Ganglioglioma Arising from Desmoplastic Medulloblastoma: a Case Report and Review of Literature Santosh Valvi, MBBS, MD, FRACP,A David S

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Ganglioglioma Arising From Desmoplastic Medulloblastoma: A Case Report and Review of Literature Santosh Valvi, MBBS, MD, FRACP,a David S. Ziegler, MBBS, BSc (Med), FRACP, MD, PhDb, c

We describe a case of medulloblastoma maturating into ganglioglioma abstract during therapy. A 10-month-old boy was diagnosed with a desmoplastic medulloblastoma and was treated with gross total resection followed by induction chemotherapy. A recurrence in the tumor bed during therapy was managed with focal radiation therapy and consolidation chemotherapy. After further progression, the recurrent tumor was resected completely. The histopathology revealed a benign ganglioglioma with no residual medulloblastoma. This case raises the possibility that a malignant medulloblastoma can differentiate into a benign tumor and suggests that differentiation therapy may have value in the treatment of medulloblastoma. a Princess Margaret Hospital for Children, Perth, Western Australia, Australia; bKids Cancer Centre, Sydney Children’s Hospital, Randwick, New South Wales, Australia; and cSchool of Women’s and Children’s Health, University of Medulloblastoma, an embryonal CASE REPORT New South Wales, Australia tumor of the cerebellum, is the most A previously well 10-month-old boy common childhood malignant brain Dr Valvi drafted and revised the initial manuscript; presented with a 6-week history of Dr Ziegler conceptualized the study and reviewed tumor. 1 The current World Health intermittent fever, irritability, and the manuscript; and all authors approved the fi nal Organization classification describes loss of developmental milestones. manuscript as submitted. a classic form with 4 distinct variants: Clinical examination was significant DOI: 10.1542/peds.2016-1403 desmoplastic, medulloblastoma for generalized hypertonia, Accepted for publication Oct 14, 2016 with extensive nodularity (MBEN), hyperreflexia, and right upper anaplastic, and large-cell forms. 2 More Address correspondence to Santosh Valvi, MBBS, limb dysmetria. Neuroimaging in MD, FRACP, Department of Pediatric and Adolescent recently it has also been stratified the form of ultrasound and MRI of Clinical Hematology and Oncology and Blood into 4 major molecular subgroups the brain revealed the presence of and Marrow Transplantation, Princess Margaret with different clinical outcomes for Hospital for Children, Roberts Rd, Subiaco WA, a large posterior fossa mass with each group. 3 Desmoplastic tumors Australia 6008. E-mail: [email protected]. accompanying hydrocephalus. An fall into the Sonic Hedgehog (SHH) au ophthalmologic review revealed the pathway group and are more common PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, presence of bilateral papilledema. in infants and adults. Infants with 1098-4275). There was no history of cancer in desmoplastic tumors have an excellent Copyright © 2017 by the American Academy of other family members. prognosis, suggesting a unique Pediatrics biology. 4 He proceeded to have an external FINANCIAL DISCLOSURE: The authors have ventricular drain inserted followed indicated they have no fi nancial relationships relevant to this article to disclose. We encountered a patient with a by a limited resection of the mass as desmoplastic medulloblastoma, he was too unwell at presentation FUNDING: No external funding. revealing complete maturation to for a more definitive procedure. POTENTIAL CONFLICT OF INTEREST: The authors adult ganglion cells during therapy. After improvement in his clinical have indicated they have no potential confl icts of interest to disclose. There have been a very small number condition, second look surgery was of previous case reports of either focal performed 3 weeks later and gross transformation of medulloblastoma total resection was achieved. A small To cite: Valvi S and Ziegler DS. Ganglioglioma into mature neuronal tumors, or metastatic nodule was found on the Arising From Desmoplastic Medulloblastoma: A complete maturation into a benign surface of the cerebellum and was Case Report and Review of Literature. Pediatrics. 2017;139(3):e20161403 tumor. resected. Histopathology revealed

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , number 3 , March 2017 :e 20161403 CASE REPORT a desmoplastic medulloblastoma (Fig 1). Immunohistochemistry revealed positive staining for YAP/ GAD, cytoplasmic β-catenin (with no nuclear staining), low level N-MYC gain (ratio 1.8:1), and wild-type for TP53. BRAF V600E was negative. The Illumina HumanMethylation 450K array and Nanostring Gene expression profiling confirmed that the initial tumor was SHH pathway medulloblastoma. FIGURE 1 The O6-methylguanine-DNA Hematoxylin and eosin stain of tumor at diagnosis. A, 4× magniﬁ cation and B, 400× magniﬁ cation methyltransferase promoter was revealing a highly cellular small blue cell tumor. The cells had small round to oval nuclei with mild to not methylated, and there were moderate hyperchromasia and minimal cytoplasm. no chromosomal abnormalities. Germline testing did not reveal any underlying suppressor of fused homolog mutations.

