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Synchronous supratentorial and infratentorial oligodendrogliomas with incongruous IDH1 mutations, a case report

Synchronous supratentorial and infratentorial oligodendrogliomas with incongruous IDH1 mutations,... Infratentorial oligodendrogliomas, a rare pathological entity, are generally considered metastatic lesions from supratentorial primary tumors. Here, we report the case of a 23‑ year‑ old man presenting with a histopathologically confirmed right precentral gyrus grade 2 oligodendroglioma and a concurrent pontine grade 3 oligodendroglioma. The pontine lesion was biopsied approximately a year after the biopsy of the precentral lesion due to disease pro‑ gression despite 4 cycles of procarbazine‑ CCNU‑ vincristine (PCV ) chemotherapy and stable supratentorial disease. Histology and genetic analysis of the pontine biopsy were consistent with grade 3 oligodendroglioma, and compari‑ son of the two lesions demonstrated common 1p/19q co‑ deletions and TERT promoter mutations but distinct IDH1 mutations, with a non‑ canonical IDH1 R132G mutation identified in the infratentorial lesion and a R132H mutation identified in the cortical lesion. Initiation of Temozolomide led to complete response of the supratentorial lesion and durable disease control, while Temozolomide with subsequent radiation therapy of 54 Gy in 30 fractions resulted in partial response of the pontine lesion. This case report supports possible distinct molecular pathogenesis in supraten‑ torial and infratentorial oligodendrogliomas and raises questions about the role of different IDH1 mutant isoforms in explaining treatment resistance to different chemotherapy regimens. Importantly, this case suggests that biopsies of all radiographic lesions, when feasible and safe, should be considered in order to adequately guide management in multicentric oligodendrogliomas. Keywords: Multifocal, Low‑ Grade Glioma, IDH mutant, Supratentorial, Infratentorial Introduction [3, 4, 6, 10, 13]. High-grade gliomas in adolescents and Oligodendrogliomas represent approximately 5% of all young adults (AYA, 15–25  years old) have been recently glial tumors in the US adult population [13]. Those aris - shown to harbor distinct molecular features compared to ing in the infratentorial compartment are rare as most both the pediatric and adult population. In this particular arise in the cerebrum. Thus far, only a few isolated case age group, WHO grade may have limited utility whereas studies have reported genetically confirmed, IDH mutant molecular subtypes have a major prognostic impact and 1p/19q-codeleted, infratentorial oligodendrogliomas [19]. Interestingly, noncanonical IDH1 mutations have been identified with a higher frequency in AYA gliomas compared to the adult patient population [19]. The role *Correspondence: aha2152@cumc.columbia.edu of distinct molecular features in selecting management Alexander H. C. W. Agopyan‑Miu and Matei A. Banu these authors strategies, however, remains unclear. contributed equally to this work Columbia University Vagelos College of Physicians and Surgeons, New The simultaneous presence of multiple lesions, espe- York, USA cially lesions with supratentorial and infratentorial Full list of author information is available at the end of the article © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Agopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 2 of 9 components, is a rare occurrence in gliomas of all type Case presentation [20]. Concurrent lesions are classified as either mul- The patient, a previously healthy 23-year-old man, first tifocal or multicentric based on radiographic and/or presented to an outside hospital with complaints of pathologic features. Multifocal lesions are those that intermittent diplopia, tinnitus and occipital pain. Due either demonstrate a path of contiguous hyperintensity to persistent headache, he underwent an MRI scan on T2 MR images, or if the pattern of dissemination which revealed synchronous, non-enhancing, T2/FLAIR can be explained by spread along white matter tracts, hyperintense lesions in the right precentral gyrus and CSF, or local spread from satellite lesions [14]. Multi- pons as well as increased signal along the right 8th cra- centric lesions, on the other hand, cannot be described nial nerve. Initial serial scans were stable and the patient by the previous features and includes those lesions remained in stable condition during that time but even- separated by time, termed metachronous lesions [14]. tually presented to our institution 8  months later for a Given the rarity of synchronous lesions, little is known second opinion. By this time, he developed headaches, about their underlying molecular/genetic relation- mild photophobia, left-sided weakness, and left facial ships. Some studies proposed independent gliomagen- numbness. Initial in-house imaging at the time demon- esis events. For example, Lee et  al. [12] suggest that strated a 3.9 × 3.1 × 4.4  cm heterogenous, but primarily multifocal/multicentric tumors are seeded from geo- T1 hypointense, T2 hyperintense, infiltrating, and mildly graphically segregated, distinct tumor clones given the expansile pontine lesion with minimal patchy contrast few shared genetic alterations they observed between enhancement and diffusion restriction that was larger multifocal/multicentric tumors. On the other hand, in size compared to imaging obtained from the outside multicentric or multifocal lesions might represent hospital. Extension into the floor of the fourth ventricle, intracranial metastasis of a primary focus, with a com- compression of the prepontine cistern, and obstructive mon clonal precursor [2, 15]. Several recent studies hydrocephalus was noted. Extension into the middle cer- have suggested potential mechanisms through early ebellar peduncles and encasement of the basilar artery divergence and parallel evolution eventually leading was also noted. MR spectroscopy revealed elevated cho- to genetically distinct lesions [1, 9]. Subclonal drivers line peak and reversal of the choline/NAA ratio, and with late occurrence rather than founder events were was overall consistent with a glial tumor. A second infil - believed to drive the evolution of such lesions [1]. In trating and expansile, non-enhancing lesion, measur- this