Primary malignant lymphoma of the central nervous system

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Primary Malignant Lymphoma of the Central Nervous System Eva Spaun, M.D., Steen Midholm, M.D., Niels Tinggaard Pedersen, M.D., and J0rgen Ringsted, M.D. Institute of Pathology and Department of Neurosurgery, Odense University Hospital, Odense, Denmark

Spaun E, Midholm S, Pedersen NT, Ringsted J. Primary malignant lymphoma of the central nervous system. Surg Neurol 1985;24:646-50.

The occurrence of primary malignant lymphomas of the central nervous system in a population of approximately 1 million people has been analyzed retrospectively. Over a 12-year period, about 1000 tumors of the central nervous system were registered, Among these, 22 were primary malignant lymphomas; incidence, 1.83 per million per year. Thirteen of these tumors were of high-grade malignancy and nine were of low-grade malignancy (Kiel classification of non-Hodgkin lymphomas). The majority of the tumors were B-ceU lymphomas, and there were no Hodgkin lymphomas. Neither spinal nor meningeal lymphomas occurred. Nine patients were treated only surgically, whereas 11 received postoperative irradiation or chemotherapy, or both. Of the latter patients, six are alive and well at the time of writing. The importance of making a correct diagnosis preoperatively is stressed, inasmuch as radical operation is unfavorable for these patients. A better prognosis is obtained with combinations of irradiation and chemotherapy. KEY WORDS: Malignant lymphoma; Central nervous system; Treatment; Prognosis

The first lesions of lymphoid malignancy in the central nervous system (CNS) were reported by Bailey in 1929 [1]. H e used terminology indicating the assumed reticuloendothelial and microglial origin o f the t u m o r cells. This terminology was also widely used for systemic lesions o f the same nature. A multitude of terms have since then been applied to these rare C N S tumors, the following being the most common: reticulum cell sarcoma, microgliomatosis, reticuloendothelial sarcoma, malignant reticuloendotheliosis, sarcoma o f the reticuloendothelial system, perivascular sarcoma, periadventitial sarcoma, reticulohistiocytic encephalitis, atypical granulomatous encephalitis, and lymphoproliferative Address reprint requests to." Eva Spaun, M.D., Institute of Pathology, Odense University Hospital, DK-5000 Odense, Denmark.

© 1985 by Elsevier Science Publishing Co., Inc.

disorder of the central nervous system [ 16]. For a period the unifying term "reticulosarcomaJmicroglioma" was widely used. In an attempt to classify this controversial group of C N S tumors, H e n r y et al [8] in 1974 reviewed a n u m b e r of cases and found the tumors morphologically identical to the spectrum of systemic lymphomas. As a consequence, they suggested the term "lymphoma of the CNS." The tumors were classified according to the classifications of Lukes and Collins and Rappaport, which were in vogue for lymphomas at that time. In the following years, publications on lymphomas in the central nervous system mainly appeared as case reports [3,4,17,20]. However, larger series were reviewed by Jellinger et al [11], H o u t h o f f et al [9], Taylor et al [19], Hassoun et al [6], and Helle et al [7]. T h e s e reports included from 15 to 83 cases, thus offering an opportunity to characterize this new entity of C N S tumors. With the advent of new hematologic, immunologic, and histochemical methods in histopathology, a more specific classification of lymphomatous cells became possible. Revision of the terminology of lymphomas seemed necessary: the Kiel classification of n o n - H o d g k i n lymphomas was introduced by Lennert in 1974 [13], and the Working Formulation of the National Cancer Institute was introduced in 1981 [15]. The aim of this investigation is to estimate the occurrence of primary malignant lymphomas in the central nervous system in a well-defined population; moreover, to characterize them morphologically and classify them according to the Kiel nomenclature and the Working Formulation for systemic lymphomas; and finally to analyze the clinical aspects of this material and compare the observations with previous similar reports. Materials This investigation is a retrospective analysis of all cases of primary tumors of the central nervous system registered at the Institute of Pathology, Odense University Hospital, during the 12-year period from January 1971 to D e c e m b e r 1982. T h e patients were inhabitants of three Danish counties, comprising approximately 2 0 % 0090-3019/85/$3.30

