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Primary Central Nervous System Lymphoma

      Primary central nervous system lymphomas constitute less than 2% of primary brain tumors. Although their cause is unknown, they are in some way related to immunosuppression. The typical patient is a middle-aged man who displays the syndrome of a subacute mass lesion. These tumors most commonly occur as a single, bulky mass in the hemispheric white matter or the deep gray matter, but multiple tumors occur in approximately a fourth of the patients. The findings on computed tomography are distinctive and nearly pathognomonic. The majority of these tumors are B-cell lymphomas with aggressive histologic changes. Surgical intervention should be reserved for tissue diagnosis because surgical removal does not seem to influence the outcome. Conventional therapy consists of whole-brain irradiation with or without chemotherapy. The prognosis for patients with such tumors is grim, the median duration of survival being less than 2 years with conventional therapy and the 5-year survival being less than 5%.
      Lymphomas are the fifth most common cause of cancer-related deaths in the United States.
      • Ultmann JE
      • Jacobs RH
      The non-Hodgkin's lymphomas.
      Approximately 50,000 new cases of lymphoma are diagnosed each year, 31,700 of which are non-Hodgkin's lymphoma. Non-Hodgkin's lymphoma may affect the nervous system at various levels and directly or indirectly cause a wide spectrum of neurologic illnesses.
      • Cairncross JG
      • Posner JB
      Neurological complications of malignant lymphoma.
      • Mead GM
      • Kennedy P
      • Smith JL
      • Thompson J
      • Macbeth FRM
      • Ryall RDH
      • Williams CJ
      • Whitehouse JMA
      Involvement of the central nervous system by non-Hodgkin's lymphoma in adults: a review of 36 cases.
      • Mackintosh FR
      • Colby TV
      • Podolsky WJ
      • Burke JS
      • Hoppe RT
      • Rosenfelt FP
      • Rosenberg SA
      • Kaplan HS
      Central nervous system involvement in non-Hodgkin's lymphoma: an analysis of 105 cases.
      Secondary involvement of the nervous system typically occurs late in the course of non-Hodgkin's lymphoma and can be predicted on the basis of such factors as young age, diffuse histologic changes, early bone marrow involvement, and widespread systemic disease.
      • Litam JP
      • Cabanillas F
      • Smith TL
      • Bodey GP
      • Freireich EJ
      Central nervous system relapse in malignant lymphomas: risk factors and implications for prophylaxis.
      • Levitt LJ
      • Dawson DM
      • Rosenthal DS
      • Moloney WC
      CNS involvement in the non-Hodgkin's lymphomas.
      Even when systemic non-Hodgkin's lymphoma initially manifests with involvement of the nervous system, the spectrum of the disease is similar—that is, epidural spinal cord compression and neoplastic meningitis.
      • Ersbøll J
      • Schultz HB
      • Thomsen BLR
      • Keiding N
      • Nissen NI
      Meningeal involvement in non-Hodgkin's lymphoma: symptoms, incidence, risk factors and treatment.
      In contrast, metastatic spread of systemic lymphoma to the cerebral parenchyma is rare (probably present in fewer than 1% of neurologic cases at autopsy).
      • Hærni-Simon G
      • Suchaud JP
      • Eghbali H
      • Coindre JM
      • Hærni B
      Secondary involvement of the central nervous system in malignant non-Hodgkin's lymphoma.
      Most intracranial malignant lymphomas are primary and are of the non-Hodgkin's lymphoma type. These primary central nervous system non-Hodgkin's lymphomas (PCNSL) are uncommon tumors of the nervous system, constituting 0.85 to 2.0% of all primary brain tumors.
      • Freeman C
      • Berg JW
      • Cutler SJ
      Occurrence and prognosis of extranodal lymphomas.
      • Schiffer D
      • Chiò A
      • Giordana MT
      • Novero D
      • Palestro G
      • Soffietti R
      • Vasario E
      Primary lymphomas of the brain: a clinco-pathologic review of 37 cases.
      The frequency of occurrence of PCNSL, however, is increasing beyond that which can be accounted for by improved diagnostic capabilities and exceeds the increasing frequency of systemic lymphoma.
      • Eby NL
      • Grufferman S
      • Flannelly CM
      • Schold Jr, SC
      • Vogel FS
      • Burger PC
      Increasing incidence of primary brain lymphoma in the US.
      Aside from the observation that PCNSL begins and develops in the nervous system, and in most cases does not spread elsewhere, the histologic findings are identical to the malignant lymphocytes of systemic non-Hodgkin's lymphoma.
      • Helle TL
      • Britt RH
      • Colby TV
      Primary lymphoma of the central nervous system: clinicopathological study of experience at Stanford.
      If one considers the unique nature of the central nervous system site, treatment principles applicable to systemic non-Hodgkin's lymphoma should also be relevant to PCNSL.

      PATHOLOGIC FEATURES

      The tumor currently called PCNSL was first described by Bailey
      • Bailey P
      Intracranial sarcomatous tumors of leptomeningeal origin.
      as a “perithelial small cell sarcoma.” Various morphologic criteria have been used to categorize the cell of origin of this tumor; thus, PCNSL has previously been referred to as reticulum cell sarcoma,
      • Kinney TD
      • Adams RD
      Reticulum cell sarcoma of the brain.
      microglioma,
      • Russell DS
      • Marshall AHE
      • Smith FB
      Microgliomatosis: a form of reticulosis affecting the brain.
      and immunoblastic sarcoma.
      • Burstein SD
      • Kernohan JW
      • Uihlein A
      Neoplasms of the reticuloendothelial system of the brain.
      The neoplastic cells of PCNSL, however, are identical to those that constitute extracranial lymphomas. On the basis of morphologic, ultrastructural, and immunologic studies, they are neoplastic lymphocytes that recapitulate the pathologic spectrum of the lymphomas that occur outside the central nervous system.
      • Helle TL
      • Britt RH
      • Colby TV
      Primary lymphoma of the central nervous system: clinicopathological study of experience at Stanford.
      • Horvat B
      • Pena C
      • Fisher ER
      Primary reticulum cell sarcoma (microglioma) of brain: an electron microscopic study.
      • Varadachari C
      • Palutke M
      • Climie ARW
      • Weise RW
      • Chason JL
      Immunoblastic sarcoma (histiocytic lymphoma) of the brain with B cell markers.
      • Allegranza A
      • Mariani C
      • Giardini R
      • Brambilla MC
      • Boeri R
      Primary malignant lymphomas of the central nervous system: a histological and immunohistological study of 12 cases.
      • Kumanishi T
      • Washiyama K
      • Saito T
      • Nishiyama A
      • Abe S
      • Tanaka T
      Primary malignant lymphoma of the brain: an immunohistochemical study of eight cases using a panel of monoclonal and heterologous antibodies.
      Modern nomenclature classifies tumors on the basis of the predominant cell type. Three major systems are currently used. Our institution uses the Working Formulation from the National Cancer Institute to classify non-Hodgkin's lymphomas, and such terminology will be used throughout this report (Table 1). The Working Formulation classification of non-Hodgkin's lymphomas for clinical usage, which was published in 1982, is a clinicopathologic schema that facilitates translation among the major systems of classification.
      • Non-Hodgkin's Lymphoma Pathologic Classification Project
      National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage.
      Table 1Pathologic Classifications of Non-Hodgkin's Lymphomas
      FCC = follicular center cell; ML = malignant lymphoma.
      Data from the Non-Hodgkin's Lymphoma Pathologic Classification Project.
      • Non-Hodgkin's Lymphoma Pathologic Classification Project
      National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage.
      Working Formulation classificationRappaport classificationLukes and Collins classification
      Low grade
       ML, small lymphocyticDiffuse lymphocytic, well differentiatedSmall lymphocytic and plasmacytoid lymphocytic
       ML, follicular, predominantly small cleaved cellNodular, poorly differentiated lymphocyticSmall cleaved FCC, follicular only or follicular and diffuse
       ML, follicular, mixed small cleaved and large cellNodular, mixed lymphocytic-histiocyticSmall cleaved FCC, follicular; large cleaved FCC, follicular
      Intermediate grade
       ML, follicular, predominantly large cellNodular histiocyticLarge cleaved or noncleaved (or both) FCC, follicular
       ML, diffuse small cleaved cellDiffuse lymphocytic, poorly differentiatedSmall cleaved FCC, diffuse
       ML, diffuse, mixed small and large cellDiffuse mixed lymphocytic-histiocyticSmall cleaved, large cleaved, or large noncleaved FCC, diffuse
       ML, diffuse large cellDiffuse histiocyticLarge cleaved or noncleaved FCC, diffuse
      High grade
       ML, large cell immunoblasticDiffuse histiocyticImmunoblastic sarcoma, T-cell or B-cell type
       ML, lymphoblasticLymphoblastic convoluted or nonconvolutedConvoluted T-cell
       ML, small noncleaved cellUndifferentiated, Burkitt's and non-Burkitt'sSmall noncleaved FCC
      Miscellaneous
       Composite
       Mycosis fungoides
       Histiocytic
       Extramedullary plasmacytoma
       Unclassifiable
      * FCC = follicular center cell; ML = malignant lymphoma.
      Most PCNSL are bulky tumors, contiguous with either the meningeal or the ventricular surface (Fig. 1). The cut surface is dark or pale gray and is characteristically granular. Some PCNSL are diffusely infiltrating lesions or have a multinodular pattern. At least 20% of patients have multiple lesions at the time of initial manifestation, and some series report incidence figures as high as 33.5%.
      • Murray K
      • Kun L
      • Cox J
      Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature.
      Although many PCNSL are supratentorial, as many as 25% occur infratentorially.

