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Primary non-Hodgkin's lymphomas of the central nervous system
Path. Res. Pract. 181,430-433 (1986)
Primary Non-Hodgkin's Lymphomas of the Central Nervous System K. H. H. Merkel Department of Pathology, University of Saarland (KHHM), 6650 Homburg/Saar, Federal Republic of Germany
M. L. Hansmann Department of Pathology, University of Kiel (MLH), 2300 Kiel, Federal Republic of Germany
SUMMARY
Thirty-five primary non-Hodgkin's lymphomas (NHL) of the central nervous system (CNS) were examined in a retrospective study and classified according to the Kiel classification 8• Diagnosis was made on surgical biopsies in 28 cases and on autopsy specimens in seven cases. The tumors were predominantly located in the frontal lobe and were unifocal in all but two cases. Patients ranged in age from seven to 74 years, with a male-female ratio of 1.3: 1. The lymphomas were probably all of B cell type. In contrast to NHLs of the lymph nodes, the NHLs of the CNS we encountered were more often high grade (immunoblastic, lymphoblastic) than low grade malignant. All but one low grade malignant NHL found in our study were lymphoplasmacytoid (LP) immunocytomas.
Introduction Primary non-Hodgkin's lymphomas (NHL) of the central nervous system (eNS) are rare tumors accounting for only about 1 % of all intracranial neoplasms 2,5,6. A rise in incidence has been claimed in some studies2,12. Immunodeficient individuals - patients with immune deficiency syndrome or undergoing immunosuppressive therapy - run a higher risk of developing these tumors1, 3, 7, 13, 15. Like neuroepithelial tumors, primary eNS lymphomas rarely include systemic involvement. Because these tumors have been shown to be true lymphomas, the terms "microglioma" and "reticulosarcoma" have become obsolete2 • Applying morphological and immunohistological methods we classified the eNS lymphomas according to the Kiel classification 8,9. The purpose of this investigation was to study first, the location and growth of primary NHLs of the eNS and secondly, the incidence of the various NHL subtypes. 0344-0338/86/0181-0430$3.50/0
Material and Methods Thirty-five cases of primary NHL of the CNS from the past 13 years were collected from the files of the lymph node registry of the German Society of Pathology at the University of Kiel and of the Department of Pathology of the University of the Saarland in West Germany. They consisted of 28 biopsy and seven autopsy specimens. The clinical diagnosis in most cases was either primary neuroepithelial tumor, lymphoma, metastases of extracranial tumor or brain infarction. Tissue was fixed in formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin (H&E), Giemsa, and periodic acid Schiff (PAS). For demonstration of intracytoplasmic immunoglobulins, lysozyme, and alpha 1-antichymotrypsin in eight cases, the peroxidase-antiperoxidase (PAP) method according to Mepham et a1. 10 was unsed on paraffin embedded sections. Antisera were purchased from DAKO (Denmark) and diaminobenzidine tetrahydrochloride (DAB) from Sigma Chemicals (USA).
© 1986 by Gustav Fischer Verlag, Stuttgart
Primary CNS Non-Hodgkin's Lymphomas . 431
Results The 35 primary NHLs of the eNS were located in all parts of the brain, most often in the frontal lobes (Table 1). Gross examination of autopsied brains sometimes found nodular grey tumor masses protruding into the ventricular wall. In all cases the tumor had invaded surrounding brain structures. All but two tumors were unifocal. 19 cases involved men, 16 women, with ages ranging from seven to 74 years. In contrast to their incidence in lymph nodes, NHL of the eNS were more often high than low grade malignant (Table 2). Immunoblastic lymphomas were the most common, accounting for 48.6% of all cases. They showed large nuclei with a prominent nucleolus and abundant cytoplasm (Fig. 1). Of interest was the large number of lymphoblastic NHLs, which constituted 14.3% of all eNS lymphomas in our study. They showed cohesive tumor cells with large, round nuclei and coarse chromatin. Two cases had the starry sky pattern typical of Burkitt's lymphoma (Fig. 2). Definite diagnosis could not be reached in two cases due to the poor quality of the biopsied tumor tissue. All other cases showed the histological characteristics typical of these tumors in lymph nodes. All low grade malignant lymphomas in our series, with the exception of one case we classified as centroblastic-centrocytic, were LP-immunocytomas, accounting for 22.8% of all cases. Histologically, these tumors consisted of small lymphocytes and cells demonstrating features of lymphoplasmacytoid or lymphoplasmacytic differentiation (Fig. 3). The single case of centroblastic-centrocytic lymphoma showed diffuse growth with band-like fibrosis and no follicle formation of the cells. The centroblasts had large nucleoli located at the nuclear periphery and a small rim of clear cytoplasm. They were dispersed between sheets of centrocytes with typical cleaved nuclei and no stainable cytoplasm.