Malignant Lymphoma of Central Nervous System

of the total Danish population. The files of the institute contained nearly 1000 primary tumors of the central nervous system, including meningiomas, but omitting pituitary and nerve sheath tumors. Methods Reports that could be suspected of representing a malignant lymphoma were reviewed, i.e., all cases with an original diagnosis of reticulosarcoma/microglioma, reticulosarcoma, ependymoblastoma, anaplastic tumor, Ewing sarcoma metastasis, Hodgkin lymphoma, malignant mesodermal tumor, malignant ependymoma, small cell malignant tumor, carcinoma metastasis, and encephalitis. Most of the material was composed of surgical biopsy samples. In a few cases, autopsy material was used when the surgical material was unsatisfactory for diagnosis. In only a minority of the cases o f unsuspected or unidentified tumor, the material derived exclusively from autopsies. Among the 1000 primary tumors of the CNS, 22 proved to be primary malignant lymphomas. All specimens have been fixed in formalin and embedded in paraffin. Selected and representative paraffin blocks were sectioned anew and stained by the following methods: hematoxylin and eosin, periodic acid-Schiff, reticutin, Giemsa, and methyl green pyronin. Indirect immunoperoxidase techniques were used for the detection of immunoglobulins and histiocytic markers (~-1-antitrypsin, ~-l-antichymotrypsin, and muramidase). The material was evaluated by two independent observers (Dr. Spaun and Dr. Pedersen) and classified after the Kiel nomenclature for non-Hodgkin lymphomas and the Working Formulation.

Results Clinical Presentation At the time of diagnosis, 11 patients had signs both of increased intracranial pressure and of a focal process. One patient had pressure signs only (infratentorial tumor). Two patients initially manifested epilepsy of the grand mal type. The preoperative diagnosis was accomplished by scintigraphy, ventriculography and pneumoencephalography, arteriography and computed tomography scanning. In most instances the process was assumed to be a glioma or a metastasis. Practically all patients were treated surgically (18 out of 22) and only four cases were not diagnosed until autopsy was performed. O f the latter, one had had slight headache and dizziness during several months as an initial symptom. Another patient had received a renal transplant several years before the first symptoms of an intracranial process appeared. The general condition was too poor to permit

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surgical treatment. Two patients were assumed to have encephalitis.

Treatment Eighteen patients were treated surgically with ablative procedures. Eleven of these received postoperative chemotherapy or irradiation, or both. Nine patients received no postoperative treatment, mainly because of exitus in the postoperative period before treatment was initiated or because of poor general condition. Treatment is summarized in Table 1. Six of the patients treated surgically and with irradiation, chemotherapy, or both are alive and well with no or minimal neurological symptoms at the time of the present report. Survival time is seen in Figure 1. Autopsy was performed on 9 of 16 deceased patients. The diagnosis was unknown until autopsy in three patients. Four patients died of immediate postoperative complications with or without residual tumor in loco. Two patients died of late postoperative complications such as pneumonia or pleuritis. One patient died with disseminated disease. Seven patients were not autopsied--in all these cases the cause of death was residual tumor with progressive paresis or increased intracranial pressure.

Macroscopic Presentation The location of tumors was as follows: 21 cases located in the cerebral hemispheres (one tumor located bilaterally); one tumor located in the cerebellum. Preoperative radiological examination and preoperative macroscopic evaluation were interpreted as glioma or metastasis in all cases. Seven tumors were considered circumscribed whereas 13 seemed infiltrative. The pre* dominant sites were frontal, frontoparietal, and temporoparietal. One patient had a tumor in the thalamus and one had an infratentorial lesion.

Microscopic Presentation The microscopic features were massive sheets of malignant lymphoid cells with varying differentiation. The malignant lymphoid cells gradually thinned out at the rim of the lesions, thus creating a diffusely infiltrative T a b l e 1. Treatment of 22 Patients with Primary Malignant

Lymphoma of the Central Nervous System Treatment

n

None (three autopsy cases) Surgical Surgical and irradiation Surgical, irradiation, and chemotherapy

5 8 5 4

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Table 2. Subclassification (Kid Nomenclature of

Non-Hodgkin's Lymphomas) of 22 Patients with Primary Malignant Lymphoma of the Central Nervous System

e-

•

High grade malignant lymph~na

o

L~

grade malignant lymphoma

o-

Subclassification

n

Type

High grade

13

Low grade

9

t Centroblastic Malignant histiocytosis

n 11 2

• Malignant histlocytosis o-..0. Q

Centroblastic/centrocytic Centrocytic Lymphoplasmocytoid immunocytoma

o,,

1971

I

92

I

73

I

74

I

75

J

76

I

77

*

78

~

79

I

80

I

81

I

82

I

83

I

4 1 4

84

Figure 1. Surt,ival of patients with primary lymphoma of the central nem,ous system, Each patient is represented by a line beginning at time of admission and ending at the time of death. Half of the patients sur*,&ed less than 1 month. Six of the patients are alive and well at the termination of follow-up (December 1984).

