Clinical, radiographic, pathological, and genetic features are summarized in Tables , and , with more detailed descriptions below.
Clinical features in cases of oligodendroglioma with ganglioglioma-like maturation
Pathologic features in cases of oligodendroglioma with ganglioglioma-like maturation
Genetic features in cases of oligodendroglioma with ganglioglioma-like maturation
This 44-year-old man presented with a 3-day history of progressive headaches. A head CT revealed a contrast enhancing right frontal mass with a posterior cystic component and associated vasogenic edema. Subsequent MRI similarly revealed a 6 × 3.9 × 5.3 cm heterogeneous, partially enhancing, partially cystic, right frontal mass with moderate cerebral edema, midline shift, and extension into the corpus callosum (Fig. a–c). A resection of the enhancing component was performed, followed by adjuvant radiation therapy (6,000 cGy over 30 fractions over 6 weeks). The patient remained stable until 1.3 years post-operatively, when he suffered worsening headaches once again. Neuroimaging revealed a focus of ring enhancement in the right frontal lobe, with several smaller nodular foci of contrast enhancement nearby. Radiologically, recurrent tumor was favored and the patient was therefore treated with temozolomide chemotherapy. Three months later, this focus appeared larger (Fig. d), prompting a second resection, which revealed radiation necrosis without any viable tumor. Over the next 6 months, the cavity margins developed further foci of contrast enhancement prompting a third surgery, which again showed only radiation necrosis. The patient was last seen 2.1 years after the initial surgery and is doing well.
Fig. 1 Pre-operative MR images from patient 1 showing a partially enhancing ill-defined right frontal lobe mass with extension into the corpus callosum on sagittal post-contrast T1-weighted (a), axial T2-weighted (b), and axial post-contrast T1-weighted (c) (more ...)
The pathology specimen from the first surgery revealed a neoplasm containing two distinct morphologic appearances with relatively sharp demarcation between them (Fig. a), but some intermingling. One portion of the tumor had classic features of anaplastic oligodendroglioma, including an infiltrative growth pattern, uniformly rounded nuclei with delicate chromatin, clear perinuclear haloes, scattered minigemistocytes, nests of slightly larger more epithelioid cells, a rich branching capillary network, increased mitotic activity (up to 10 per 10 high powered fields), microvascular proliferation, and foci of non-palisading tumor necrosis (Fig. b, d, f). The second component resembled ganglioglioma and included large dysmorphic cells arranged in nests and sweeping fascicles, subsets of which had discernable Nissl substance and/or showed binucleation (Fig. c, e, g). Additionally, there was focal perivascular lymphocytic cuffing and scattered spindled cells with eosinophilic cytoplasm resembling astrocytes. However, no eosinophilic granular bodies (EGBs) were detected. Mitotic figures were hard to find and there was no necrosis or microvascular proliferation. On immunohistochemical studies, GFAP highlighted gliofibrillary oligodendrocytes and minigemistocytes within the oligodendroglioma component and astrocytic cells within the GGLF (Fig. a, b). Synaptophysin expression was similarly seen in both components, but yielded a cytoplasmic dot-like pattern in the oligodendroglioma (Fig. c) and cytoplasmic and/or membrane staining in the dysmorphic ganglion cells of the GGLF (Fig. d). Cytoplasmic neurofilament expression was seen in only a minor subset of oligodendroglioma cells, although entrapped axons were highlighted, consistent with an infiltrative growth pattern (Fig. e). Strong neurofilament positivity was seen in ganglion cells and their processes within the GGLF (Fig. f). A CD34 stain highlighted endothelial cells, but all tumor cells were immunonegative. The Ki-67 labeling index was markedly elevated in the oligodendroglial portions, reaching up to 44% (Fig. g). In contrast, only rare Ki-67 positive nuclei were seen in the GGLF, some of which likely represented perivascular inflammatory cells (Fig. h). FISH analysis revealed 1p and 19q codeletion in both components (Fig. ).
Fig. 2 The histology from case 1 showed relative demarcation of areas resembling oligodendroglioma (a; left) and areas resembling ganglioglioma (a; right). Higher magnification images are shown of the oligodendroglioma (b, d, f) and GGLF (c, e, g). Classical (more ...)