      O'Neill BP, Banks PM, O'Fallon JR, Earle JD, Colgan JP: Primary CNS non-Hodgkin's lymphoma (PCNSL): a clinical, radiologic, and pathologic study of 64 patients in the CT era (1974–1986) (submitted for publication)

      Some sites, such as the corpus callosum and basal ganglia, are sufficiently characteristic to approach diagnostic significance
      • Jack Jr, CR
      • O'Neill BP
      • Banks PM
      • Reese DF
      Central nervous system lymphoma: histologic types and CT appearance.
      (Table 2).
      Figure thumbnail gr1
      Fig. 1Coronal section from 64-year-old man with primary central nervous system lymphoma. Note bulky basal ganglia tumor (large arrow) and second smaller tumor in corpus callosum (small arrow).
      Table 2Location of Primary Central Nervous System Lymphomas in 424 Cases
      From Murray and associates.
      • Murray K
      • Kun L
      • Cox J
      Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature.
      By permission of the American Association of Neurological Surgeons.
      Total
      LocationSubgroup (%)No.%
      Supratentorial22152.1
       Frontal26.2
       Temporal15.4
       Parietal14.0
       Occipital4.5
       Deep nuclei13.8
       Pineal0.5
       Other
      Not otherwise specified.
      28.5
      Infratentorial6114.4
       Cerebellum80.3
       Brain stem16.4
       Spinal cord3.3
      Multiple
      Multiple lesions within a single hemisphere, lesions involving more than one hemisphere, or involvement of the meninges.
      14233.5
      * Not otherwise specified.
      Multiple lesions within a single hemisphere, lesions involving more than one hemisphere, or involvement of the meninges.
      In all cases studied, the main microscopic pathologic feature has been a diffuse cytologic process; follicular forms (in the Working Formulation; nodular forms in the Rappaport classification) do not occur. In general, these tumors begin as perivascular infiltrates, spread centrifugally, and eventually invade intact brain parenchyma (Fig. 2). In advanced tumors, large expansive areas of lymphoma retain no perivascular relationship. The cellular infiltrate, which usually is dense, consists of a mixture of cells including perivascular histiocytes, microglia, plasma cells, and several types of lymphocytes; the predominant cell type determines the pathologic classification. In most cases, the pathologic infiltrate consists predominantly of large lymphoid cells. Necrosis may occasionally be present.
      • O'Neill BP
      • Kelly PJ
      • Earle JD
      • Scheithauer B
      • Banks PM
      Computer-assisted stereotaxic biopsy for the diagnosis of primary central nervous system lymphoma.
      The periphery of the tumor may be composed of hypertrophic reactive astrocytes that, if sufficient pleomorphism occurs, may mimic a low-grade astrocytoma.
      • Kepes JJ
      Astrocytomas: old and newly recognized variants, their spectrum of morphology and antigen expression.
      Thus, as in extranodal lymphomas elsewhere in the body, diagnostic confusion can occur if biopsy specimens are obtained from the peripheral part of the tumor.
      Figure thumbnail gr2
      Fig. 2Perivascular accumulation (arrow) of neoplastic lymphocytes and infiltration of surrounding brain. (Hematoxylin-eosin; ×100.)
      Unlike malignant gliomas, endothelial proliferation is not a feature of non-Hodgkin's lymphomas; instead, an intense vascular response and perivascular infiltration are evident. The histologic hallmark of cerebral lymphomas is the multiplication of basement membranes of those blood vessels that are involved by the lymphomatous process.
      • Henry JM
      • Heffner Jr, RR
      • Dillard SH
      • Earle KM
      • Davis RL
      Primary malignant lymphomas of the central nervous system.
      When stained with silver reticulum stains (Fig. 3), this buildup is strikingly demonstrated (a finding that prompted the earlier term “reticulum cell sarcoma”).
      Figure thumbnail gr3
      Fig. 3Perivascular infiltration with reticulum production in cerebral lymphoma. (Reticulum stain; ×100.)
      In the Working Formulation classification, most non-Hodgkin's lymphomas are of intermediate to high grade and typically are of either diffuse large cell or diffuse mixed cell histologic type. Less common forms are the immunoblastic and small cleaved cell types (more detailed histologic descriptions are provided elsewhere
      • Ultmann JE
      • Jacobs RH
      The non-Hodgkin's lymphomas.
      • Non-Hodgkin's Lymphoma Pathologic Classification Project
      National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage.
      • DeVita Jr, VT
      • Hellman S
      Hodgkin's disease and the non-Hodgkin's lymphomas.
      • Rappaport H
      Tumors of the hematopoietic system.
      ). Also, we and others have recently seen primary T-cell lymphomas of the brain without clinical evidence of systemic T-cell lymphoma or acquired immunodeficiency syndrome (AIDS).
      • O'Neill BP
      • Kelly PJ
      • Earle JD
      • Scheithauer B
      • Banks PM
      Computer-assisted stereotaxic biopsy for the diagnosis of primary central nervous system lymphoma.
      • Grant JW
      • Gallagher PJ
      • Jones DB
      Primary cerebral lymphoma: a histologic and immunohistochemical study of six cases.
      Immunohistochemical studies can provide a more accurate classification of lymphoid tumors, which can be applied to biopsy material even when it is obtained by means of a stereotactic procedure.
      • O'Neill BP
      • Kelly PJ
      • Earle JD
      • Scheithauer B
      • Banks PM
      Computer-assisted stereotaxic biopsy for the diagnosis of primary central nervous system lymphoma.
      In our recent review of 64 patients with PCNSL (Table 3), immunohistochemical data were available for 13.

