FLAIR) hyperintense in the right frontal lobe with a new faint region of gadolinium enhancement in the lateral right frontal lobe that had not previously been visible and was concerning for progression to higher grade. The patient was taken to the operating room where maximal safe subtotal resection was performed. Pathology revealed an infiltrative glial neoplasm with round nuclei, perinuclear halos, rare microcalcifications, and an elevated Ki-67 labeling index up to 10%. A final diagnosis of anaplastic oligodendroglioma (WHO grade III) was made. The patient was treated with repeat radiation with concurrent and adjuvant temozolomide chemotherapy with clinical response to treatment and was able to taper antiepileptic regimen to levetiracetam monotherapy at 1500 mg twice daily.

Teaching Points: Approach to Anaplastic Oligodendrogliomas. Anaplastic oligodendrogliomas (AOs) are rare high-grade diffuse gliomas. They are responsible for less than 1% of all primary intracranial neoplasms. Although the annual incidence of AO is 1–2 in a million, they are not uncommon in neuro-oncology subspecialty clinics due to their 10-fold longer survival than those with glioblastoma. Patients’ median age of 50 years at diagnosis places AOs on the older end of the spectrum of IDH mutant tumors. However, they are much younger than those with glioblastomas. AOs are thought to be tumors that develop slowly, and are usually diagnosed de novo . They less commonly progress from a grade II oligodendroglioma after an approximate 6–7-year lead time. ^,

Pathology. Anaplastic oligodendrogliomas are characterized by infiltrative cells with round nuclei and perinuclear halo producing a “fried egg” appearance. They have delicate networks of branching capillaries resembling “chicken wire” and variable amounts of microcalcification ( Fig. 12.2 ). Unlike the three-tiered grading system of astrocytomas, oligodendrogliomas are either classified as WHO grade II or III, where the presence of brisk mitotic activity, microvascular proliferation, and necrosis denote the anaplastic (grade III) group. Molecularly, AOs are IDH mutant and 1p/19q co-deleted similarly to their low-grade counterparts; polyploidy is a feature that is more commonly seen in high-grade oligodendrogliomas.

Conventional MRI of an anaplastic oligodendroglioma. This patient was initially diagnosed with a grade II oligodendroglioma with an extensive T2/FLAIR hyperintense volume. Over time, faint gadolinium enhancement developed on the T1-weighted images (see in the right frontal lobe), which was confirmed to be grade III oligodendroglioma on subsequent resection. FLAIR , Fluid attenuated inversion recovery.

Location and presentation. AOs are almost exclusively supratentorial with a strong predilection to the frontal lobe. They seldom affect infratentorial structures or the spine through leptomeningeal spread. There are a few case reports describing spread beyond the confines of the central nervous system (CNS); however, this is exceedingly rare. As expected, the presenting symptoms depend on the location of the tumor. Partial seizures with or without secondary generalization are by far the most common presenting symptoms of AOs. Seizures affect about 60% AOs, which is only slightly less common than in their low-grade counterparts. The high seizure frequency in these tumors may be explained by the combination of frequent cortical infiltration and 2HG production (see Management of tumor-induced seizures , below). Only 20% of patients present with focal neurologic deficits, which are typically less pronounced than one would expect based on the tumor’s localization and extent. This is most likely due to the slow growth allowing concurrent functional brain reorganization and thus compensation for potential neurologic deficits.

Imaging. AOs present with heterogeneous signal intensity on T2/FLAIR. They often infiltrate the cerebral cortex with variable amount of mass effect on adjacent brain parenchyma ( Fig. 12.2 ). Their margins are relatively indistinct, although they tend to be better demarcated on MRI than glioblastomas. More than 70% of AOs enhance gadolinium-contrast with a typically diffuse and often dotty configuration. This is thought to be the radiographic manifestation of the histologic “chicken wire” vascular pattern and is shared with many grade II oligodendrogliomas. Consequently, contrast-enhanced MRI has a very limited ability to distinguish high- and low-grade oligodendrogliomas. Intratumoral microhemorrhages are common in AOs and can often present with T1-hyperintensities. Oligodendrogliomas in general are the most commonly calcified brain tumors. However, calcification can be observed with other neoplasms such as in pilocytic astrocytomas, ependymal, and glioneuronal tumors and is therefore not pathognomonic.

