Contributed by Katherine E. Schwetye, MD, PhD1, David Rodriguez, MD2, Robert E. Schmidt, MD, PhD1, Sonika Dahiya, MD1
Department of 1Pathology and Immunology, Division of Neuropathology, 2Mallinckrodt Institute of Radiology, Department of Neuroradiology
Washington University School of Medicine, St. Louis, MO, USA
The patient was a 60-year-old woman with a history of hypertension, hyperlipidemia, diabetes mellitus, and sickle cell trait. She initially presented in January 2013 with altered mental status, and was found to have multiple left middle cerebral artery (MCA) distribution subcortical strokes as well as left internal carotid artery stenosis and multifocal stenosis of the left MCA branches (Figs. 1A, 1B). The patient was readmitted in early October 2014 and early December 2014 with similar symptoms. An extensive laboratory work-up in October 2014 included multiple CSF analyses, skin and muscle biopsy, all of which were negative for malignancy. Similarly, an extensive work-up for infectious etiologies and a hepatitis panel were negative. A serum ANA was positive at 1:5120 (nucleolar), and there was a reported history of lupus in her mother. Following treatment with high-dose intravenous steroids, the patient showed marked improvement in her mental status. She was seen as an outpatient in late November 2014, and was started on CellCept in addition to prednisone.
She re-presented in early December 2014 with word-finding difficulty and bilateral lower extremity weakness. MRI showed multiple punctate infarcts again within the left MCA territory as well as new punctate infarcts within the right frontal and parietal lobes compatible with the right MCA territory (Fig. 1C). The absent flow void compatible with left internal carotid artery high-grade stenosis or occlusion was unchanged. Again, extensive laboratory work-up revealed no infectious etiologies and a bone marrow aspirate was likewise negative for malignancy. Following treatment with high-dose intravenous steroids and a dose of Cytoxan, the patient again showed marked improvement in her mental status, and was discharged to inpatient rehabilitation in mid-December 2014.
She was re-admitted on December 29, 2014, presenting with worsening symptoms. She was initially started on empiric therapies for possible bacterial and viral infections, and was soon intubated due to respiratory distress and transferred to the Intensive Care Unit. MRI performed December 31, 2014 showed more extensive areas of acute infarcts involving both cerebral hemispheres, most prominent in the left MCA territory (Fig. 1D). There was also linear enhancement along the brain surface. An EEG showed seizure activity, although the patient was given maximum doses of various anti-epileptic agents. Steroids were held until a brain biopsy could be obtained. The day of the planned biopsy, the patient had worsening mental status with blown pupils. A head CT scan showed diffuse cerebral edema resulting in uncal and tonsillar herniation. The patient was given 1000 mg of methylprednisolone, with no improvement. Osmotics were started but were withdrawn due to elevated sodium levels. The patient expired and a limited (brain only) autopsy was performed.
The unfixed brain weighed 1460 gm. Although the dura was unremarkable, the leptomeninges appeared mildly opacified. The entire brain appeared softened and discolored. Coronal sections of the cerebrum showed diffuse effacement of the sulci, consistent with edema along-with widespread discoloration of both gray and white matter, especially in periventricular regions, a larger focus of punctate red-brown discoloration in the right occipital region (Fig. 1E), foci of laminar necrosis in the right and left occipital cortices, and minute red-brown lesions in bilateral basal ganglia and thalami (Fig. 1F), suggestive of micro-infarcts. The white matter throughout appeared friable, and particularly so in the corpus callosum. Transverse sections of the brainstem showed antero-posterior elongation in the midbrain, and multifocal areas of red-brown discoloration, suggestive of infarction, in the pons. The medulla was diffusely discolored and softened. Radial sections of the cerebellum showed hemorrhage and softening of the bilateral tonsils.
Microscopic examination revealed widespread involvement of leptomeningeal and intraparenchymal vessels by numerous discohesive, partially necrotic, malignant-appearing cells (Figs. 1I, 1J), with round, variably-sized, irregularly-contoured nuclei and coarse chromatin with some prominent nucleoli (Fig. 1K). Some vessels were partially or completely occluded by tumor and fibrin thrombi (Fig. 1H). In some foci, the tumor cells were seen within the vessel walls (Fig. 1H), although they were not unequivocally noted in the parenchyma. 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 (Fig. 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 (Fig. 1M), CD56 (Fig. 1N), and granzyme B (Fig. 1O) as well as for in-situ hybridization of Epstein-Barr virus encoding RNA (EBER; Fig. 1P), but predominantly negative for CD20 except for rare, small cells (Fig. 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?