      O'Neill BP, Banks PM, O'Fallon JR, Earle JD, Colgan JP: Primary CNS non-Hodgkin's lymphoma (PCNSL): a clinical, radiologic, and pathologic study of 64 patients in the CT era (1974–1986) (submitted for publication)

      As expected, most tumors were of the B-cell type, but three T-cell lymphomas were identified. The small numbers of T-cell PCNSL may simply reflect the recent routine application of immunohistochemical studies. Occasionally, a relatively undifferentiated “small, blue cell tumor” poses a diagnostic challenge to neuropathologists. For such lesions, immunohistochemical staining, as well as staining for common leukocyte antigen, epithelial membrane antigen, and S-100 protein, and also electron microscopy are often useful. In these instances, electron microscopy reveals no junctional complexes (desmosomes), a feature that distinguishes non-Hodgkin's lymphomas from epithelially derived tumors.
      • Kepes JJ
      Astrocytomas: old and newly recognized variants, their spectrum of morphology and antigen expression.
      Table 3Distribution of Histologic Findings
      Based on the working formulation classification of non-Hodgkin's lymphomas proposed by the National Cancer Institute.
      in Series of 64 Mayo Patients With Primary Central Nervous System Lymphoma (1974–1986)
      FindingNo. of cases
      Light microscopy
       Diffuse large cell35
       Diffuse large cell, immunoblastic8
       Diffuse mixed cell10
       Small lymphocytic2
       Other9
      Small cleaved cell5
        Small noncleaved cell4
        Burkitt's1
        Non-Burkitt's3
      Immunohistochemistry
       B cell10
        κ3
        λ5
       T cell3
        Helper T cell1
      * Based on the working formulation classification of non-Hodgkin's lymphomas proposed by the National Cancer Institute.
      The frequency and distribution of PCNSL histologic types were calculated by Hobson and associates
      • Hobson DE
      • Anderson BA
      • Carr I
      • West M
      Primary lymphoma of the central nervous system: Manitoba experience and literature review.
      from reports of 352 patients in the literature. On the basis of their findings, one can conclude that diffuse large cell lymphoma (or histiocytic lymphoma in the Rappaport classification) is the most common histologic type, occurring in more than half of the cases. Our experience has been similar (Table 3); 43 of 64 patients had diffuse large cell lymphoma, 8 of which were immunoblastic.
      • O'Neill BP
      • Kelly PJ
      • Earle JD
      • Scheithauer B
      • Banks PM
      Computer-assisted stereotaxic biopsy for the diagnosis of primary central nervous system lymphoma.
      Only the study by Jellinger and colleagues
      • Jellinger K
      • Radaskiewicz T
      • Slowik F
      Primary malignant lymphomas of the central nervous system in man.
      showed a trend toward more favorable histologic features—that is, well-differentiated and poorly differentiated lymphocytic lymphomas (Rappaport classification) in most of their patients—a finding that other studies have not confirmed. Our data suggest that tumors with favorable histologic features are uncommon; of our 64 patients, only 2 and 5 patients had well-differentiated or poorly differentiated histologic findings, respectively (small lymphocytic and diffuse small cleaved cell lymphomas in the Working Formulation).