regard, the role of early events during gliomagen- ing 2.7 × 2.2 × 1.5  cm, in the right precentral gyrus with esis, such as IDH1 mutations, in driving multicentric similar imaging characteristics to the pontine lesion was gliomas remains elusive. The clinical utility of classi- also seen and noted to have increased in size compared fying multiple concurrent gliomas as either multifocal to imaging studies obtained from the outside hospital or multicentric remains unclear. In the absence of spe- (Fig. 1). MR perfusion demonstrated low relative cerebral cific guidelines, management largely resembles that of blood volume and flow values, suggestive of a low-grade solitary lesions despite the worse prognosis associated glioma. with multifocal/multicentric gliomas [8, 14]. A ventriculoperitoneal shunt was placed to treat the Here, we present a rare case of a 23-year-old man patient’s hydrocephalus. He subsequently underwent an with synchronous, genetically confirmed right precen- awake craniotomy with sensorimotor mapping for an tral grade 2 and pontine grade 3 oligodendroglioma. excisional biopsy of the right peri-rolandic lesion. A sub- The two lesions harbored similar 1p/19q-codeletions total resection was carried out, to avoid inducing a left- and TERT mutations but have different IDH1 muta- hand sensory deficit. tions: a canonical IDH1 R132H was identified in the Final pathological analysis of the biopsied right peri- precentral lesion while a noncanonical IDH1 R132G rolandic lesion demonstrated a low grade diffusely mutation was identified in the pontine lesion. Impor- infiltrating glial neoplasm with no microvascular pro - tantly, the two lesions differed in their response to liferation, necrosis, or mitotic activity. The Ki-67 pro - four cycles of procarbazine-CCNU-vincristine (PCV) liferation index was modestly increased, labeling up to chemotherapy. The case illustrates one possible patho- approximately 1.5% of tumor cells. The cells were posi - genesis of multifocal/multicentric oligodendrogliomas, tive for GFAP, SOX2, IDH1 R132H, and PDGFR-A by via early subclonal divergence and parallel evolution, immunohistochemistry (Fig.  2), and ATRX staining and suggests the possible importance of performing was preserved. Rare cells showed weak p53 staining, biopsies of all radiographically visible lesions, when and immunostains for H3 K27M and EGFR were nega- safe and technically feasible, as it may impact subse- tive. Targeted next generation sequencing panel (Foun- quent treatment decisions. dationOne CDx, Foundation Medicine, Boston, MA) revealed the presence of a TERT promoter mutation A gopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 3 of 9 (variant allele fraction, VAF, of 23%) and confirmed the Three small cores of tissue were obtained from the IDH1 R132H mutation (VAF of 19%), while consistent enhancing portion of the pontine lesion. Final pathologi- with immunostain result, no mutation in H3F3A was cal analysis of the biopsied brainstem lesion revealed a seen (Table  1) Further studies confirmed the presence glial neoplasm of increased cellularity, nuclear pleomor- of 1p/19q-codeletion via fluorescence in  situ hybridi - phism, and proliferative activity with up to 3 mitotic zation (FISH) and an unmethylated MGMT promoter figures in this small biopsy and a Ki-67 labeling index by bisulfite-treatment PCR and melting curve analysis. of nearly 10%. No tumor necrosis or microvascular pro- Based on these findings, the final diagnosis was oligo - liferation was appreciated. Similar to the supratentorial dendroglioma, IDH-mutant and 1p/19q-codeleted, tumor cells, these tumor cells were positive for GFAP, WHO Grade 2. SOX2, and ATRX. However, IDH1 R132H was unex- Imaging a month later demonstrated a decrease in size pectedly negative by immunohistochemistry. FISH con- of the ventricular system, a stable peri-rolandic lesion, firmed the presence of 1p/19q-codeletion. Targeted next and stable faint patchy enhancement within the pon- generation sequencing panel revealed a TERT promoter tine lesion that again demonstrated an interval increase mutation (VAF 55%) identical to the peri-rolandic lesion in size compared to the initial scan obtained at the out- and an IDH1 R132G mutation (VAF 46%) not seen in side hospital. Despite these changes the pontine lesion the patient’s supratentorial tumor. No other mutations was considered to likely be an oligodendroglioma given were identified on this laboratory-developed platform the pathology of the peri-rolandic lesion, albeit with fea- which includes assessment of IDH1, IDH2, H3F3A and tures concerning for a grade 3 lesion on imaging. After HIST1H3B (Columbia Solid Tumor Panel, Personalized a comprehensive multidisciplinary tumor board discus- Genomic Medicine at Columbia University, New York, sion considering the risks associated with biopsy of the NY). The MGMT promoter was partially methylated brainstem lesion and the patient’s treatment preference, (Table 1). Based on the overall findings, the final diagno - the decision was made to proceed with a standard PCV sis was anaplastic oligodendroglioma, IDH-mutant and chemotherapy regimen alone. During chemotherapy, the 1p/19q-codeleted, WHO Grade 3. patient’s course was complicated by mild peripheral neu- The patient tolerated the procedure well and experi - ropathy and asymptomatic thrombocytopenia necessitat- enced complete resolution of his headaches. Post-oper- ing a 25% dose reduction for the third cycle, and a further atively he underwent radiation therapy to the brainstem 25% dose reduction at the start of the fourth cycle in light lesion, 54 Gy in 30 fractions, concurrently with systemic of recurring thrombocytopenia. Overall, his clinical pic- Temozolomide chemotherapy for 6  weeks followed by ture improved, with resolution of headaches, improve- adjuvant Temozolomide, which he continues to this date. ment in diplopia, and interval MRI scans up to 8 months He continues to improve clinically, with a KPS of 80 and is out showed stable disease. able to ambulate independently at the time of this report. Imaging at 9 months after initiation of chemotherapy He initially developed diplopia which has remained sta- demonstrated new small foci of enhancement in the ble since initiation of chemoradiotherapy. He has been off brainstem lesion, herniation of the cerebellar