MAY 2007 CASE 1 A 63-YEAR-OLD MAN WITH DEMENTIA, ATAXIA AND VI NERVE PALSY Michel Mittelbronn1*; Stefan M. Kröber5*; Annika Wersebe2; Michael Weller3; Walter Hewer4; Richard Meyermann1; Edwin Kaiserling5; Rudi Beschorner1 1 Institute of Brain Research, 2 Department of Radiology, 3 Department of General Neurology Hertie Institute for Clinical Brain Research and 5 Institute of Pathology, University of Tuebingen, Tuebingen, Germany 4 Psychiatric and Neurological Hospital, Rottenmünster, Germany * M. Mittelbronn and S.M. Kröber contributed equally to this publication and thus share first authorship blood vessels (Figure 4). Multifocal infiltration was seen in the leptomeningeal and the ventricular spaces as well as in the brain parenchyma. On the right side, the VI nerve showed infiltration by tumor cells. Here, tumor cells were both located intravascular and extravascular spaces, the latter forming a mass with diffuse infiltration of adjacent tissue. Brisk mitotic figures were seen. The MIB-1-proliferation index focally reached 80%. The neoplastic cells were strongly positive for LCA, CD20, CD62-L, CD79a, Pax-5 and MUM-1. In one area of the sellar mass, intravascular tumor cells were surrounded by normal pituitary gland tissue (Figure 5). However, in other adjacent areas, the mass entirely consisted of CD20-positive neoplastic cells. The tumor cells were negative for CD3, CD5, CD29, markers of germinal center (CD10, bcl-6), and CD138. About 5% of the cells were T-cells by CD3 immunostains and most of these cells were CD8 positive. Nearly all organs were involved, with conspicuous sparing of the bone marrow, spleen and peripheral lymph nodes. CLINICAL HISTORY A 63-year-old man presented in February with three episodes of syncope accompanied by nausea, vomiting and sweating. In June, the patient became indifferent and began a 15 kg weight loss over the next 6 months. In July, ataxia, visual and cognitive decline were reported. Computed tomography (CT) and magnetic resonance imaging (MRI) scans were unremarkable. In August, CT scan revealed vascular encephalopathy and mild cerebral atrophy. By October he was suffering a right VI nerve palsy, increased ataxia, alternating hemiparesis, somnolence, myoclonus, dysarthria and progressive dementia. CT and MRI scans now showed small osteolytic zones in the dorsal sella. Furthermore, a 12-mm left periventricular enhancement led to the suspicion of an inflammatory disease. A CT scan in November revealed a 3.2 cm mass with heterogeneous contrast enhancement in the sellar region with partial destruction of the clivus and infiltration of the sphenoid sinus (Figure 1; arrow). The radiological differential diagnosis favored metastatic disease because of the presence of other suspect lesions in the left kidney and bilateral adrenal glands (not shown), but some sort of brainstem encephalitis was also considered. Later in November, he died of cardio-respiratory insufficiency. Figure 2. Figure 1. Figure 3. Figure 4. GROSS AND MICROSCOPIC PATHOLOGY Autopsy revealed a 4-cm gray-white mass in the parasellar area involving the clivus and the pituitary gland (Figure 2 arrows). Histological examination revealed large atypical cells (Figure 3) in sheets and within most of the intra- and extracerebral 466 Correspondence © 2007 The Authors Journal Compilation © 2007 International Society of Neuropathology • Brain Pathology Figure 5. DIAGNOSIS AND DISCUSSION Molecular pathology. DNA was extracted from the specimens by standard methods and analyzed by polymerase chain reaction (PCR) with primers for gene rearrangements of IgH by a standard protocol. PCR products were purified and analyzed by direct sequencing. Published sequences were used as references for the germline IgH V genes. In the index case, the PCR revealed an identical clonal IgH rearrangement in the intravascular and extravascular component, confirming involvement by the same intravascular large cell lymphoma (IVLL) cells. Sequence analysis of the PCR-amplified IgH gene demonstrated somatic mutations of the IgH gene. Diagnosis. Intravascular large B-cell lymphoma with extensive sellar involvement. Discussion. We report a 63-year-old man showing a fulminant clinical course consisting of progressive dementia, cerebellar ataxia, myoclonus, alternating hemiparesis, right VI nerve palsy and somnolence. Radiological changes appeared late, and the differential diagnosis comprised primarily a metastatic disease (eg, primary