growth pattern. Very few cases were characterized by a well-demarcated process that simulated an epithelial metastasis. Bleeding and necrosis were found in almost all cases, although abnormal vascular proliferation was not conspicuous. A slight admixture of polymorphs was seen in necrotic areas, and foamy macrophages formed a constant but varying part of the tumor tissue--mainly appearing as scattered cells throughout the neoplastic growth. Perhaps the most characteristic pattern seen in these tumors was the tendency to grow in the Virc h o w - R o b i n space. This p h e n o m e n o n was seen in almost all cases. Histochemical and immunohistochemical reactions o f the lymphomas in our series did not differ from the reactions seen in systemic lymphomas. Subclassification o f our CNS lymphonas after the Kiel nomenclature of non-Hodgkin lymphomas gave 13 of highgrade malignancy and 9 of low-grade malignancy. The details o f classification are shown in Table 2. In the terminology o f the Working Formulation there were 4 lymphomas of low-grade malignancy, 5 lymphomas of intermediate-grade malignancy, and 11 lymphomas of high-grade malignancy. Additionally, there were two malignant histiocytoses (Table 3). N o Hodgkin lymphomas were found, and lymphomas located exclusively in the meninges and spinal cord were not observed. Discussion In the following discussion, the results of the present investigation o f primary malignant lymphomas of the central nervous system are compared with those of reports in the literature. The estimated incidence of primary malignant lymphoma of the CNS was 1.83 per million per year. N o comparable incidence figures seem to be available. Primary malignant lymphomas o f the CNS comprised

2.3 % of all primary tumors of the CNS (excluding nerve sheath tumors and tumors of the pituitary region). Kepes et al [12] in a publication from 1984 cite an incidence of 1.28% for a U.S. sample, 2.3% for a Taiwan sample, and an overall incidence of 1.7%. Jellinger et al in 1975 found 0.85% malignant CNS lymphomas [1 i]. Our material showed no sexual preponderance, although other authors [7,9,11,19] report a male predominance, which in fact may be due to male dominance in the patient population. The patients in the present investigation had a mean age o f 56.3 years, with range from 21 to 71 years. Most other workers have also found that lymphoma of the CNS is a disease of late middle age [6,9,11,12,14]. Symptoms in our patients were as they have been in other investigations, nondescript, indicative of a lesion occupying the intracranial space. The duration of symptoms was usually short--in our material, weeks to a few months--compared with the mean duration of 2.5 months reported by H e n r y et al [8] and 2.3 months reported by Jellinger et al [11]. N o preoperative conventional diagnostic procedure proved valuable in the differentiation of CNS lymphomas from other malignant CNS tumors. Previous attempts at preoperative diagnosis have been equally unsuccessful. Jellinger et al [11] claims the efficacy of cytologic examination of cerebrospinal fluid, finding

Table 3. Subclassification cWorking Formulation) of 22

Primary Malignant Lymphomas of the Central Nervous System Subclassification

n

Type

n

High grade

11

Diffuse, large noncleaved cell

11

Miscellaneous

2

Intermediate grade

5

Low grade

4

Malignant histiocytosis Diffuse, small cleaved cell ~ Diffuse and mixed small and large cell Small cell lymphocytic

