POLYCLONAL BIPHASIC OLIGOASTROCYTOMA OF THE SPINAL CORD
Oligoastrocytoma (OA) is a diffusely infiltrating glioma composed of a conspicuous mixture of two distinct neoplastic cell types morphologically resembling the tumor cells in oligodendroglioma and diffuse astrocytoma (5). The tumor may be subdivided into two histomorphologic subtypes. The first is composed of two distinct tumor components and has been referred to in the literature as the biphasic, discrete and compact subtypes (17). The second is defined by the intermixing of the two components and has been referred to in the literature as diffuse, intermingled, admixed and intermixed (27). There is no routinely accepted cut-off value for what quantity of the minor tumor component must be present to classify a tumor as an OA instead of an oligodendroglioma (O) or astrocytoma (A). Hart and Maintz noted the biphasic OA (OAb) to be more common, but Fuller and Thon noted the intermingled OA (OAi) to be more common (14, 17, 28, 42). Some OA have areas where the two components are distinct and other areas where the neoplastic astrocytes are admixed with neoplastic oligodendrocytes (2).
Hart et al wrote, “tumors composed of approximately 75% oligodendroglioma (O) and 25% astrocytoma (A) showed no different survival rates than those composed of 25% oligodendroglioma and 75% astrocytoma (17). Shaw further subdivided OA based on the predominant histologic subtype into mostly astrocytoma (MA), mostly oligodendroglioma (MO), or roughly equal portions (O=A). Shaw did not identify a significant difference in 5 or 10-year survival among the three groups of OA (40). OAs have been shown to have an intermediate prognosis when compared to O and A(30). Therefore, accurate histologic classification is paramount in the provision of excellent patient care (15). OA is a rare tumor of the spinal cord with a paucity of cases in the literature. Hart documented a mixed glioma of the spinal cord, but did not specify whether the neoplastic elements were astrocytic and oligodendroglial or oligodendroglial and ependymal (17, 32). Three spinal mixed gliomas of non-ependymal origin were document in the study by Minehan who showed that overall survival of spinal cord astrocytic neoplasia is affected by grade (1). Several studies have identified a lower interobserver concordance in the diagnosis of and classification of gliomas (7, 15). Michalowska documented an anaplastic oligoastrocytoma of the spinal cord (29). Shimizu described a OAb II of the spinal cord occurring in a ten-year-old girl. Shimizu performed microsatellite analysis on two frozen specimens performed 22 months apart and detected LOH for 1p and 19q in the first frozen specimen and LOH for 1p only, in the second. We present a polyclonal OAb II of the spinal cord with fluorescent in-situ hybridization (FISH) revealing loss of heterozygosity (LOH) for 1p/19q only in the cells of oligodendroglial morphology and aneuploidy with a relative gain of chromosome 7 only in the cells with astrocytic morphology. Coon documented an OAi II with areas aneuploidy (8).
The patient is a 10-year-old female who developed scoliosis. Pre-operative MRI showed an intradural tumor extending from T9 to T12 (Figures 1A, 1B). On exam the patient was without neurological deficit. The patient was treated with debulking surgery consisting of T9-T12 laminotomies utilizing monitoring and microscope with CO2 handheld laser. Post-operative (post-op) dexamethasone was administered but no radiotherapy or chemotherapy was utilized. During surgery the tumor was noted to be gray, tenacious, without obvious planes of dissection and there was a syrinx superior to the tumor. There was intraoperative loss of somatosensory evoked responses on the right side. Later there was loss of some motor potential on the right side. Post-op, the patient was having difficulty with movement and sensation of the right lower extremity (RLE). Movement and sensation steadily improved but not to baseline and the patient was discharged 8 days after procedure. 556 days post-op the patient was doing well, progressing in school, enjoying match and had only minimal neurologic deficit, some fatigue with walking, right patellar reflex of 0, ankle reflexes 3 and left patellar reflex 2. MRI performed 2 days postoperatively (post-op) exhibited a 26 x 5.3 mm cystic/solid lesion in the distal cord with some small areas of patchy enhancement. This remained stable in size and amount of enhancement at 364 and 555 days post-op. 262 days post-op, the patient underwent release of a tethered spinal cord. Pathological examination was negative for tumor exhibits only fibrous tissue and reactive changes. The patient is followed with annual spinal MRI.
