A 77‐year‐old Woman with a Right Cerebellar Lesion

Clinical History

A 77‐year‐old woman presented with progressive dizziness over several months. She also reported bilateral tinnitus, but denied headache. Physical exam revealed an unsteady, wide‐based gait, slow finger to nose test bilaterally and inability to walk toes to heel. The patient had been diagnosed with mantle cell lymphoma (MCL) 3 years ago and she has completed six cycles of bendamustine and rituximab, followed by 2 years of rituximab maintenance therapy that was completed 2 months prior to onset of her symptoms. A recent bone marrow biopsy showed no evidence of residual lymphoma. MRI of the brain showed a right cerebellar lesion with central high T2 signal and peripheral rim enhancement (Figure 1A).

Figure 1.

Microscopic Pathology

Stereotactic biopsy of the cerebellar lesion showed small fragments of cerebellar tissue with focal small lymphocytic infiltrates, gliosis, granulation tissue and reactive changes, including some atypical large glial nuclei (Figure 1B). Immunohistochemistry reactions for CD3, CD20, cyclin D1 and CD68 (Figure 1C–F) revealed that virtually all lymphocytes are T cells. Stain for Cyclin D1 did not label the lymphocytes, but labeled scattered glial nuclei, including some of the large atypical glial nuclei. Stain for CD68 revealed many macrophages/microglia. Stain for Ki67 showed focally increased labeled nuclei in both lymphocytes and atypical glial cells (Figure 1G). Stain for p53 labeled scattered atypical glial nuclei (Figure 1H). An in situ study confirmed the diagnosis. What is your diagnosis?

Diagnosis

Atypical gliosis with reactive changes, no evidence of MCL. The overall features are suggestive of progressive multifocal leukoencephalopathy (PML).

An in situ hybridization study performed at a referring medical center (Mayo Clinic) for JC virus was positive (Figure 2).

Figure 2.

Discussion

The John Cunningham (JC) virus is a polyoma virus that causes PML, a demyelinating disorder of the CNS. The JC virus infects glial cells including both astrocytes and oligodendrocytes, and some neurons 1, 2. Replication within oligodendrocytes causes cell lysis and myelin breakdown 1. Histologically, variable lymphocytic inflammation and reactive gliosis with bizarre astrocytes are often seen in addition to demyelination with microglia/macrophages and residual oligodendrocytes containing abnormal nuclear inclusions 1. Clinically, PML presents as deficits corresponding to the location of the lesions, which tend to be localized in the subcortical areas of the cerebrum 1, 2. In this case, the cerebellar lesion caused coordination problems, dizziness and gait abnormalities.

It has been theorized that most people are infected in childhood by an archetype JC virus strain that is unable to invade glial cells. The archetype virus establishes latency in various body sites where it must undergo mutations of the noncoding control region in order to become neurotropic and replicate inside glial cells 4. However, only those who become immunosuppressed have the potential to progress to PML 4.

PML occurrence initially increased during the HIV era, when 5% of HIV patients developed PML 2. Recently, monoclonal antibodies such as natalizumab, efalizumab and rituximab have been shown to increase susceptibility to development of PML. Rituximab targets CD20+ B lymphocytes causing cell death and depletion, and it has been used effectively with chemotherapy regimens for treatment of non‐Hodgkin lymphoma (NHL) as well as some autoimmune diseases 3. The mechanism involved in rituximab causing PML is still an unresolved issue 4.

With limited drug options, treatment for PML has been focused on recovery of the immune system 1. Rapid increase in the cellular response, usually after starting cART therapy in HIV+ patients or discontinuation of immunosuppression in HIV patients, can cause immune reconstitution inflammatory syndrome (IRIS) characterized by severe inflammation and worsening of symptoms not explained by the original PML disease 1, 3. MRI shows contrast enhancement, mass effect or swelling, which are absent in PML without IRIS 2. Optimal care of PML patients with immune reconstitution must be closely monitored for possible IRIS complications 1.

The current patient's MCL remains in remission and she has not shown clinical progression of her PML with conservative supportive therapy.