2 1 4

4

Malignant Lymphoma of Central Nervous System

neoplastic cells in 2 5 % of the fluids from patients with CNS lymphomas. Cytological examination of cerebrospinal fluid has not been performed on our patients. Specific macroscopic preoperative appearance has neither been found in our material nor in other published materials. Lymphomas were present as focal or diffuse, uni- or bilateral affections. In our material, the lesions were usually assumed to be metastases. Spillane et al [18] and Helle et al [7] have noted a pattern of avascularity and homogeneous enhancement of solitary lymphomas with computed tomographic scanning, making them difficult to distinguish from meningiomas. The radiologic examination of the patients of our material has not presented this pattern. Conclusive diagnosis of primary malignant lymphoma of the CNS can be accomplished only by microscopic examination of tumor tissue either histologically or cytologically. Light microscopic examination of our material revealed tumors that are rather characteristic for lymphomas. Conspicuous were growth in the Virchow-Robin space and diffuse centrifugal spread into neighboring parenchyma, as well as necrosis, bleeding, and especially occurrence of foamy macrophages. Abnormal vascular proliferation, well known in gliomas, is apparently not a characteristic feature in CNS lymphomas, a fact that may explain the radiologic appearance found by Spillane et al [18] and Helle et al [7]. A most exhaustive and precise description of the histologic pattern of CNS lymphomas is given by H e n r y et al [8] in their review of 83 cases. However, the cytologic picture, and especially the result of immunohistochemical techniques, is the crucial point in diagnosis of lymphoma. The tumor cells can be identified as an abnormal lymphoid population with varying differentiation, most often along the B-cell line. Most of the more recent reviews have shown similar dominance of B-cell proliferations, mainly of high-grade malignancy [6,7,9,11]. We diagnosed 13 high-grade and 9 low-grade lymphomas in our material; subclassifications after the Kiel nomenclature and the Working Formulation, respectively, are shown in detail in Tables 2 and 3. All lesions were of the diffuse type, i.e., there were no follicular lymphomas. We found no Hodgkin lymphomas, while Bertelsen [2] reported 2 cases, H e n r y et al [8] 23 cases, and Hassoun et al [6] 1 case. T h e r e were two cases of malignant histiocytosis in our material. Previous materials contain only one possible case of malignant histiocytosis; see Taylor et al [19]. In comparing the relative frequency of the various types of non-Hodgkin lymphomas of the CNS with that of "systemic" lymphomas, we found a predominance of high-grade malignant tumors of B-cell origin in accordance with the findings ofJellinger et al [ 11] and Hassoun

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et al [6]. In contrast, "systemic" lymphomas are dominated by low-grade malignant lymphomas of B-cell origin; see Lennert [13]. Treatment of the patients in the present series consisted of radical surgery, which in several cases was followed by chemotherapy or irradiation, or both. Survival was generally poor. In an analysis of survival times in their series of 22 patients, Helle et al [7] observed that the median length of survival in those patients alive at follow-up observation was longer than that of those who died. This was interpreted as indicative that primary malignant lymphoma of the CNS is nonuniform in its natural course. Our material confirms this observation, in that we have two rather distinct groups of patients: some dying very shortly after diagnosis, and some with a reasonable time of survival. As an explanation of this phenomenon, Helle et al [12] suggest that the tumor histology and location might be important prognostic factors. Our findings, however, do not speak in favor of this view. Our survivor group includes lymphomas both of high-grade and of low-grade malignancy, and the only one of our patients who had an infratentorial tumor survived for more than 7 years. Therefore, we have looked for another explanation of the survival pattern observed by Helle et al [7] and confirmed by us. The cause of death in those of our patients who died very quickly after diagnosis was hemorrhage, increased intracranial pressure, or pneumonia, i.e., immediate postoperative complications resulting from extensive surgery. We propose that the most important prognostic factor is the choice of treatment. If primary malignant tymphomas of the CNS are treated in the same way as meningiomas, gliomas, or metastases, the prognosis is generally poor, whereas it is to be hoped that limited surgical intervention, aiming only at establishing a diagnosis, followed by irradiation or chemotherapy according to the lymphoma at hand, will give a much better prognosis, even for lymphomas of high-grade malignancy. In the future, the highly characteristic cytologic appearance of primary malignant lymphomas of the central nervous system may prove to facilitate their preoperative diagnosis using smear techniques on excisional and fine-needle biopsies. This technique has been described and recommended by H u m e Adams et al [10]. In an attempt to improve the diagnostic accuracy, we have initiated a prospective study of CNS lymphomas using an extended tissue-sampling technique, including smear preparations, cryostat sections, gluteraldehydefixed tissue for electron microscopy, and frozen tissue for immunohistochemistry, in addition to samples for paraffin embedding. The impression today is that the lymphomas present a clear cytologic pattern in smear preparations. We hope that immunohistochemical stains, including the use of monoclonal antibodies, will further

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increase the understanding of the CNS lymphomas and thus contribute to improvement in patient survival. 11.

References

12.

