Case 5 -

Oligodendroglioma Tarik Tihan Associate Professor of Pathology UCSF Medical Center San Francisco

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Click here to view (or print) handout in single page format. (4.06 MB) Note: Any slides will be printed in color. Click here to view (or print) black and white handout. (1.31 MB) Note: Text will be in single page format and any slides will be in 6-per-page format. Case History The patient is a 51-year-old right-handed female who recently underwent a fine needle aspiration/drainage of a thyroid cyst, after which she developed low-grade but persistent headaches. Due to the prolonged nature of her headaches she was readmitted to determine a possible cause. She had history of thyroid cysts, cesarean section 16 years ago, and a history of iron deficiency anemia. A CT imaging study showed a calcified mass in the left frontal area consistent with a neoplasm. MRI studies revealed a large, wedge-shaped, well-demarcated T2/FLAIR-hyperintense lesion measuring approximately 5.2 x 5.3 in transaxial dimension located in the left middle and inferior frontal lobes extending from the cortical surface to the adjacent ventricle, also affecting a portion of the left external/extreme capsule as well as the subinsular region, and impacting the anterior limb of the left internal capsule. This lesion demonstrated areas of T2 hypointensity which may be due to calcification. The mass did not demonstrate significant enhancement except for a small focus located in the inferior aspect of the left gyrus rectus. The degree of mass effect for a lesion this size was minimal. Perfusion imaging demonstrated increased cerebral blood volume within the mass compared to adjacent normal brain, and this raised the possibility of an oligodendroglioma. She was admitted for elective resection, and underwent a left frontotemporal craniotomy. During the course of language mapping, frequent, self-limited, brief after-discharges were elicited from multiple sites. Spontaneous epileptiform discharges were also recorded adjacent to the mass. Post operative MRI of the brain showed a near gross total resection of a T2- hyperintense lesion in the left frontotemporal lobe, with residual FLAIR in the medial and posterior resection cavity, with a thin area of reduced diffusion around the resection cavity. Two slides from the tumor are provided. Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Case 5 - Figure 1 a,b - Axial fluid attenuated inversion recovery (FLAIR) and T2-weighted images showing a hyperintense mass in the left frontal lobe with no significant mass effect or peritumoral edema. Case 5 - Figure 2 a,b - Axial pre- and post-contrast T1-weighted images showing a mass that is slightly hypointense to gray matter with no appreciable enhancement. Case 5 - Figure 3 a,b - Coronal T2-weighted and post-contrast T1-weighted images showing the extent of tumor in the left frontal lobe and a small focus of enhancement in the inferior aspect of the mass. Case 5 - Figure 4 a,b - MR perfusion image and graphic representation of perfusion in two selected regions of tumor (1,3) and two regions of normal-appearing parenchyma in the contralateral hemisphere (2,4). Case 5 - Figure 5 a,b,c - Postoperative axial pre-contrast T1, FLAIR, and post-contrast T1-weighted images showing no appreciable residual signal attributable to residual tumor. Case 5 - Figure 6 a,b - Postoperative FLAIR and diffusion-weighted images showing a narrow rim of diffusion abnormality around the resection cavity. Case 5 - Figure 7 Medium power H&E image of one tumor component showing a rather monotonous population of cells. Case 5 - Figure 8 Higher power H&E image of the monotonous population showing "fried-egg" (perinuclear halo) cells and delicate vasculature. Case 5 - Figure 9 Medium power H&E image of another area of the tumor showing a more pleomorphic population of cells and delicate hypervascularity. Case 5 - Figure 10 Medium-high power H&E image of the second tumor pattern showing only rare cells with a "fried-egg" appearance and delicate vascular background. Case 5 - Figure 11 High power H&E image of a third morphologic pattern within the tumor showing a population of pleomorphic cells that exhibit elongated and irregular nuclei with hyperchromasia. Case 5 - Figure 12 High power H&E image of the third pattern highlighting the nuclear and chromatin structure of the cells. Diagnosis: Oligodendroglioma Discussion : The final diagnosis in this case represents a personal point of view and is of lesser importance than the point to be made. The diagnosis of this case can be debated, like many others in the astrocytoma-oligoastrocytoma-oligodendroglioma spectrum. Despite a higher rate of agreement among neuropathologists, astrocytoma and oligodendroglioma also suffer from high interobserver variability, but the problem is confounded by a magnitude for the "mixed glioma" or oligoastrocytoma. It seems that we have created a predicament that is not quite resolvable based on the current paradigm and our pre-conceived notions. This brief discussion will highlight some historical curiosities, and give a brief review of a highly convoluted and confusing amount of data in the