MR spectroscopy can detect a signal derived from 2HG in vivo . This method may be used to identify and monitor the IDH mutant tumor volume. However, these images are technically difficult to acquire and therefore have not yet made into day-to-day clinical practice. ^, AOs seem to have the highest apparent diffusion coefficients (ADCs) among high-grade gliomas. Interestingly, oligodendrogliomas generally have elevated relative cerebral blood volume (rCBV) regardless of grade and prognosis. This is again thought to be a correlate of the underlying tortuous microvascular system. Consequently, perfusion-weighted imaging has limited role in the diagnosis or surveillance of these tumors. ^, A similar phenomenon had been described with PET using amino acid tracers, where both low- and high-grade oligodendrogliomas exhibit high uptake compared with astrocytomas. ^,

Surgical approach. The diagnosis of high-grade glioma requires histopathologic confirmation unless such cannot be achieved without significant morbidity. Even with a prior history of histologically proven low-grade oligodendroglioma, surgical confirmation of grade may be helpful, as these tumors often exhibit contrast enhancement without underlying malignant transformation. Furthermore, adequate surgical samples are essential as genetic profiling may have immediate clinical implications. Although resection in anaplastic oligodendroglial tumors has been consistently associated with favorable outcomes, data is lacking from a purely 1p/19q co-deleted AO population. ^, Hence, the current recommendation of maximal safe resection of the T2/FLAIR hyperintense and/or contrast enhancing volume is extrapolated from low-grade oligodendroglial and mixed high-grade glioma cohorts. Of note, reorganization of functional brain networks is often observed in slower growing tumors, such as AOs progressing from a low-grade intermediary. Consequently, extensive resections are often achievable in tumors situated in conventionally “eloquent” regions. Surgical removal of epileptogenic foci may also improve seizure control in AOs. Nonetheless, surgery is virtually never curative in AOs, and additional treatment covering the infiltrative part of the tumor is fundamental for prolonging survival. Radiation and chemotherapy. Anaplastic oligodendrogliomas are relatively radiosensitive. Monotherapy via standard fractionated external beam radiation has been associated with a median overall survival of approximately 8 years ( Table 12.2 ). Addition of a chemotherapy regimen combining procarbazine, CCNU (lomustine), and vincristine (PCV) administered in 6-week cycles has nearly doubled survival in these patients, as evidenced by two independent randomized controlled phase III trials. ^, One of these studies reported an almost 15-year overall survival with this regimen. Thus, radiotherapy preceded or followed by PCV has become the standard approach for anaplastic oligodendrogliomas ( Fig. 12.3A ). Although PCV was proven effective, it was also proven relatively toxic, as only half of the patients tolerated four or more cycles. Dose reductions and treatment delays were frequent. Grade III hematologic toxicities were noted in more than 50% of patients enrolled in these trials with neutropenia and thrombocytopenia being the most common. ^, Myelosuppression is mainly attributed to CCNU and procarbazine, and typically occurs 2–8 weeks after the start of treatment, with a recovery taking 4–6 weeks or longer. CCNU is often associated with a cumulative and even more prolonged cytopenias that may persist years after completion of the treatment. Nausea and emesis affect up to 90% of patients taking this regimen and can be controlled with antiemetics in most cases. Procarbazine also has a weak monoamine oxidase inhibitor effect and thus interacts with enzyme-inducing antiepileptic drugs (AEDs) and selective serotonin reuptake inhibitors and necessitates a low-tyramine diet. Additionally, vincristine’s penetration into brain tumors has been called into question, yet it is a common culprit of peripheral neurotoxicity. This typically manifests as a dose-dependent distal symmetrical sensorimotor axonal neuropathy first presenting with loss of the ankle jerk reflex, followed by often painful paresthesia, and loss of distal vibratory sensation. Vincristine may also contribute to significant constipation due to autonomic neuropathy.

(A) illustrates the timeline of the PCV protocol with radiotherapy followed by 6-week cycles of CCNU on day 1, vincristine (VCR) on day 8 and 29, and daily procarbazine from day 8 through day 21. (B) illustrates the Stupp protocol with 6 weeks of combined radiotherapy and low-dose temozolomide (TMZ) followed by 4-week cycles of standard dose temozolomide given day 1 through day 5.