tonsils, steroids. The most recent MRI at the time of this report, and a stable cortical lesion (Fig.  3). The patient had at 27 months post diagnosis, revealed decrease in size of now developed progressive suboccipital headaches. The the pontine lesion with near complete resolution of the decision was made to proceed with  surgery for suboc- peri-rolandic lesion and no new supratentorial lesions. cipital decompression of the acquired Chiari malforma- Notably, the peri-rolandic lesion showed radiographic tion together with biopsy of the pontine lesion to guide response prior to initiation of Temozolomide suggesting further management. PCV chemotherapy benefit. (See figure on next page.) Fig. 1 MRI of multifocal lesions on presentation. A Axial T2‑FLAIR demonstrating a hyperintense round lesion, measuring 2.7 × 2.2 × 1.5 cm (CC × AP × transverse), in the precentral gyrus. Initial measurements prior to presentation at our institution: 2.2 × 1.7 × 1.5 cm. B Left greater than right hyperintensity in the cerebral peduncles on axial T2‑FLAIR. C Axial T2‑FLAIR demonstrates a heterogenous, hyperintense lesion in the pons, measuring 3.9 × 3.1 × 4.4 cm, with extension into bilateral cerebellopontine cisterns and middle cerebellar peduncles. Encasement of the basilar artery is also present with no obstruction of flow. Initial measurements prior to presentation at our institution: 3.5 × 3.1 × 4.3 cm. D Axial T1 post‑ contrast image of the pontine lesion demonstrating subtle patchy contrast enhancement. E Sagittal T2 image of the precentral lesion with compression of the central sulcus. F Large heterogenous, T1 hypointense pontine lesion extending from the floor the fourth ventricle to the prepontine cistern ventrally. G Pontine lesion as described with heterogenous hyperintensity on this sagittal T2 slice. H Subtle patchy enhancement is again appreciated within the pontine lesion on this T1 post‑ contrast sagittal slice Agopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 4 of 9 Fig. 1 (See legend on previous page.) A gopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 5 of 9 Discussion and may have become the predominant population after Oligodendrogliomas are relatively rare, well-differen - PCV chemotherapy secondary to a subclonal selection tiated neuroepithelial tumors that more commonly process. occur in the cerebral hemispheres compared to the In future studies of multicentric gliomas, synchro- infratentorial space [10]. We present here a unique case nous longitudinal biopsies coupled with in-depth genetic of synchronous supratentorial and infratentorial oligo- sequencing could help us infer the timing of clonal sep- dendrogliomas in a young adult patient with no known aration between the R132G and R132H populations predisposing germline mutations. The stark difference in during tumorigenesis. In this case, we are unable to response to four cycles of PCV between the cortical and definitively draw conclusions about the pathogenesis of pontine lesions necessitated the biopsy of the latter and these spatially distributed oligodendrogliomas but pro- provided the opportunity to compare genetic and his- vide a roadmap for future studies. Furthermore, we pro- topathologic characteristics. Such studies can provide vide evidence that distinct lesions with distinct mutations insight into the origin of distinct tumors and the evolu- may have different sensitivities to various chemotherapy tionary trajectories of IDH-mutant oligodendrogliomas. and radiation regimens, therefore having important clini- The most striking finding from the pontine biopsy was cal implications. the presence of a non-canonical IDH1 R132G mutation The role of IDH1 mutations in predicting response to that differed from the canonical IDH1 R132H mutation chemotherapy for oligodendrogliomas has been difficult encountered in the supratentorial lesion. This finding to establish, in contrast to the well-established predic- suggests two possible avenues of pathogenesis. tive value of 1p/19q-codeletions in predicting sensitivity One hypothesis is the presence of two distinct, multi- to PCV. The presence of IDH1 mutations in conjunction centric tumors that evolved synchronously and indepen- with 1p/19q-codeletions may indicate a positive progno- dently of each other. Greater rates of non-canonical IDH1 sis in oligodendroglioma patients treated with adjuvant mutations have been reported in infratentorial gliomas PCV following radiation therapy [7, 21, 22, 26]. How- compared to supratentorial gliomas, and in lower grade ever, it is unclear how many patients in these studies had gliomas overall [5, 16, 18, 23]. Given that both canonical infratentorial lesions or non-canonical IDH1 mutations. and non-canonical IDH1 mutations likely represent early Furthermore, there are few studies comparing the predic- clonal mutations that may even precede 1p/19q-code- tive and prognostic value of non-canonical IDH1 muta- letions [11, 23–25], the divergent IDH1 mutations may tions to the canonical IDH1 R132H mutation. Enzyme suggest the synchronous development of two independ- kinetics have been shown to differ between mutant iso - ent low grade gliomas whose distribution is consistent forms, and isoforms that produce greater amounts of with the reported anatomic distribution and prevalence D-2-hydroxyglutarate, like the R132G isoform, are disad- of mutant IDH1 isoforms thus far. vantaged by the toxicity associated with the metabolite’s An alternative hypothesis is that the infratentorial buildup [17]. This mechanism may underlie the proposed lesion is in fact a metastatic lesion originating from the favorable prognostic associations with non-canonical supratentorial tumor. In this case, the distinct IDH1 mutations in oligodendrogliomas [23]. Thus, determin - mutations may indicate an evolutionary trajectory that ing whether the divergent IDH1 mutations played a role led to a more aggressive subclone, capable of metastatic in the differential treatment response is difficult. It is also spread. Therefore, the IDH1 R132G mutation may mark important to note that, after discussion of available treat- a unique subclone with increased ability to metastasize ment options, a chemotherapy only as opposed to radio- via corticospinal tract fibers or CSF. Furthermore, it is therapy plus adjuvant chemotherapy treatment plan was