Review Histopathology, Pathogenesis and Molecular Genetics in Primary

Histol Histopathol (2004) 19: 211-219 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review Histopathology, pathogenesis and molecular genetics in primary central nervous system lymphomas M. Nakamura, K. Shimada, E. Ishida and N. Konishi Department of Pathology, Nara Medical University, Nara, Japan Summary. Recent increases in the incidence of primary or lymphatics within the nervous system, however, the central nervous system lymphoma (PCNSL), a rare non- pathogenesis and histogenetic origin of PCNSL in Hodgkin’s lymphoma arising in the brain, have been immunocompetent patients is still poorly understood noted in both immunodeficient and immunocompetent regardless of the phenotypic similarities between CNS patients. Compared with lymphomas originating outside and non-CNS lymphomas. the central nervous system, the biology of PCNSL at the molecular or cytogenetic level has not been well Epidemiology characterized, yet it is important to thoroughly understand the etiology of this rare malignant lymphoma The incidence of PCNSL has been increasing if effective therapies are to be developed. This review steadily since the 1970s. Data from the Surveillance, will focus on the epidemiology, clinical aspects, Epidemiology and End Results (SEER) database of the histopathology, pathogenesis, and molecular genetics of National Cancer Institute show that PCNSL increased this aggressive, extranodal lymphoma in more than 10-fold from 0.025/100000 in 1973 to immunocompetent patients. 0.3/100,000 in 1991 and the forecasted incidence for the year 2000 is 0.5/100,000 (Corn et al., 1997). The Key words: Primary central nervous system PCNSL/glioblastoma rate was 1/250 in 1974 and rose to lymphomas, 6q LOH, R-PTP-κ, p14ARF, p16INK4A 1/36 in 1980, reaching 1/6 in 1991 (Eby et al., 1988). PCNSLs thus account for more than 6% of all intracranial tumors (Cote et al., 1996) and for 1-2% of Introduction all extranodal lymphomas (Fine et al., 1993; Miller et al., 1994). Primary central nervous system lymphoma (PCNSL) The rising incidence of PCNSL can be explained, in is defined as a diffuse lymphoma presenting in the brain part, by the increasing spread of the human or spinal cord in the absence of systemic lymphoma. immunodeficiency virus (HIV) over the last two decades Morphologically, 98% of these tumors are large B-cell, and the more prevalent use of immunosuppressive diffuse, lymphomas categorized as high-grade non- agents. In fact, PCNSL is diagnosed in ~9.0% of the Hodgkin’s type (Harris et al., 1994; Weber et al., 2000). HIV-infected population (Rosenblum et al., 1988). The Once considered a rare tumor, accounting for less than reason for the increased frequency of the disease in 1% of all systemic non-Hodgkin’s lymphomas (NHLs), immunocompetent individuals, however, is less clear the incidence of PCNSLs in immunocompetent patients and cannot be explained by advances in neuroimaging or has been markedly increasing over the past decades other diagnostic techniques. Neither have suspected (Cote et al., 1996). Although it remains relatively rare, it environmental or behavioral risk factors been proposed. is, therefore, an increasingly important differential As PCNSL primarily affects individuals aged 60 and diagnosis for the physician presented with intracranial over, the general aging of the population might offer an lesions. explanation; however, the data indicate an increase Recent improvements in histopathology and across all age groups. For whatever reason or reasons, it immunohistochemical techniques have definitively appears that the number of patients with PCNSL is likely established the lymphoid nature of both PCNSLs and to continue to increase over the next decade. systemic lymphomas. Because there are no lymph nodes Clinical aspects Offprint requests to: Noboru Konishi, Department of Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan. To understand the specific issues related to the Fax: +81 744 23 5687. e-mail: [email protected] treatment and diagnosis of PCNSL, one must first 212 Histopathogenesis in PCNSL recognize the unique pathophysiology of the tumor. As and those that contain high-grade Burkitt-like cells previously mentioned, PCNSL has been described in (Bataille et al., 2000). Approximately 98% of PCNSLs patients at all ages, but most cases arise in the sixth are CD20+ B-cell lymphomas (Fig. 1C), usually of the decade with a male to female ratio of 1.5 (Fine et al., diffuse large-cell, immunoblastic, or lymphoblastic 1993). Because of the high replicative index, the interval subtypes, and can be identified immunohistochemically between the onset of symptoms and diagnosis is usually with the B-cell marker L26. In a series of 226 patients, short (1-3 months); focal motor