Fig. 3 Immunohistochemical studies in case 1 with the oligodendroglioma component on the left and the ganglioglioma-like component on the right. GFAP highlighted gliofibrillary oligodendrocytes (a) and astrocytic cells (b). Synaptophysin yielded a cytoplasmic (more ...)
Fig. 4 FISH studies in the oligodendroglioma component revealed 1p and 19q codeletion with most nuclei being near diploid (not shown). In the ganglioglioma-like foci, there was similarly a codeletion pattern with a mixture of near-diploid (1 test and 2 reference (more ...)
This 58-year-old man presented with progressive dyscalculia and short-term memory loss. MRI revealed a poorly demarcated, non-enhancing left temporo-parietal mass felt radiologically to be consistent with a diffuse glioma. A stereotactic biopsy was performed, but was non-diagnostic. This was followed by a subtotal resection utilizing cavitronic ultrasonic aspiration (CUSA), followed by intraoperative Gliadel® wafer implantation within the surgical cavity. Unfortunately, the resulting specimen was poorly preserved and only a descriptive diagnosis of “diffuse glioma” was possible at that time (slides from outside hospital unavailable for further review). No definite neuronal component was evident by report, although this may have been difficult to discern due to poor specimen quality. The patient was subsequently treated with standard fractionated radiotherapy over 4 months and the tumor remained stable for the next 4.4 years, at which time neuroimaging revealed a new focus of contrast enhancement consistent with recurrence. The enhancing component was resected. The patient was subsequently treated with a temozolomide and marimastat chemotherapy regimen with good response and stable disease for the next 3 years. At this time, temozolomide therapy was reinstituted due to another new focus of contrast enhancement. However, the tumor continued to progress and the patient expired 7.5 years from initial presentation.
The pathology of the recurrent tumor resembled anaplastic oligodendroglioma, WHO grade III in the majority of slides (Fig. a). Features included diffuse infiltration, uniform round nuclei with small nucleoli and clear perinuclear haloes, branching “chicken-wire” capillaries, scattered minigemistocytes, increased mitotic activity, and microvascular proliferation. No necrosis was seen. Focally, GGLF were identified and they appeared mostly demarcated from the adjacent oligodendroglioma pattern (Fig. b). This portion included a microcystic background and scattered markedly enlarged, mildly dysmorphic ganglion cells with occasional binucleate or multinucleate forms (Fig. c). Rare bizarre astrocytes were also noted (Fig. d). No EGBs were found. Immunohistochemical studies revealed GFAP positivity in a subset of the oligodendroglioma cells, morphologically consistent with minigemistocytes and gliofibrillary oligodendrocytes. The rare bizarre astrocytes were also positive. Dysmorphic ganglion cells were immunoreactive for synaptophysin and Neu-N, while oligodendroglioma cells were negative. CD34 was negative in tumor cells, but labeled endothelial cells appropriately. The Ki-67 labeling index was estimated at 4% within the oligodendroglioma component and <1% in the GGLF. FISH analysis revealed 1p and 19q codeletion in the oligodendroglioma. There were insufficient numbers of dysmorphic ganglion cells for reliable counts in the GGLF.
Fig. 5 The histological features in case 2 were predominantly those of an anaplastic oligodendroglioma, including round regular nuclei, small nucleoli, clear perinuclear haloes, and a rich branching capillary network (a). The oligodendroglioma (b; left) was (more ...)
This 40-year-old man developed daily headaches and was referred to an ophthalmologist when these were complicated by visual blurring. Fundoscopic exam revealed papilledema, prompting imaging studies. Head CT and MRI scans demonstrated a 5-cm partially calcified, partially enhancing right frontoparietal mass with extension into the splenium of the corpus callosum. There was associated cerebral edema and mass effect with compression of the right lateral ventricle. On the day of the MRI, the patient developed left sided weakness and had a seizure. The patient subsequently underwent a craniotomy with resection of the contrast enhancing component and a portion of the non-enhancing component. Adjuvant therapy included 12 cycles of temozolomide chemotherapy, but this had to be discontinued after the 12th cycle due to severe rash. The last MRI scan performed 4.9 years after initial presentation showed stable disease with residual non-enhancing tumor and otherwise, the patient is doing well.