Considering all the above, a practical approach to this regimen is to first administer radiotherapy, which is generally well tolerated and “secures” the tumor, then proceed with PCV about 4 weeks after completion of radiation. Although the goal is to administer up to six cycles of PCV, dose reductions are almost always necessary, and maintaining CCNU dosing should be prioritized over procarbazine, whereas discontinuation of vincristine should be considered if any sign of neuropathy emerges ( Fig. 12.3A ).

There is a great desire to adopt a less toxic regimen than PCV, yet it is the regimen with the most evidence of long-term efficacy at the present time. In a trial of anaplastic gliomas comparing monotherapy of radiation, or chemotherapy with either temozolomide or PCV, neither treatment modalities provided superior overall survival to one another. In a retrospective analysis of 1p/19q co-deleted AOs, PCV monotherapy was associated with longer progression-free survival compared with temozolomide alone; those who received radiotherapy combined with either chemotherapy regimen did better than those receiving monotherapy. The results suggest that radiotherapy with concurrent temozolomide, followed by adjuvant temozolomide (i.e., Stupp protocol, Fig. 12.3B ), could serve as an alternative to PCV. This question is currently assessed in the phase III CODEL trial (NCT00887146) comparing the two regimens. Using temozolomide as initial treatment of AOs outside the above trial is generally discouraged unless there are well-justified concerns about PCV not being tolerated or inaccessible.

Case. A 24-year-old woman presents with a 2-month history of progressive worsening left leg weakness, falls, and tripping. She is an extremely active triathlete who was seen by her primary physician for difficulty in competition and underwent contrast-enhanced MRI brain revealing an infiltrating T2/FLAIR hyperintense lesion in the right posterior frontal lobe with a small focus of contrast enhancement in the anterior portion of the lesion ( Fig. 12.4 ). She underwent awake craniotomy with near complete resection of the lesion and transiently worsening left-sided weakness, which improved postoperatively. Pathology revealed abundant astrocytic cells with nuclear atypia, mitotic activity, and elevated Ki-67 labeling index up to 8% and regions of increased vascular endothelial proliferation. On immunohistochemistry, there was strong nuclear staining for mutant IDH1 R132H and p53 with loss of ATRX staining. A final diagnosis of anaplastic astrocytoma (WHO grade III), IDH mutant was made. Standard radiation with concurrent temozolomide was initiated 4 weeks postoperatively, which was tolerated well except for thrombocytopenia (nadir 65,000/μL), prompting discontinuation of temozolomide 1 week early. One month after completion of the concurrent therapy she had a Karnofsky performance scale score of 80%, a stable neurologic examination, and blood counts that revealed normal platelet counts but substantial lymphopenia (TLC 400). Adjuvant temozolomide was pursued, and she completed six cycles of treatment with stable imaging findings.

(A) Anaplastic astrocytoma with the characteristic T2/FLAIR mismatch sign for IDH mutant tumors. Note the mostly homogeneous T2 signal with the relatively hypointense FLAIR abnormality with a hyperintense halo. (B) This patient has a multifocal high-grade astrocytoma. Although the biopsy of the right occipital lesion suggested anaplastic astrocytoma, the presence of necrosis in the trigonum bilaterally is suggestive of glioblastoma. The histopathologic diagnosis is likely a result of sampling error. FLAIR , Fluid attenuated inversion recovery.

Teaching Points: Approach to Anaplastic Astrocytomas. Anaplastic astrocytomas (AAs) are responsible for approximately 10% of all gliomas. They are typically found de novo but can progress from a low-grade intermediary. About 50% of low-grade astrocytomas progress into anaplastic glioma within 5 years of diagnosis. AAs consist of two sharply distinct groups based on IDH status. IDH mutants represent 70–80% of AAs and are the youngest population of high-grade gliomas with a typical presentation in the late 30s and a prognosis closer to AOs. IDH wild-type AAs are much less common. They typically present at older ages, between 45 and 55, and have a prognosis similar to glioblastoma. Although the current diagnostic and treatment approach is essentially the same for all astrocytic high-grade gliomas, this chapter will focus on some of the unique features and nuances that distinguish AAs from other high-grade gliomas with emphasis on those with IDH mutation.

