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Neuropathology
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Case 3 -
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Anaplastic/Large Cell Medulloblastoma
Arie Perry, University of California, San Francisco Medical Center, San Francisco, CA
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Clinical History
This 11-yo boy presented with a 1 week history of headaches, nausea/vomiting, and gait difficulties. Head CT revealed a paravermian left cerebellar mass with associated obstructive hydrocephalus. A subtotal resection was performed.
Case 3 - Slide 1
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Case 3 - Figure 5
Atypical mitotic figure and several pyknotic/apoptotic nuclei
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Case 3 - Figure 6
Focal papillary architecture and large cell cytology
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Case 3 - Figure 7
Large cell features with oval nuclei, open chromatin, large nucleoli, and increased cytoplasm. Cell wrapping is still evident
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Case 3 - Figure 8
Focal area with less anaplastic cytology and suggestion of both neuropil formation and vague Homer Wright rosettes
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Introduction:
This case was difficult due to the extreme anaplasia encountered histologically. The differential
diagnosis for such cases in the posterior fossa of children is discussed
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Sections revealed a highly cellular and anaplastic appearing neoplasm, arranged in loosely cohesive
sheets and vague nodules separated by delicate vasculature. At higher magnification, marked nuclear
pleomorphism is noted, with cells ranging from "small round cells" to large, multinucleated giant cells.
Cell wrapping is prominent in many areas and there are numerous mitotic figures including atypical forms,
as well as pyknotic/apoptotic cells and foci of frank necrosis. In addition to cell wrapping, cellular
"cannibalism" is evident, with smaller tumor cells being engulfed by larger ones. Focally, the cells
display a more "large cell" appearance, wherein tumor cells contain oval nuclei with open chromatin,
large cherry red nucleoli, and increased quantities of eosinophilic cytoplasm. Delicate fibrillary
material resembling neuropil and vague structures resembling Homer Wright rosettes were seen focally.
Immunohistochemical studies revealed variable, though relatively widespread synaptophysin positivity,
with smaller subsets displaying GFAP, S-100 protein, or smooth muscle actin (SMA) immunoreactivity. The
Ki-67 labeling index was markedly elevated and there was extensive nuclear positivity for p53 protein.
Nuclear expression of BAF47/INI-1 protein was retained throughout. The tumor was negative for
cytokeratin, epithelial membrane antigen (EMA), desmin, and HMB-45. Fluorescence in situ hybridization
(FISH) revealed high-level MYCN gene amplification and polysomies (gains) of chromosomes 2, 8, and 17.
There was no evidence of either isochromosome 17q or MYCC amplification.
Differential Diagnoses:
- Anaplastic/Large Cell Medulloblastoma
- Atypical Teratoid/Rhabdoid Tumor
- Giant Cell Glioblastoma
- Pleomorphic Sarcoma
- Metastatic Malignancy
Final Diagnosis:
Anaplastic/Large Cell Medulloblastoma
Case Discussion:
The classification of embryonal neoplasms has long been contentious and has undergone extensive
revisions over time
[2,
6].
In the 2007 WHO scheme, they are now divided into the following variants,
some of which have associated clinicopathologic correlates: classic, desmoplastic/nodular, extensively
nodular, large cell, and anaplastic. The previously designated "medullomyoblastoma" and "melanotic
medulloblastoma" have now been relegated to patterns designated "…with myogenic differentiation" and
"…with melanotic differentiation", since they can be encountered focally within a background of several
other major morphologic subtypes. Additionally, the term "supratentorial PNET" has been replaced by "CNS
PNET" to reflect the fact that these non-cerebellar, medulloblastoma-like neoplasms may also be seen in
the brainstem and spinal cord. Recent studies suggest that there are several clinically and molecularly
distinct subsets of medulloblastoma, such that further refinement of routine and ancillary diagnostic
workups is likely to impact surgical neuropathology in the near future
[3,
5].
The large cell
medulloblastoma is defined by a relatively monomorphic proliferation of enlarged tumor cells with oval
vesicular nuclei, prominent nucleoli, and increased cytoplasm, whereas the anaplastic medulloblastoma is
characterized by a more pleomorphic population of enlarged tumor cells with irregular, hyperchromatic
nuclei
[4,
9,
10,
11].
