A Practical Approach to the Diagnosis of Common Hematopoietic and Solid Tumors of Childhood
Case 11 -
Medulloblastoma, Large Cell/Anaplastic Type
D. Ashley Hill, M.D.
Mihaela Onciu M.D.
A 13-year-old girl who presented with headache. Examination
showed cranial nerve XI palsy. Radiographic studies showed an enhancing posterior fossa mass and
cerebrospinal fluid dissemination of tumor.
Several small pieces of purple-pink, friable tumor were
received. A small piece was snap frozen in liquid nitrogen and stored at -80oC for biologic
Sections showed a malignant embryonal neoplasm
characterized by diffuse sheets of relatively cohesive cells with large, rounded, hyperchromatic nuclei
and minimal eosinophilic cytoplasm. Occasional groups of cells with large prominent central nucleoli
were seen. Rare cells showing "cell wrapping" phenomenon were also seen. There were numerous apoptotic
cells. Frequent mitotic figures were seen.
Medulloblastoma with large cell/anaplastic features
Medulloblastomas (MB) are malignant embryonal tumors of the cerebellum that have a predilection for
children. The peak age for MB is 7 years; 70% of patients are less than 16 years of age at diagnosis.
Approximately three-quarters of MB arise from the cerebellar vermis with the remainder involving the
cerebellar hemispheres. Patients with MB typically present with either signs of cerebellar dysfunction
or symptoms associated with blockage of cerebrospinal fluid (CSF) flow. Radiographically, the tumors are
discrete, solid, contrast-enhancing masses. Poor clinical prognostic factors include the presence of CSF
dissemination (present in 1/3 of patients at the time of diagnosis) and gross residual tumor following
resection. While advances in therapy have led to overall improved survival, the secondary effects of
high-dose chemotherapy and particularly radiation therapy on developing brains can lead to significant
morbidity and decreased intellectual potential. As with other pediatric tumors, finding better ways to
risk stratify these patients and individualize the treatment is an important goal. Although all MB are
considered grade IV/IV tumors, it has become clear with recent studies that certain histologic subtypes
may be predictive of outcome. The new World Health Organization (WHO) classification for MB recognizes
four primary subtypes: classic, desmoplastic
(nodular), medulloblastomas with extensive nodularity and large cell/anaplastic medulloblastomas (Table 4.1). The latter two categories
represent favorable prognosis and poor prognosis tumors respectively.
Classic MB are characterized by diffuse sheets of loosely cohesive malignant small cells. On high
power, the tumor cells have hyperchromatic round or angular nuclei and show some size and shape
variability. Mitotic figures and apoptotic bodies may be frequent. MB may show neuroblastic or neuronal
differentiation exhibited by the presence of Homer Wright rosettes or by linear columns of tumors cells
vertically traversing the molecular layer. Rare MB contain cells with features of differentiating
ganglion cells or astrocytic differentiation. Binucleation and a lack of uniform distribution or
anatomic layering are features helpful in distinguishing tumor cells differentiating into ganglion cells
from entrapped neurons. The significance of glial differentiation in MB is controversial.
Desmoplastic (Nodular) Medulloblastoma
Desmoplastic (also referred to as nodular) MB are tumors characterized by nodular foci referred to as
"pale islands", hypercellular, more primitive internodular regions and increased connective tissue
(reticulin-rich). The nodular foci consist of tumor cells showing neurocytic differentiation with bland,
round nuclei and abundant cytoplasmic processes as indicated by the fine fibrillary background. The
proliferative rate within the nodules is low. At the periphery of these nodules, the tumor cells are
more condensed, show more primitive features and are mitotically active. Reticulin-rich areas in which
primitive tumor cells grow in a linear arrangement between collagen fibers is another pattern. A
comparison of the staining pattern for Ki-67 and synaptophysin will look like a photograph and its
negative with the nodules showing strong staining for synaptophysin and a lack of Ki-67 and the
internodular areas showing strong Ki-67 positivity and little synaptophysin. Mild to moderate degrees of
nodularity do not appear to affect prognosis with the exception of those cases showing extensive
nodularity (see below).