tumor like renal cell cancer or melanoma), a systemic hematopoietic disease or a brainstem encephalitis. A sellar mass of 3.2 cm in maximum diameter was demonstrated radiologically 1 month before death. Autopsy revealed a widespread IVLL with a prominent sellar mass. IVLL is a rare neoplasm characterized by the proliferation of lymphoma cells predominantly within the blood vessels. It most likely originates from a unique subtype of B cells, their normal counterpart being the germinal center/post germinal center B-cell (6). Immunohistochemical and gene expression profiles delineate IVLL as an activated diffuse large B-cell lymphoma. According to the WHO classification, IVLL is considered a subtype of diffuse large B-cell lymphoma (3). As IVLL often shows extensive extravascular infiltration, some cases previously diagnosed as primary CNS lymphomas may have included IVLL cases (4). PCR studies revealed that IVLL might be associated with EBV infection, but in the majority of cases such an association could not be established (1). Clinical manifestations are typically neurologic and dermatologic, but it is often diagnosed solely at autopsy (5). In general, IVLL is a very aggressive lymphoma which responds poorly to chemotherapy, and in most cases death, occurs a short time after presentation. The peculiar phenotype of intravascular proliferation of lymphoma cells is not well understood. Possibly, the tumor cells are unable to extravasate because of the disturbance of adhesion profile on the tumor cells and/or endothelial cells. Of these, the ß1-integrin CD29 is documented to be lacking on IVLL (7). In our case, the patient presented with a mass lesion which initially could be seen only 2 months before death, but reaching a diameter of 4 cm by the time of his death. The determinant histologic feature of IVLL is the intraluminal presence of tumor cells and thus the extensive extravascular involvement of CNS with diffuse infiltration of lymphoma cells seen in our cases is remarkable as this finding is described in only 13 cases in the literature (4). Beside the mass in the CNS, the large tumor in the adrenal glands and surrounding tissue is a known feature of IVLL (2, 8) and probably contributed to the fever (8) that is often encountered in IVLL (9). This is the first published case of an intravascular B-cell lymphoma to become predominantly manifest as a large sellar tumor mass. system: a report of five cases. Pathol Int 54:231– 236. 5. Khoury H, Lestou VS, Gascoyne RD, Bruyere H, Li CH, Nantel SH, Dalal BI, Naiman SC, Horsman DE (2003) Multicolor karyotyping and clinicopathological analysis of three intravascular lymphoma cases. Mod Pathol 16:716–724. 6. Kröber SM, Aepinus C, Bültmann B, Kaiserling E (2001) Intravascular large B-cell lymphoma. Histogenesis—a molecular biological study. Pathol Res Pract 197:342A. 7. Ponzoni M, Arrigoni G, Gould VE, Del CB, Maggioni M, Scapinello A, Paolino S, Cassisa A, Patriarca C (2000) Lack of CD 29 (beta1 integrin) and CD 54 (ICAM-1) adhesion molecules in intravascular lymphomatosis. Hum Pathol 31:220–226. 8. Wick MR, Mills SE, Scheithauer BW, Cooper PH, Davitz MA, Parkinson K (1986) Reassessment of malignant “angioendotheliomatosis”. Evidence in favor of its reclassification as “intravascular lymphomatosis”. Am J Surg Pathol 10:112–123. 9. Zeidman A, Horowitz A, Fradin Z, Cohen A, Wolfson L, Elimelech O (2004) Fulminant intravascular lymphoma presenting as fever of unknown origin. Leuk Lymphoma 45:1691–1693. ACKNOWLEDGMENTS We thank Gudrun Albrecht, Institute of Brain Research, University Tuebingen, Germany, for excellent photographical preparations. REFERENCES 1. Abe S, Kumanishi T (1995) Molecular genetic analysis of intravascular malignant lymphomatosis cells. Rinsho Shinkeigaku 35:1473–1475. 2. Demirer T, Dail DH, Aboulafia DM (1994) Four varied cases of intravascular lymphomatosis and a literature review. Cancer 73:1738–1745. 3. Gatter KC, Warnke RA (2001) Intravascular large B-cell lymphoma. In: Pathology and Genetics. Tumours of Haematopoietic and Lymphoid Tissues. ES Jaffe, NL Harris, H Stein, JW Vardiman (eds), pp. 177–178. WHO: IARC Press, Lyon. 4. Imai H, Kajimoto K, Taniwaki M, Miura I, Hatta Y, Hashizume Y, Watanabe M, Shiraishi T, Nakamura S (2004) Intravascular large B-cell lymphoma presenting with mass lesions in the central nervous Correspondence 467 © 2007 The Authors Journal Compilation © 2007 International Society of Neuropathology • Brain Pathology