important to note that the biopsies were separated in chosen to respect patient preferences. The addition of time and therefore may in fact capture the temporal evo- radiation later in the course with subsequent improved lution of different subclones. The IDH1 R132G mutant control may indicate the need for more aggressive multi- cells may have had increased chemoresistance at baseline modality approaches in such lesions. (See figure on next page.) Fig. 2 Genetically divergent multifocal glioma involving cerebrum and brainstem. A–D Biopsies of the cortical mass revealed a diffusely infiltrating glial neoplasm with perineuronal satelitosis and perinuclear clearing (A, 4×; B, 400×). The neoplastic cells expressed SOX2 (brown chromogen) and GFAP (red chromogen) (B inset, 200×), and harbored the IDH1 R132H onco‑protein (C, 200×) with retained nuclear expression of ATRX (D, 200×). E–I Biopsies of the pontine mass revealed a diffusely infiltrating glial neoplasm with increased cellularity and prominent mini‑ gemistocytic cytomorphology (E, 200×; F, 400×). As opposed to the cortical mass, the pontine mass lacked the IDH1 R132H onco‑protein (G, 200×) however nuclear expression of ATRX was similarly retained (H, 200×). Ki‑67 index was increased in the pontine biopsy – a representative image is provided (I, 200×). (Scale bar = 50 um.) Agopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 6 of 9 Fig. 2 (See legend on previous page.) A gopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 7 of 9 Table 1 Comparison of genetic findings between the precentral and pontine lesion Precentral Pontine IDH1 R132H by IHC and next gen sequencing IDH1 R132G by next gen sequencing 1p/19q‑ codeleted by FISH 1p/19q‑ codeleted by FISH TERT promoter mutation 146 C > T by next gen sequencing TERT promoter mutation 146 C > T by next gen sequencing ATRX preserved by IHC ATRX preserved by IHC Unmethylated MGMT by MGMT methylation promoter assay Partial MGMT methylation by a MGMT methylation promoter assay PDGFR‑A positive H3 K27M negative by IHC and next gen sequencing H3 K27M negative by IHC and next gen sequencing Fig. 3 Follow up MRI following four cycles of PCV. A Hyperintense lesion of similar size and appearance in the precentral gyrus on axial T2FLAIR. ‑ B Homogenous hyperintense lesions in the left and right cerebral peduncles on axial T2FLAIR. ‑ C Large, primarily hypointense pontine lesion on sagittal T1 measuring 6.1 × 4.8 × 3.9 cm. Note herniation of the cerebellar tonsil. D Axial T2FLAIR demonstrating ne ‑ w hyperintense foci along the left anterior base of the lesion that extends into the cerebellopontine cistern and internal auditory canal. Again, encasement of the basilar artery is noted but flow is patent Agopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 8 of 9 Authors’ contributions With respect to overall management, we believe that AHCWAM, MB, and CT collated case information for the report and con‑ this case highlights the importance of (1) performing tributed to the writing of the manuscript. MLM, GH, and PC performed biopsies on all radiographically visible lesions if safe to do histological examinations of brain tissue and provided editorial feedback on the manuscript. MLM also contributed to the figures for the case report and so, (2) performing biopsies of treatment resistant lesions, reviewed the manuscript. TW, AH, NF, and GMM were involved with patient even later in the treatment course and (3) sequencing care and provided guidance on the writing of the manuscript. PC, AH, and the IDH1 exon if initial immunohistochemical staining is GMM also provided editorial feedback on the manuscript. All authors read and approved the final manuscript. negative. Even if one subscribes to a multicentric or mul- tifocal theory of pathogenesis, this case shows that there Funding can be notable heterogeneity between foci, and this het- Not applicable. erogeneity may impact treatment response [12]. Further, Availability of data and materials Visani et al. [23] note that a significant proportion of low- Data sharing is not applicable to this article as no datasets were generated or grade gliomas in their case series would have been mis- analyzed during the current study. classified by WHO 2016 criteria if an investigation only for the canonical R132H mutation was performed. While Declarations there is little evidence to suggest a difference in prognos - Ethics approval and consent to participate tic or predictive value between canonical and non-canon- Not applicable. ical IDH1 mutations at present, knowing the precise Consent for publication genetic makeup of multicentric or multifocal lesions can The patient has consented to the use of their information for the purposes of guide treatment decisions as more data is uncovered. this case report. A signed consent form is available for review upon request. Competing interests The authors declare that they have no competing interests. Conclusion We present here a rare case of multifocal high grade Author details oligodendroglioma with supratentorial and infratento- Columbia University Vagelos College of Physicians and Surgeons, New York, USA. Department of Neurosurgery, Columbia University Irving Medical rial lesions, distinct IDH1 mutations, and differential Center, New York, USA. Department of Pathology and Cell Biology, Columbia response to PCV chemotherapy. This case illustrates 4 University Irving Medical Center, New York, USA. Department of Radiation one potential evolutionary trajectory of multicentric Oncology, Columbia University Irving Medical Center, New York, USA. Depar t‑ ment of Neuro‑Oncology, Columbia University Irving Medical Center, New oligodendrogliomas and provides insight into best York, USA. management practices for these rare tumors. 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Synchronous supratentorial and infratentorial oligodendrogliomas with incongruous IDH1 mutations, a case report

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Abstract