Both frequently feature prominent cell wrapping (often elliptical tumor cells wrapped
around other viable or apoptotic tumor cells), apoptotic lakes (collections of pyknotic nuclei), and
other aggressive features, such as markedly elevated proliferative indices and demonstrable CSF
dissemination. Since it is not uncommon to find morphologic features of both variants within the same
tumor, some authors have advocated the combined term of anaplastic/large cell (or large cell/anaplastic)
medulloblastoma. Additionally, both variants (either alone or combined) are frequently associated with
MYC gene amplifications (either MYC, a.k.a. c-myc or MYCN, a.k.a. N- myc), poor response to conventional
chemotherapeutic regimens, and decreased survival times. As such, anaplastic and large cell
medulloblastomas are considered to represent "unfavorable histology" and this places the corresponding
patients into a "high risk" category clinically. This scenario is somewhat analogous to the definitions
and worsened prognosis associated with anaplasia in other pediatric neoplasms, such as Wilm's tumors of
the kidney and neuroblastomas of the peripheral nervous system. Nonetheless, the current case is
somewhat unusual in its particularly extreme level of anaplasia, including large bizarre multinucleated
giant cells with cellular cannibalism, reminiscent of other differential diagnostic considerations,
including giant cell GBMs and pleomorphic sarcomas. However, more classic features were found focally
and ancillary studies confirmed the impression of medulloblastoma. Additionally, it may be difficult to
distinguish such tumors from atypical teratoid/rhabdoid tumors (AT/RT), since occasional cells may appear
vaguely rhabdoid and some AT/RTs have few to no classic rhabdoid cells. The use of the BAF47/INI-1
antibody is extremely helpful in this distinction [7]. Similarly, the use of FISH to demonstrate
medulloblastoma (MYC amplifications or isochromosome 17q) versus AT/RT (INI-1/22q deletions) associated
alterations may be helpful in this setting [8]. Lastly, it should be noted that similar anaplastic or
large cell features may be encountered in other embryonal neoplasms such as pineoblastomas and CNS PNETs
[1].
Conclusion(s):
Marked anaplasia within medulloblastomas and other CNS PNETs may cause considerable
confusion and lead to misdiagnoses such as giant cell GBM, pleomorphic sarcoma, or other malignancies.
Both immunohistochemistry and FISH are useful in this setting. Furthermore, the stratification of
medulloblastomas into clinically meaningful subsets has been rapidly evolving over the past few years and
it is likely that both histopathologic classification and ancillary molecular testing will become routine
for such cases in the future.
References:
- Behdad A, Perry A (2010) Central nervous system primitive neuroectodermal tumors: a clinicopathologic and genetic study of 33 cases. Brain Pathol.20(2):441-50.
- Brat DJ, Parisi JE, Kleinschmidt-DeMasters BK, Yachnis AT, Montine TJ, Boyer PJ, Powell SZ, Prayson RA, McLendon RE (2008) Surgical neuropathology update: a review of changes introduced by the WHO classification of tumours of the central nervous system, 4th edition. Arch Pathol Lab Med.132(6):993-1007.
- Eberhart C (in press) Molecular Diagnostics in Embryonal Brain Tumors. Brain Pathol.
- Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC (2002) Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer.94(2):552-60.
- Ellison DW, Kocak M, Dalton J, Megahed H, Lusher ME, Ryan SL, Zhao W, Nicholson SL, Taylor RE, Bailey S, Clifford SC (2010) Definition of Disease-Risk Stratification Groups in Childhood Medulloblastoma Using Combined Clinical, Pathologic, and Molecular Variables. J Clin Oncol.
- Giangaspero F, Eberhart CG, Haapasalo H, Pietsch T, Wiestler OD, Ellison DW (2007) Medulloblastoma. In: WHO classification of tumours of the central nervous system, Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, (eds.), pp. 132-40, IARC: Lyon.
- Judkins AR (2007) Immunohistochemistry of INI1 Expression: A New Tool for Old Challenges in CNS and Soft Tissue Pathology. Adv Anat Pathol.14(5):335-9.
- Perry A, Fuller CE, Judkins AR, Dehner LP, Biegel JA (2005) INI1 expression is retained in composite rhabdoid tumors, including rhabdoid meningiomas. Mod Pathol.18(7):951-8.
- Pfister SM, Korshunov A, Kool M, Hasselblatt M, Eberhart C, Taylor MD (2010) Molecular diagnostics of CNS embryonal tumors. Acta Neuropathol.
- Rutkowski S, von Hoff K, Emser A, Zwiener I, Pietsch T, Figarella-Branger D, Giangaspero F, Ellison DW, Garre ML, Biassoni V, Grundy RG, Finlay JL, Dhall G, Raquin MA, Grill J (2010) Survival and Prognostic Factors of Early Childhood Medulloblastoma: An International Meta- Analysis. J Clin Oncol.
- von Hoff K, Hartmann W, von Bueren AO, Gerber NU, Grotzer MA, Pietsch T, Rutkowski S (2009) Large cell/anaplastic medulloblastoma: Outcome according to myc status, histopathological, and clinical risk factors. Pediatr Blood Cancer.
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