      ETIOLOGIC FACTORS

      Although the cause of PCNSL is unknown, interesting advances in the knowledge about etiologic mechanisms have been made from patients with AIDS and with tropical spastic paraparesis.
      • Ioachim HL
      • Cooper MC
      • Hellman GC
      Lymphomas in men at high risk for acquired immune deficiency syndrome (AIDS): a study of 21 cases.
      • Osame M
      • Matsumoto M
      • Usuku K
      • Izumo S
      • Ijichi N
      • Amitani H
      • Tara M
      • Igata A
      Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells.
      What may be accepted as true today, however, may change dramatically as new data emerge. Other useful reviews have been published about the pathogenesis of lymphomas.
      • DeVita Jr, VT
      • Hellman S
      Hodgkin's disease and the non-Hodgkin's lymphomas.
      • Mann RB
      • Jaffe ES
      • Berard CW
      Malignant lymphomas—a conceptual understanding of morphologic diversity: a review.
      PCNSL are more likely to occur in certain clinical situations and within certain identifiable groups. An increased risk of developing PCNSL is associated with the following conditions: collagen vascular diseases such as Sjögren's syndrome,
      • Kassan SS
      • Hoover R
      • Kimberly RP
      • Budman DR
      • Decker JL
      • Chused TM
      Increased incidence of malignancy in Sjögren's syndrome (abstract).
      systemic lupus erythematosus,
      • Lipsmeyer EA
      Development of malignant cerebral lymphoma in a patient with systemic lupus erythematosus treated with immunosuppression.
      and rheumatoid arthritis;
      • Good AE
      • Russo RH
      • Schnitzer B
      • Weatherbee L
      Intracranial histiocytic lymphoma with rheumatoid arthritis.
      chronic immunosuppression as seen in cardiac, thymic, and renal transplantation
      • Weintraub J
      • Warnke RA
      Lymphoma in cardiac allotransplant recipients: clinical and histological features and immunological phenotype.
      • Borzy MS
      • Hong R
      • Horowitz SD
      • Gilbert E
      • Kaufman D
      • DeMendonca W
      • Oxelius V-A
      • Dictor M
      • Pachman L
      Fatal lymphoma after transplantation of cultured thymus in children with combined immunodeficiency disease.
      • Penn I
      Development of cancer as a complication of clinical transplantation.
      and congenital immunodeficiency syndromes;
      • FrizzerA G
      • Rosai J
      • Dehner LP
      • Spector BD
      • Kersey JH
      Lymphoreticular disorders in primary immunodeficiencies: new findings based on an up-to-date histologic classification of 35 cases.
      and AIDS.
      • Snider WD
      • Simpson DM
      • Aronyk KE
      • Nielsen SL
      Primary lymphoma of the nervous system associated with acquired immune-deficiency syndrome (letter to the editor).
      • Levy RM
      • Bredesen DE
      • Rosenblum ML
      Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature.
      • Gill PS
      • Levine AM
      • Meyer PR
      • Boswell WD
      • Burkes RL
      • Parker JW
      • Hofman FM
      • Dworsky RL
      • Lukes RJ
      Primary central nervous system lymphoma in homosexual men: clinical, immunologic, and pathologic features.
      PCNSL is now the most common noninfectious space-occupying lesion in patients with AIDS and is the fourth leading cause of death in such patients. Rosenblum and co-workers
      • Choucair AK
      • Levy RM
      • Levin VA
      • Rosenblum ML
      Primary CNS lymphoma: a new epidemic (abstract).
      • Rosenblum ML
      • Levy RM
      • Bredesen DE
      • So YT
      • Wara W
      • Ziegler JL
      Primary central nervous system lymphomas in patients with AIDS.
      recently stated that the yearly incidence of PCNSL will exceed that of low-grade astrocytomas and approach the yearly incidence of meningiomas. A more alarming statistic, from a recent report by the Surveillance, Epidemiology, and End-Results program (SEER) at the National Cancer Institute,
      • Eby NL
      • Grufferman S
      • Flannelly CM
      • Schold Jr, SC
      • Vogel FS
      • Burger PC
      Increasing incidence of primary brain lymphoma in the US.
      suggested that the actual incidence of PCNSL is increasing beyond the general increase in cases of lymphoma. The SEER data are even more noteworthy because that study attempted to avoid an AIDS bias by eliminating never-married men from their analysis. Hobson and associates
      • Hobson DE
      • Anderson BA
      • Carr I
      • West M
      Primary lymphoma of the central nervous system: Manitoba experience and literature review.
      suggested that this increase may reflect the availability and the ready use of immunosuppressant drugs in a wide variety of clinical situations.
      Theories about why PCNSL develop revolve around one of several possibilities, perhaps enhanced by exogenous or endogenous immunosuppression. Hochberg and colleagues
      • Hochberg FH
      • Miller G
      • Schooley RT
      • Hirsch MS
      • Feorino P
      • Henle W
      Central-nervous-system lymphoma related to Epstein-Barr virus.
      found the Epstein-Barr virus genome in neoplastic lymphocytes from one patient with PCNSL and demonstrated immunohistochemical localization of the Epstein-Barr virus antigen in the region of brain lymphoma from other patients. This finding suggested selective incorporation of the virus in tumor cells or actual viral induction of the tumor. Such an association should be even more likely in AIDS because of the increased frequency of occurrence of antibody to Epstein-Barr virus. Recently, Murray and co-workers
      • Murray RS
      • Rosenberg NL
      • DeMasters BK
      • Jones J
      Relationship between primary central nervous system lymphoma and Epstein-Barr virus in acquired immune deficiency syndrome: in situ hybridization studies (abstract).
      reported the demonstration of the Epstein-Barr virus genome in tumor tissue from four patients with AIDS and PCNSL but not in brain tissue from nine patients with AIDS but no PCNSL. On the basis of the AIDS experience, Rosenberg and colleagues
      • Rosenberg NL
      • Hochberg FH
      • Miller G
      • Kleinschmidt-DeMasters BK
      Primary central nervous system lymphoma related to Epstein-Barr virus in a patient with acquired immune deficiency syndrome.
      suggested that a decrease in immunologic surveillance may allow conversion of a polyclonal B-cell proliferation to an overt malignant lesion. Furthermore, they speculated that B-cell-tropic Epstein-Barr viruses potentially “immortalize” their respective target lymphocytes.
      • Rosenblum ML
      • Levy RM
      • Bredesen DE
      • So YT
      • Wara W
      • Ziegler JL
      Primary central nervous system lymphomas in patients with AIDS.
      • Kieff E
      • Dambaugh T
      • Hummel M
      • Heller M
      Epstein-Barr virus transformation and replication.
      Most patients with PCNSL are clinically and immunologically normal before the typically abrupt onset of their symptoms. Because most patients with PCNSL are in the sixth decade of life or older, occurrence of the tumor may simply reflect the diminished immune surveillance in elderly persons. Chromosomal breaks or viral stimulation may cause B-cell proliferation and eventually give rise to a single clone of cells with growth potential. This clonal excess in lymphoproliferative tissues can progress to oligoclonal or monoclonal lymphomas because of faulty T-cell suppression.
      • Louie S
      • Daoust PR
      • Schwartz RS
      Immunodeficiency and the pathogenesis of non-Hodgkin's lymphoma.
      • Yarchoan R
      • Redfield RR
      • Broder S
      Mechanisms of B cell activation in patients with acquired immunodeficiency syndrome and related disorders.
      This outcome may be particularly likely when such growth occurs in an immunlogically “privileged” extranodal site such as the brain.
      • Rosenblum ML
      • Levy RM
      • Bredesen DE
      • So YT
      • Wara W
      • Ziegler JL
      Primary central nervous system lymphomas in patients with AIDS.
      The interaction of the diminished immune surveillance in elderly persons and the chronic stimulation by chromosomal abnormalities can be seen in Richter's syndrome, in which large cell lymphoma develops in the setting of chronic lymphocytic leukemia.
      • Trump DL
      • Mann RB
      • Phelps R
      • Roberts H
      • Conley CL
      Richter's syndrome: diffuse histiocytic lymphoma in patients with chronic lymphocytic leukemia; a report of five cases and review of the literature.
      Such a transformation evolved in two of our older male patients, one of whom had never received chemotherapy.
      • O'Neill BP
      • Habermann TM
      • Banks PM
      • O'Fallon JR
      • Earle JD
      Primary central nervous system lymphoma as a variant of Richter's syndrome in two patients with chronic lymphocytic leukemia.
      Some evidence has suggested that the lymphoma develops as a dedifferentiation of the leukemic cell, inasmuch as clones of cells from chronic and acute phases have demonstrated similar immunologic characteristics.
      • Delsol G
      • Laurent G
      • Kuhlein E
      • Familiades J
      • Rigal F
      • Pris J
      Richter's syndrome: evidence for the clonal origin of the two proliferations.
      A hereditary influence on the development of lymphomas has been suggested by the high frequency of occurrence in families of patients with immunologic disorders and in patients with inherited immunologic deficiency diseases.
      • DeVita Jr, VT
      • Ultmann JE
      Hodgkin's disease and the lymphocytic lymphomas.
      In reference to PCNSL, however, little information is available. Our recent review suggested such an increased risk—30% of our patients with PCNSL had a family history of cancer, including two patients with other family members who had a lymphoproliferative disorder. Another five patients had a prior personal history of cancer, two of whom had been treated with immunosuppressive agents.

      O'Neill BP, Banks PM, O'Fallon JR, Earle JD, Colgan JP: Primary CNS non-Hodgkin's lymphoma (PCNSL): a clinical, radiologic, and pathologic study of 64 patients in the CT era (1974–1986) (submitted for publication)

      CLINICAL FINDINGS

      The typical patient with PCNSL is a middle-aged man with a recent appearance of nonfocal neurologic symptoms. Most frequently, involvement occurs in patients from 40 to 60 years old, and in most series, a 2-to-1 male-to-female distribution has been reported.
      • Helle TL
      • Britt RH
      • Colby TV
      Primary lymphoma of the central nervous system: clinicopathological study of experience at Stanford.
      • Murray K
      • Kun L
      • Cox J
      Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature.
      • Hobson DE
      • Anderson BA
      • Carr I
      • West M
      Primary lymphoma of the central nervous system: Manitoba experience and literature review.
      • Spillane JA
      • Kendall BE
      • Moseley IF
      Cerebral lymphoma: clinical radiological correlation.
      • Jiddane M
      • Nicoli F
      • Diaz P
      • Bergvall U
      • Vincentelli F
      • Hassoun J
      • Salamon G
      Intracranial malignant lymphoma: report of 30 cases and review of the literature.
      The duration of symptoms from onset to diagnosis is approximately 3 months. A survey by Hobson and associates
      • Hobson DE
      • Anderson BA
      • Carr I
      • West M
      Primary lymphoma of the central nervous system: Manitoba experience and literature review.
      found nonfocal and nonspecific symptoms in more than 50% of the patients. At the time of initial examination, most of these patients had headache, nausea, vomiting, and symptoms of increased intracranial pressure. In 42% of the patients, focal signs and symptoms were present. Approximately a third of the patients had changes in mental status, and only 9% had seizures. In a retrospective review of 83 cases of PCNSL from the Armed Forces Institute of Pathology, Henry and colleagues
      • Henry JM
      • Heffner Jr, RR
      • Dillard SH
      • Earle KM
      • Davis RL
      Primary malignant lymphomas of the central nervous system.
      found a similar distribution of clinical manifestations.
      In our recent review,