Fig. 1. Immunoblastic lymphoma showing large nucleoli with a prominent, centrally located nucleolus. Giemsa x 640.
Table 1. Localization of 35 primary CNS lymphomas Localization
Cases
Frontal lobe Temporal lobe Parietal lobe Occipital lobe Basal ganglia Cerebellum
15 5
4
6
4 1
Table 2. Histological types of 35 primary CNS lymphomas Cases Sex Age Range (m: f) years male female M.L. LP immunocytoma M.L. centroblastic-centrocytic M.L. centro blastic M.L. immunoblastic M.L. lymphoblastic M.L. high grade malignant - not classifiable Total
8 1 2 17 5 2
4:4 1 1: 1 10:7 3:2 1:1
7-65 59 52-72 34-74 44-70 51-63
19: 16
7-74
M.L. = Malignant Lymphoma LP = Lymphoplasmocytoid Immunocytoma
Immunohistological examination of the immunoblastic lymphomas revealed cytoplasm containing IgM in three cases, lambda light chain in two cases, and kappa light chain in two cases. One lymphoblastic lymphoma had lambda light chain (Table 3). The immunoreaction could not be clearly interpreted in one case of LP-immunocytoma due to poor tissue fixation and hemorrhage.
432
K. H. H. Merkel and M. L. Hansmann
Fig. 2. Lymphoblastic lymphoma with coarse chromatin and several nucleoli. Giemsa x 640.
~
;j Table 3. Immunohistological examination of eight primary eNS lymphomas Diagnosis
IgA
IgM
K
L
+
Immunoblastic Lymphoplasmacytoid Immunoblastic Immunoblastic Lymphoblastic
+ +
Immunoblastic
+
Lymphoblastic
IgG
+
+ + +
IgA = Immunoglobulin A IgM = Immunoglobulin M IgG = Immunoglobulin G K = Kappa light chain L = Lambda light chain
Fig. 3. Immunocytoma demonstrating lymphoplasmacytic differentiation of tumor cells (_) H & E. x 400.
Primary CNS Non-Hodgkin's Lymphomas . 433
Discussion The NHL of the eNS included in our stud!. could all be classified according to the Kiel classification' 9, except for two cases of poor technical quality. Primary NHLs of the eNS showed no significant histological or cytological differences from NHL occurring in the lymph nodes. There was a remarkable difference, however, in the distribution of the various NHL subtypes in the eNS relative to their distribution in the lymph nodes. All CNS lymphomas in our study seemed to be of B cell origin, which coincides with the findings of Taylor et al. 4,5,6,14. The tumors all displayed a diffuse growth pattern, including the centroblastic-centrocytic lymphoma. The B cell nature of five cases of NHL could be determined by immunohistochemical demonstration of monotypic Ig production in tumor cells. No conclusive evidence of Ig could be found in the other cases, probably due to inadequate fixation. The predominance of immunoblastic lymphoma among the NHLs of the brain found in our study has also been reported by others5, 6, 14, 16. Among the low grade malignant eNS lymphomas we found, one was classified as centroblastic-centrocytic, all the others as LPimmunocytomas. Differential diagnosis of primitive neuroectodermal tumor ll or of a metastatic tumor such as small cell bronchogenic carcinoma could be excluded in these cases by cytologic and histologic criteria. The single case of centroblastic-centrocytic lymphoma contained a relatively large number of centroblasts within sheets of centrocytes. The growth pattern was diffuse with marked fibrosis. We encountered no histiocytic tumor of the CNS. One case had many lysozyme positive large cells with small, round, regular nuclei showing no atypia. These cells were interpreted as reactive histiocytes. The smalllymphocytes found between these histiocytes were larger, lay close together, and showed occasional lymphoplasmacytoid differentiation. Hence the tumor was classified as an LP-immunocytoma with a pronounced histiocytic reaction. No case of primary Hodgkin's disease was found in our series. NHL in the eNS occurs in all age groups, most often, however, during the fourth and fifth decades. On the whole, high grade malignant lymphomas of the CNS seem to affect an older age group than their low grade malignant counterparts. Acknowledgments We thank Prof. Dr. K. Lennert for his constructive criticism of the manuscript.