Medulloblastoma with Extensive Nodularity and Advanced Neuronal Differentiation
Giangaspero et al initially identified this subtype of MB as
being associated with a good clinical outcome. These tumors consist almost exclusively of nodules with
differentiating neurocytes embedded in abundant fibrillary material and minimal internodular tissue.
Imaging studies can detect the nodularity of the tumor and is described as "grape-like". Patients with
this variant are typically less than 3 years of age and have a good outcome. These tumors in the past
were referred to as cerebellar neuroblastomas.
Large Cell/Anaplastic Medulloblastoma
Large cell/anaplastic MB (LC/A MB) are tumors characterized by increased mitotic activity, increased
apoptosis (either as individual cells or "lakes" of dying cells), cytologic atypia and a poor prognosis.
Tumors with "large cell" features have large round nuclei, vesicular chromatin and prominent nucleoli
whereas "anaplastic" tumor cells are large, angular and pleomorphic with hyperchromatism and frequent
molding. Both tumors also show a peculiar "cell wrapping" phenomenon in which a viable cell encircles
another tumor cell or apoptotic body. Since both large cell and anaplastic features can be seen in
combination, and both can arise within a classic or desmoplastic (nodular) MB, they are grouped together.
A recent study by Eberhart and colleagues reviewed features of anaplasia within a large group of
pediatric MB. By their definition, moderately anaplastic tumors contained unambiguously enlarged nuclei
+/- cell wrapping and increased mitotic and apoptotic figures and severely anaplastic tumors contained
markedly enlarged cells (at least twice the size of non-anaplastic cells) with cell wrapping and clusters
of apoptotic cells. Tumors with moderately or severely anaplastic cells (representing 24% of all cases
reviewed) showed a significantly worse event-free and overall survival. This effect on prognosis applies
to both diffuse and focal anaplasia. The predictive effect of anaplasia on outcome appears to be
independent of clinical stage.
Other Medulloblastoma-Related Entities
Tumors with extensive differentiation toward neuronal lines are designated cerebellar ganglioneuroblastomas. Rare MB will show skeletal muscle
differentiation, medullomyoblastoma or true
melanocytic differentiation, melanotic
medulloblastoma. Medullomyoblastomas are the more common of these rare variants and are
characterized by a biphasic appearance of classic MB intermixed with reasonably well differentiated
rhabdomyoblasts. The primitive skeletal muscle component usually consists of large cells with long tails
of abundant eosinophilic cytoplasm "strap cells" but occasional globular rhabdomyoblasts are seen.
Immunohistochemical stains for synaptophysin and desmin will highlight the MB and skeletal muscle
components of the tumor respectively. Some studies, however, suggest that patients with
medullomyoblastoma may do worse than those with classic MB but the numbers are small. In melanotic MB,
melanocytes can be clustered in tubular or papillary structures or can be dispersed singly among the
small cells. Immunohistochemistry for melanocytic markers is confirmatory. The prognostic significance
of divergent differentiation in a melanocytic MB is unclear.
For a discrete cerebellar lesion in a child, the primary clinical differential diagnosis is MB,
ependymoma and juvenile pilocytic astrocytoma (JPA). Radiographic studies will typically be able to
differentiate between the often cystic, contrast enhancing JPA from both the solid ependymoma and MB.
Histologically, differentiating between MB and ependymoma is usually straightforward but ependymomas can
occasionally be highly cellular and an occasional MB shows perivascular pseudorosettes. Ependymomas
generally have a more abundant fibrillary background and show variation in cellularity with paucicellular
areas. In difficult cases, immunohistochemical stains can be applied. Perivascular pseudorosettes in an
ependymoma will be GFAP positive whereas in MB they will be synaptophysin positive. One of the more
problematic differential diagnostic entities, primarily for the large cell/anaplastic category is the
atypical teratoid/rhabdoid tumor (ATRT) or rhabdoid tumor. ATRT's are rare tumors with a predilection
for very young children, almost always less than 2 years of age. Histologically, they have a widely
variable appearance (thus the teratoid appelation) that often includes small cell areas resembling MB.