The pathologic findings in case 3 were nearly identical to those of case 2, except that there was a greater degree of intermingling between the two elements and the zones of infarct-like necrosis within the oligodendroglial component were larger. Synaptophysin staining revealed strong cytoplasmic and Golgi pattern positivity in dysmorphic ganglion cells, while only rare oligodendroglial cells showed cytoplasmic reactivity. There was extensive GFAP positivity with most positive cells showing morphologic features of gliofibrillary oligodendrocytes. However, irregular cells with elongate processes were also seen, suggesting a minor astrocytic component. Both components were Neu-N negative. The CD34 stain highlighted endothelial cells only; tumor cells were negative. The Ki-67 labeling index was low to moderate, focally reaching a maximal staining of 15% in the oligodendroglial component; it was <1% in GGLF. FISH analysis revealed chromosome 19q deletion in both components, while chromosome 1 studies were non-informative due to weak signals. Nevertheless, loss of heterozygosity studies were also performed on this tissue at the Memorial Sloan Kettering Cancer Center and allelic losses of both 1p and 19q were detected. Therefore, this tumor was interpreted as being codeleted.
This 29-year-old woman was previously healthy until she awoke with a severe left frontal headache associated with nausea and vomiting. A few days later, she had a similar episode, prompting medical attention. A head MRI scan demonstrated a large, partially enhancing, left frontal lesion with some mass effect including mild left-to-right shift and compression of the ipsilateral ventricle. There was some high attenuation on pre-gadolinium images. It also had some hypodense and cystic areas. It did not appear to cross the corpus callosum. A left frontal craniotomy with intraoperative motor and speech mapping was performed and the entire enhancing component was resected. A decision was made not to treat the neoplasm with radiation or chemotherapy, but to follow with frequent MRI scans.
Over the next 2 years, the patient remained asymptomatic and MRI scans were stable. Eventually however, they revealed gradually increasing areas of FLAIR abnormality and a small area of new enhancement situated near the anterior pole of the surgical cavity. The corpus callosum was thickened and the neoplasm had now extended into the right frontal lobe. Therefore, a second resection was performed roughly 2.2 years after her initial presentation. The patient was treated post-operatively with 12 cycles of temozolomide chemotherapy. At her last follow-up visit 3.5 years from the first surgery, she was doing well with stable disease on imaging studies.
The first pathology specimen revealed a neoplasm that was mostly consistent with oligodendroglioma, WHO grade II, but focally showed small foci of enlarged epithelioid cells with increased cytoplasm, nucleolar prominence, and increased mitotic activity of up to 6 mitoses per 10 high powered fields, warranting a designation of focal anaplasia, WHO grade III. Small clusters of minigemistocytes were seen in a few areas. In addition there were multiple small GGLF that were mostly intermingled with the rest of the tumor. These foci included large, dysmorphic, occasionally binucleate ganglion cells embedded within collections of loose to microcystic, delicate fibrillary matrix, consistent with tumor-associated neuropil. A small subset of these dysmorphic cells contained discernable Nissl substance. No EGBs or bizarre astrocytes were seen in either component. The recurrent tumor showed similar features, but had only rare GGLF. Additionally, there was focal microvascular proliferation as well as focal pseudopalisading necrosis, further evidence of its anaplastic nature. Immunohistochemical studies revealed cytoplasmic and Golgi-like synaptophysin positivity in both dysmorphic ganglion cells and a subset of the oligodendroglioma cells. The dysmorphic ganglion cells were also variably immunoreactive for neurofilament protein and Neu-N, while the oligodendroglioma cells were negative. Subsets of tumor cells were strongly GFAP positive, mostly showing morphologic features of minigemistocytes and gliofibrillary oligodendrocytes. Endothelial cells stained appropriately for CD34, although tumor cells were negative. The Ki-67 labeling index was mostly low, but focally reached up to 12% in the oligodendroglial component. Dysmorphic ganglion cells were negative. FISH studies were performed on the recurrent tumor and showed 1p and 19q codeletion. However, there were too few dysmorphic ganglion cells to reliably analyze the GGLF portion.