Infratentorial oligodendrogliomas, a rare pathological entity, are generally considered metastatic lesions from supratentorial primary tumors. Here, we report the case of a 23‑ year‑ old man presenting with a histopathologically confirmed right precentral gyrus grade 2 oligodendroglioma and a concurrent pontine grade 3 oligodendroglioma. The pontine lesion was biopsied approximately a year after the biopsy of the precentral lesion due to disease pro‑ gression despite 4 cycles of procarbazine‑ CCNU‑ vincristine (PCV ) chemotherapy and stable supratentorial disease. Histology and genetic analysis of the pontine biopsy were consistent with grade 3 oligodendroglioma, and compari‑ son of the two lesions demonstrated common 1p/19q co‑ deletions and TERT promoter mutations but distinct IDH1 mutations, with a non‑ canonical IDH1 R132G mutation identified in the infratentorial lesion and a R132H mutation identified in the cortical lesion. Initiation of Temozolomide led to complete response of the supratentorial lesion and durable disease control, while Temozolomide with subsequent radiation therapy of 54 Gy in 30 fractions resulted in partial response of the pontine lesion. This case report supports possible distinct molecular pathogenesis in supraten‑ torial and infratentorial oligodendrogliomas and raises questions about the role of different IDH1 mutant isoforms in explaining treatment resistance to different chemotherapy regimens. Importantly, this case suggests that biopsies of all radiographic lesions, when feasible and safe, should be considered in order to adequately guide management in multicentric oligodendrogliomas. Keywords: Multifocal, Low‑ Grade Glioma, IDH mutant, Supratentorial, Infratentorial Introduction [3, 4, 6, 10, 13]. High-grade gliomas in adolescents and Oligodendrogliomas represent approximately 5% of all young adults (AYA, 15–25  years old) have been recently glial tumors in the US adult population [13]. Those aris - shown to harbor distinct molecular features compared to ing in the infratentorial compartment are rare as most both the pediatric and adult population. In this particular arise in the cerebrum. Thus far, only a few isolated case age group, WHO grade may have limited utility whereas studies have reported genetically confirmed, IDH mutant molecular subtypes have a major prognostic impact and 1p/19q-codeleted, infratentorial oligodendrogliomas [19]. Interestingly, noncanonical IDH1 mutations have been identified with a higher frequency in AYA gliomas compared to the adult patient population [19]. The role *Correspondence: aha2152@cumc.columbia.edu of distinct molecular features in selecting management Alexander H. C. W. Agopyan‑Miu and Matei A. Banu these authors strategies, however, remains unclear. contributed equally to this work Columbia University Vagelos College of Physicians and Surgeons, New The simultaneous presence of multiple lesions, espe- York, USA cially lesions with supratentorial and infratentorial Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Agopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 2 of 9 components, is a rare occurrence in gliomas of all type Case presentation [20]. Concurrent lesions are classified as either mul- The patient, a previously healthy 23-year-old man, first tifocal or multicentric based on radiographic and/or presented to an outside hospital with complaints of pathologic features. Multifocal lesions are those that intermittent diplopia, tinnitus and occipital pain. Due either demonstrate a path of contiguous hyperintensity to persistent headache, he underwent an MRI scan on T2 MR images, or if the pattern of dissemination which revealed synchronous, non-enhancing, T2/FLAIR can be explained by spread along white matter tracts, hyperintense lesions in the right precentral gyrus and CSF, or local spread from satellite lesions [14]. Multi- pons as well as increased signal along the right 8th cra- centric lesions, on the other hand, cannot be described nial nerve. Initial serial scans were stable and the patient by the previous features and includes those lesions remained in stable condition during that time but even- separated by time, termed metachronous lesions [14]. tually presented to our institution 8  months later for a Given the rarity of synchronous lesions, little is known second opinion. By this time, he developed headaches, about their underlying molecular/genetic relation- mild photophobia, left-sided weakness, and left facial ships. Some studies proposed independent gliomagen- numbness. Initial in-house imaging at the time demon- esis events. For example, Lee et  al. [12] suggest that strated a 3.9 × 3.1 × 4.4  cm heterogenous, but primarily multifocal/multicentric tumors are seeded from geo- T1 hypointense, T2 hyperintense, infiltrating, and mildly graphically segregated, distinct tumor clones given the expansile pontine lesion with minimal patchy contrast few shared genetic alterations they observed between enhancement and diffusion restriction that was larger multifocal/multicentric tumors. On the other hand, in size compared to imaging obtained from the outside multicentric or multifocal lesions might represent hospital. Extension into the floor of the fourth ventricle, intracranial metastasis of a primary focus, with a com- compression of the prepontine cistern, and obstructive mon clonal precursor [2, 15]. Several recent studies hydrocephalus was noted. Extension into the middle cer- have suggested potential mechanisms through early ebellar peduncles and encasement of the basilar artery divergence and parallel evolution eventually leading was also noted. MR spectroscopy revealed elevated cho- to genetically distinct lesions [1, 9]. Subclonal drivers line peak and reversal of the choline/NAA ratio, and with late occurrence rather than founder events were was overall consistent with a glial tumor. A second infil - believed to drive the evolution of such lesions [1]. In trating and expansile, non-enhancing lesion, measur- this regard, the role of early events during gliomagen- ing 2.7 × 2.2 × 1.5  cm, in the right precentral gyrus with esis, such as IDH1 mutations, in driving multicentric similar imaging characteristics to the pontine lesion was gliomas remains elusive. The clinical utility of classi- also seen and noted to have increased in size compared fying multiple concurrent gliomas as either multifocal to imaging studies obtained from the outside hospital or multicentric remains unclear. In the absence of spe- (Fig. 1). MR perfusion demonstrated low relative cerebral cific guidelines, management largely resembles that of blood volume and flow values, suggestive of a low-grade solitary lesions despite