The study was presented in part at the 6th Annual Meeting of the American Association of Neuropathologists, June 14-17, 1984, Holiday Inn at the Embarcadero San Diego, California
References 1 Barnett LB, Schwartz E (1974) Cerebral reticulum cell sarcoma after multiple renal transplants. J Neurol Neurosurg Psrchiatry 37: 966-970 Henry JM, Heffner RR JR, Dillard SH, Earl KM, Davis RL (1974) Primary malignant lymphomas of the central nervous system. Cancer 34: 1295-1302 3 Hoover R, Fraument JF Jr (1973) Risk of cancer in renal transplant recipients. Lancet 2: 55-57 4 Houthoff HJ, Poppema S, Ebels EJ, Elema JD (1978) Intracranial malignant lymphomas. A morphologic and immunocytologic study of twenty cases. Acta neuropathol (Berl) 44: 203-210 5 Jellinger K, Radaskiewicz TH, Slowik F (1975) Primary malignant lymphomas of the central nervous system in man. Acta neuropathol (Berl) Suppl VI: 95-102 6 Jellinger K (1983) Maligne Lymphome und Leukiimien im Zentralnervensystem. Verh dtsch Ges Path 67: 556-573 7 Kersey JH, Spector BD (1975) Immunodeficiency diseases. In: Fraument JF JR, (Ed.7 Persons at High Risk of Cancer: An Approach in Cancer Etiology and Control. (p. 55-67) Academic Press, New York 8 Lennert K (1975) Morphology and classification of malignant lymphomas and so-called reticuloses. Acta neuropathol (Bed) Suppl VI: 1-16 9 Lennert K (1978) Malignant lymphomas other than Hodgkin's disease. In: Uelinger E (Ed.) (Handbuch der speziellen pathologischen Anatomie und Histologie Bd.1) Teil 3, Lymph Nodes; Part B, Malignant Lymphomas. (Springer, Berlin) 10 Mepham BL, Frater W, Mitchell BS (1979) The use of proteolytic enzymes to improve immunoglobulin staining by the PAP technique. Histochem J 11: 345-357 11 Rubinstein LJ (1971) Cytogenesis and differentiation of primitive central neuroepithelial tumors. J Neuropathol Exp Neurol 30: 7-26 12 Schaumburg HH, Planck CR, Adams RD (1972) The reticulum cell sarcoma-micro glioma group of brain tumors. A consideration of their clinical features and therapy. Brain 95: 199-212 13 Schneck SA, Penn I (1971) De-novo tumors in renal transplant recipients. Lancet 1: 983-6 14 Taylor CR, Russell R, Lukes RJ, Davis RL (1978) An immunohistological study of immunoglobulin content of primary central nervous system lymphomas. Cancer 41: 2197-2205 15 Ulrich J, Wiithrich R (1974) Multiple sclerosis: reticulum cell sarcoma of the nervous system in a patient treated with immunosuppressive drugs. Eur Nerol 12: 65-78 16 Varadachari Ch, Palutke M, Climie ARW, Weise RW, Chason JL (1978) Immunoblastic sarcoma (histiocytic lymphoma) of the brain with B cell markers. J Neurosurg: 49: (887-892
Received October 21, 1985 . Accepted December 11, 1985
Key words: Non Hodgkin's lymphomas - Kiel classification - Central nervous system - B-ceillymphoma PD Dr. K. H. H. Merkel, Department of Pathology, Hospital Am Urban, Dieffenbachstr. 1, D-1000 Berlin 61, Federal Republic of Germany