literature regarding oligoastrocytomas. Recognition of infiltrating astrocytomas and oligodendrogliomas represents a significant advance in our understanding of primary CNS tumors [1]. The infiltrative and resilient nature of these two entities, their progressive character along with the ability to exhibit a variety of phenotypic patterns, and their genomic instability have been well recognized. These features provide two well-established clinicopathological entities that are of practical value in neuro-oncology. While it can be difficult to classify a tumor in any one of these categories, most experts agree that the classical forms of both entities are readily distinguishable. Thus, for most experts, there is little ambiguity in the validity of astrocytoma and oligodendroglioma as clinicopathological entities, even though diagnostic criteria suffer from poor reproducibility. As if this were not a challenge sufficient enough, the pathologist would be thrown into a mayhem with the introduction oligoastrocytoma [2]. The dilemma begins when a tumor shows typical features of neither entity. The "easy way out" is to classify such lesions as oligoastrocytoma. The birth of oligoastrocytoma is as curious as many other controversies that surround this enigmatic entity. The first use of term has been rightfully attributed to a Eugenia Rose Aylmer Cooper, a lecturer in histology at the University of Manchester [3]. Dr. Cooper's manuscript in 1935 described a set of tumors only in terms of their microscopic appearance. The tumors had been operated by a Prof Geoffrey Jefferson of the Manchester Royal infirmary. The article mentions fifteen pure astrocytomas, seven oligocytomas and "a group of mixed tumors numbering ten". There is no clinical or demographic information of any sort, and the only data presented about these mixed tumors are composed of four images (Figures 1, 2). Figure 1, 2: Reproductions from ERA Cooper, J. Pathol Bacteriol 1935: v41 p259 Dr. Cooper states "at the moment the writer is of the opinion that astrocytes can be transformed into oligocytes by the swelling and hyalinization of the cytoplasm with consequent withdrawal of the processes ". She goes on to speculate on the theoretical mechanism of this transformation as a process that could take place in normal brain as well. This appears to be the one and only manuscript published by the author about astrocytic or oligodendroglial neoplasms. While this publication would probably be rejected by every journal reviewer today due to lack adequate clinicopathological information, it provides a striking example of how earlier studies have already iterated the allegedly novel ideas of today. Dr. Cooper's idea of astrocytes transforming into oligodendrocytes has been suggested in many recent studies. In particular, types of cells recently identified as GFAP-positive astrocytes in the subventricular zone of mice, referred to as type B cells, have been proposed as progenitors of oligodendrocytes in normal brain [4]. A series of studies in the early 90s marked the critical turning point for the importance of distinguishing astrocytomas from oligodendrogliomas. The desire to find an oligodendroglial component in any infiltrating glioma came after the reports that oligodendrogliomas were responsive to chemotherapy, and were also associated with combined deletions of chromosomes 1p and 19q [5, 6, 7]. These discoveries have, in the words of Peter C. Burger, "resulted in the desire that no oligodendroglioma escape detection, and no affected patient be deprived of the relatively prognostic optimism associated with the tumor" [8]. The molecular and therapeutic advances preceded a dramatic increase in the incidence of oligodendroglial tumors, and especially oligoastrocytoma, that reached mini-epidemic proportions by mid 90s. One population-based study enrolled 21 low grade astrocytomas, 27 oligodendrogliomas, and 43 oligoastrocytomas among a total of 457 tumors [9]. The percentage of oligoastrocytomas among astrocytic/oligodendroglial neoplasms in this study was 10%. A comparable population-based study from Europe in 2005 encompassing 987 tumors reported the incidence as 2% [10]. Other formal or informal accounts of the incidence of oligoastrocytoma have ranged from 1% to 19% [11]. Almost synchronous with the beginning of the dot-com bubble, in 1994 the number of oligoastrocytomas diagnosed at UCSF far exceeded the number astrocytomas and oligodendrogliomas combined. The clinicopathological characteristics of oligoastrocytomas are indistinguishable from astrocytoma in some cases, and indistinguishable from oligodendroglioma in other cases. Most studies to date identify oligoastrocytomas as monoclonal neoplasms, but rare oligoclonal or bi-clonal tumors have also been described [12]. In many studies p53 mutations and 1p19q co-deletions have been found to be mutually exclusive [13]. Grading of oligoastrocytomas is often considered as being similar to oligodendroglioma, such that the presence of a few mitoses is not considered sufficient for a WHO grade III (anaplastic) designation. In addition, tumors with features such as vascular proliferation or palisading necrosis can be considered either glioblastoma with