the worse prognosis associated glioma. with multifocal/multicentric gliomas [8, 14]. A ventriculoperitoneal shunt was placed to treat the Here, we present a rare case of a 23-year-old man patient’s hydrocephalus. He subsequently underwent an with synchronous, genetically confirmed right precen- awake craniotomy with sensorimotor mapping for an tral grade 2 and pontine grade 3 oligodendroglioma. excisional biopsy of the right peri-rolandic lesion. A sub- The two lesions harbored similar 1p/19q-codeletions total resection was carried out, to avoid inducing a left- and TERT mutations but have different IDH1 muta- hand sensory deficit. tions: a canonical IDH1 R132H was identified in the Final pathological analysis of the biopsied right peri- precentral lesion while a noncanonical IDH1 R132G rolandic lesion demonstrated a low grade diffusely mutation was identified in the pontine lesion. Impor- infiltrating glial neoplasm with no microvascular pro - tantly, the two lesions differed in their response to liferation, necrosis, or mitotic activity. The Ki-67 pro - four cycles of procarbazine-CCNU-vincristine (PCV) liferation index was modestly increased, labeling up to chemotherapy. The case illustrates one possible patho- approximately 1.5% of tumor cells. The cells were posi - genesis of multifocal/multicentric oligodendrogliomas, tive for GFAP, SOX2, IDH1 R132H, and PDGFR-A by via early subclonal divergence and parallel evolution, immunohistochemistry (Fig.  2), and ATRX staining and suggests the possible importance of performing was preserved. Rare cells showed weak p53 staining, biopsies of all radiographically visible lesions, when and immunostains for H3 K27M and EGFR were nega- safe and technically feasible, as it may impact subse- tive. Targeted next generation sequencing panel (Foun- quent treatment decisions. dationOne CDx, Foundation Medicine, Boston, MA) revealed the presence of a TERT promoter mutation A gopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 3 of 9 (variant allele fraction, VAF, of 23%) and confirmed the Three small cores of tissue were obtained from the IDH1 R132H mutation (VAF of 19%), while consistent enhancing portion of the pontine lesion. Final pathologi- with immunostain result, no mutation in H3F3A was cal analysis of the biopsied brainstem lesion revealed a seen (Table  1) Further studies confirmed the presence glial neoplasm of increased cellularity, nuclear pleomor- of 1p/19q-codeletion via fluorescence in  situ hybridi - phism, and proliferative activity with up to 3 mitotic zation (FISH) and an unmethylated MGMT promoter figures in this small biopsy and a Ki-67 labeling index by bisulfite-treatment PCR and melting curve analysis. of nearly 10%. No tumor necrosis or microvascular pro- Based on these findings, the final diagnosis was oligo - liferation was appreciated. Similar to the supratentorial dendroglioma, IDH-mutant and 1p/19q-codeleted, tumor cells, these tumor cells were positive for GFAP, WHO Grade 2. SOX2, and ATRX. However, IDH1 R132H was unex- Imaging a month later demonstrated a decrease in size pectedly negative by immunohistochemistry. FISH con- of the ventricular system, a stable peri-rolandic lesion, firmed the presence of 1p/19q-codeletion. Targeted next and stable faint patchy enhancement within the pon- generation sequencing panel revealed a TERT promoter tine lesion that again demonstrated an interval increase mutation (VAF 55%) identical to the peri-rolandic lesion in size compared to the initial scan obtained at the out- and an IDH1 R132G mutation (VAF 46%) not seen in side hospital. Despite these changes the pontine lesion the patient’s supratentorial tumor. No other mutations was considered to likely be an oligodendroglioma given were identified on this laboratory-developed platform the pathology of the peri-rolandic lesion, albeit with fea- which includes assessment of IDH1, IDH2, H3F3A and tures concerning for a grade 3 lesion on imaging. After HIST1H3B (Columbia Solid Tumor Panel, Personalized a comprehensive multidisciplinary tumor board discus- Genomic Medicine at Columbia University, New York, sion considering the risks associated with biopsy of the NY). The MGMT promoter was partially methylated brainstem lesion and the patient’s treatment preference, (Table 1). Based on the overall findings, the final diagno - the decision was made to proceed with a standard PCV sis was anaplastic oligodendroglioma, IDH-mutant and chemotherapy regimen alone. During chemotherapy, the 1p/19q-codeleted, WHO Grade 3. patient’s course was complicated by mild peripheral neu- The patient tolerated the procedure well and experi - ropathy and asymptomatic thrombocytopenia necessitat- enced complete resolution of his headaches. Post-oper- ing a 25% dose reduction for the third cycle, and a further atively he underwent radiation therapy to the brainstem 25% dose reduction at the start of the fourth cycle in light lesion, 54 Gy in 30 fractions, concurrently with systemic of recurring thrombocytopenia. Overall, his clinical pic- Temozolomide chemotherapy for 6  weeks followed by ture improved, with resolution of headaches, improve- adjuvant Temozolomide, which he continues to this date. ment in diplopia, and interval MRI scans up to 8 months He continues to improve clinically, with a KPS of 80 and is out showed stable disease. able to ambulate independently at the time of this report. Imaging at 9 months after initiation of chemotherapy He initially developed diplopia which has remained sta- demonstrated new small foci of enhancement in the ble since initiation of chemoradiotherapy. He has been off brainstem lesion, herniation of the cerebellar tonsils, steroids. The most recent MRI at the time of this report, and a stable cortical lesion (Fig.  3). The patient had at 27 months post diagnosis, revealed decrease in size of now developed progressive suboccipital headaches. The the pontine lesion with near complete resolution of the decision was made to proceed with  surgery for suboc- peri-rolandic lesion and no new supratentorial lesions. cipital decompression of the acquired Chiari malforma- Notably, the peri-rolandic lesion showed radiographic tion together with biopsy of the pontine lesion to guide response prior to initiation of Temozolomide suggesting further management. PCV chemotherapy benefit. (See figure on