Primary central nervous system lymphoma: coming or going?

PCNSL is a rare disease, affecting about 1200 people each year in the United States. Its very name highlights its most unique feature: a diffuse, large B-cell lymphoma limited to the CNS. It may involve the brain, cerebrospinal fluid, spinal cord, or the eyes which are actually neural tissue. How does such a malignancy arise in the only organ system of the body that is devoid of lymph nodes and lymphatics?

A small number of predominately T lymphocytes traffic in and out of the nervous system normally, and can be attracted to the central nervous system (CNS) by a wide variety of pathologic processes including infection. Normal B cells can also move into the CNS, but are less prominent than T cells. They can also be attracted by pathologic processes, such as multiple sclerosis, where the initiating insult is unknown. So how does primary central nervous system lymphoma (PCNSL) develop? Does a B cell become transformed during its excursion through the brain and get trapped there, or does a cell transformed in the periphery find its way into the CNS where it lodges and proliferates?

Clinical data give a few hints but no real answers to this question. Fewer than 10% of patients with presumed PCNSL have an identifiable site of systemic involvement at diagnosis, and often the search for that single site of extra-CNS disease must be meticulous or it is missed.¹  Because these sites are often small and involve a single extranodal area, it is unclear whether they represent the initial site of tumor that then spreads to the CNS, or if the direction of the tumor spread is in the opposite direction. Furthermore, about 10% of patients with PCNSL ultimately relapse with clinically apparent systemic disease, although more than 25% have systemic sites detected by (18)F-fluorodeoxyglucose PET imaging when they develop CNS relapse.¹  This may occur years after their initial diagnosis and apparently successful therapy. However, the 25% estimate is lower than expected if one postulates a systemic source of tumor cells, present at diagnosis, and treated only by a CNS-directed chemotherapy regimen, which is usually inadequate to eradicate systemic disease. The source of these cells and their biology has clinical as well as academic relevance. Understanding the origin of this disease and its potential triggers may hold an important key to improved therapies which are sorely needed.

In this spirit, the work of McCann and colleagues makes a valuable contribution.²  They demonstrated restricted V_H gene usage, particularly asymmetric usage of the V_H4 family, favoring the V4-34 gene in the tumor tissue of 12 patients with PCNSL. These findings expand previous data in a disease where securing tumor tissue can be particularly challenging. In addition, they also had blood and bone marrow specimens taken at diagnosis from 3 patients and were able to demonstrate a tumor-related subclone in the peripheral specimens of all three. They could also show that the subclones identified in the periphery were not present in the brain specimen and that continued diversification occurred in the systemic sites, but these subclones do not appear to reenter the CNS. These cells were present in blood or marrow of patients at diagnosis when there was no clinical evidence of systemic tumor. As noted by the authors, this work confirms the observations of Jahnke et al, who described the presence of a PCNSL clone in the blood and marrow of 2 of 24 patients.³  However, the CNS clone was not found systemically in the majority of their patients, and it seemed to carry no clinical significance as neither patient developed systemic lymphoma in the 2 years of their follow-up. McCann et al's study goes further by demonstrating additional changes in the peripheral clone, raising important questions as to the stimulus driving this continued differentiation. One limitation to the study of PCNSL has always been the paucity of pathologic material. McCann et al's study is no exception. Their specimens were obtained by stereotactic biopsy and after administration of dexamethasone. Could the limited size of the tissue sample and preoperative glucocorticoid use account for the apparent lack of subclones found in the brain sample? Were they just missed because of a sampling error or selective destruction by the steroid? The lack of movement of the subclones back into the CNS argues against trafficking into the CNS originally or the cells may have lost their ability to pass through the blood-brain barrier. Answers to these interesting questions demand more research and a larger sample size, but McCann et al have provided intriguing initial evidence that points the way.