Primary Non-Hodgkin's Lymphomas of the Central Nervous System K. H. H. Merkel Department of Pathology, University of Saarland (KHHM), 6650 Homburg/Saar, Federal Republic of Germany
M. L. Hansmann Department of Pathology, University of Kiel (MLH), 2300 Kiel, Federal Republic of Germany
SUMMARY
Thirty-five primary non-Hodgkin's lymphomas (NHL) of the central nervous system (CNS) were examined in a retrospective study and classified according to the Kiel classification 8• Diagnosis was made on surgical biopsies in 28 cases and on autopsy specimens in seven cases. The tumors were predominantly located in the frontal lobe and were unifocal in all but two cases. Patients ranged in age from seven to 74 years, with a male-female ratio of 1.3: 1. The lymphomas were probably all of B cell type. In contrast to NHLs of the lymph nodes, the NHLs of the CNS we encountered were more often high grade (immunoblastic, lymphoblastic) than low grade malignant. All but one low grade malignant NHL found in our study were lymphoplasmacytoid (LP) immunocytomas.
Introduction Primary non-Hodgkin's lymphomas (NHL) of the central nervous system (eNS) are rare tumors accounting for only about 1 % of all intracranial neoplasms 2,5,6. A rise in incidence has been claimed in some studies2,12. Immunodeficient individuals - patients with immune deficiency syndrome or undergoing immunosuppressive therapy - run a higher risk of developing these tumors1, 3, 7, 13, 15. Like neuroepithelial tumors, primary eNS lymphomas rarely include systemic involvement. Because these tumors have been shown to be true lymphomas, the terms "microglioma" and "reticulosarcoma" have become obsolete2 • Applying morphological and immunohistological methods we classified the eNS lymphomas according to the Kiel classification 8,9. The purpose of this investigation was to study first, the location and growth of primary NHLs of the eNS and secondly, the incidence of the various NHL subtypes. 0344-0338/86/0181-0430$3.50/0
Material and Methods Thirty-five cases of primary NHL of the CNS from the past 13 years were collected from the files of the lymph node registry of the German Society of Pathology at the University of Kiel and of the Department of Pathology of the University of the Saarland in West Germany. They consisted of 28 biopsy and seven autopsy specimens. The clinical diagnosis in most cases was either primary neuroepithelial tumor, lymphoma, metastases of extracranial tumor or brain infarction. Tissue was fixed in formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin (H&E), Giemsa, and periodic acid Schiff (PAS). For demonstration of intracytoplasmic immunoglobulins, lysozyme, and alpha 1-antichymotrypsin in eight cases, the peroxidase-antiperoxidase (PAP) method according to Mepham et a1. 10 was unsed on paraffin embedded sections. Antisera were purchased from DAKO (Denmark) and diaminobenzidine tetrahydrochloride (DAB) from Sigma Chemicals (USA).
