Extraneural metastases of medulloblastoma: Desmoplastic variants may have prolonged survival

Young, Robert J.; Khakoo, Yasmin; Yhu, Stephen; Wolden, Suzanne L.; Braganca, Kevin C. De; Gilheeney, Stephen W.; Dunkel, Ira J.

doi:10.1002/pbc.25354

Cited by 12 publications

(10 citation statements)

References 14 publications

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“…15 High grade malignancies, such as retinoblastoma and medulloblastoma seem to retain their high grade histologic appearance within metastatic foci. 13,14 While metachronous and distant extranueral metastases cannot be completely ruled out in the case presented, the histomorphology of the cutaneous lesions does not resemble that of the AT/RT. In fact the resemblance is much closer to that of ES.…”

Section: Discussionmentioning

confidence: 74%

“…12 Despite their rarity, metastases from high grade CNS malignancies have been documented multiple years after their original diagnosis in subjects with longer term survival. 13,14 Sites of extraneural metastases from CNS lesions include viscera, bone, soft tissue, and skin. 15 High grade malignancies, such as retinoblastoma and medulloblastoma seem to retain their high grade histologic appearance within metastatic foci.…”

Section: Discussionmentioning

confidence: 99%

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Epithelioid Sarcoma Arising in a Long-Term Survivor of an Atypical Teratoid/Rhabdoid Tumor in a Patient With Rhabdoid Tumor Predisposition Syndrome

et al. 2021

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Rhabdoid tumor predisposition syndrome (RTPS) is defined as the presence of a SMARCB1 or SMARCA4 genetic aberration in a patient with malignant rhabdoid tumor. Patients with RTPS are more likely to present with synchronous or metachronous rhabdoid tumors. Based on the current state of rhabdoid tumor taxonomy, these diagnoses are based largely on patient demographics, anatomic location of disease, and immunohistochemistry, despite their nearly identical histologic and immunohistochemical profiles. Thus, the true distinction between such tumors remains a diagnostic challenge. Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) is a rare, aggressive, primarily pediatric malignancy with variable histologic features and a well documented association with loss of SMARCB1 expression. Epithelioid sarcoma (ES) is a rare soft tissue tumor arising in patients of all ages and characteristically staining for both mesenchymal and epithelial immunohistochemical markers while usually demonstrating loss of SMARCB1 expression. To our knowledge we herein present the first documented case of a patient with RTPS who presented with metachronous AT/RT and ES.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Epithelioid Sarcoma Arising in a Long-Term Survivor of an Atypical Teratoid/Rhabdoid Tumor in a Patient With Rhabdoid Tumor Predisposition Syndrome

et al. 2021

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“…Although molecular subtype data was not available in the largest reported series of extraneural metastatic MB [ 5 ], the correlation between desmoplastic histology and SHH activation [ 12 ] suggests that the majority of long-term survivors belong to the SHH-MB subgroup [ 5 ]. Similar to our case, most of desmoplastic MB patients only received CSI as the initial treatment, raising the question of the validity of systematic chemotherapy to eradicate subclinical metastatic extraneural disease in this MB subgroup.…”

Section: Discussionmentioning

confidence: 99%

“…For patients with recurrent SHH-MB, survival is dismal [ 2 ]. Although disease recurrence is usually confined within the CNS, extraneural metastases may rarely develop [ 3 – 5 ].…”

Section: Introductionmentioning

confidence: 99%

Recurrent extraneural sonic hedgehog medulloblastoma exhibiting sustained response to vismodegib and temozolomide monotherapies and inter-metastatic molecular heterogeneity at progression