Frozen section revealed a low-grade astrocytic neoplasm. The surgical biopsy showed a biphenotypic population of neoplastic cells composed of an infiltrating fibrillary astrocytoma with minimal nuclear pleomorphism and an oligodendroglioma (Figure 3A). The astrocytic component was a moderately cellular neoplasm with diffuse growth pattern with dense fibrillary background and foci of microcystic changes. The cells within the compact areas show oval nuclei with long hair-like processes and a few eosinophilic granular bodies (EGB) (Figure 3B). Cells of the loose areas are slightly pleomorphic having variable round to oval nuclei; many cells show vesicular nuclei and others reveal nuclear atypia with dense chromatin and inconspicuous nucleoli (Figure 3C). Two typical mitoses are seen in 10 high power fields. There is hyalinization of and partially calcified blood vessels. Hemosiderin pigment deposits are focally prominent. The histology of oligodendroglioma was well described by Daumas-Duport and the tumor cells exhibit a clear swollen cytoplasm surrounded by a well-defined membrane, associated with a capillary-sized blood vessels arranged in an acutely branching pattern and the infiltrative portion of the tumor exhibits characteristics of fibrillary astrocytoma (10).
Glial Fibrillary Acidic Protein (GFAP) Immunohistochemical stain (IHC) shows diffuse positive staining of the processes of the neoplastic cells in both the loose and compact areas. Neurofilament Protein (NFP) IHC highlights the axons, mostly in the compact area with few axons staining in the loose area. P53 IHC highlights some of the neoplastic cells in both areas. Epithelial Membrane Antigen (EMA) IHC is negative in the neoplastic areas. The Ki-67 labeling index is 5.7%. G-banded karyotype performed on a portion of fresh tumor revealed please provide with or insert karyotype.
In 2006 Jenkins and Griffin identified a translocation (1;19)(q10,p10) as the probable mechanism underlying 1p/19q deletion in oligoastrocytomas and oligodendroglioma (16, 23). Furthermore, Jenkins highlighted that the translocation is not specific to oligodendrogliomas and should be evaluated in the context of histology, highlighted by the case of extraventricular neurocytoma that exhibited the deletion (23).
FISH was performed on interphase nuclei in paraffin-embedded tumor tissue utilizing DNA probes for loci on chromosomes 1p36 (TP73), 1q25 (ANGPTL), 19p13 (ZNF443), 19q13 (GLTSCR), and for chromosome 7 centromere (D7Z1) and chromosome 17p13.1 (TP53) shows two histologically distinct areas. The oligodendroglial component is more cellular with small cells and the astrocytic component is less cellular with large cells. The oligodendroglial component exhibits LOH loss at both the 1p36 and the 19q13 loci, and no significant gains of TP53 or chromosome 7. The astrocytic component is aneuploid with up to six signals for chromosome 1p36 and 1q25 and up to five signals for chromosome 19p13 and 19q13 with a ratio of ~1.0.; up to four signals for the TP53 gene and six signals for chromosome 7 with a ratio of TP53:D7Z1 of 0.75, which indicates relative gain of chromosome 7 and no LOH for 1p36 or 19q13. The combined loss of 1p36 and 19q13 regions is a pattern associated with oligodendroglioma (18, 21, 22, 36, 37, 41). Furthermore combined deletion has been identified as a prognostic factor of increased progression-free survival (PFS) and overall survival (OS) (43). Allelic loss of chromosome 1p and 19 is a powerful predictor of chemotherapeutic response and longer recurrence free-survival following chemotherapy in patients with anaplastic oligodendroglioma (3, 4). The FISH results from oligodendroglial component of this tumor show loss of both 1p36 and 19q13 chromosome loci consistent with the conventional chromosome analysis results.
