Cerebellar Liponeurocytoma

More than 40 cases of cerebellar liponeurocytoma have been reported in the English literature.4 Patients usually present between the ages of 58 to 60 years. The mean age is approximately 53 years.5 That is in stark contrast to classic medulloblastoma, which typical affects children and young adults. Men and women are affected equally. Presenting signs and symptoms are most often related to increased intracranial pressure, including headache, vomiting, and altered consciousness. Other manifestations include dizziness, unsteadiness, gait disturbance, frequent falls, visual symptoms, and other signs of cerebellar or brainstem dysfunction.

Cerebellar liponeurocytoma most commonly involves the cerebellar hemispheres but may be located in the paramedian region or vermis and may extend to the cerebellopontine angle or fourth ventricle. Cerebellar liponeurocytoma is typically well circumscribed but may show mass effects on adjacent structures (eg, fourth ventricle). On computed tomography scans, the tumor is variably isodense or hypodense relative to brain parenchyma with focal areas of marked hypoattenuation corresponding to fat density (Figure 1).6 On T1-weighted magnetic resonance imaging images, the tumor appears isointense to hypointense, with patchy areas of hyperintensity corresponding to regions of high lipid content. Contrast enhancement is often heterogeneous (Figure 2) and may be minimal. On T2-weighted magnetic resonance images, the tumor appears slightly hyperintense to the surrounding brain, with focal areas of more pronounced hyperintensity (Figure 3). Peritumoral edema is typically absent or minimal. Fat-suppressed images may be helpful in supporting a preoperative diagnosis of liponeurocytoma.6 

Liponeurocytoma is a circumscribed tumor of the cerebellum (Figure 4), composed of small neurocytic cells, some of which have prominent cytoplasmic vacuolation (Figure 5). The individual tumor cells are morphologically similar to the prototypical neurocytic tumor of the central nervous system, the central neurocytoma. The neurocytic tumor cells are arranged in sheets or lobules and possess regular, round to oval nuclei enclosed within clear or pale-staining cytoplasm (Figure 6). Cytoplasmic borders are usually well defined. Characteristically, a variable proportion of the tumor cells display cytoplasmic vacuoles that are typically single and large (Figure 6). In those areas of lipidization, the tumor nuclei are displaced and compressed to the periphery of the cell, causing the tumor cells to resemble mature adipocytes. Intraoperatively, this feature is easily appreciated on cytologic preparations (Figure 7) and can be readily distinguished from the “freeze artifact” common with frozen tissue histology. Intracytoplasmic lipid can be confirmed by oil red O staining of frozen tissue sections.7 Mitotic activity is typically low. Necrosis and vascular endothelial proliferation are rare but have been associated with more aggressive biologic behavior (see prognosis below). One reported case8 showed striated muscle differentiation in addition to lipidization, whereas another reported case9 included a prominent glial component having pilocytic features.

Immunohistochemistry can be used to confirm the neurocytic nature of the tumor. The tumor cells typically express synaptophysin (Figure 8), neuron-specific enolase, and microtubule-associated protein 2 (MAP-2). Expression of glial fibrillary acidic protein (GFAP) has been reported in most cases, although staining is typically focal and of limited intensity. The MIB-1 (Ki-67) labeling index is typically between 1% and 3% but may be higher.10,11 

Ultrastructural studies have confirmed large, nonmembrane-bound lipid deposits within the cytoplasm of tumor cells. Such cells nevertheless retain features of neuronal differentiation, including dense core neurosecretory granules, microtubules, and synaptic junctions containing clear vesicles.5,12 

Lipomatous variants of more typical central nervous system tumors are well known, including variants of ependymoma, glioblastoma, meningioma, among others. In contrast, there are only rare reports of central neurocytomas (involving the lateral ventricles) featuring lipidized cells.13,14,15 Neurocytomas of the cerebellum nearly always have lipomatous elements (only 2 cases did not, according to the WHO 2007 classification). In fact, the presence of lipidized tumor cells helps to define cerebellar liponeurocytoma as a distinct entity.