et al. 2018

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BackgroundResponse to targeting and non-targeting agents is variable and molecular information remains poorly described in patients with recurrent sonic-hedgehog-driven medulloblastoma (SHH-MB).Materials and MethodsClinical and PET/CT findings during treatment with successive hedgehog antagonists and temozolomide monotherapies are described in a heavily pre-treated patient with recurrent extraneural metastases from PTCH1 mutated/ wild type smoothened (SMO) CNS SHH-MB. Molecular tests were prospectively performed in tissue from two extraneural sites at progression.ResultsSustained clinical/metabolic response was obtained to vismodegib. At progression, itraconazole was ineffective, but salvage temozolomide treatment results in a response similar to vismodegib. At further progression, acquired SMO and PIK3CA mutations were identified in bone (G477L and H1047A, respectively) and epidural (L412P and H1065L, respectively) metastases. No response was observed with subsequent sonidegib treatment.ConclusionsThis is the first clinical report of recurrent extraneural PTCH1 mutated SHH-MB exhibiting: 1) a sustained response to vismodegib and temozolomide, and 2) inter-metastatic molecular heterogeneity and acquired SMO-G477L, SMO-L412P, and PIK3CA-H1065L mutations at progression, highlighting the need for a multitarget treatment approach.

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“…MB commonly spreads through the cerebrospinal fluid (CSF) and disseminates to the surfaces of the brain and spinal cord. The overall 5-year survival rate of patients with MB is approximately 70 % [1, 2]. Many studies have demonstrated that tumor dissemination (seeding) into the cerebrospinal fluid may have the strongest impact on patient prognosis [3, 4].…”

Section: Introductionmentioning

confidence: 99%

In vivo bioluminescence imaging for leptomeningeal dissemination of medulloblastoma in mouse models

et al. 2016

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BackgroundThe primary cause of treatment failure in medulloblastomas (MB) is the development of leptomeningeal dissemination (seeding). For translational research on MB seeding, one of the major challenges is the development of reliable experimental models that simulate the seeding and growth characteristics of MBs. To overcome this obstacle, we improved an experimental mouse model by intracisternal inoculation of human MB cells and monitoring with in vivo live images.MethodsHuman MB cells (UW426, D283 and MED8A) were transfected with a firefly luciferase gene and a Thy1.1 (CD90.1) marker linked with IRES under the control of the CMV promoter in a retroviral DNA backbone (effLuc). The MB-effLuc cells were injected into the cisterna magna using an intrathecal catheter, and bioluminescence images were captured. We performed histopathological analysis to confirm the extent of tumor seeding.ResultsThe luciferase activity of MB-effLuc cells displayed a gradually increasing pattern, which correlated with a quantitative luminometric assay. Live imaging showed that the MB-effLuc cells were diffusely distributed in the cervical spinal cord and the lumbosacral area. All mice injected with UW426-effLuc, D283-effLuc and MED8A-effLuc died within 51 days. The median survival was 22, 41 and 12 days after injection of 1.2 × 106 UW426-effLuc, D283-effLuc and MED8A-effLuc cells, respectively. The histopathological studies revealed that the MB-effLuc cells spread extensively and diffusely along the leptomeninges of the brain and spinal cord, forming tumor cell-coated layers. The tumor cells in the subarachnoid space expressed a human nuclei marker and Ki-67. Compared with the intracerebellar injection method in which the subfrontal area and distal spinal cord were spared by tumor cell seeding in some mice, the intracisternal injection model more closely resembled the widespread leptomeningeal seeding observed in MB patients.ConclusionThe results and described method are valuable resources for further translational research to overcome MB seeding.

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Extraneural metastases of medulloblastoma: Desmoplastic variants may have prolonged survival

Cited by 12 publications

References 14 publications

Epithelioid Sarcoma Arising in a Long-Term Survivor of an Atypical Teratoid/Rhabdoid Tumor in a Patient With Rhabdoid Tumor Predisposition Syndrome

Epithelioid Sarcoma Arising in a Long-Term Survivor of an Atypical Teratoid/Rhabdoid Tumor in a Patient With Rhabdoid Tumor Predisposition Syndrome

Recurrent extraneural sonic hedgehog medulloblastoma exhibiting sustained response to vismodegib and temozolomide monotherapies and inter-metastatic molecular heterogeneity at progression

In vivo bioluminescence imaging for leptomeningeal dissemination of medulloblastoma in mouse models

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