This 55-year-old man was admitted for a several-month history of personality change and more recently had been becoming increasingly drowsy and was noted to be dragging his left foot. A CT scan of the head revealed a large cystic mass in the right frontal lobe with compression of the frontal horn of the right lateral ventricle and right-to-left shift. Decreased signal was seen extending throughout the white matter of the frontal lobe across the genu of the corpus callosum into the left frontal lobe. An MRI of the head confirmed the large complex mass with contrast enhancement of the solid component, as well as a portion of the rim of the cystic component. However, the enhancing component did not extend into the corpus callosum. The differential diagnosis was glioblastoma or possibly a metastatic deposit. While in the hospital, his condition deteriorated and he was given dexamethasone with some improvement. A CT scan of the head revealed a new large intratumoral hemorrhage. An emergent craniotomy was performed with drainage of the cyst and a subtotal resection of the tumor, which appeared to extend into the temporal lobe. The patient received adjuvant external beam radiotherapy with a total dose of 59.4 Gy in 33 fractions. MRI studies performed 6 months post-operatively revealed a new focus of contrast enhancement suspicious for recurrence, which decreased in size on the most recent imaging 2 months later. However, the extent of the surrounding non-enhancing T2/FLAIR signal abnormality had increased. The latest plan was to see him again in 3 months, with the possibility of chemotherapy if imaging revealed tumor progression.
The pathology specimen was very similar in appearance to case 1, except that the oligodendroglial component appeared low-grade (WHO grade II), with low mitotic activity and no evidence of either microvascular proliferation or necrosis (Fig. a). Dysmorphic ganglion cells (Fig. b) displayed strong cytoplasmic and membrane pattern positivity for synaptophysin (Fig. d), but were nearly uniformly negative for Neu-N (Fig. f). No EGBs were seen. Weak cytoplasmic positivity for synaptophysin was seen in occasional oligodendroglioma cells as well, but mostly highlighted entrapped neuropil (Fig. c); Neu-N stained only entrapped cortical neurons (Fig. e). Scattered GFAP-positive cells were seen in both components, although in the GGLF they appeared consistent with tumoral astrocytes (Fig. h), while in the oligodendroglioma portion most positive cells looked like reactive astrocytes (Fig. g). Occasional gliofibrillary oligodendrocytes were also noted. Tumor cells were CD34 negative, while intratumoral endothelial cells were positive. The Ki-67 stain reached a maximal labeling index of roughly 8% in the oligodendroglioma component, but stained only rare small perivascular cells in the GGLF (similar to Fig. h). FISH studies showed chromosome 1p deletion in both components (Fig. a, b), while chromosome 19 studies showed a normal disomic (2 copies) dosage in both regions (Fig. c, d), i.e., there was no evidence of 19q deletion.
Fig. 6 The oligodendroglioma and GGLF in case 5 are displayed on the left and right sides, respectively. The former appeared low-grade (a), while tight clusters of unmistakably dysmorphic ganglion cells characterized the latter (b). The majority of oligodendroglioma (more ...)
FISH images from the oligodendroglioma region and GGLF of case 5 are illustrated on the left and right sides, respectively. Both components showed evidence of chromosome 1p deletion (a, b), but retained chromosome 19 dosages (c, d)
This 63-year-old woman presented with a 2-week history of progressive ataxia, falls, confusion, and word finding difficulties. She also had headaches for a few days. After a few falls and increasingly bizarre behavior, her husband brought her to the hospital for medical attention. Head CT and MRI were eventually included in the workup and they showed a large, minimally enhancing left frontal lobe mass with speckled calcifications, an infiltrative pattern, and extension across the corpus callosum to the right frontal lobe (Fig. ). There was moderate associated edema and considerable mass effect with partial compression of the left lateral ventricle. A large, but subtotal resection was performed. The patient is currently undergoing combined chemoradiotherapy, with temozolomide as the chemotherapeutic agent. No additional follow-up is available given that the patient was only recently diagnosed.
