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The history of the pathologic evaluation of CNS lymphoma provides an interesting perspective on this neoplasm of mysterious origin. In 1929, Bailey (36) reported two cases of brain tumors that he called "perithelial sarcoma"; these cases are now regarded as probably the first reported primary CNS lymphomas. Over the next 20 years, there were occasional reports in the pathology and neurosurgery literature of other tumors with similar features. However, because of considerable confusion over nomenclature and limited knowledge of histopathology, these tumors received many different names, including histiocytic sarcoma, reticulum cell sarcoma, microgliomatosis, perivascular sarcoma, perithelial sarcoma, periadventitial sarcoma, adventitial sarcoma, reticuloendothelial sarcoma, plasmacytic myeloma, round cell sarcoma, and reticulohistiocytic granulomatous encephalitis (36,37,38,39).
In 1948, Russell and colleagues (39) were the first to report that the histopathologic features of tumors in their series and those of other cases previously reported were similar. They proposed that the cell of origin was the microglia and postulated that it represented the reticuloendothelial system of the CNS, because its staining characteristics were similar to those of macrophages elsewhere in the body. They classified these lesions as "microgliomatosis," thereby popularizing a term introduced by two German pathologists, Benedek and Juba (40), a few years earlier (39). In 1963, Burstein et al (5) reported 41 cases of "primary sarcoma of the brain" and concluded that the histiocyte was the cell of origin. This hypothesis was further supported and clarified by Henry et al (6), who reported 83 brain tumors, in which the cell of origin was a "primitive, fixed, poorly-differentiated, pluripotential mesenchymal" cell located in the perivascular areas throughout the body. Because the histologic appearance of these tumors was within the spectrum of extraneural lymphomas, Henry et al (6) introduced the term primary malignant lymphoma of the CNS and showed that the tumor is composed of transformed lymphocytes, not transformed histiocytes (6).
This conclusion produced its own set of contradictions and controversy. First, the brain has no endogenous lymphoid tissue. Second, the blood-brain barrier protects and isolates the brain from the normal immune response seen in the rest of the body. Finally, the brain does not possess a major histocompatibility complex antigen expression. How, then, can a lymphocyte exist outside blood vessels in the CNS? The answer to this question is still being sought.
Today, it is generally agreed that CNS lymphoma and systemic extracerebral non-Hodgkin lymphoma share the same cell of origin (41). However, the actual cell of origin remains a mystery. There are two theories: (a) lymphocytes are attracted to the CNS because of an infection or inflammatory process, probably viral in nature, followed by a transformation event, which turns the lymphocytes into neoplastic cells; and (b) B lymphocytes that are already carrying a CNS-specific binding marker are activated, proliferate, and undergo neoplastic transformation (7).
Historical Perspective