Case 5 -
Large Cell/Anaplastic Melanotic Medullomyoblastoma
Memorial Kettering Cancer Center
New York, NY
Click on each slide thumbnail image for an enlarged view
This two-year and two-month-old previously healthy boy presented with a one-month history of intermittent, progressive vomiting followed by gait ataxia. His pediatrician ordered a cranial MRI that revealed a 4 cm diameter, heterogeneously enhancing posterior fossa mass, probably arising from the cerebellar vermis. Subtle enhancement was also present overlying the medulla, raising the possibility of leptomeningeal disease. The patient was taken to surgery and gross total resection was achieved.
Case 5 - Figure 1 - Sagittal T1-weighted post-contrast MR image showing fourth ventricular mass.
Case 5 - Figure 2 - Axial T1-weighted post-contrast (left) and T2-weighted (right) MR images showing fourth ventricular mass.
Case 5 - Figure 3 - Low power view of tumor showing sheets of round cells.
Case 5 - Figure 4 - Higher power view showing round cells with macronucleoli.
Case 5 - Figure 5 - Intratumoral "apoptotic lakes".
Case 5 - Figure 6 - Tubular epithelial structures in one part of the tumor: note the intracytoplasmic finely granular pigment.
Large Cell/Anaplastic Melanotic Medullomyoblastoma
Summary of the case
Patient age (2 years) and tumor location (posterior fossa, with involvement of cerebellar vermis) are
typical for medulloblastoma, and the histologic appearance of a small blue cell tumor is characteristic.
However, the presence of prominent nucleoli and collections of apoptotic figures indicate large cell
variant of medulloblastoma. Furthermore, the presence of frankly epithelial foci with well-formed
tubules composed of cells containing cytoplasmic melanin pigment is typical of melanotic
medulloblastoma. Finally, some sections showed convincing rhabdomyoblasts; these and small blue cell
areas where skeletal muscle differentiation was not evident histologically showed immunopositivity for
desmin, muscle specific actin and myogenin (i.e. medullomyoblastoma).
Although medulloblastoma is generally a straightforward diagnosis when the pathologist is confronted
with a small blue cell tumor of the cerebellum, this diagnostic category has become more complicated over
the past 15 years as clinicopathologic studies have uncovered histologic features with prognostic
significance. The result is that this aggressive, WHO grade IV neoplasm can (and should) be examined for
features which portend an especially poor prognosis with unresponsiveness to therapy. Although it might
seem superfluous to histologically substratify an aggressive small blue cell tumor for prognostic
purposes, an analogous situation exists for other pediatric embryonal tumors such as Wilms tumor and
neuroblastoma where anaplasia and Shimada classification, respectively, are important predictors of
In 1992, Giangaspero et. al. published four cases of large cell
medulloblastoma characterized by tumor cells with large, vesicular nuclei, prominent nucleoli, and strong
expression of synaptophysin; c-myc amplification was demonstrated in one case . All four
cases pursued an aggressive course with early CSF dissemination despite radiation and chemotherapy.
Perhaps because of thoughts that this tumor might be a variant of AT/RT, little else was published on the
topic until 2000 when a Pediatric Oncology Group study suggested a special category of "large
cell/anaplastic" medulloblastoma . This designation placed large cell medulloblastoma (as
described in 1992) and anaplastic tumors showing large, irregularly shaped nuclei with coarse chromatin
together in a single, prognostically adverse category. Both large cell and anaplastic types frequently
showed large collections of apoptotic bodies ("apoptotic lakes"), increased mitotic activity, and a
tendency for tumor cells to wrap around one another. This study confirmed the earlier finding of c-myc
amplification and found evidence of genetic changes typical of medulloblastoma (isochromosome 17q) but
not AT/RT (monosomy 22). The study concluded that LC/A medulloblastoma was separable from AT/RT but
acknowledged that the tumors shared some histologic features and an aggressive clinical course with a
tendency to early CSF dissemination.
Since the POG study, several series have confirmed the significance of the large cell/anaplastic
(LC/A) category for medulloblastoma and presented evidence that LC/A tumors evolve from classic
4]. One of these studies examined the importance of degrees and extent of
histologic anaplasia, finding that moderate or severe anaplasia was prognostically significant and that
tumors with diffuse anaplasia (defined as anaplasia present in all low power fields) were associated with
a poorer outcome than those showing focal anaplasia . Large cell tumors are considered
prognostically equivalent to medulloblastomas with severe anaplasia. Probably because the criteria for
anaplasia are subjective, the frequency of the LC/A category among all medulloblastomas has varied from 4
to 24% in childhood medulloblastoma. Although histologic anaplasia has not yet been incorporated into
criteria for risk stratification for pediatric medulloblastoma, there is considerable discussion of the
topic among pediatric neuro-oncologists. Interestingly, a recent report suggests that anaplasia is a
rare finding in adults where it does not influence prognosis .