      O'Neill BP, Banks PM, O'Fallon JR, Earle JD, Colgan JP: Primary CNS non-Hodgkin's lymphoma (PCNSL): a clinical, radiologic, and pathologic study of 64 patients in the CT era (1974–1986) (submitted for publication)

      at the time of diagnosis of PCNSL approximately equal percentages of patients had generalized symptoms (such as headache, increased intracranial pressure, and generalized seizures), focal symptoms (hemimotor or hemisensory symptoms, visual field changes, and focal seizures), and combinations of generalized and focal symptoms (Table 4). In contrast to some prior studies, however, focal signs such as aphasia, hemimotor or hemisensory deficits, visual field losses, and brain-stem or cerebellar signs were noted in approximately 45% of those patients, whereas 16% had diffuse signs such as encephalopathy, dementia, and papilledema. A review of the published reports in which sufficient evidence was present about the initial manifestations generally supported these observations. Overall, approximately equal numbers of patients will have neurologic symptoms of generalized or focal origin or both. Seizures occur in 0 to 30% of patients.
      • Helle TL
      • Britt RH
      • Colby TV
      Primary lymphoma of the central nervous system: clinicopathological study of experience at Stanford.
      • Hobson DE
      • Anderson BA
      • Carr I
      • West M
      Primary lymphoma of the central nervous system: Manitoba experience and literature review.
      • Spillane JA
      • Kendall BE
      • Moseley IF
      Cerebral lymphoma: clinical radiological correlation.
      • Jiddane M
      • Nicoli F
      • Diaz P
      • Bergvall U
      • Vincentelli F
      • Hassoun J
      • Salamon G
      Intracranial malignant lymphoma: report of 30 cases and review of the literature.
      Table 4Clinical Characteristics at the Time of Diagnosis of Primary Central Nervous System Lymphoma in 64 Mayo Patients
      The median age of the 64 patients was 60 years (mean age, 58.4 years).
      Patients
      CharacteristicNo.%
      Sex
       Men4164
       Women2336
      Symptoms
       Generalized2336
       Focal2234
       Both1930
      Signs
       Generalized1016
       Focal2945
       Both2133
       None46
      Duration of symptoms (wk)
       0–43352
       5–121930
       13–20711
       21–10458
      * The median age of the 64 patients was 60 years (mean age, 58.4 years).
      In a review of more than 1,200 cases of AIDS, Rosenblum and co-workers
      • Rosenblum ML
      • Levy RM
      • Bredesen DE
      • So YT
      • Wara W
      • Ziegler JL
      Primary central nervous system lymphomas in patients with AIDS.
      found that PCNSL developed in 1.9% of all such patients during their life-span, including 0.6% whose tumor was the first manifestation of AIDS. The clinical manifestations in this group of patients are similar to those in other patients with PCNSL; however, the mean age is younger, and the tumors are more often multifocal at the time of diagnosis. These findings may reflect the more aggressive histologic patterns of the AIDS-associated PCNSL. Whereas large cell immunoblastic and small cell, noncleaved types (in the working formulation classification) occurred in only 12.5% and 6.25% of all non-AIDS PCNSL cases, these are the most common types in AIDS-associated PCNSL (30% and 60%, respectively). This finding compares with high-grade lymphomas noted in more than half of the systemic lymphomas associated with AIDS and less than 20% in the general population (Table 5).
      Table 5Clinical Differences in Patients Who Have Primary Central Nervous System Lymphoma With or Without Acquired Immunodeficiency Syndrome (AIDS)
      DLC = diffuse large cell; DMC = diffuse mixed cell; LC = large cell. Cerebrospinal fluid, computed tomographic, magnetic resonance imaging, and angiographic data were similar in the two groups. Survival data were not comparable because of AIDS.
      FactorAIDSNon-AIDS
      Pathology
       Light microscopyLC immunoblastic, small noncleavedDLC, DMC
       ImmunohistochemistryB cellT cell >20%
      Multiple lesions (%)
       At initial examination>40≤25
       At autopsy10044
      Age distribution4th decade6th decade
      Initial manifestationDiffuse > focalDiffuse ≥ focal
      Duration of symptomsDays to weeks1–3 mo
      * DLC = diffuse large cell; DMC = diffuse mixed cell; LC = large cell. Cerebrospinal fluid, computed tomographic, magnetic resonance imaging, and angiographic data were similar in the two groups. Survival data were not comparable because of AIDS.
      A typical pattern of initial manifestation has been established for PCNSL. Nevertheless, several uncommon neurologic syndromes occur in patients with PCNSL, and their features are sufficiently characteristic to suggest the possibility of PCNSL above other diagnostic considerations.
      • O'Neill BP
      • Colgan JP
      • Earle JD
      Primary central nervous system lymphoma: unusual but characteristic clinical presentations (abstract).
      These syndromes include a uveocyclitis coincident with or before the diagnosis of PCNSL, a subacute encephalitis with subependymal infiltration, a syndrome with multifocal central nervous system lesions, and a multiple sclerosis-like illness with exacerbations and corticosteroid-induced (or rarely spontaneous) remissions.
      The finding of uveitis is particularly significant. Eye symptoms may precede cerebral symptoms by months to years. Although they may initially respond to topical or systemic corticosteroids, at least two-thirds of the patients with uveitis eventually have PCNSL, usually ipsilateral to the only or the most severely affected eye.
      • Qualman SJ
      • Mendelsohn G
      • Mann RB
      • Green WR
      Intraocular lymphomas: natural history based on a clinicopathologic study of eight cases and review of the literature.
      The pathologic finding is a dense infiltration of the vitreous and retina, particularly at the posterior pole, 79% of which cases are bilateral.
      • Neault RW
      • Van Scoy RE
      • Okazaki H
      • MacCarty CS
      Uveitis associated with isolated reticulum cell sarcoma of the brain.
      The correct diagnosis is usually made after vitreous biopsy when the patient fails to respond to corticosteroid therapy.
      • Rosenbaum TJ
      • MacCarty CS
      • Buettner H
      Uveitis and cerebral reticulum-cell sarcoma (large-cell lymphoma): case report.
      In our experience, 11% of patients with PCNSL had episodes of uveitis that preceded the diagnosis of PCNSL by months to years. In another 6%, uveitis was diagnosed coincident with the discovery of the tumor when a thorough ophthalmologic examination was done as part of a standard staging process.

      O'Neill BP, Banks PM, O'Fallon JR, Earle JD, Colgan JP: Primary CNS non-Hodgkin's lymphoma (PCNSL): a clinical, radiologic, and pathologic study of 64 patients in the CT era (1974–1986) (submitted for publication)

      • O'Neill BP
      • Colgan JP
      • Earle JD
      Primary central nervous system lymphoma: unusual but characteristic clinical presentations (abstract).
      In those cases of a relapsing remitting course, initially diagnosed as multiple sclerosis, no patient had optic neuritis or spinal cord dysfunction, two sites particularly affected by multiple sclerosis. Some unusual sites for occurrence of PCNSL have been in the meninges manifesting as a primary meningeal lymphoma,
      • Lachance DH
      • Witzig TE
      • Li C-Y
      • O'Neill BP
      Diagnosis of primary meningeal lymphoma with immunocytochemical analysis (abstract).
      in the spinal cord manifesting as a primary intramedullary lymphoma,
      • Hautzer NW
      • Aiyesimoju A
      • Robitaille Y
      “Primary” spinal intramedullary lymphomas: a review.
      and in the brain stem in association with an encephalopathy-dementia syndrome.
      • Wallack EM
      • Reavis Jr, WM
      • Hall CD
      Primary brain stem reticulum cell sarcoma causing dementia.