next page.) Fig. 1 MRI of multifocal lesions on presentation. A Axial T2‑FLAIR demonstrating a hyperintense round lesion, measuring 2.7 × 2.2 × 1.5 cm (CC × AP × transverse), in the precentral gyrus. Initial measurements prior to presentation at our institution: 2.2 × 1.7 × 1.5 cm. B Left greater than right hyperintensity in the cerebral peduncles on axial T2‑FLAIR. C Axial T2‑FLAIR demonstrates a heterogenous, hyperintense lesion in the pons, measuring 3.9 × 3.1 × 4.4 cm, with extension into bilateral cerebellopontine cisterns and middle cerebellar peduncles. Encasement of the basilar artery is also present with no obstruction of flow. Initial measurements prior to presentation at our institution: 3.5 × 3.1 × 4.3 cm. D Axial T1 post‑ contrast image of the pontine lesion demonstrating subtle patchy contrast enhancement. E Sagittal T2 image of the precentral lesion with compression of the central sulcus. F Large heterogenous, T1 hypointense pontine lesion extending from the floor the fourth ventricle to the prepontine cistern ventrally. G Pontine lesion as described with heterogenous hyperintensity on this sagittal T2 slice. H Subtle patchy enhancement is again appreciated within the pontine lesion on this T1 post‑ contrast sagittal slice Agopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 4 of 9 Fig. 1 (See legend on previous page.) A gopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 5 of 9 Discussion and may have become the predominant population after Oligodendrogliomas are relatively rare, well-differen - PCV chemotherapy secondary to a subclonal selection tiated neuroepithelial tumors that more commonly process. occur in the cerebral hemispheres compared to the In future studies of multicentric gliomas, synchro- infratentorial space [10]. We present here a unique case nous longitudinal biopsies coupled with in-depth genetic of synchronous supratentorial and infratentorial oligo- sequencing could help us infer the timing of clonal sep- dendrogliomas in a young adult patient with no known aration between the R132G and R132H populations predisposing germline mutations. The stark difference in during tumorigenesis. In this case, we are unable to response to four cycles of PCV between the cortical and definitively draw conclusions about the pathogenesis of pontine lesions necessitated the biopsy of the latter and these spatially distributed oligodendrogliomas but pro- provided the opportunity to compare genetic and his- vide a roadmap for future studies. Furthermore, we pro- topathologic characteristics. Such studies can provide vide evidence that distinct lesions with distinct mutations insight into the origin of distinct tumors and the evolu- may have different sensitivities to various chemotherapy tionary trajectories of IDH-mutant oligodendrogliomas. and radiation regimens, therefore having important clini- The most striking finding from the pontine biopsy was cal implications. the presence of a non-canonical IDH1 R132G mutation The role of IDH1 mutations in predicting response to that differed from the canonical IDH1 R132H mutation chemotherapy for oligodendrogliomas has been difficult encountered in the supratentorial lesion. This finding to establish, in contrast to the well-established predic- suggests two possible avenues of pathogenesis. tive value of 1p/19q-codeletions in predicting sensitivity One hypothesis is the presence of two distinct, multi- to PCV. The presence of IDH1 mutations in conjunction centric tumors that evolved synchronously and indepen- with 1p/19q-codeletions may indicate a positive progno- dently of each other. Greater rates of non-canonical IDH1 sis in oligodendroglioma patients treated with adjuvant mutations have been reported in infratentorial gliomas PCV following radiation therapy [7, 21, 22, 26]. How- compared to supratentorial gliomas, and in lower grade ever, it is unclear how many patients in these studies had gliomas overall [5, 16, 18, 23]. Given that both canonical infratentorial lesions or non-canonical IDH1 mutations. and non-canonical IDH1 mutations likely represent early Furthermore, there are few studies comparing the predic- clonal mutations that may even precede 1p/19q-code- tive and prognostic value of non-canonical IDH1 muta- letions [11, 23–25], the divergent IDH1 mutations may tions to the canonical IDH1 R132H mutation. Enzyme suggest the synchronous development of two independ- kinetics have been shown to differ between mutant iso - ent low grade gliomas whose distribution is consistent forms, and isoforms that produce greater amounts of with the reported anatomic distribution and prevalence D-2-hydroxyglutarate, like the R132G isoform, are disad- of mutant IDH1 isoforms thus far. vantaged by the toxicity associated with the metabolite’s An alternative hypothesis is that the infratentorial buildup [17]. This mechanism may underlie the proposed lesion is in fact a metastatic lesion originating from the favorable prognostic associations with non-canonical supratentorial tumor. In this case, the distinct IDH1 mutations in oligodendrogliomas [23]. Thus, determin - mutations may indicate an evolutionary trajectory that ing whether the divergent IDH1 mutations played a role led to a more aggressive subclone, capable of metastatic in the differential treatment response is difficult. It is also spread. Therefore, the IDH1 R132G mutation may mark important to note that, after discussion of available treat- a unique subclone with increased ability to metastasize ment options, a chemotherapy only as opposed to radio- via corticospinal tract fibers or CSF. Furthermore, it is therapy plus adjuvant chemotherapy treatment plan was important to note that the biopsies were separated in chosen to respect patient preferences. The addition of time and therefore may in fact capture the temporal evo- radiation later in the course with subsequent improved lution of different subclones. The IDH1 R132G mutant control may indicate the need for more aggressive multi- cells may have had increased chemoresistance at baseline modality approaches in such lesions. (See figure on next page.) Fig. 2 Genetically divergent multifocal glioma involving cerebrum and brainstem. A–D Biopsies of the cortical mass revealed a diffusely infiltrating glial neoplasm with perineuronal satelitosis and perinuclear clearing (A, 4×; B, 400×). The