and/or sensitive Blay and colleagues (Blay et al., 1998) found that more neurological deficits are frequent, with manifestations of than 90% of PCNSLs fell within the Working intracranial hypertension, personality disturbances, and Formulation groups designated G (diffuse large cells) behavioral changes when the frontal lobe is affected. and H (immunoblastic) with only 5% characterized as Systemic symptoms are very rare and epileptic seizures group J (Burkitt-type cells); only a very few were are less frequent than in glial tumors due to the phenotypically low-grade small lymphocytic tumors. preferential involvement of the white matter and deep The majority of the tumors express monoclonal surface structures as opposed to the cortex (Fine et al., 1993; or cytoplasmic immunoglobulins, the most frequent Herrlinger et al., 1999). combination being IgM/kappa. In up to 70% of cases, the lymphomatous lesion is In contrast, T-cell-rich B-lymphoma, true T- usually supratentorial and single at diagnosis, but phenotype lymphoma (Villegas et al., 1997), CD30/Ki- frequently becomes multifocal in the late phase of the 1+ anaplastic large cell lymphoma, and primary disease. The most frequent sites of origin are, in most Hodgkin’s disease of the brain (Klein et al., 1999) are cases, the basal ganglia, the corpus callosus, and/or the very rare and must be distinguished from true T-cell periventricular subependymal tissues. This peculiarity lymphoma. T-cell lymphomas only constitute about 2% accounts for the frequent liquoral spread of neoplastic of all PCNSL and are seen mainly in immunocompetent lymphocytes, even though cytological examination of patients. They occur more frequently in posterior fossa the cerebrospinal fluid (CSF) is positive in no more than locales, particularly in the cerebellum, and also show a 40% of patients. Only 7% of PCNSL have an propensity to arise in the leptomeninges. Some subsets exclusively leptomeningeal localization (Lachance et al., of Ki-1 lymphomas are considered to be of T-cell origin. 1991); a single and circumscribed involvement of the The diagnosis of Hodgkin’s disease rests on the spine is a very sporadic finding (McDonald et al., 1995). identification of Reed-Sternberg cells confirmed by immunohistochemistry. Prior to more modern Histopathology immunohistochemical techniques, many cases diagnosed as “primary intraparenchymal Hodgkin’s disease”, based Histologically, PCNSL is indistinguishable from on the presence of atypical immunoblasts resembling systemic NHL; furthermore, analysis of cell surface Reed-Sternberg cells, may have actually been large-cell markers, including NCAM and integrins, is also anaplastic or pleomorphic lymphomas. identical to that of systemic lymphoma. Biologically, Angiotropic lymphomas, also known as PCNSL behaves in an aggressive fashion, and it should intravascular lymphomas, affect multiple organ systems. be considered a high-grade tumor. Microscopically, (Fig. 1D) Accumulations of large B-cells within small PCNSL diffusely infiltrates brain parenchyma with an and medium vessels lead to vascular occlusion and angiocentric growth pattern forming collars or disseminated small infarcts. Absent or reduced perivascular cuffing by tumor cells; some tumors may expression of beta-2 integrins on tumor cells may even invade the blood vessel wall (Fig. 1A,B). In contribute to an impaired capability for extravasation. addition to malignant lymphoma cells, there are varying numbers of small, benign, reactive T-lymphocytes Pathogenesis infiltrating the tumor; reactive astrocytes are also common. Tumor cells freely invade the normal In immunosuppressed patients, PCNSL virtually surrounding brain, giving the appearance of encephalitis, always arises from Epstein-Barr virus (EBV)-infected B- and autopsy studies demonstrate widespread infiltration lymphocytes (Forsyth et al., 1996; Lutz et al., 1994). The of normal tissue. Virtually all PCNSLs show a diffuse cells are latently infected after primary viral infection growth pattern; a follicular growth pattern has not been and reside within the individual for the remainder of described. their life. When either iatrogenic or acquired The malignant cells are clearly identified as white immunosuppression develops, loss of suppressor T-cells blood cells with leukocyte common antigen (LCA) controlling the immortalized latently-infected immunostaining, but a small number of PCNSLs may be lymphocytes allows these precursors to proliferate immunonegative. These reactive infiltrative cells are uncontrollably and develop into a neoplasm. typically CD4+ T-lymphocytes. According to the The pathogenesis in immunocompetent patients, Revised European-American Classification of Lymphoid however, is not so well-documented.

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