A second striking feature of our case is a focus of well formed tubules; while the presence of
glandular elements in a small blue cell tumor of the cerebellum might raise the possibility of AT/RT,
these tubules show cytoplasmic brown, finely granular pigment consistent with melanin. This appearance
fits with the "malignant melanin-forming tumor of the cerebellum" originally described by Fowler and
Simpson  in 1962 which has come to be known as melanotic medulloblastoma. The pigment is
oculocutaneous melanin (as opposed to neuromelanin), and melanosomes have been demonstrated by electron
microscopy. It is worth noting that the WHO 2000 makes a somewhat more inclusive definition of melanotic
medulloblastoma: "A rare tumor of childhood with a predominant element of small round cells closely
resembling classic medulloblastoma and a minor component of melanin-forming neuroepithelial
cells" . This definition therefore accepts as melanotic medulloblastoma a subset of tumors
which demonstrate melanin in the cytoplasm of small round cells rather than in tubulopapillary
9]; the relationship of these tumors to melanotic medulloblastoma with an
epithelial component is not clear. Tubules typically stain for cytokeratin and may show positivity for
S-100 protein. Although melanotic medulloblastoma is very rare with less than 20 reported cases,
examples with rhabdomyoblasts have been described .
Although melanotic medulloblastoma is too rare a tumor to carry out survival analysis on series of
cases, virtually all reported cases of the classic tubulopapillary variety have behaved aggressively,
most seeding the CSF and causing death
12]. And while it is difficult to assess these cases
retrospectively for evidence of LC/A features, some describe or illustrate large cells with prominent
nucleoli suggesting large cell elements
Although they are not well represented in the slides we distributed for the conference, our case also
showed rhabdomyoblasts which stained for muscle-specific actin, desmin, and myogenin: this third feature
of the tumor leads us to the diagnosis of medullomyoblastoma. Pure medullomyoblastoma (first described
by Marinesco and Goldstein in 1933) is a cerebellar small blue cell tumor with histologic evidence of
striated muscle elements . It should be noted that classic medulloblastoma not uncommonly
expresses desmin in the absence of rhabdomyoblasts by histology, and these cases are generally not
considered medullomyoblastomas. There is a 3 or 4:1 male predominance, and most patients are children.
Unlike melanotic medulloblastoma, medullomyoblastoma is not clearly more aggressive than classic
medulloblastoma. For instance, a series of 6 medullomyoblastomas (five of which showed LC/A histology)
found survival similar to that for classic medulloblastoma with median follow up of 92
months . This study also found that biphasic nodularity on imaging studies correlated with
discrete islands of small blue cells and rhabdomyoblasts by histology.
The histogenesis of medulloblastomas with rhabdomyoblasts and pigmented epithelium has been debated.
Currently, there is no reason to suppose that these components represent more than an example of
divergent differentiation characteristic of PNET in general. However, a neural crest origin has been
suggested, specifically for medullomyoblastoma. Ectomesenchyme is a neural crest (i.e. ectodermal)
derivative which in some parts of the body (like the head and neck) gives rise to skeletal muscle.
Portions of the leptomeninges are thought to be derived from ectomesenchyme, and this may explain the
occasional presence of heterotopic meningeal skeletal muscle and rhabdomyosarcoma.
Given the presence of epithelial and rhabdoid elements, differential diagnosis in this case should
include AT/RT. AT/RT frequently includes a small blue cell component indistinguishable from
medulloblastoma, but the typical large cells with pale, vesicular nuclei, eosinophilic cytoplasm and
prominent cytoplasmic vacuolation/ballooning are absent. Genetic studies are also helpful: in this
case, sequencing of the INI1 gene did not demonstrate a mutation, making AT/RT unlikely. Cytogenetic or
FISH studies for 22q abnormalities would also be helpful in excluding AT/RT. Immunostaining for the INI1
gene product is a readily available technique which essentially excludes AT/RT if the tumor shows nuclear
Pigmented epithelial elements, synaptophysin, cytokeratin, and S-100 staining can all be seen in
melanotic neuroectodermal tumor of infancy (melanotic progonoma, retinal anlage tumor). This tumor
(which generally affects the craniofacial region, rarely the brain) lacks the histologic anaplasia
evident in our case, and shows a more orderly architecture with pigmented epithelial cells forming a
peripheral rim around nests of small blue, neuroblastic cells. Rhabdomyoblasts are not expected in MNTI.
