A 60‐Year‐Old Woman with Multifocal Subcortical Infarcts

Clinical History

This 60‐year‐old woman presented in January 2013 with altered mental status and was found to have left MCA stenosis and multiple subcortical strokes (Fig 1A, 1B). The patient was readmitted in early October 2014 (Fig 1C) and early December 2014 with similar symptoms and both times an extensive workup was negative. However, she showed marked improvement with high‐dose steroids both times. Her symptoms worsened and following intubation an MRI showed additional infarcts (Fig 1D). Before a biopsy could be done she developed cerebral edema with herniation and death. A brain‐only autopsy revealed numerous widespread lesions. Coronal sections revealed focal red‐brown discoloration in the right occipital lobe (Fig 1E) and in the basal ganglia bilaterally (Fig 1F).

Figure 1.

 

Microscopic Pathology

Microscopic examination revealed widespread involvement of leptomeningeal and intraparenchymal vessels by numerous discohesive, partially necrotic, malignant‐appearing cells (Figure 1I,J), with round, variably‐sized, irregularly contoured nuclei and coarse chromatin with some prominent nucleoli (Figure 1K). Some vessels were partially or completely occluded by tumor and fibrin thrombi (Figure 1H) and tumor cells were seen within the vessel walls (Figure 1H). Sections of the neocortex and periventricular areas of discoloration and softening showed multiple foci of microinfarcts, many of which were near the gray–white matter junction (Figure 1G), particularly in areas where the vessels were much more severely and diffusely occluded by intravascular tumor. Ancillary work‐up showed the intravascular tumor cells to be immunopositive for CD3 (Figure 1M), CD56 (Figure 1N) and granzyme B (Figure 1O) as well as for in situ hybridization of Epstein‐Barr virus encoding RNA (EBER; Figure 1P), but predominantly negative for CD20 except for rare, small cells (Figure 1L). All tumor cells were immunonegative for CD30, Alk‐1 and EMA. A Ki‐67 immunostain labeled a subset of tumor cells. What is your diagnosis?

Diagnosis

Intravascular NK/T‐cell lymphoma with associated multifocal microinfarcts.

Discussion

This is a highly unusual case both from the clinical and neuropathological perspectives. At autopsy, neuropathologic examination showed intravascular lymphoma that was immunophenotypically of an NK/T‐cell type. Intravascular large cell lymphoma (IVLCL), a rare variant of extranodal non‐Hodgkin lymphoma, is thought to remain localized within vessels because of the absence of certain adhesion molecules, preventing diapedesis, although the exact mechanism is not well‐characterized 2. IVLCL is most commonly of a B‐cell immunophenotype, but T‐cell and natural killer (NK)‐cell variants have been described in < 30 reports in the literature 1. Because precise determination of lineage requires flow cytometric and gene rearrangement studies, the paucity of tumor cells in cases of IVLCL precludes further subtyping beyond what can be determined by immunohistochemistry as a generic “NK/T‐cell” phenotype. As opposed to B‐cell IVLCL, the NK/T‐cell phenotype is frequently positive by in‐situ hybridization for Epstein‐Barr virus encoding RNA (EBER) 2, 3. Clinical behavior is usually aggressive, but varies depending on the stage, and extent of disease.

There is no stereotypic radiological presentation for intravascular lymphoma. In the current case, the radiologic differential diagnosis initially included embolic disease given the multifocal punctate infarcts. However, the favorable symptomatic response to steroid therapy and recurrent infarcts involving multiple vascular territories made a more chronic steroid‐responsive process, such as lupus cerebritis, primary angiitis of the central nervous system (CNS) and intravascular lymphoma, more likely. When she re‐presented with new symptoms and radiologic findings, as well as a positive, high‐titer, nucleolar pattern ANA, the clinical suspicion shifted to include lupus cerebritis, given a reported history of lupus in the patient's mother, and malignancy, specifically intravascular lymphoma, although no systemic involvement was found on antemortem pathology examinations of skin, muscle and bone marrow biopsies. A brain biopsy was scheduled, but the patient expired prior to surgery.

While NK/T‐cell IVLCL often shows systemic involvement, particularly in the skin, a subset of cases is also detected in the brain, most commonly at autopsy 1. CNS involvement may account for the primary symptomatic presentation 5, and is often associated with the presence of microinfarcts 4, as in our case. Finally, although only a limited antemortem workup was performed, this case may represent the sole report of apparently exclusive CNS involvement by NK/T cell IVLCL, with the caveat of a lack of complete autopsy.