—  SPECIALTY CONFERENCE  —

Neuropathology

Case 3 - Desmoplastic Infantile Ganglioglioma (WHO Grade I)

Thomas J. Cummings
Duke University Medical Center
Durham, North Carolina


Click on each slide thumbnail image for an enlarged view
Clinical History:
A 1-year-old Caucasian female presented with a seizure. Neurological examination showed no deficits. Magnetic resonance imaging (MRI) of the brain showed a large cystic lesion with contrast enhancement in the right temporal lobe. She underwent a right temporal craniotomy and gross total resection of the lesion, which intraoperatively appeared to have a distinct margin with the surrounding brain. She did not receive any postoperative chemotherapy or radiation therapy. Two years postoperative she is seizure-free, has no focal deficits, and has no evidence of tumor recurrence.

Diagnosis - Desmoplastic Infantile Ganglioglioma (WHO Grade I)


Case 3 - Figure 1 - Desmoplastic Infantile Ganglioglioma. T1-weighted coronal magnetic resonance image (MRI) shows a large cyst-enhancing lesion in the right temporal lobe typical of the DIG.
Case 3 - Figure 2 - Desmoplastic Infantile Ganglioglioma. Prominent desmoplasia and a spindled appearance is a characteristic feature of this neoplasm (H&E).
Case 3 - Figure 3 - Desmoplastic Infantile Ganglioglioma. A neoplastic neuronal component separates DIG from the desmoplastic infantile astrocytoma (H&E).


Case 3 - Figure 4 - Desmoplastic Infantile Ganglioglioma. Focal areas of small primitive neuroblastic appearing cells are typically seen (H&E).
Case 3 - Figure 5 - Trichrome - Desmoplastic Infantile Ganglioglioma. A Masson trichrome histochemical stain shows the prominent green-staining collagen content.
Case 3 - Figure 6 - Reticulin - Desmoplastic Infantile Ganglioglioma. A histochemical stain for reticulin shows a dense pericellular reticulin network.

Pathologic Findings
Microscopic examination showed a glioneuronal neoplasm extending to the leptomeninges. The neoplasm was characterized by aggregates of neoplastic neurons embedded within a densely fibrous and fibrillary stroma. A hypercellular aggregate of primitive-appearing cells with high nuclear to cytoplasmic ratios and punctate nucleoli was seen focally. Rare cells in mitosis were seen within this embryonal-like component. The glial cells within the fibrous stroma were characterized by mildly pleomorphic nuclei and fibrillar cytoplasm. Microvascular proliferation and necrosis were not seen. Collections of mature perivascular lymphocytes were occasionally seen. A histochemical stain for reticulin confirmed a dense and diffuse pericellular reticulin pattern, and a Masson trichrome stain highlighted the dense fibrous stroma. An immunohistochemical stain for glial fibrillary acidic protein (GFAP) highlighted the neoplastic glial population, while neurofilament protein (NFP) and synaptophysin were positive in the neuronal population. Collagen type IV showed strong pericellular and vascular reactivity.

Discussion
The current 2002 World Health Organization (WHO) Classification of Tumours of the Nervous System combines the discussion of desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) as a single entity 1. They are defined by the WHO as large cystic tumors of infants that involve superficial cerebral cortex and leptomeninges, often are attached to the dura mater, and have a favorable prognosis if surgically resected. DIAs and DIGs share similar clinical features. They are rare supratentorial tumors that typically occur in the age range of 1-24 months. Neuroimaging with T1- weighted MRI is characterized by a large uniloculated or multiloculated cystic component and a contrast-enhancing component, with enhancement of the overlying dura 2. The desmoplastic component remains dark on T2-weighted MR imaging 15. Histologically DIAs and DIGs are characterized by a prominent reticulin-rich network and desmoplastic stroma, and in some cases aggregates of highly cellular embryonal-type cells. They are distinguished by the presence of a neuroepithelial component composed either exclusively of neoplastic astrocytes (DIA), or of astrocytes and a neuronal component (DIG) 3;4. Both are WHO Grade I neoplasms.