Pre-operative MRI from patient 6 showed a minimally enhancing diffuse left frontal lobe mass with extension across the corpus callosum into the right frontal lobe on axial post-contrast T1-weighted (a) and axial FLAIR (b) images
The pathological findings in this case were striking for at least two distinct morphological appearances, which were sharply demarcated from one another focally (Fig. a), but were intimately intermingled in most areas. The predominant cell type was that of an anaplastic oligodendroglioma with classical cytological features (Fig. b), up to 6 mitoses per 10 high powered fields, and focal necrosis, but no definite microvascular proliferation. Additionally, scattered enlarged, bizarre and sometimes multinucleated astrocytes were interspersed among the oligodendroglioma cells (Fig. b); it was unclear whether these represented reactive, dysplastic, or neoplastic elements. Moreover, there were several small foci of neurocytic differentiation with delicate neuropil formation and neurocytic rosettes (Fig. d). The GGLF featured microcystic spaces (Fig. c) and large dysmorphic neurons, including binucleate forms (Fig. e; arrow). Even in these areas, however, there were scattered smaller oligodendroglioma cells, including minigemistocytes (Fig. e; arrowheads). No EGBs were seen. Neuronal markers, such as synaptophysin, chromogranin, neurofilament protein, and Neu-N variably stained the dysmorphic ganglion cells in GGLF, as well as entrapped native elements within the oligodendroglioma regions (Fig. ). GFAP highlighted scattered astrocytic elements in both foci, including the enlarged bizarre forms (Fig. e, f). Intratumoral endothelial cells stained appropriately for CD34, but tumor cells were negative. The Ki-67 labeling index was estimated at roughly 10% in the oligodendroglioma component and <1% in the GGLF. Codeletion of 1p and 19q was seen in both components using FISH (Fig. ). Most of the dysmorphic ganglion cells appeared near-tetraploid with two test and four reference probe signals, while most of the oligodendroglioma cells appeared near-diploid with one test and two reference probe signals.
Fig. 9 The histologic examination of case 6 showed focal demarcation between the oligodendroglioma (a; left) and ganglioglioma-like (a; right) components, but also consisted of intermingled elements. The oligodendroglial cytology had classic features (b, d), (more ...)
Fig. 10 Immunohistochemical results in case 6, with the oligodendroglioma component on the left and the ganglioglioma component on the right. Chromogranin highlighted scattered small entrapped cortical ganglion cells in the oligodendroglial element (a) and the (more ...)
Fig. 11 FISH in case 6 showed a 1p (a) and 19q (b) codeletion pattern similar to that encountered in case #1 (see Fig. ). In ganglioglioma-like foci, the majority of enlarged dysmorphic ganglion cells showed a tetraploid pattern (2 test and 4 reference (more ...)
This 42-year-old man presented with a 1-month history of progressive headaches, nausea, and vomiting. MRI studies revealed an 8.2 × 6.9 × 5 cm heterogeneously enhancing mass in the right frontal lobe with marked mass effects, including a 16-mm midline shift and compression of both frontal horns of the lateral ventricles. There were several cystic regions and one region with imaging characteristics of intratumoral hemorrhage. The radiographic impression was that of a high-grade diffuse glioma. A subtotal resection was recently performed and there are plans to treat the patient further with combined radiation and temozolomide therapy.
In the majority of slides from the resection specimen, the tumor had features of an anaplastic oligoastrocytoma, WHO grade III, wherein the oligodendroglial (classic and minigemistocytic) and astrocytic (fibrillary and gemistocytic) elements were intermixed. Anaplastic features included up to 9 mitoses per 10 high-powered fields and focal microvascular proliferation. No necrosis was found. GGLF were found in one slide, showing both demarcated and intermixed borders with adjacent glial elements. Multinucleated forms were common and the mitotic index was low in these regions, but no EGBs were seen. Strong GFAP positivity was seen in glial elements from both components. Dysmorphic ganglion cells showed widespread membrane and Golgi-like patterns of immunoreactivity for synaptophysin, while the glial elements were mostly negative. Rare dysmorphic ganglion cells displayed chromogranin positivity, but they were negative for both neurofilament protein and Neu-N. Endothelial cells strongly expressed CD34, but all tumor cells were negative. The Ki-67 labeling index was estimated at 12% in the glioma component, while dysmorphic ganglion cells were essentially negative. FISH studies showed polysomies (gains) of both chromosomes 1 and 19, with no evidence of deletions.