Other Types of Medulloblastoma
The terms nodular and desmoplastic medulloblastoma are often used interchangeably in reference to
those tumors with a combination of pale islands (which resemble lymphoid follicles with germinal centers)
made up of large cells with advanced neuronal/neurocytic differentiation and internodular desmoplastic
zones in which cells typical of classic medulloblastoma grow in linear arrays in a collagenous
background. Such tumors have been described in association with Gorlin's syndrome (nevoid basal cell
carcinoma syndrome, caused by mutations in PTCH gene) and there is conflicting evidence about whether
this histologic pattern is associated with a superior prognosis. However, there are examples of
medulloblastoma in which nodularity is extensive and in which nodules show cells with advanced neurocytic
differentiation, rare mitoses, and prominent neuropil. Such tumors generally occur in infants, often
show a peculiar grapelike appearance on neuroimaging, and are associated with a favorable
prognosis . The term medulloblastoma with extensive nodularity
is currently favored over the older "cerebellar neuroblastoma" for such tumors.
Cerebellar liponeurocytoma is the name currently given to cerebellar tumors (formerly "lipomatous
medulloblastoma" or "medullocytoma") of adulthood which combine advanced neurocytic and adipocytic (and
even myogenic) differentiation with low proliferative potential and favorable prognosis .
These terms are best separated from classic medulloblastoma (to which their genetic relationship is
unclear) in order to avoid unnecessarily aggressive treatment.
- Giangaspero F, Rigobello L, Badiali et. al. Large cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol 16(7):687-693, 1992.
- Brown HG, Kepner JL, Perlman EJ et. al. "Large cell/anaplastic" medulloblastomas: A Pediatric Oncology Group study. J Neuropathol Exp Neurol 59(10):857-865, 2000.
- Eberhart CG, Kepner JL, Goldthwaite PT et. al. Histopathologic grading of medulloblastomas. A Pediatric Oncology Group Study. Cancer 94:552-60, 2002.
- Leonard JR, Cai DX, Rivet DJ et. al. Large cell/anaplastic medulloblastomas and medullomyoblastomas: clinicopathological and genetic features. J Neurosurg 95:82-88, 2001.
- Giordana MT, D'Agostino C, Pollo B et. al. Anaplasia is rare and does not influence prognosis in adult medulloblastoma. J Neuropathol Exp Neurol 64(10):869-874, 2005.
- Fowler M, Simpson DA. A malignant melanin-forming tumor of the cerebellum. J Path Bact 84:307-311, 1962.
- Kleihues P, Cavenee WK. Tumors of the Central Nervous System. Pathology and Genetics. Lyon: IARC Press, 2000.
- Jimenez CL, Carpenter BF, Robb IA. Melanotic cerebellar tumor. Ultrastruct Pathol 11:751-759, 1987.
- Kalimo H, Paljarvi L, Ekfors T, Pelliniemi LJ. Pigmented primitive neuroectodermal tumor with multipotential differentiation in cerebellum (pigmented medullomyoblastoma). Pediat Neurosci 13:188-195, 1987.
- Banerjee AK, Kak JK. Teratoid tumor of the cerebellum. J Path 111:285-287, 1973.
- Sung JH, Mastri AR, Segal EL. Melanotic medulloblastoma of the cerebellum. J Neuropathol Exp Neurol 32:437-445, 1973.
- Dolman CL. Melanotic medulloblastoma. A case report with immunohistochemical and ultrastructural examination. Acta Neuropathol 76:528-531, 1988.
- Marinesco G, Goldstein M. Sur une forme anatomique, non encore decrite, de medulloblastoma: meddulo-myoblastome. Ann Anat Pathol 10:513-525, 1933.
- Helton KJ, Fouladi M, Boop FA, et. al. Medullomyoblastoma: A radiographic and clinicopathologic analysis of six cases and review of the literature. Cancer 2004 101:1445-1454, 2004.
- Giangaspero F, Perilongo P, Fondelli MP et. al. Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91:971-977, 1999.
- Giangaspero F, Cenacchi G, Roncaroli F et. al. Medullocytoma (lipidized medulloblastoma): a cerebellar neoplasm of adults with favorable prognosis. Am J Surg Pathol 20:656-664, 1996.