Polyclonal Biphasic-and-Discrete Oligoastrocytoma. A Case Report of Spinal Neoplasia with Novel Genetic Insights.
Author: Brett Snodgrass, MD
Date published online: 12 August 2016
Oligoastrocytoma(OA) is a diffusely infiltrating glioma composed of a mixture of two distinct neoplastic cell types morphologically resembling tumor cells found in oligodendroglioma and diffuse astrocytoma[NA1] (2). These types of tumor cells range from xxx to xxxx, which can be classified as minor or major. The tumor may be subdivided into two histomorphologic subtypes. The first is composed of three distinct tumor [NA2] components, which can be classified as“biphasic”, “discrete”, “compact”. The second subtype is defined by the intermixing of the two components and has been referred to in the literature “diffuse”, “intermingled” and “intermixed”. Furthermore, the WHO 2007 suggests that the biphasic variant is rare,. of the two tumor types is necessary for the subtype designation intermixed has varied in the literature with some studies documenting intermixed areas and discrete areas. The significance of subclassification of OAs into two histomorphologic subtypes is subject to the limitations of sampling. Data comparing the two is lacking. Hart et al wrote, “tumors composed of approximately 75% oligodendroglioma and 25% astrocytoma showed no different survival rates than those composed of 25% oligodendroglioma and 75% astrocytoma(8). Oligoastrocytoma of the spinal cord is a rare tumor. A paper by Shimizu documents the second reported case of oligoastrocytoma, grade II of the spinal cord(16). Michalowska documented an anaplastic oligoastrocytoma of the spinal cord (11). In the paper by Hart et al, one of the mixed gliomas was documented in the spinal cord. However, did not specify whether the neoplastic elements were astrocytic and oligodendroglial or oligodendroglial and ependymal(8). Here we present a case, confirming prior findings that at least a subset of oligoastrocytomas, discrete subtype are characterized by significant cytogenetic differences in the respective oligodendroglial and astrocytic components. In addition, FISH studies identified loss of heterozygosity isolated to the tumor component with oligodendroglial morphology. Furthermore, the astrocytic tumor component exhibited aneuploidy, suggestive of tetraploidy with a relative gain of chromosome 7. Aneuploidy in OA grade 2 was well documented by Coon(4).
The patient is a 10-year-old female who developed scoliosis[NA3] . MRI showed an intradural tumor extending from T9 to T12 (Figure 1). On exam, the patient was without neurological deficit. [NA4] The patient was treated with debulking surgery consisting of T9-T12 laminotomies utilizing intraoperative neuromonitoring (bilateral SSEPs, EMGs, ....) and microscope with CO2 handheld laser. Post-operative dexamethasone was utilized. No radiotherapy or chemotherapy was utilized. During surgery, the tumor was noted to be gray, tenacious, without obvious planes of dissection and a syrinx superior to the tumor. There was intraoperative loss of somatosensory evoked responses on the right side [NA5] shortly after entering the tumor and beginning the debulking of the central aspect of this tumor. Later there was loss of some motor potential [NA6] on the right side. Anal sphincters were persevered.
Post-operatively, the patient was having difficulty with movement and sensation of the right lower extremity. Movement and sensation steadily improved and the patient was discharged eight days after the procedure. MRI performed two days postoperatively showed a small area of enhancement above the conus medullaris[NA7] , and a MRI brain was negative for tumor[NA8] . On post-op day 262, 262 days after the initial surgery, the patient had a release of tethered spinal cord[NA9] ; pathological examination was negative for tumor revealing only fibrous tissue and reactive changes. On post-op day 364, 364 days after initial surgery MRI showed an area [NA10] within the distal cord that measures 5.3 mm AP x 26 mm CC . There is an area of rim-like enhancement within the conus which currently measures 8.2 mm AP x 21 mm CC. This has decreased in size slightly since xxx. There are xxx number ofmore xxx mm x xxx mm size caudal areas of patchy enhancement and intrinsic T1 signal hyperintensity within the distal cord. Overall, this pattern of enhancement has diminished in the interval. On post-op day 555, MRI showed a cystic/solid lesion in the distal cord with some small areas of patchy enhancement is stable in appearance (Figure 2). Physical exam performed 556 days after the initial surgery revealed able to walk with only a tendency to get weak in the right leg with fatigue. Right patellar reflex was 0, left patellar reflex was 2+, and ankle reflexes were 3+. Patient is continuing to be followed annually, with repeat xxxx studies of the thoracic cord.
