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2019 NPB-10

This case was originally published in 2019. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

Clinical History

A 5-year-old girl presented with motor delay, toe walking, and sensorineural hearing loss. MRI revealed a nodular leptomeningeal tumor involving T8-T11 of the spinal cord, enlargement of the lateral and third ventricles, and small, nodular, and cystic-appearing lesions scattered over the surface of the brain.

The patient underwent neurosurgical decompression of the thoracic spine but died three years later with widespread involvement of the central nervous system (CNS) by tumor.

Tissue Site
Spinal cord, brain

Whole Slide Image

The whole slide image provided is an H&E-stained image of the spinal cord from an autopsy.

Questions

  1. Which of the following is the BEST diagnosis?

    1. Atypical teratoid/rhabdoid tumor

    2. Diffuse leptomeningeal glioneuronal tumor

    3. Metastatic renal cell carcinoma

    4. Oligodendroglioma

    5. Pilocytic astrocytoma, disseminated

  2. What molecular profile characterizes the lesion?

    1. -1p or codeletion 1p/19q, KIAA1549-BRAF gene fusion

    2. Alterations in either the SMARCB1 or SMARCA4 genes

    3. BRAF V600E mutation

    4. Codeletion 1p/19q, IDH mutation, ATRX-wildtype

    5. Mutations in the VHL gene

  3. Staining for which IHC marker is usually absent in neoplastic cells in this entity?

    1. GFAP

    2. OLIG2

    3. S100

    4. Synaptophysin

    5. Vimentin

View Answer Key

Discussion and Diagnosis

The final diagnosis is diffuse leptomeningeal glioneuronal tumor (DLGNT), a provisional entity recently added to the 2016 WHO Classification of Tumours of the Central Nervous System. The entity has also been referred to as disseminated oligodendroglioma-like leptomeningeal neoplasm and primary leptomeningeal oligodendrogliomatosis.

DLGNT is a very rare neoplasm that preferentially affects children, with the median age at diagnosis of five years, although the age range extends well into adulthood. Males are affected more frequently than females.

DLGNT may be confined to the leptomeninges or may involve the brain or spinal cord parenchyma (Image A, Image B, and Image C). DLGNT shows moderate cellularity with areas commonly resembling oligodendroglioma (Image D, Image E, and Image F). IHC stains for S100, OLIG2, and MAP2 are typically positive, and up to approximately two-thirds of cases show immunoreactivity for synaptophysin (Image G). IHC staining for GFAP is typically negative, and when present, is restricted to a small population of neoplastic cells within the tumor. Ultrastructural findings include electron-dense core neurosecretory granules and a background rich in neuropil.

Image A: Spinal cord, cross section.

Image A: Spinal cord, cross section.

Image B: Brain, coronal section.

Image B: Brain, coronal section.

Image C: Cerebellum, coronal section.

Image C: Cerebellum, coronal section.

Image D: H&E stain.

Image D: H&E stain.

Image E: H&E stain.

Image E: H&E stain.

Image F: H&E stain.

Image F: H&E stain.

Image G: IHC stain, Synaptophysin.

Image G: IHC stain, Synaptophysin.

By definition, DLGNTs lack mutations in the IDH1 (Image H) or IDH2 genes. They can show solitary 1p deletion or 1p/19q codeletion. Prior to recognizing the central role of IDH mutations in diffuse gliomas, the cytologic appearance and presence of 1p/19q codeletion led to diagnostic confusion with oligodendroglioma. However, oligodendrogliomas are now defined by the WHO as having both an IDH mutation and 1p/19q codeletion. In DLGNT, copy number abnormalities of chromosomes 1 and/or 19 are often accompanied by KIAA1549-BRAF gene fusion, which is also found in approximately 70% of pilocytic astrocytomas.

Image H: IHC stain, IDH1 R132H.

Image H: IHC stain, IDH1 R132H.

Copy number alterations or mutations of the sort that are typical for IDH-wildtype glioblastoma, including gains of chromosome 7, loss of chromosome 10, and EGFR amplification are not encountered, but rare TERT promoter mutations have been identified.

While dissemination is currently part of the WHO definition of DLGNT, at least one case of spinal glioneuronal neoplasm without dissemination has been reported that bore the microscopic and molecular hallmarks (1p/19q codeletion, KIAA1549-BRAF fusion) of the disease. Hence, this attribute may be subject to future discussion and possible refinement.

Given the rarity of the neoplasm and limited clinical follow-up, a WHO grade has not yet been assigned to this tumor. Early work with methylation profiling suggests that two molecular subgroups exist: methylation class-1 (MC-1) characterized by more frequent codeletion of 1p/19q, and methylation class-2 (MC-2) characterized by more frequent gain of chromosome arm 1q. Initial clinical comparisons suggest that MC-1 tumors tend to occur in younger patients and have better overall survival.

Diffuse leptomeningeal glioneuronal tumor

Take Home Points

  • DLGNT is a recently proposed tumor class that typically affects the young.
  • DLGNT is usually associated with marked CNS dissemination and areas with oligodendroglioma-like histology.
  • DLGNT has a high incidence of 1p deletion or 1p/19q codeletion, often in combination with KIAA1549-BRAF fusion.
  • Currently, no grade has been designated for this new entity.
  • While often slowly progressing, death commonly results from widespread involvement of the CNS.

References

  1. Cho HJ, Myung JK, Kim H, et al. Primary diffuse leptomeningeal glioneuronal tumors [Epub ahead of print 2014 Apr 26]. Brain Tumor Pathol. 2015;32(1):49-55. doi:10.1007/s10014-014-0187-z.
  2. Collins VP, Jones DT, Giannini C. Pilocytic astrocytoma: Pathology, molecular mechanisms and markers. Acta Neuropathol. 2015 Jun;129(6):775-88.
  3. Deng MY, Sill M, Chiang J, et al. Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features [Epub ahead of print 2018 May 15]. Acta Neuropathol. 2018 Aug;136(2):239-53. doi:10.1007/s00401-018-1865-4.
  4. Kang JH, Buckley AF, Nagpal S, Fischbein N, Peters KB. A diffuse leptomeningeal glioneuronal tumor without diffuse leptomeningeal involvement: Detailed molecular and clinical characterization. J Neuropathol Exp Neurol. 2018;77(9):751-6. doi:10.1093/jnen/nly053.
  5. Louis D, Ohgaki H, Wiestler O, et al. WHO Classification Of Tumours Of The Central Nervous System. Revised 4th ed. Lyon, France: International Agency for Research on Cancer (IARC); 2016.

Answer Key

  1. Which of the following is the BEST diagnosis?
    A. Atypical teratoid/rhabdoid tumor
    B. Diffuse leptomeningeal glioneuronal tumor
    C. Metastatic renal cell carcinoma
    D. Oligodendroglioma
    E. Pilocytic astrocytoma, disseminated
  2. What molecular profile characterizes the lesion?
    A. -1p or codeletion 1p/19q, KIAA1549-BRAF gene fusion
    B. Alterations in either the SMARCB1 or SMARCA4 genes
    C. BRAF V600E mutation
    D. Codeletion 1p/19q, IDH mutation, ATRX-wildtype
    E. Mutations in the VHL gene
  3. Staining for which IHC marker is usually absent in neoplastic cells in this entity?
    A. GFAP
    B. OLIG2
    C. S100
    D. Synaptophysin
    E. Vimentin
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