The histologic differential diagnosis, therefore, includes variants of more common tumors featuring lipidized cells (mentioned previously), as well as tumors showing morphologic features similar to cerebellar liponeurocytoma. First among that group is medulloblastoma. As mentioned previously, most, if not all, cases previously reported as lipomatous medulloblastoma or similar entities represent liponeurocytoma. Classic medulloblastomas may occasionally feature foamy histiocytes admixed with more-typical, primitive neuroectodermal cells; however, those cases should not be classified as liponeurocytoma. Both desmoplastic medulloblastoma and medulloblastoma with extensive nodularity feature nodules of tumor cells showing advanced neuronal-neurocytic differentiation. The distinctive nodular architecture of the neurocytic cells, the presence of a classic medulloblastoma component, and the absence of vacuolated tumor cells mimicking adipocytes serve as distinguishing features.

Akin to the situation with central neurocytoma, oligodendroglioma and clear cell ependymoma enter into the differential diagnosis of cerebellar liponeurocytoma. Both typically lack immunohistochemical expression of neuronal markers, such as synaptophysin and MAP-2. Cerebellar liponeurocytoma may display perivascular anucleate zones (resembling the perivascular pseudorosettes of ependymoma), which may stain for GFAP. This underscores the importance of careful interpretation of a wide immunohistochemical panel of neuronal and glial markers. In rare cases, classic ependymomas may show lipomatous differentiation.16 There is also one report, to our knowledge, of a fourth ventricle neurocytoma with both lipomatous and ependymal differentiation.17 

Rounding out the differential diagnosis of adult cerebellar tumors that contain prominent “clear cells” are capillary hemangioblastoma and metastatic renal cell carcinoma. Both have tumor cells that lack the morphology of adipocytes while featuring a prominent arborizing vasculature. In small or otherwise suboptimal biopsies, immunohistochemistry (cytokeratin, epithelial membrane antigen, and renal cell carcinoma antigen for renal cell carcinoma, and α-inhibin and D2-40 for hemangioblastoma) can readily help distinguish these tumors from liponeurocytoma.

There are limited data on the molecular genetic abnormalities associated with cerebellar liponeurocytoma. Horstmann et al10 evaluated 20 cases of cerebellar liponeurocytoma for molecular genetic abnormalities more typical of medulloblastoma. No cases of cerebellar liponeurocytoma showed mutations of PTCH, APC, or β-catenin. All cases were also negative for isochromosome 17q by fluorescent in situ hybridization. Complementary DNA expression analysis revealed similarities to central neurocytoma and distinct differences from classic medulloblastoma. Although these data emphasize its distinction from classic medulloblastoma, few data exist regarding molecular abnormalities unique to cerebellar liponeurocytoma. Such study, particularly of those liponeurocytomas with more aggressive behavior, may shed light on the biology and prognosis of these rare tumors.

Because of its rarity and the paucity of long-term follow-up data, prognostication is difficult. Initial reports stressed a favorable prognosis for cerebellar liponeurocytoma, particularly in comparison to classic medulloblastoma. In fact, liponeurocytoma was considered a grade I tumor in the WHO 2000 classification.2 However, reported cases with longer follow-up have indicated a substantial rate of recurrence, leading to its reclassification as a grade II tumor in the 2007 WHO revision. In one collective series, 6 of 15 patients (40%) with available follow-up information had recurrence during a period ranging from 1 to 12 years.10 Recurrent tumors may display increased mitotic activity, increased proliferative activity as assessed by MIB-1 staining, vascular proliferation, and necrosis.18–20 However, some tumors recur in the absence of such atypical histopathologic features.21,22 It remains to be seen whether these atypical features are truly predictive of more aggressive biologic behavior.

Whenever feasible, the standard treatment of cerebellar liponeurocytoma is complete surgical resection. Patients may have prolonged recurrence-free survival following surgical resection alone. In light of that, the WHO 2000 working group sought to distinguish liponeurocytoma from medulloblastoma to avoid aggressive and potentially unnecessary adjuvant therapy.23 Radiation therapy may still have a role, given the potential for local recurrence. Due to the paucity of long-term follow-up data, it is unclear whether radiation should be given in the immediate postoperative period or be reserved for recurrent tumor, which may occur many years following initial surgery.10,11 When administered, radiotherapy is generally limited to the posterior fossa.5 No cases of spinal drop metastasis from cerebellar liponeurocytoma have been reported to date.

Cerebellar liponeurocytoma has distinctive morphologic and immunophenotypic features. No specific molecular genetic alterations have been detected thus far, and cases studied to date have lacked molecular genetic alterations typical of classic medulloblastoma. It is classified as a distinct clinicopathologic entity in the most recent revision (2007) of the WHO classification of central nervous system tumors. The available follow-up data suggest a substantial rate of local recurrence, justifying its classification as a WHO grade II tumor.