The surgical biopsy performed showed a diffuse growth pattern with dense fibrillary background and foci of microcystic changes. The tumor has low to moderate cellularity and shows thin and a few thick hyalinized blood vessels[NA11] . There are a xxxxlessthanxxxper hpf eosinophilic granular bodies. The cells within 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. The cells within the compact areas show oval nuclei with long hair-like processes. 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. GFAP stain shows diffuse positive staining of the processes of the neoplastic cells in both the loose and compacted areas. NFP stain highlights the axons, mostly in the compact area with few axons staining in the loose area. P53 stains some of the neoplastic cells in both areas. EMA stain is negative in the lesion area. Ki-67 shows a labeling index of 5.7%. Fluorescence in-situ hybridization (FISH) analysis of interphase nuclei in paraffin-embedded tumor tissue identified two adjacent areas with different signal patterns for the probes used to detect loss of 1p36 and 19q13. The oligodendroglial component is more cellular with small cells and the astrocytic component" is less cellular with large cells. FISH using Vysis DNA probes for loci on chromosomes 1p36 (TP73), 1q25 (ANGPTL), 19p13 (ZNF443), and 19q13 (GLTSCR) shows loss at both the 1p36 and the 19q13 loci in oligodendroglial component but not in astrocytic component. 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. FISH using Vysis DNA probes for chromosome 7 centromere (D7Z1) and chromosome 17p13.1 (TP53) shows no significant loss or gain of TP53 or chromosome 7 in oligodendroglial component. Astrocytic component is aneuploid with 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. The combined loss of 1p36 and 19q13 regions is a pattern associated with oligodendroglioma. 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. In addition, FISH shows aneuploidy in 'astrocytic component' with gain of chromosome 7 without 1p36 and 19q13 loss
The histogenesis of oligoastrocytomas is unresolved and this paper identifys mutually exclusive genetic alterations in the respective morphologic components of biphasic oligoastrocytoma. Previous studies noted that there is an inverse correlation of 1p loss and 17p loss and distinct molecular subsets of OA5. TP53 mutations and allelic losses on chromosomes 1p and 19q were inversely correlated in oligoastrocytomas p<0.011(10). The inverse correlation between when analysed by microsatellite analysis for LOH, von Demling et al. found Oligoastrocytomas to exhibit an inverse incidence of TP53 mutations and LOH1p LOH 19q(19). Scheie et al. confirmed previous findings in finding that combined 1p/19q loss and allelic losses at 17p13 are virtually mutually exclusive (14). Three oligoastrocytomas published by Kraus exhibited loss of heterozygosity for 1p and 19q in both the oligodendroglial and astrocytic components (9). One study by Maintz evaluated 38 OAs. Thirty-three of the cases were classified as compact or discrete (compact) and five were subclassified as diffuse (intermixed). The relative predominance of the discrete (compact) subtypes was also noted in the paper by Hart but not in the paper by Fuller (7, 8, 10). 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). The study by Fuller included 31 of the Oligoastrocytomas studied by Maintz(7). Fuller showed Oligoastrocytomas to have an inverse association between LOH 1p and TP53 mutation; inverse association between LOH 19q and TP53 mutation.
Dong et al. evaluated 11 Biphasic OA for LOH by microsatellite analysis (5). Seven were grade 2. Of these seven, 3 showed LOH 1p/19q in the astrocytic & OD components (OA1/OAS2/OA3). One of seven biphasic OAII showed LOH for 17 in the astrocytic and oligodendroglial components (OA11). One of seven biphasic OAII showed LOH for 1p/19q & 10 in the astrocytic & OD components; and showed 3 allelic losses isolated to the astrocytic components (OA5). One of seven biphasic OA2 showed LOH 19 and 10 isolated to the oligodendroglial component, and the presence of p53 mutation isolated to the astrocytic component (OA4). One of the seven biphasic OAII showed of the six makers 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 (13). 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 4 of those six probes (case 5). In one of the seven biphasic OA2 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, one of eight oligoastrocytomas exhibited both LOH for 1p/19q and TP53 mutation (case 34). Thon et al. used PCR of homogenized tumor DNA (17). 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 (17). The astrocytic component of this tumor exhibited polysomy, suggestive of tetraploidy. 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(4). 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 (13, 18). Distinguishing oligoastrocytomas from oligodendroglioma and astrocytomas is important because anaplastic astrocytomas carry a shorter median survival compared to anaplastic astrocytoma(3).
In the paper by Perry, polyploid tumors with relative deletions of 19q were identified by FISH(12). 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. In a paper by Scheie isolated 19q deletion was noted as poor prognostic factor (15). The study by Eoli showed that OA with LOH on 1p behave like WHO grade II or III oligodendrogliomas with 1p loss (6). Yi examined three anaplastic oligoastrocytomas, and cultured a stem cell. When implanted into a mouse, grew tumors cells that were positive for GFAP and BMP, suggesting that the stem cell gave rise to astrocytic and oligodendroglial components. This double lineage theory indicates that committed oligodendrocytes and type II astrocytes are progeny derived from oligodendrocyte type II astrocyte progenitors. One in-vivo study identified a cell type in the 7-day optic nerve of a rat that develops into a fibrous astrocyte or oligodendrocyte(1).
With oligoastrocytomas exhibiting a heterogeneous tumor population with unique molecular findings, labeling of a tumor as 1p/19q positive or negative should always be interpreted in the limitations of the test.
The absence of 1p/19q LOH in the astrocytic area, and the presence of aneuploidy isolated to the astrocytic area suggest that the astrocytic component and oligodendroglial component may represent divergence from a precursor cell. In conclusion, we present a second case report of grade II Oligoastrocytoma, discrete is a rare neoplasm of the spinal cord that deserves further study into the frequency of its morphologic subtypes and their relationship to genetic findings and outcome.
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[NA1]Talk about what kind of tumor cells and avoid referring to oligodendroglioma and astrocytoma
[NA3]What kind of scoliosis. Grade, severity of scolosis. Age of onset.
The patient is a 10-year-old female, who developed progressively severe scoliosis located between Txxx and Txxx, since the age of xxxx
[NA4]On neurological exam, the patient was found to be without focal neurological deficits.
[NA6]Which one what latenies.
[NA8]Why was not MRI of the brain done earlier?
[NA9]It needs to say that the tethered spine was present before surgery.
[NA10]What kind of area? What kind of enhancement?
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