The history of the classification of DIGs and DIAs is interesting. In 1976, Horten and Rubinstein described a series of 35 primary cerebral neuroblastomas 5. Within this series they noted that four cases were of "particular interest" in that the pattern of growth was primarily extracerebral and within the leptomeninges, and that all four cases originated in patients under the age of twelve months; these cases were classified as the desmoplastic variant of primary cerebral neuroblastoma. In 1982, Taratuto et al., described six cases of dural-based, superficial, meningocerebral, reticulin-rich, mesenchymal-mimicking astrocytomas in infants 6. The term "desmoplastic cerebral astrocytomas of infancy" (DCAI) was coined and additional documented cases followed 7;8. In 1987, VandenBerg et al., described eleven cases of "desmoplastic neuroepithelial tumors of infancy with divergent differentiation potential", and proposed the name "desmoplastic infantile ganglioglioma" for these lesions 4. This series included the four cases of "particular interest" from the Horten and Rubinstein series (primary cerebral neuroblastoma, desmoplastic variant), as those infants were found to have survived an extended period of time and were thus culled from the neuroblastoma category 4. These eleven cases were similar in all aspects to those labeled as DCAIs except they contained a neoplastic neuronal component in addition to the astrocytic component.

Differential diagnosis
The histologic differential diagnosis includes ganglioglioma, pleomorphic xanthoastrocytoma, malignant gliomas (glioblastoma and gliosarcoma) solitary fibrous tumor, fibroblastic meningioma, fibrosarcoma and other meningeal sarcomas, fibrous histiocytoma, hemangiopericytoma, and fibromatosis. Usually, however, awareness of DIG as a distinct clinicopathologic entity of infancy with typical neuroimaging features, in addition to the glioneuronal histologic features, desmoplastic and reticulin-rich stroma, and glioneuronal immunohistochemical profile, should allow for a confident diagnosis in most cases.

Ganglioglioma:
In some cases the distinction of DIG from ganglioglioma can be difficult, or even semantical, as some cases appear to have histologic features that overlap 9. However the distinct clinical presentation of DIG and the desmoplastic stroma with aggregates of small primitive cells should readily permit the diagnosis of DIG. Gangliogliomas typically occur in older children and young adults, are more common in the temporal lobe, and the glial component of the neoplasm usually resembles pilocytic astrocytoma.

Pleomorphic xanthoastrocytoma:
Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that shares some features with DIGs including the typical superficial location, similar neuroimaging features, pericytoplasmic basal lamina (reticulin network), desmoplasia, leptomeningeal involvement, and a favorable prognosis 10. They differ, however, in that PXAs are typically characterized by markedly pleomorphic cells, some of which may contain cytoplasmic microvesicular lipid lending a xanthomatous appearance, occur in older children and young adults rather than infants, and lack the neuronal elements of DIGs. Nonetheless, DIGs have been proposed to be infantile, pre-lipidized variants of PXA 8.

Malignant astrocytomas:
Glioblastoma and gliosarcoma (WHO grade IV) are characterized by the presence of microvascular proliferation and zones of necrosis pseudopalisaded by neoplastic cells. They diffusely infiltrate brain and disrupt the reticulin network. Gliosarcomas have an intersecting spindled or sarcomatous fascicular pattern that is reticulin-rich and lends a biphasic appearance to the neoplasm.

Solitary fibrous tumor and Fibroblastic meningioma:
The diffuse sclerosing variant of solitary fibrous tumor (SFT) is characterized by a dense collagen matrix and can mimic the fibroblastic variant of meningioma (FM) which may lack psammoma bodies and whorl formations. These entities are readily distinguished from each other by their immunohistochemical profiles: solitary fibrous tumors are CD34 and bcl-2 positive, while meningiomas are vimentin positive, EMA positive, and can be focally CD34 positive. Although their fibroblastic appearance can superficially resemble DIAs/DIGs, SFTs and FMs lack the convincing GFAP, neurofilament protein, and synaptophysin positivity of DIAs/DIGs. Furthermore, SFTs and FMs are typically contrast-enhancing, non-cystic, extra-axial neoplasms of adults.

Gliofibroma:
Gliofibroma is a controversial, ill-defined, low cellular astrocytic neoplasm of young adults characterized by a prominent reticulin-rich desmoplastic stroma among the neoplastic astrocytes. It has not yet been officially graded by the WHO, but may represent a variant of desmoplastic astrocytoma.

Meningeal sarcomas:
Fibrosarcomas or other meningeal-based primary malignant sarcomas should also be differed by their high-grade sarcomatous appearance and immunohistochemical profile, distinct from the glioneuronal appearance of DIGs.

Primitive neuroectodermal tumors:
PNETs may also show neuronal and glial differentiation, but in contrast to DIG, the overwhelming majority of cells are embryonal or primitive in PNET, whereby a small percentage of cells in DIG appear undifferentiated.

