Resident Program - Case of the Month

Discussion:

The diagnosis in this case was a subtle oligodendroglioma with IDH-mutant and 1p/19q co-deletion, based on morphology, immunohistochemistry, and molecular testing. The slides show mildly hypercellular neural tissue with an infiltrate of cells with moderately enlarged uniform round to ovoid nuclei and fine chromatin. There are no high-grade features such as mitoses, necrosis, or microvascular proliferation appreciated. The immunohistochemical stains show that these infiltrating cells are SOX-2 and Olig 2 (not shown) positive, indicating that this is a glial population. Also, there is an IDH1(R132H) mutation, ATRX is retained (wild type), and there is a low proliferation index by Ki67. All these findings support a diagnosis of oligodendroglioma, WHO grade II.

WHO grade II oligodendrogliomas are rare primary brain tumors that account for 1-2% of primary neuro tumors annually in adults. Patients are diagnosed at a median age of 43 years. These tumors occur more frequently in men than women. There is ongoing investigation for potential risk factors that cause oligodendrogliomas. Similar to other primary brain tumors, the symptoms experienced are based on the size and location of the tumor and the rate of growth. The most common presenting symptom is seizure, seen in 90% of patients with oligodendroglioma. Seizures are also a characteristic symptom of a low-grade glioma. Other symptoms that can be commonly seen are headache, focal neurological deficits, and cognitive changes.

Before 2016, oligodendrogliomas were diagnosed mostly by their histologic morphology. In 2016, the WHO Classification of Brain Tumors was revised to integrate molecular findings. Now, oligodendrogliomas and anaplastic oligodendrogliomas are diffuse glial tumors that require both an IDH gene family mutation and combined whole-arm chromosomal losses of 1p and 19q (1p/19q codeletion) for diagnosis.

In adults, oligodendrogliomas have a predilection for the supratentorial area and commonly involve the cortex where they arise from the white matter. These tumors are commonly seen primarily in the frontal lobe, followed by the parietal lobes. These tumors are indolent, slow growing and grow in an infiltrative manner. Due to the diffuse nature of the tumor, surgical excision may not completely remove the entire lesion. Oligodendrogliomas often infiltrate into the overlying cortex or adjacent gray matter which on gross inspection will cause a blurring of the gray and white matter interface. Grossly, these lesions are usually solid, soft, and gray-pink. Other findings that may be present include cystic areas, hemorrhage, and calcifications.

The tumor arises from oligodendrocytes and demonstrates a small, round nucleus with scant cytoplasm and very few cellular processes. In paraffin embedded tissue, the cytoplasm typically creates an artefactual perinuclear halo, imparting a “fried egg” appearance, due to delayed formalin fixation. This clearing will not be present in a frozen preparation, such as for an intraoperative consultation. Also important to note is that the perinuclear clearing seen in oligodendrogliomas is not specific and can be seen in other tumors. The nucleus will typically have a small distinct nucleolus. The tumor cells often aggregate around neurons within cortical gray matter, along vasculature, and within the subpial regions, a pattern termed “secondary structures of Scherer” and that are seen primarily in diffuse gliomas.
Other histologic findings include tumoral calcifications and prominent branching vessels.

The 2016 WHO separates oligodendrogliomas into two grades, grade II and grade III. Grade III anaplastic oligodendrogliomas are usually more hypercellular with more nuclear pleomorphism and have mitotic counts of 6 or more per 10 high-power fields or have microvascular proliferation. To note, nuclear atypia and occasional mitosis can be seen in a grade II oligodendroglioma. A Ki-67 stain can be used, with grade III oligodendrogliomas demonstrating higher Ki-67 staining. However, there is no precise cutoff to distinguish between grade II and III oligodendrogliomas.

More than 90% of oligodendrogliomas have a mutation of the isocitrate dehydrogenase (IDH)-1 mutation from substitution of arginine (R) for histidine (H) at codon 132, also known as R132H. The IDH1 R132H mutation is often detected by immunohistochemistry, as seen in this case. However, in the event the this IHC is negative, sequencing of IDH1 codon 132 and IDH2 codon 172 is recommended. Oligodendrogliomas usually remain wild-type for ATRX (α-thalassemia/mental retardation syndrome X-linked), as in it is retained, and remain wild-type for TP53. The ATRX and P53 status helps differentiate a grade II or III oligodendroglioma from a grade II or III diffuse astrocytoma where the ATRX is mutated and lost in most cases and are mutated for P53 in most cases.

Sources:

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3. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds): WHO Classification of Tumors of the Central Nervous System (Revised 4th edition). IARC: Lyon 2016.
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5. Volovetz J, Yamamoto E, Prayson RA. Chapter 8 – histopathology and molecular biology of oligodendrogliomas. . In: Oligodendroglioma. Academic Press; 2019.