1. Bailey P. Intracranial sarcomatous tumors of leptomeningeal origin. Arch Surg 1929;18:1359-99. 2. Bertelsen K. Primary cerebral reticulosarcoma. Acta Pathol Microbiol Scand (A) 1970;78:209-14. 3. Bruni J, Bilbao JM, Gray T. Primary intramedullary malignant lymphoma of the spinal cord. Neurology (NY) 1977;27:896-8. 4. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 32-1983. N Engl J Med 1983;309:359-69. 5. Gdrard-Marchant R, Hamlin I, Lennert K, Rilke F, Sransfeld AG, van Unnik JAM. Classification of non-Hodgkin's lymphomas. (Letter to the editor). Lancet 1974;ii:406-8. 6. HassounJ, Andrac L, Gambarelli D, Toga M. Lymphomes malins primitifs du syst~me nerveux central. Etude anatomoclinique, ultrastructurale et immunocytochimique. Apropos de 23 cas. Ann Pathol 1981;1:193-203. 7. Helle TL, Britt RH, Colby TV. Primary lymphoma of the central nervous system. Clinicopathological study of experience at Stanford. J Neurosurg 1984;60:94-103. 8. HenryJM, Heffner RR, Dillard SH, Earle KM, Davis ILL. Primary malignant lymphomas of the central nervous system. Cancer 1974;34:1293-1302. 9. Houthoff HJ, Poppema S, Ebels EJ, Elema JD. Intracranial malignant lymphomas. A morphological and immunocytologic study of twenty cases. Acta Neuropathol 1978;44:203-10. 10. Hume Adams J, Graham DI, Doyle D. Brain biopsy. The smear

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technique for neurosurgical biopsies. London: Chapman and Hall, 1981. Jellinger K, Radaskiewicz T, Slowik F. Primary malignant lymphomas of the central nervous system in man. Acta Neuropathol 1975;Suppl VI:95-102. KepesJJ, Chen WYK, Pang I-C, Kepes M. Tumors of the central nervous system in Taiwan, Republic of China. Surg Neurol 1984;22:149-56. Lennert K. Histopathology of the non-Hodgkin's lymphomas. (Based on the Kiel classification). Berlin-Heidelberg-New York: Springer-Verlag. 1981. Littman P, Wang CC. Reticulum cell sarcoma of the brain. A review of the literature and a study of 19 cases. Cancer 1975;35:1412-20.

15. Rosenberg SA, et al. National Cancer Institute sponsored study of classification of non-Hodgkin's lymphomas. Summary and discussion of a working formulation for clinical usage. Cancer 1982;49:2112-35. 16. Russel DS, Rubinstein LJ. Pathology of tumors of the central nervous system. 3rd ed. London: Edward Arnold. 1971. 17. Satodate R, Sasou S, Suzuki A, Nishimura K, Takahashi S, Kanaya H. Primary cerebral malignant lymphoma of the histiocytic type. Acta Pathol Jpn 1980;30:1009-17. 18. SpiUane JA, Kendall BE, Moseley I F. Cerebral lymphoma: clinical radiological correlation. J Neurol Neurosurg Psychiatry 1982;45:199-208. 19. Taylor CR, Russel R, Lukes RJ, Davis RL. An immunohistological study of immunoglobulin content of primary central nervous system lymphomas. Cancer 1978;41:2197-2205. 20. Triller M, Pialat J, Chazot G, Bourrat C, Schott B. Lymphome non-Hodgkinien "primitif" de l'enc6phale. Sarcoidose. Cancer thyroidien. D6ficit immunitaire cellulaire. Rev Neurol (Paris) 1982;138:241-8.

Editorial N o t e I have long debated with myself on whether or not to recommend this paper, and finally have concluded that it should be accepted for publication because it represents a retrospective study of malignant lymphomas in the brain among a large segment of the population of Denmark. This information alone is worth spreading among neurosurgeons and oncologists. My most serious doubts concerned the omission by the authors of probably the best treatise to date on the subject as published in 1974 in Acta Pathologica (Suppl VI) under the editorship of Jellinger and Seitelberger. This represents the conclusions of an international symposium held in Vienna on the subject. I was concerned by the reasons for the choice by the authors of Lennert's classification of lymphomas. Not all oncologists and hematologists agreed originally with this classification, and there are signs that it is already partially being abandoned. What sense is there in a histologic classification of "high-grade malignancy" and "low-grade malignancy" of tumors in patients who survive for long periods with the former diagnosis and die promptly with the latter? But this criticism may not be all-important; therefore I have recommended publication of this paper. H. M. Z I M M E R M A N , M.D. Bronx, N e w Y o r k