We present the third report of polyclonality in OA and discuss that this is a neoplasm of unresolved histogenesis (11, 25, 33, 34). Others have suggested that there are distinct molecular subtypes of OA responsible for the marked genetic exclusivity when examining the OA (28). With the assumption of a monoclonal OA, it is not surprising that there is interest in diagnosing any tumor with oligodendroglial histology and 1p/19q loss as O (15). In the reporting of 1p/19q status some have selected the O component as the tumor’s entire status without consideration to astrocytic genetic aberrations. Kim et al examined 9 OA II and 3 AOA and microdissected the oligodendroglial and astrocytic component for analysis by LOH, and reported the O LOH findings as that for the entire tumor (24). Tumors with astrocytic morphology have been associated with loss of chromosome 17p and a p53 mutations (18). The finding of LOH 1p/19q has been strongly associated with oligodendroglioma and tumors with the histomorphologic composition of oligodendroglioma . The LOH is less prevalent in oligoastrocytomas . Tumors with more of an oligodendroglial morphology had more frequent occurrences of 1p/19q deletions identified in the reports of Miller and Cairncross (3, 23). Previous studies noted that the presence of LOH 1p/19q is inversely correlated with the occurrence of astrocytic related genetic events (TP53 mutations & 17p deletion) (20, 22, 28, 31, 37, 38, 42, 45, 47). Three OAb published by Kraus exhibited LOH for 1p and 19q in both the oligodendroglial and astrocytic components (25). They noted that there was a difference in detection of the residual bands and noted that it presumably results from a greater number of non-neoplastic elements in the astrocytic component. An alternative hypothesis is that the weak bands are the result of rare oligodendroglial tumor cells contaminating an area of neoplastic astrocytes that have the normal quantity of 1p/19q. One study by Maintz evaluated 38 OAs (33 OAb and 5 OAi). Maintz subclassified the 33 cases of discrete (compact) subtype into three classifications based upon the semiquantitative assessment of portion of oligodendroglial and astrocytic components. The predominance of astrocytic differentiation in OA was associated with TP53 mutations (P<0.023) and inversely associated with LOH 1p (p<0.04) (28). The study by Fuller included 31 of the oligoastrocytomas studied by Maintz (14). Fuller showed OAs to have an inverse association between LOH 1p and TP53 mutation; inverse association between LOH 19q and TP53 mutation.
Dong et al. evaluated 11 OAb (7 OAb II and 4 were Anaplastic (AOAb)) for LOH by microsatellite analysis (11). Of the 7, 3 showed LOH 1p/19q in the A & O components (OA1/OAS2/OA3). 1 of 7 OAb II showed LOH for chr. 17 in the A and O components (11). 1 of 7 OAb II showed LOH for 1p/19q & 10 in the A & O components; and showed three allelic losses isolated to the astrocytic components (OA5). 1 of 7 OAb II showed LOH 19 and 10 isolated to the O component, and the presence of p53 mutation isolated to the A component (OA4). 1 of the 7 OAb II showed of the six markers that showed LOH in both histologic elements, the losses were found on different alleles at the corresponding loci.
Qu et al. evaluated 11 OAII, 7 of which were of the biphasic and 4 were of the intermixed subtype (34). One of the seven biphasic OAII showed p53 mutation by PCR isolated to the astrocytic component of the tumor, increased p53 expression by IHC that was more conspicuous in the astrocytic component (case 1). Furthermore, case 1 exhibited LOH 19q isolated to the OD component. Three of the seven biphasic OA2 showed identical allelic loss in the astrocytic and OD components (cases 2, 3, 4). One of the seven biphasic OA2 showed p53 mutation in the astrocytic and oligodendroglial components and increased p53 expression by IHC in both components (case 7). One of the seven biphasic OA2 showed identical allelic loss of all markers for 19q, and while the oligodendroglial component showed loss of all six probes on chromosome 1 p, the astrocytic component contained LOH for only four of those six probes (case 5). In one of the seven biphasic OAII, both the astrocytic and oligodendroglial components exhibited loss of 5/6 probes for 19q (case 6). By definition, the study by Qu was unable to microdissect the oligodendroglial and astrocytic components for separate comparison as they were intermixed.