      CEREBROSPINAL FLUID

      In most studies, cerebrospinal fluid examinations were limited to those patients with PCNSL in whom increased intracranial pressure was not a concern and in whom a lumbar puncture could be performed safely. In a review by Murray and associates,
      • Murray K
      • Kun L
      • Cox J
      Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature.
      cerebrospinal fluid studies were performed in 92 of 267 patients (34%), and of these 92, only 9 (10%) had evidence of lymphoma cells. Hobson and colleagues,
      • Hobson DE
      • Anderson BA
      • Carr I
      • West M
      Primary lymphoma of the central nervous system: Manitoba experience and literature review.
      who reviewed five other articles and their own experience, concluded that more than 80% of patients in whom cerebrospinal fluid studies were done had an elevated protein level and more than 40% had an increased cell count. Therefore, one can conclude that the cerebrospinal fluid findings are usually abnormal but the abnormalities may be nonspecific, and increased cerebrospinal fluid protein is the most common abnormality. A mononuclear cell pleocytosis was also frequently seen, but cytologic results are probably positive in fewer than 10% of cases. Application of new techniques to identify lymphoma cells may show that a greater number of patients have meningeal involvement.

      RADIOGRAPHIC CHARACTERISTICS

      No computed tomographic appearance is absolutely diagnostic of PCNSL (Table 6); however, a homogeneously enhancing lesion (or lesions) located in the central gray matter or corpus callosum should be considered highly suggestive of PCNSL because few other lesions have this type of appearance. In most series, at least 60% of cases have been denser than adjacent normal brain tissue, and less than 10% have been hypodense.
      • Hobson DE
      • Anderson BA
      • Carr I
      • West M
      Primary lymphoma of the central nervous system: Manitoba experience and literature review.
      • Spillane JA
      • Kendall BE
      • Moseley IF
      Cerebral lymphoma: clinical radiological correlation.
      In our experience, however, most PCNSL (67%) were isodense relative to gray matter, and none was hypodense.
      • Jack Jr, CR
      • O'Neill BP
      • Banks PM
      • Reese DF
      Central nervous system lymphoma: histologic types and CT appearance.
      When a contrast agent can be administered, virtually all tumors enhance, and the majority (70%) show a dense homogeneous pattern (Fig. 4). In some patients with PCNSL (4 to 10%), ringlike enhancement or clearly defined “cystic” areas within the lesion were noted. This ringlike lesion may mimic the radiographic appearance of an abscess; however, the wall of a PCNSL is usually much thicker than the wall of an abscess.
      • Jack Jr, CR
      • O'Neill BP
      • Banks PM
      • Reese DF
      Central nervous system lymphoma: histologic types and CT appearance.
      Most PCNSL (75%) are in contact with either the ependymal or the meningeal surface, or both. This finding and the distinct contrast enhancement suggest a meningioma (pseudomeningioma pattern); however, the location, lack of calcification, and tendency toward multiplicity favor PCNSL.
      • Jack Jr, CR
      • O'Neill BP
      • Banks PM
      • Reese DF
      Central nervous system lymphoma: histologic types and CT appearance.
      A radiographic observation that has attained almost diagnostic significance is the prompt partial to complete resolution of the computed tomographic abnormality after the administration of corticosteroids. A “ghost tumor”
      • Vaquero J
      • Martínez R
      • Rossi E
      • López R
      Primary cerebral lymphoma: the “ghost tumor.”.
      is illustrated in Figure 5. Whether actual cytoreduction or simply stabilization of the blood-brain barrier (or both) accounts for this phenomenon is unknown.
      Table 6Computed Tomographic Characteristics of Primary Central Nervous System Lymphomas
      DensityMass effectLocation
      • Without contrast
        • >60% hyperdense
        • <10% hypodense
      • With contrast
        • >70% dense, homogeneous
        • <10% ringlike
      • Majority
        • Deep lesions
        • Well demarcated
        • Little mass effect
      • Minority
        • Subcortical
        • Poorly demarcated
        • Variable mass effect
      • >75% ependymal or meningeal contact
      • Approximately 60% lobar
      • Approximately 25% deep midline structures
        • Septum pellucidum
        • Basal ganglia
        • Corpus callosum
      • 10–30% multiple
      Figure thumbnail gr4
      Fig. 4Computed tomographic scans of large frontal lobe primary central nervous system lymphoma. A, Without contrast medium, demonstrating increased noncontrasted density. B, After administration of contrast agent, showing dense homogeneous, avid enhancement.
      Figure thumbnail gr5
      Fig. 5Computed tomographic scans of primary central nervous system lymphoma at foramen of Munro. A, At time of initial examination (open arrow). B, After 1 week of corticosteroid treatment, note so-called ghost tumor (closed arrow).
      Approximately 50 to 60% of PCNSL are located peripherally (in the hemispheric gray matter or adjacent lobar white matter), and another 25% are located in deep midline structures (the septum pellucidum, basal ganglia, or corpus callosum). At the time of initial examination, 10 to 30% of patients have multiple lesions. Most tumors, however, are single, at the periphery, and in the frontal lobe.
      • Jack Jr, CR
      • O'Neill BP
      • Banks PM
      • Reese DF
      Central nervous system lymphoma: histologic types and CT appearance.
      The amount of computed tomographic mass effect varies. Thomas and MacPherson
      • Thomas M
      • MacPherson P
      Computed tomography of intracranial lymphoma.
      defined two groups of patients: (1) those with deeper lesions that were well demarcated with little mass effect or surrounding “edema” (hypodensity) and that had appreciable homogeneous enhancement and (2) those with poorly demarcated superficial lesions with variable density, contrast enhancement, and mass effect. Our findings correspond to their descriptions.
      Skull roentgenograms typically show normal findings. Magnetic resonance imaging of PCNSL has not yet been widely reported. The few available reports suggest that no imaging feature is pathognomonic for PCNSL. In one report,
      • Brant-Zawadzki M
      • Berry I
      • Osaki L
      • Brasch R
      • Murovic J
      • Norman D
      Gd-DTPA in clinical MR of the brain. 1. Intraaxial lesions.
      magnetic resonance imaging features of PCNSL in a patient with AIDS were not sufficiently characteristic to distinguish the tumor from an abscess, and enhancement with gadolinium diethylenetriaminepentaacetic acid did not prove useful. In our experience with six patients, magnetic resonance imaging provided no more information than that obtained from computed tomography, in terms of either lesion detectability or lesion specificity.
      • Jack Jr, CR
      • O'Neill BP
      • Banks PM
      • Reese DF
      Central nervous system lymphoma: histologic types and CT appearance.
      If PCNSL are located subependymally, the magnetic resonance imaging signal differential between that of the cerebrospinal fluid and that of the tumor may be insufficient for detection of such lesions. Therefore, in this situation, computed tomographic scanning with use of a contrast agent is more beneficial (Fig. 6). The use of new signaling techniques such as proton-weighted scanning may avoid this problem.
      Figure thumbnail gr6
      Fig. 6Periventricular primary central nervous system lymphoma, depicted better on computed tomographic scan (A) than on magnetic resonance image (B, arrow). (See text for further discussion.)
      Although cerebral angiography discloses abnormal findings in more than 90% of cases of PCNSL studied, the abnormalities are often nonspecific. The most common abnormality is an avascular mass (occurring in approximately 60% of cases).
      • Helle TL
      • Britt RH
      • Colby TV
      Primary lymphoma of the central nervous system: clinicopathological study of experience at Stanford.
      • Hobson DE
      • Anderson BA
      • Carr I
      • West M
      Primary lymphoma of the central nervous system: Manitoba experience and literature review.
      • Schaumburg HH
      • Plank CR
      • Adams RD
      The reticulum cell sarcoma—microglioma group of brain tumours.
      • Letendre L
      • Banks PM
      • Reese DF
      • Miller RH
      • Scanlon PW
      • Kiely JM
      Primary lymphoma of the central nervous system.
      Another 30 to 40% of the tumors display diffuse homogeneous staining or a blush that persists from the capillary to the venous phase, again suggestive of the imaging appearance of a meningioma.
      • Jack Jr, CR
      • O'Neill BP
      • Banks PM
      • Reese DF
      Central nervous system lymphoma: histologic types and CT appearance.
      • Hobson DE
      • Anderson BA
      • Carr I
      • West M
      Primary lymphoma of the central nervous system: Manitoba experience and literature review.
      Thus, a densely contrast-enhancing lesion on computed tomography that is avascular or nearly so on angiography should alert the clinician to the probability of a PCNSL—and even more so if multiple and deep-seated lesions are detected.