neoplastic cells expressed SOX2 (brown chromogen) and GFAP (red chromogen) (B inset, 200×), and harbored the IDH1 R132H onco‑protein (C, 200×) with retained nuclear expression of ATRX (D, 200×). E–I Biopsies of the pontine mass revealed a diffusely infiltrating glial neoplasm with increased cellularity and prominent mini‑ gemistocytic cytomorphology (E, 200×; F, 400×). As opposed to the cortical mass, the pontine mass lacked the IDH1 R132H onco‑protein (G, 200×) however nuclear expression of ATRX was similarly retained (H, 200×). Ki‑67 index was increased in the pontine biopsy – a representative image is provided (I, 200×). (Scale bar = 50 um.) Agopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 6 of 9 Fig. 2 (See legend on previous page.) A gopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 7 of 9 Table 1 Comparison of genetic findings between the precentral and pontine lesion Precentral Pontine IDH1 R132H by IHC and next gen sequencing IDH1 R132G by next gen sequencing 1p/19q‑ codeleted by FISH 1p/19q‑ codeleted by FISH TERT promoter mutation 146 C > T by next gen sequencing TERT promoter mutation 146 C > T by next gen sequencing ATRX preserved by IHC ATRX preserved by IHC Unmethylated MGMT by MGMT methylation promoter assay Partial MGMT methylation by a MGMT methylation promoter assay PDGFR‑A positive H3 K27M negative by IHC and next gen sequencing H3 K27M negative by IHC and next gen sequencing Fig. 3 Follow up MRI following four cycles of PCV. A Hyperintense lesion of similar size and appearance in the precentral gyrus on axial T2FLAIR. ‑ B Homogenous hyperintense lesions in the left and right cerebral peduncles on axial T2FLAIR. ‑ C Large, primarily hypointense pontine lesion on sagittal T1 measuring 6.1 × 4.8 × 3.9 cm. Note herniation of the cerebellar tonsil. D Axial T2FLAIR demonstrating ne ‑ w hyperintense foci along the left anterior base of the lesion that extends into the cerebellopontine cistern and internal auditory canal. Again, encasement of the basilar artery is noted but flow is patent Agopyan‑Miu et al. acta neuropathol commun (2021) 9:160 Page 8 of 9 Authors’ contributions With respect to overall management, we believe that AHCWAM, MB, and CT collated case information for the report and con‑ this case highlights the importance of (1) performing tributed to the writing of the manuscript. MLM, GH, and PC performed biopsies on all radiographically visible lesions if safe to do histological examinations of brain tissue and provided editorial feedback on the manuscript. MLM also contributed to the figures for the case report and so, (2) performing biopsies of treatment resistant lesions, reviewed the manuscript. TW, AH, NF, and GMM were involved with patient even later in the treatment course and (3) sequencing care and provided guidance on the writing of the manuscript. PC, AH, and the IDH1 exon if initial immunohistochemical staining is GMM also provided editorial feedback on the manuscript. All authors read and approved the final manuscript. negative. Even if one subscribes to a multicentric or mul- tifocal theory of pathogenesis, this case shows that there Funding can be notable heterogeneity between foci, and this het- Not applicable. erogeneity may impact treatment response [12]. Further, Availability of data and materials Visani et al. [23] note that a significant proportion of low- Data sharing is not applicable to this article as no datasets were generated or grade gliomas in their case series would have been mis- analyzed during the current study. classified by WHO 2016 criteria if an investigation only for the canonical R132H mutation was performed. While Declarations there is little evidence to suggest a difference in prognos - Ethics approval and consent to participate tic or predictive value between canonical and non-canon- Not applicable. ical IDH1 mutations at present, knowing the precise Consent for publication genetic makeup of multicentric or multifocal lesions can The patient has consented to the use of their information for the purposes of guide treatment decisions as more data is uncovered. this case report. A signed consent form is available for review upon request. Competing interests The authors declare that they have no competing interests. Conclusion We present here a rare case of multifocal high grade Author details oligodendroglioma with supratentorial and infratento- Columbia University Vagelos College of Physicians and Surgeons, New York, USA. Department of Neurosurgery, Columbia University Irving Medical rial lesions, distinct IDH1 mutations, and differential Center, New York, USA. Department of Pathology and Cell Biology, Columbia response to PCV chemotherapy. This case illustrates 4 University Irving Medical Center, New York, USA. Department of Radiation one potential evolutionary trajectory of multicentric Oncology, Columbia University Irving Medical Center, New York, USA. Depar t‑ ment of Neuro‑Oncology, Columbia University Irving Medical Center, New oligodendrogliomas and provides insight into best York, USA. management practices for these rare tumors. We speculate that the infratentorial lesion may be a meta- Received: 17 August 2021 Accepted: 16 September 2021 static, higher grade lesion arising from the supratento- rial mass, and that the non-canonical IDH1 mutation marked sub-clones with increased tumor invasiveness References and/or chemoresistance which diverged early on in 1. Abou‑El‑Ardat K, Seifert M, Becker K, Eisenreich S, Lehmann M, Hackmann tumorigenesis. Alternatively, the supratentorial and K, Rump A, Meijer G, Carvalho B, Temme A et al (2017) Comprehen‑ infratentorial oligodendrogliomas may represent com- sive molecular characterization of multifocal glioblastoma proves its monoclonal origin and reveals novel insights into clonal evolution and pletely separate, synchronous lesions with distinct heterogeneity of glioblastomas. Neuro Oncol 19:546–557. https:// doi. genetic alterations. Irrespective of time course in glio- org/ 10. 1093/ neuonc/ now231 magenesis, this case report highlights the importance 2. 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Acta Neuropathologica Communications – Springer Journals

Published: Sep 29, 2021

Keywords: Multifocal; Low-Grade Glioma; IDH mutant; Supratentorial; Infratentorial

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