oligodendroglial component or anaplastic oligoastrocytoma, depending on the preference of the observer. The outcome for oligoastrocytoma seems to be in between that of astrocytoma and oligodendroglioma [10]. One study suggested that anaplastic astrocytoma with oligodendroglial component had a better survival rate, but this still requires verification [14]. Finally: There are many unanswered questions about oligoastrocytomas, and the author does not pretend to know the answers. While the emergence of this entity is not secondary to solid, irrefutable data, there are certainly compelling examples of infiltrating gliomas that are neither oligodendroglioma nor astrocytoma, and some of them even appear to be a good mixture of these two distinct entities. More typical, however, is an infiltrating tumor that seems to be a different breed. Thus, a perfect solution to this dilemma is still pending. In the interim, I would like to present some of the questions that still demand a satisfying answer, at least in the opinion of this author: Is oligoastrocytoma a unique, specific entity? If so what are the diagnostic criteria? Is the "gold standard" =H&E stain, specific and sensitive enough? How do we differentiate oligoastrocytoma from oligodendroglioma or astrocytoma if the gold standard fails to do so reliably and reproducibly? How do we reconcile the fact that we consider oligoastrocytoma a mixture of two distinct neoplasms, yet mostly monoclonal? Is it possible to consider diffuse gliomas as having more than two distinct entities? What are minigemistocytes or gliofibrillary oligodendrocytes? Do all infiltrating gliomas arise from the same bipotential precursor cells? Does the ever-reputable O2A cell exist in humans? ...(your questions here)... Take Home Messages One of the most critical issues in the diagnosis of gliomas in surgical pathology is the recognition of two distinct glioma categories: circumscribed and infiltrating. These two categories are histologically, biologically, genetically and clinically different. It is important to categorize infiltrating gliomas as astrocytoma or oligodendroglioma, since grading criteria for these two neoplasms are different. Even among the most experienced neuropathologists, there is less than a satisfactory level of agreement on the classification of tumors as astrocytoma or oligodendroglioma. This issue is even more pronounced for the so-called mixed gliomas or oligoastrocytomas. Even though the current definition of oligoastrocytoma is "two distinct neoplastic cell types", there is no convincing data that such tumors do in fact harbor two separate tumor subsets that are genetically or functionally distinct. It is critically important to employ all of the available analytical methods to determine the true biological nature of infiltrating gliomas, rather than subscribing to a dogmatic or poorly reproducible approach in classifying astrocytomas and oligodendrogliomas. An objective and reproducible approach to classification of infiltrating gliomas remains elusive. References Louis DN, Holland EC, Cairncross JG. Glioma classification: a molecular reappraisal. Am J Pathol 2001e:159;779-86. Giannini C, Scheithauer BW, Weaver AL, Burger PC, Kros JM, Mork S, Graeber MB, Bauserman S, Buckner JC, Burton J, Riepe R, Tazelaar HD, Nascimento AG, Crotty T, Keeney GL, Pernicone P, Altermatt H. Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading. J Neuropathol Exp Neurol 2001e:60;248-62. Cooper ERA. The relation of oligocytes and astrocytes in cerebral tumours. J Pathol Bacteriol 1935e:41;259-66. Menn B, Garcia-Verdugo JM, Yaschine C, Gonzalez-Perez O, Rowitch D, Alvarez-Buylla A. Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci 2006e:26;7907-18. Cairncross JG, Macdonald DR. Oligodendroglioma: a new chemosensitive tumor. J Clin Oncol 1990e:8;2090-1. Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP. Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 1994e:145;1175-90. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998e:90;1473-9. Burger PC. What is an oligodendroglioma? Brain Pathol 2002e:12;257-9. Aldape K, Simmons ML, Davis RL, Miike R, Wiencke J, Barger G, Lee M, Chen P, Wrensch M. Discrepancies in diagnoses of neuroepithelial neoplasms: the San Francisco Bay Area Adult Glioma Study. Cancer 2000e:88;2342-9. Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005e:64;479-89. Surawicz TS, McCarthy BJ, Kupelian V, Jukich PJ, Bruner JM, Davis FG. Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990-1994. Neuro Oncol 1999e:1;14-25. Dong ZQ, Pang JC, Tong CY, Zhou LF, Ng HK. Clonality of oligoastrocytomas. Hum Pathol 2002e:33;528-35. Maintz D, Fiedler K, Koopmann J, Rollbrocker B, Nechev S, Lenartz D, Stangl AP, Louis DN, Schramm J, Wiestler OD, von Deimling A. Molecular genetic evidence for subtypes of oligoastrocytomas. J Neuropathol Exp Neurol 1997e:56;1098-104. Donahue B, Scott CB, Nelson JS, Rotman M, Murray KJ, Nelson DF, Banker FL, Earle JD, Fischbach JA, Asbell SO, Gaspar LE, Markoe AM, Curran W. Influence of an oligodendroglial component on the survival of patients with anaplastic astrocytomas: a report of Radiation Therapy Oncology Group 83-02. Int J Radiat Oncol Biol Phys 1997e:38;911-4.