      SURGICAL TREATMENT

      There is ample evidence, and almost unanimous belief, that aggressive surgical decompression with partial or gross total removal of a PCNSL is of no benefit to the patient.
      • Henry JM
      • Heffner Jr, RR
      • Dillard SH
      • Earle KM
      • Davis RL
      Primary malignant lymphomas of the central nervous system.
      This outcome is partly attributable to the characteristics of the tumor (large mass, subacute course) and of the patients (elderly) and partly attributable to the multifocal diffuse nature of the neoplasm. Murray and associates
      • Murray K
      • Kun L
      • Cox J
      Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature.
      reviewed the results in 85 patients with PCNSL who underwent only surgical treatment. The median reported survival time was 1 month, and long-term survival was achieved in only one patient. The extent of surgical resection had no effect on the duration of survival.
      The main role of neurosurgical intervention in PCNSL is for tissue diagnosis. Our preferred method of obtaining tissue for diagnosis is by computer-assisted stereotactic biopsy. We have recently demonstrated that, with this technique, sufficient tissue can be obtained safely from patients with PCNSL to yield an accurate diagnosis, provide histologic subtype classifications, and even allow immunohistochemical studies.
      • O'Neill BP
      • Kelly PJ
      • Earle JD
      • Scheithauer B
      • Banks PM
      Computer-assisted stereotaxic biopsy for the diagnosis of primary central nervous system lymphoma.

      RADIATION THERAPY

      Radiation therapy significantly improves survival of patients with PCNSL over that of no treatment or surgical treatment only.
      • Murray K
      • Kun L
      • Cox J
      Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature.
      • Henry JM
      • Heffner Jr, RR
      • Dillard SH
      • Earle KM
      • Davis RL
      Primary malignant lymphomas of the central nervous system.
      • Sagerman RH
      • Collier CH
      • King GA
      Radiation therapy of microgliomas.
      • Gonzalez Gonzalez D
      • Schuster-Uitterhoeve ALJ
      Primary non-Hodgkin's lymphoma of the central nervous system: results of radiotherapy in 15 cases.
      • Yasunaga T
      • Takahashi M
      • Uozumi H
      • Takada C
      • Kawano S
      • Baba Y
      • Nakamura I
      • Sonoda H
      • Matsukado Y
      Radiation therapy of primary malignant lymphoma of the brain.
      • Di Marco A
      • Rosta L
      • Campostrini F
      • Bonetti A
      • Palazzi M
      • Garusi G
      The role of radiation therapy in the management of primary non-Hodgkin lymphomas of the central nervous system: clinical study of 10 cases.
      Investigators, however, do not agree about what the total dose of irradiation should be and whether the dose is best delivered to the whole brain or locally. Also, controversy surrounds the issue of irradiation of the spinal axis for prevention of relapse.
      Dose-response information suggests that an improved survival time is associated with whole-brain treatment dosages of 50 Gy or more (Fig. 7); Cox and colleagues
      • Cox JD
      • Koehl RH
      • Turner WM
      • King FM
      Irradiation in the local control of malignant lymphoreticular tumors (non-Hodgkin's malignant lymphoma).
      and Berry and Simpson
      • Berry MP
      • Simpson WJ
      Radiation therapy in the management of primary malignant lymphoma of the brain.
      demonstrated improved local control and survival with doses that exceeded 45 Gy and 50 Gy, respectively. Littman and Wang
      • Littman P
      • Wang CC
      Reticulum cell sarcoma of the brain: a review of the literature and a study of 19 cases.
      suggested 45 Gy in conjunction with a 10-Gy tumor boost and additional irradiation to the spine if the cerebrospinal fluid cytology is positive, and Mendenhall and co-workers
      • Mendenhall NP
      • Thar TL
      • Agee OF
      • Harty-Goldner B
      • Ballinger Jr, WE
      • Million RR
      Primary lymphoma of the central nervous system: computerized tomography scan characteristics and treatment results for 12 cases.
      extended these guidelines by recommending prophylactic irradiation to the spinal axis in a dose of 30 to 35 Gy.
      Figure thumbnail gr7
      Fig. 7Graph showing survival time in 188 cases from the literature and 10 additional cases of primary central nervous system lymphoma treated with whole-brain irradiation. Solid line = patients receiving a dosage of 50 Gy or more. Broken line = patients receiving a dosage of less than 50 Gy. The difference was statistically significant (P<0.05).
      (From Murray and associates.
      • Murray K
      • Kun L
      • Cox J
      Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature.
      By permission of the American Association of Neurological Surgeons.)
      Most clinicians, however, have not advocated spinal axis irradiation in the absence of spinal signs or symptoms even when the cytologic results are positive, because it necessitates irradiation of the spine and pelvic bone marrow stores that are needed if the patient is to tolerate chemotherapy and because symptomatic spinal recurrences of PCNSL are extremely rare.