Pathology and predictive markers . As mentioned in the general histopathology section, AAs are characterized by astrocytic cells showing nuclear atypia, increased cellularity, and mitotic activity (Ki-67 5–10%), while they lack necrosis or vascular proliferation. Oligodendroglioma-like components are often present, but lack of 1p/19q co-deletion rules out oligodendroglioma. If IDH mutation is present, most patients have the canonical R132H alteration, whereas IDH2 mutations such as R172K are very rare. On immunohistochemistry, IDH mutant AAs typically exhibit strong nuclear staining for p53 because of mutation in gene TP53 ( Table 12.1 ). Mutation of the ATRX gene manifests as loss of ATRX staining. Although ATRX may be preserved in low-grade IDH mutant astrocytomas, this mutation is ubiquitous for IDH mutant AAs. In contrast, IDH wild-type AAs often have a TERT mutation, EGFR gene amplification, or whole chromosome 7 gain or 10 loss. The presence of any of these alterations confer the diagnosis of “molecular glioblastoma” based on the similarly poor prognosis.

IDH mutation is a decisive factor in the cascade of hypermethylation in diffuse gliomas. As a result, those hypermethylated (often referred to as G-CIMP positive) have higher sensitivity to both radiation and chemotherapy. MGMT p methylation is mostly the result of the hypermethylated state as reflected by its similar incidence to IDH mutations, and has limited predictive value in the IDH mutant population. In contrast, MGMT p methylation is indeed predictive of higher chemotherapy sensitivity in IDH wild-type AAs.

Location and presentation. Similar to other high-grade gliomas, AAs are supratentorial tumors. They have a predilection to the frontal lobe, but often present in a gliomatosis cerebri pattern, involving three or more lobes in the brain. Consequently, their presenting symptoms develop and progress slowly over months. These most commonly include cognitive impairment and hemiparesis aphasia, whereas signs and symptoms related to ICP elevation are rare. Inaugural seizures may happen in all AAs, but are more common in those with IDH mutation as attributed to the production of 2HG.

Imaging. AAs are T2/FLAIR hyperintense on MRI with blurry margins and no intralesional calcification. Most of them enhance contrast in a nodular, patchy, or less commonly ring pattern. According to a 1p/19q agnostic analysis, 32% of IDH1 mutant anaplastic gliomas lack enhancement, compared with 12% of non-enhancing IDH wild-type tumors. More recently, a constellation of hyperintense T2 and relatively hypointense FLAIR signal with a hyperintense peripheral rim has been described IDH mutant astrocytomas. Although this “T2-FLAIR mismatch” sign was found to be 100% specific yet only 51% sensitive for IDH mutants in independent cohorts, caution should be exercised when interpreting these findings ( Fig. 12.4 ).

Advanced MRI may be useful in the initial evaluation of these tumors. Elevated rCBV is highly sensitive in the distinction of high- and low-grade gliomas, but this feature lacks specificity. MR spectroscopic detection of 2HG peak may also be helpful in identifying IDH mutant AAs, yet again this technique is not yet widely adopted. Additionally, 2HG production may be a less important factor in these tumors as they had already undergone malignant transformation. IDH wild-type AAs have distinctly low ADCs only comparable with IDH wild-type glioblastomas. In comparison, oligodendrogliomas have the highest ADC of all high-grade gliomas, and IDH mutant AAs are in between. Of course, none of these techniques replace histopathologic confirmation.

Initial treatment approach. The IDH mutation is being evaluated as a direct or indirect therapeutic target. However, at present, the standard initial treatment approach of high-grade astrocytomas is IDH agnostic. It includes maximal safe resection followed by chemoradiation and adjuvant temozolomide. The exact benefit of concurrent and/or adjuvant temozolomide was evaluated by the CATNON trial (NCT00626990). ³⁶ Preliminary data from this study suggest that IDH mutant AAs may benefit from temozolomide and radiotherapy. In this cohort, patients with IDH mutant AAs had an overall survival of 9.7 years versus the 1.6 years in the IDH wild-type group.