He was treated as per the Children’s Oncology Group protocol ACNS0334, 5 with a plan for 3 cycles of induction chemotherapy followed by 3 cycles of consolidation chemotherapy with stem cell support. An MRI repeated after 3 cycles of induction chemotherapy revealed tumor recurrence with a discreet nodule in the tumor bed ( Fig 2). The surgical attempt at resection was FIGURE 2 unsuccessful but a biopsy revealed MRI scan at recurrence. A, Sagittal and B, axial MRIs at relapse, revealing a discrete enhancing some viable tumor cells. In view nodule in the tumor bed. of this disease recurrence, he received focal stereotactic radiation ganglioglioma, with no correlative in the multimodal therapy, the therapy (RT) at a dose of 4500 rads. features with the original SHH prognosis has significantly improved The next MRI after RT had some medulloblastoma. BRAF mutation for the majority of the patients. 1 features suggestive of further tumor testing revealed no evidence of Gangliogliomas are rare, World progression, but postradiation flair V600E mutation or BRAF fusions. Health Organization Grade 1 ganglion was considered in the differential. He completed his consolidation cell tumors with a mixture of mature He proceeded to have 1 cycle of chemotherapy without any further neurons and glial cells, as well as a consolidation chemotherapy with complications and remains alive neoplastic glial component.7, 8 The thiotepa and carboplatin followed and well 6 years since his original prognosis is good with only surgical by stem cell rescue. A repeat MRI diagnosis. intervention necessary in most after this revealed persistence cases. 9, 10 of the enlarged nodule. A further resection was successfully achieved, Extensive posttherapeutic neuronal DISCUSSION with complete resection of a maturation, which is commonly calcified, well circumscribed nodule. Medulloblastoma, the most common encountered in peripheral Histopathology revealed a well malignant brain tumor of childhood, 1 neuroblastoma, 11 is rarely seen differentiated ganglioglioma with no is a heterogeneous disease and in medulloblastoma. There have evidence of medulloblastoma ( Fig 3). histologically described as a classic been 5 previous case reports of The Illumina HumanMethylation form with 4 variants. 6 More recently, differentiation of medulloblastoma 450K array confirmed a it has been classified molecularly into mature neural or glial methylation pattern consistent with into 4 subgroups. 3 With advances components after treatment (Table 1).

Downloaded from www.aappublications.org/news by guest on September 27, 2021 e2 VALVI and ZIEGLER TABLE 1 Case Reports of Medulloblastoma Differentiating Into a Benign Tumor Age at Pathology at Diagnosis Treatment at Diagnosis Age at Pathology at Relapse Outcome Diagnosis Relapse Cai et al11 3 mo Desmoplastic medulloblastoma Surgery 11 mo Exclusive gangliocytoma Died at 28 mo Chemotherapy Cai et al11 3 y Medulloblastoma Surgery 11 y Extensive gangliocytoma Alive RT Chemotherapy Chelliah et 22 mo MBEN Surgery 28 mo Gangliocytoma Alive al14 Chemotherapy Kudo et al12 15 y Medulloblastoma Subtotal resection 17 y Medulloblastoma with focal Died at 19 y RT ganglioglioma Chemotherapy Kubota et al 13 8 y Medulloblastoma Surgery 8 y Medulloblastoma Alive at 10 y Chemotherapy Focal gangliocytoma RT Bernert et 2 wk MBEN Surgery 6 mo Nodular lesion in posterior Not discussed in al15 fossa the article Ganglioglioma Chemotherapy Peri-medullary Both MBEN and ganglioglial enhancement, especially differentiation were seen in the cauda equine in the tumor at the time region of diagnosis without any previous therapy