      CHEMOTHERAPY

      Drugs effective in systemic non-Hodgkin's lymphomas, such as bleomycin, cyclophosphamide, doxorubicin, and vincristine, have poor penetration of the blood-brain barrier. Although many studies have demonstrated alteration of the blood-brain barrier in patients with intracranial neoplasms, Neuwelt and co-workers
      • Neuwelt EA
      • Frenkel EP
      • Gumerlock MK
      • Braziel R
      • Dana B
      • Hill SA
      Developments in the diagnosis and treatment of primary CNS lymphoma.
      suggested that only a partial permeability of the blood-brain barrier is present in patients with PCNSL. To counter this, they administered hyperosmolar concentrations of mannitol intra-arterially to allow penetration of the blood-brain barrier with methotrexate. In 12 patients with multiagent chemotherapy in conjunction with blood-brain barrier modification, they found a 75% 1-year survival with a mean follow-up of 19 months after diagnosis; this analysis included 7 patients who had recurrent or progressive disease after radiation therapy. All these patients, however, received systemic chemotherapy and corticosteroids; thus, assessing the effect of barrier modification is difficult. In addition to that study, anecdotal reports have described benefits from various chemotherapeutic regimens
      • Frick JC
      • Hansen RM
      • Anderson T
      • Ritch PS
      Successful high-dose intravenous cytarabine treatment of parenchymal brain involvement from malignant lymphoma.
      • Ervin T
      • Canellos GP
      Successful treatment of recurrent primary central nervous system lymphoma with high-dose methotrexate.
      • Stewart DJ
      • Russell N
      • Atack EA
      • Quarrington A
      • Stolbach L
      Cyclophosphamide, doxorubicin, vincristine, and dexamethasone in primary lymphoma of the brain: a case report.
      • Kawakami Y
      • Tabuchi K
      • Ohnishi R
      • Asari S
      • Nishimoto A
      Primary central nervous system lymphoma.
      • Amadori S
      • Papa G
      • Avvisati G
      • Petti MC
      • Motta M
      • Salvagnini M
      • Meloni G
      • Martelli M
      • Monarca B
      • Mandelli F
      Sequential combination of systemic high-dose ara-C and asparaginase for the treatment of central nervous system leukemia and lymphoma.
      In the published reports of formal trials, however, most of the studies have included a small number of patients, have been retrospective, and have been poorly standardized. Furthermore, in many of these studies, no long-term follow-up has been available.

      PROGNOSIS

      Among the various reports of prognosis of patients with PCNSL (Table 7), Jellinger and associates
      • Jellinger K
      • Radaskiewicz T
      • Slowik F
      Primary malignant lymphomas of the central nervous system in man.
      estimated that patients who receive no treatment have a median survival of 1.8 months. The combination of surgical treatment, irradiation, and chemotherapy extended the duration of survival to 17.2 months in a group in which most patients had what were considered “good prognosis” histologic findings. Henry and colleagues
      • Henry JM
      • Heffner Jr, RR
      • Dillard SH
      • Earle KM
      • Davis RL
      Primary malignant lymphomas of the central nervous system.
      reported a mean survival of 3.3 months for patients with PCNSL who received no treatment and 4.6 months for those who had surgical treatment only. In most studies of radiation therapy for the management of PCNSL, the survival data from Berry and Simpson
      • Berry MP
      • Simpson WJ
      Radiation therapy in the management of primary malignant lymphoma of the brain.
      are cited—a 47% 1-year median survival and a 16% 2-year median survival. Their report of a median duration of survival of 10 months is in close agreement with that of the Radiation Therapy Oncology Group, which found a median survival of 45+ weeks in a recently completed study (personal communications). In a review of 693 cases of PCNSL, Murray and co-workers
      • Murray K
      • Kun L
      • Cox J
      Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature.
      found an 8% 3-year survival and a 3% 5-year survival.
      Table 7Prognosis of Patients With Primary Central Nervous System Lymphoma and Patterns of Recurrence
      Median survival (mo)
       No therapy1.8
       Radiation therapy10.0
       Combination therapy17.2
      Survival (%)
       1-year47
       2-year16
       3-year8
       5-year3
      Pattern of recurrence (%)
       Local93
       Distant7
      Loeffler and associates
      • Loeffler JS
      • Ervin TJ
      • Mauch P
      • Skarin A
      • Weinstein HJ
      • Canellos G
      • Cassady JR
      Primary lymphomas of the central nervous system: patterns of failure and factors that influence survival.
      reported that approximately 78% of PCNSL recur, usually about 15 months after treatment. Late recurrences are also possible. In the study by Murray and colleagues,
      • Murray K
      • Kun L
      • Cox J
      Primary malignant lymphoma of the central nervous system: results of treatment of 11 cases and review of the literature.
      half of the patients who survived 5 years had a relapse between 5 and 12.5 years after diagnosis. Our experience has been similar.

      O'Neill BP, Banks PM, O'Fallon JR, Earle JD, Colgan JP: Primary CNS non-Hodgkin's lymphoma (PCNSL): a clinical, radiologic, and pathologic study of 64 patients in the CT era (1974–1986) (submitted for publication)

      Of the recurrences, 93% are confined to the central nervous system and 7% are outside the central nervous system. In our review of 64 cases, symptomatic recurrences outside the central nervous system were in the kidney, colon, and testis. This pattern of systemic failure brings into focus an unresolved issue about PCNSL—that is, whether they are simply another type of extranodal lymphoma with potential for systemic failure, or whether they are a primary brain tumor with a unique histologic pattern. Local recurrences may be found at the original tumor site, but in those patients who have had a complete response at the original site, we have typically found a recurrence at another central nervous system site.
      • O'Neill BP
      • O'Fallon JR
      • Jack Jr, CR
      • Banks PM
      • Colgan JP
      • Earle JD
      Patterns of failure in primary central nervous system non-Hodgkin's lymphoma (PCNSL) (abstract).
      Our own experience indicates that the currently available histologic data show no clear correlation with survival, a finding distinctly different from non-Hodgkin's lymphoma at other extranodal sites. Although the histologic type of the putative recurrent lesion has seldom been confirmed, when such studies have been done, the histologic characteristics of the original and recurrent tumors have been identical.
      • O'Neill BP
      • O'Fallon JR
      • Jack Jr, CR
      • Banks PM
      • Colgan JP
      • Earle JD
      Patterns of failure in primary central nervous system non-Hodgkin's lymphoma (PCNSL) (abstract).

      CONCLUSION

      PCNSL is a rare tumor, constituting less than 2% of primary brain tumors and 1% of all non-Hodgkin's lymphomas. Its clinical manifestation is typically that of a subacute mass lesion. No clear predilection for focal versus general findings has been noted. Rather, increased intracranial pressure, headache, nausea, vomiting, changes in mental status, and dementia are the most common clinical manifestations. Results of cerebrospinal fluid examination are often nonspecifically abnormal (increased protein concentration), and fewer than 10% of cases show positive cytology. The radiologic features are distinctive and virtually pathognomonic: a large, single, hyperdense, homogeneously contrast-enhancing mass with a tendency to occur in the hemispheric white matter or the deep gray matter. Multiple and deep central lesions on computed tomography are highly suggestive of PCNSL, particularly if the angiogram displays an avascular mass or a mass with a faint tumor stain.
      The pathologic features are those of a diffuse histiocytic lymphoma (Rappaport classification) or a diffuse large cell lymphoma (Working Formulation classification). PCNSL are mostly of B-cell origin, and the histologic pattern recapitulates that found in non-Hodgkin's lymphomas elsewhere in the body. Occult systemic lymphomas should be excluded by a staging procedure that includes routine blood and urine studies, chest roentgenography, computed tomography of the abdomen, bone marrow analysis, cerebrospinal fluid cytology (if the clinical situation permits), slit-lamp examination of both eyes, and ultrasound studies of the testes (in male patients).
      Surgical intervention should be reserved for tissue diagnosis. Whole-brain irradiation with or without chemotherapy is the most common treatment. Chemotherapy for PCNSL is still in the developmental stage. The prognosis for patients with this tumor is grim; the median duration of survival is less than 2 years, and the 5-year survival is less than 5%.

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