DIGs and DIAs are believed to share a common histogenesis from subpial astrocytes. Ultrastructural studies have shown the neoplastic glial elements in DIGs and DIAs to have at least focal deposition of pericytoplasmic basal lamina 4. This is a feature characteristic of subpial astrocytes, whose processes are typically surrounded by basement membrane and separated by collagen fibers 12. Unlike diffuse astrocytomas, TP53 mutations have not been identified in the few cases of DIGs/DIAs studied with molecular techniques 7;13.

The long term outlook for patients diagnosed with DIGs is favorable if complete surgical resection can be obtained 14. Ostensibly ominous histologic features such as high cellularity, cells in mitosis, microvascular proliferation, necrosis, and an elevated proliferation index, can be seen in DIGs. Although these features have been noted in cases of tumor progression and patient death, they also have been noted in patients with extended survival, and thus do not appear to represent the negative implications of other infiltrating astrocytomas 3;11.

Take home point of this case
The diagnosis of desmoplastic infantile ganglioglioma can be made with confidence in a child younger than 2 years of age with the typical neuroimaging features of a large cystic, superficial supratentorial mass, and the characteristic reticulin-rich desmoplastic stroma, glioneuronal elements, and immunohistochemical profile.

References

  1. Taratuto AL, VandenBerg SR, Rorke LB. Desmoplastic infantile astrocytoma and ganglioglioma. World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Nervous System. Edited by Paul Kleihues and Webster K. Cavenee. pp 99-102. IARC Press, Lyon 2000.
  2. Martin DS, Levy B, Awwad EE, Pittman T. Desmoplastic infantile ganglioglioma: CT and MR features. AJNR Am J Neuroradiol. 1991;12:1195-1197.
  3. VandenBerg SR. Desmoplastic infantile ganglioglioma and desmoplastic cerebral astrocytoma of infancy. Brain Pathol. 1993;3:275-281.
  4. VandenBerg SR, May EE, Rubinstein LJ, Herman MM, Perentes E, Vinores SA, Collins VP, Park TS. Desmoplastic supratentorial neuroepithelial tumors of infancy with divergent differentiation potential ("desmoplastic infantile gangliogliomas"). Report on 11 cases of a distinctive embryonal tumor with favorable prognosis. J Neurosurg. 1987;66:58-71.
  5. Horten BC, Rubinstein LJ. Primary cerebral neuroblastoma. A clinicopathological study of 35 cases. Brain. 1976;99:735-756.
  6. Taratuto AL, Monges J, Lylyk P, Leiguarda R. Superficial cerebral astrocytoma attached to dura. Report of six cases in infants. Cancer. 1984;54:2505-2512.
  7. Louis DN, von Deimling A, Dickersin GR, Dooling EC, Seizinger BR. Desmoplastic cerebral astrocytomas of infancy: a histopathologic, immunohistochemical, ultrastructural, and molecular genetic study. Hum Pathol. 1992;23:1402-1409.
  8. de Chadarevian JP, Pattisapu JV, Faerber EN. Desmoplastic cerebral astrocytoma of infancy. Light microscopy, immunocytochemistry, and ultrastructure. Cancer. 1990;66:173-179.
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  10. Kepes JJ, Rubinstein LJ, Eng LF. Pleomorphic xanthoastrocytoma: a distinctive meningocerebral glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer. 1979;44:1839-1852.
  11. Shao L, Tihan T, Burger P. Desmoplastic infantile ganglioglioma: a clinical and pathologic review of eight cases. J Neuropathol Exp Neurol. 2002;61:466.
  12. Ramsey H.J. Fine structure of the surface of the cerebral cortex of human brain. The Journal of Cell Biology. 1965;26:323-333.
  13. Kros JM, Delwel EJ, De Jong TH, Tanghe HL, Van Run PR, Vissers K, Alers JC. Desmoplastic infantile astrocytoma and ganglioglioma: a search for genomic characteristics. Acta Neuropathol (Berl). 2002;104:144-148.
  14. Sugiyama K, Arita K, Shima T, Nakaoka M, Matsuoka T, Taniguchi E, Okamura T, Yamasaki H, Kajiwara Y, Kurisu K. Good clinical course in infants with desmoplastic cerebral neuroepithelial tumor treated by surgery alone. J Neurooncol. 2002;59:63-69.
  15. Burger PC, Scheithauer BW, Vogel FS. Surgical Pathology of the Nervous System and its Coverings. Fourth Edition. pp 270-273. Churchill Livingstone, 2002.