Granule neuron precursor cell is the candidate cell of origin for desmoplastic medulloblastoma in young children. 16 Secondary to certain biological factors, like persistent SHH stimulation, granule neuron precursor cells fail to differentiate and develop into medulloblastoma. As this case demonstrates, and other case reports have shown, medulloblastoma FIGURE 3 cells may have a potential for Hematoxylin and eosin stain of tumor at recurrence. A, 4× magnifi cation and B, 400× magnifi cation, differentiation into more mature revealing reduced cellularity and large mature-appearing ganglion cells with variable dysmorphic 14 features, including clumped Nissl substance and occasional binucleate neurons. There is evidence cells like neurons and glia. This of dead tumor with dystrophic calcifi cation suggesting the possibility of treatment effect. There are provides a rationale for employing no primitive elements seen. differentiation therapy as a novel therapeutic strategy to attempt This maturation can be either focal medulloblastoma. After chemotherapy to transform the highly malignant as described by Kudo et al 12 or and RT, no medulloblastoma cells medulloblastoma cells into more Kubota et al 13 or near complete as were identified in the recurrent mass mature and benign cells. Retinoic in the cases reported by Cai et al11 lesion. Instead, mature ganglion cells acids are used for this purpose in or Chelliah et al. 14 Spontaneous in the form of ganglioglioma were the treatment of neuroblastoma. maturation of medulloblastoma seen. Given the time course, and the Similarly, their activity is currently into ganglioglioma at diagnosis location of the second tumor, it is being investigated in an ongoing has also been reported. 15 Notably, most likely the ganglioglioma was clinical trial in medulloblastoma. 3 of these cases described tumors not a primary tumor, rather, the Young age at diagnosis is a recognized that were desmoplastic (or MBEN), original medulloblastoma remnants adverse prognostic factor for whereas histology was unclear in the differentiated into the mature cells. medulloblastoma, principally because remaining 3. It is possible that chemotherapy and of the inability to use craniospinal RT In the case reported here, the initial RT triggered this process although in young infants.17, 18 However, the tumor also revealed the classic spontaneous maturation cannot be prognosis is modified by other factors histologic features of desmoplastic excluded. including the histologic and molecular

Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 139 , number 3 , March 2017 e3 subtypes, the presence or absence of more common in children younger Medulloblastoma: clinical presentation metastatic disease, and the degree than 3 years of age and has a better and management. Experience of residual tumor. Infants with SHH prognosis.14 As in neuroblastoma, at the hospital for sick children, pathway tumors and desmoplastic maturation of medulloblastoma Toronto, 1950-1980. J Neurosurg. histology have a far better prognosis cells may be associated with a better 1983;58(4):543–552 compared with older children. Even prognosis.11 This case suggests that 7. Lagares A, Gomez PA, Lobato RD, without RT, young children with some types of medulloblastoma may Ricoy JR, Ramos A, de la Lama A. desmoplastic medulloblastoma tend have more potential for maturation, Ganglioglioma of the brainstem: to have a good outcome.19 –21 There and research to identify the pathways report of three cases and review are also suggestions that RT may be that induce differentiation may of the literature. Surg Neurol. successfully delayed in patients with facilitate the development of novel 2001;56(5):315–322; discussion 322–324 desmoplastic subtypes.22 A meta- therapeutic approaches. analysis confirmed desmoplastic 8. McLendon RE, Provenzale J. histology as an independent favorable Glioneuronal tumors of the central prognostic factor prompting the ABBREVIATIONS nervous system. Brain Tumor Pathol. 2002;19(2):51–58 authors to suggest controlled MBEN: medulloblastoma with 23 deescalation of treatment. It is extensive nodularity 9. Lang FF, Epstein FJ, Ransohoff unclear whether focal RT to the RT: radiation therapy J, et al. Central nervous tumor bed is of benefit for these SHH: Sonic hedgehog system gangliogliomas. Part 2: children; however, the majority are clinical outcome. J Neurosurg. cured even with the omission of 1993;79(6):867–873 craniospinal RT.20 The maturation REFERENCES 10. Zentner J, Wolf HK, Ostertun B, et al. of medulloblastoma into a benign Gangliogliomas: clinical, radiological, lesion at a younger age, as seen 1. Gerber NU, Mynarek M, von Hoff K, and histopathological ﬁ ndings in Friedrich C, Resch A, Rutkowski S. in our patient, as well as in the 51 patients. J Neurol Neurosurg Recent developments and current reported cases in the literature, Psychiatry. 1994;57(12):1497–1502 may also suggest unique biological concepts in medulloblastoma. Cancer Treat Rev. 2014;40(3):356–365 characteristics at this age, as is true in 11. 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Downloaded from www.aappublications.org/news by guest on September 27, 2021 Ganglioglioma Arising From Desmoplastic Medulloblastoma: A Case Report and Review of Literature Santosh Valvi and David S. Ziegler Pediatrics 2017;139; DOI: 10.1542/peds.2016-1403 originally published online February 23, 2017;

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