In the study by Thon, 1of 8 OA exhibited both LOH for 1p/19q and TP53 mutation (case 34). Thon et al. used PCR of homogenized tumor DNA (42). One of the limitations of PCR for evaluating for the presence or absence of LOH at 1p/19q is that the method is not single cell selective (42). The astrocytic component of this tumor exhibited aneuploidy, suggestive of polyploidy. The study by Coons et al. identified variable percentages of near diploid and near tetraploid populations, possibly secondary to sampling of the oligodendroglial and astrocytic components, respectively (8). In our case, we noted p53 via immunohistochemistry to exhibit some nuclear staining of the tumor cells in both regions. This finding of positivity has been seen in the absence of p53 mutations and may explain why the genetically distinct oligodendroglial tumor component exhibits staining (44). Distinguishing oligoastrocytomas from oligodendroglioma and astrocytomas is important because AA carry a shorter median survival compared to AOA and AO (7). In the paper by Perry, polyploid tumors with relative deletions of 19q were identified by FISH (33). Perry noted the presence of combined 1p/19q deletion in 60% (28/47) and 75% (12/16) of those surviving more than 5 and 10 years, respectively. However, solitary 19q deletion was noted only in 11% (5/47) and 6% (1/16) of those surviving more than 5 and 10 years, respectively (33). In a paper by Scheie isolated 19q deletion was noted as poor prognostic factor (39). The study by Eoli showed that OA with LOH on 1p behave like WHO grade II or III oligodendrogliomas with 1p loss (12).
Fallon et al. made the assumption that recurrent gliomas with combined 1p/19q deletions were assumed to also have them in the primary specimen, whereas those lacking both deletions were similarly assumed not to have them in the primary (13). Ichimura confirmed the exclusivity of TP53 mutations and total 1p/19q loss. Ichimura did not subclassify the 20 OA II, and noted that 10 of them had IDH1 mutations. In this particular study, only one of the 20 OA exhibited total 1p/19q loss (22). The studies by Kraus and Thon lack single cell examination and the homogenization of tumor may have resulted in “false positives”.
The study by Walker identified chromosome 10 loss predominately in the astrocytic component of glioblastomas with and oligodendroglial component and in only (1/5) areas of the oligodendroglial component (46).
In 2007 Kros stated that FISH analysis is their technique of choice for the detection of the presence of clonal heterogeneity within samples of mixed cell populations (26).
However of the 8 AOA, none had 1p loss and although O appear genetically homogenous, the same cannot be said of OA.
The most common mutation in Isocitrate Dehydrogenase is heterozygous R132H (h or c?), and this results in a gain of function catalytic activity is the ability to catalsyse direct NADPH-dependt reduction of alpha-ketoglutarate to the R isomer of 2-hydroxy glutarate (9).
Watanbe, Yan, Hartmann and Ichimura examined gliomas for mutations in IDH1. Combing the data reveals IDH1 mutations at the following frequencies with respect to tumor morphology: (289/382) 75.6 % of A II; (219/276) 79.3% O II and 78.9 (109/138) in OA II (19, 22, 48, 49).
Capper documented that in mixed gliomas, there was strong mIDH1R132H binding observed in both the astrocytic and oligodendroglial differentiated cells (6). Based on in-vivo models of gliomas, it would seem probable that oligoastrocytomas originate from a clonal neoplasm with heterozygous mutation in IDH-1. This clone perhaps acquires the 1p/19q deletion and exhibits oligodendroglial morphology. Through other mechanisms including gain of chromosome 7, a subclone of the IDH1 mutated cells develop astrocytic morphological features. Future studies characterizing the IDH1 mutation status of the respective compents along with examination of the 1p/19q status and TP53 mutations.
An explanation for the numerous studies that reveal astrocytic and oligodendroglial neoplasms have.
Yi examined three anaplastic oligoastrocytomas, isolated and cultured a stem cell from the tumors (50). When the stem cell was implanted into an immune-deficient mouse, grew tumors cells that were positive for GFAP and BMP, suggesting that the tumor stem cell gave rise to astrocytic and oligodendroglial components. This double lineage theory suggests that committed oligodendrocytes and type II astrocytes are progeny derived from oligodendrocyte type II astrocyte progenitors. This finding is supported by an in-vivo study that identified a cell type in the 7-day optic nerve of a rat that develops into a fibrous astrocyte or oligodendrocyte (35). This In vitro model may represent a parallel mechanism in neoplasia. The etiology of OA may arise from a stem cell; however, the 1p/19q deletion may occur later in development, in the cells with oligodendroglial morphology.
In conclusion, OAb II is a rare neoplasm of the spinal cord that is biclonal in at least several of the reported cases. FISH analysis by a pathologist trained in AP and CP may elucidate molecular findings in the respective histomorphologic components.
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