In its classic form, the ATRT contains cells with large vesicular nuclei, prominent nucleoli and
paranuclear eosinophilic globules of intermediate filaments (rhabdoid inclusions). Both tumors can have
similarly notable mitotic activity, necrosis and apoptosis. In general, ATRT cells are larger, paler,
have more cytoplasm, and ATRTs are more disorganized and histologically variable than MB. Adequate
sampling to identify the diagnostic cytoplasmic inclusions and a panel of immunohistochemical stains is
imperative in suspect cases (see below).
Special Studies – Immunohistochemistry/FISH
Most MB contain individual cells that are positive for synaptophysin. Staining will be more intense
in those tumors with neuronal differentiation such as Homer Wright rosettes or nodular desmoplastic
tumors. GFAP positivity may also occur in MB. Most GFAP-positive cells within a MB will be reactive
astrocytes that are recognizable as stellate, and evenly spaced with a preferential concentration around
vessels. Occasionally, tumor cells will show glial differentiation based on immunoreactivity for GFAP or
ultrastructural features. The pattern of GFAP staining is usually patchy in comparison to that of an
ependymoma or a high grade infiltrating astrocytoma if those diagnoses are a consideration.
Immunohistochemical stains useful in differentiating ATRT from MB include vimentin, cytokeratin,
epithelial membrane antigen, smooth muscle actin and synaptophysin. The first four stains will highlight
the tumor cells of the ATRT. ATRT cells are typically negative for synaptophysin.
The most common specific cytogenetic abnormality in MB is an isochromosome 17q which can be found in
approximately 50% of cases. This abnormality can be detected by fluorescent in situ hybridization
(FISH). MYC (c-myc) and MYCN amplification can be seen in as many as 10% of cases and has been reported to
have a higher frequency in the large cell MB subtype. Preliminary studies suggest that MYC amplification portends a worse prognosis. FISH is also useful in detecting
the INI1 deletion on chromosome 22q11.2 characteristic of ATRT.
Clinical Prognostic Factors
The presence of CSF dissemination (Table 4.2) or radiographically measured residual disease > 1.5
cm3 in localized tumors (M0) represent poor prognostic factors. Patients aged less than 3
years also tend to have an inferior survival which may be attributable to lower therapeutic dose of
radiation given in this age group. CSF analysis and spinal MR used in conjunction appear to be more
sensitive for detecting metastatic disease than either one alone. In addition, lumbar CSF examination
appears to be more sensitive than shunt specimen examination for detection of tumor cells.
Table 11.1 WHO Classification of Medulloblastoma – Summary of histologicfeatures
Classic medulloblastoma Diffuse sheets of malignant small cells
Round or angular hyperchromatic nuclei with shape and size variability
May show neuronal differentiation in the form of Homer Wright rosettes
Contain synaptophysin-positive cells
Desmoplastic (nodular) medulloblastoma |
Nodular, hypocellular foci termed "pale islands"
Hypercellular internodular regions containing more primitive hyperchromatic cells of classic MB
- cells with neurocytic differentiation
- low Ki-67
- high synaptophysin staining
Linear arrangement of tumor cells between collagen fibers is another pattern seen in some tumors
- high Ki-67
- low synaptophysin staining
Medulloblastoma with extensive nodularity and advanced neuronal differentiation
Consists almost exclusively of nodules of differentiating neurocytes in fibrillary background
Minimal internodular tissue
Previously termed "cerebellar neuroblastomas"
Good prognosis subtype
Large cell/anaplastic medulloblastoma
Large cell features - large round nuclei with prominent nucleoli
Anaplastic features - large, angular, pleomorphic, hyperchromatic nuclei with molding
Increased mitotic activity
Abundant apoptosis, individual cells and groups of cells "lakes"
Cell wrapping phenomenon
Table 11.2 Chang Classification of Metastasis Staging for medulloblastoma
| M stage|| |
| M0 ||No gross subarachnoid or hematogenous metastasis|
| M1 ||Microscopic tumor cells found in CSF|
| M2 ||Gross nodular seeding in cerebellum, cerebral subarachnoid space or 3rd or 4th ventricles|
| M3 ||Gross nodular seeding in spinal subarachnoid space|
| M4 ||Extraneuraxial metastasis|
Adapted from Chang CH, Houseplan EM, Herbert C: An operative staging system for a megavoltage
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