© 1986 by Gustav Fischer Verlag, Stuttgart
Primary CNS Non-Hodgkin's Lymphomas . 431
Results The 35 primary NHLs of the eNS were located in all parts of the brain, most often in the frontal lobes (Table 1). Gross examination of autopsied brains sometimes found nodular grey tumor masses protruding into the ventricular wall. In all cases the tumor had invaded surrounding brain structures. All but two tumors were unifocal. 19 cases involved men, 16 women, with ages ranging from seven to 74 years. In contrast to their incidence in lymph nodes, NHL of the eNS were more often high than low grade malignant (Table 2). Immunoblastic lymphomas were the most common, accounting for 48.6% of all cases. They showed large nuclei with a prominent nucleolus and abundant cytoplasm (Fig. 1). Of interest was the large number of lymphoblastic NHLs, which constituted 14.3% of all eNS lymphomas in our study. They showed cohesive tumor cells with large, round nuclei and coarse chromatin. Two cases had the starry sky pattern typical of Burkitt's lymphoma (Fig. 2). Definite diagnosis could not be reached in two cases due to the poor quality of the biopsied tumor tissue. All other cases showed the histological characteristics typical of these tumors in lymph nodes. All low grade malignant lymphomas in our series, with the exception of one case we classified as centroblastic-centrocytic, were LP-immunocytomas, accounting for 22.8% of all cases. Histologically, these tumors consisted of small lymphocytes and cells demonstrating features of lymphoplasmacytoid or lymphoplasmacytic differentiation (Fig. 3). The single case of centroblastic-centrocytic lymphoma showed diffuse growth with band-like fibrosis and no follicle formation of the cells. The centroblasts had large nucleoli located at the nuclear periphery and a small rim of clear cytoplasm. They were dispersed between sheets of centrocytes with typical cleaved nuclei and no stainable cytoplasm.
Fig. 1. Immunoblastic lymphoma showing large nucleoli with a prominent, centrally located nucleolus. Giemsa x 640.
Table 1. Localization of 35 primary CNS lymphomas Localization
Cases
Frontal lobe Temporal lobe Parietal lobe Occipital lobe Basal ganglia Cerebellum
15 5
4
6
4 1
Table 2. Histological types of 35 primary CNS lymphomas Cases Sex Age Range (m: f) years male female M.L. LP immunocytoma M.L. centroblastic-centrocytic M.L. centro blastic M.L. immunoblastic M.L. lymphoblastic M.L. high grade malignant - not classifiable Total
8 1 2 17 5 2
4:4 1 1: 1 10:7 3:2 1:1
7-65 59 52-72 34-74 44-70 51-63
19: 16
7-74
M.L. = Malignant Lymphoma LP = Lymphoplasmocytoid Immunocytoma
Immunohistological examination of the immunoblastic lymphomas revealed cytoplasm containing IgM in three cases, lambda light chain in two cases, and kappa light chain in two cases. One lymphoblastic lymphoma had lambda light chain (Table 3). The immunoreaction could not be clearly interpreted in one case of LP-immunocytoma due to poor tissue fixation and hemorrhage.
432
K. H. H. Merkel and M. L. Hansmann
Fig. 2. Lymphoblastic lymphoma with coarse chromatin and several nucleoli. Giemsa x 640.
~
;j Table 3. Immunohistological examination of eight primary eNS lymphomas Diagnosis
IgA
IgM
K
L
+
Immunoblastic Lymphoplasmacytoid Immunoblastic Immunoblastic Lymphoblastic
+ +
Immunoblastic
+
Lymphoblastic
IgG
+
+ + +
IgA = Immunoglobulin A IgM = Immunoglobulin M IgG = Immunoglobulin G K = Kappa light chain L = Lambda light chain
Fig. 3. Immunocytoma demonstrating lymphoplasmacytic differentiation of tumor cells (_) H & E. x 400.
Primary CNS Non-Hodgkin's Lymphomas . 433
Discussion The NHL of the eNS included in our stud!. could all be classified according to the Kiel classification' 9, except for two cases of poor technical quality. Primary NHLs of the eNS showed no significant histological or cytological differences from NHL occurring in the lymph nodes. There was a remarkable difference, however, in the distribution of the various NHL subtypes in the eNS relative to their distribution in the lymph nodes. All CNS lymphomas in our study seemed to be of B cell origin, which coincides with the findings of Taylor et al. 4,5,6,14. The tumors all displayed a diffuse growth pattern, including the centroblastic-centrocytic lymphoma. The B cell nature of five cases of NHL could be determined by immunohistochemical demonstration of monotypic Ig production in tumor cells. No conclusive evidence of Ig could be found in the other cases, probably due to inadequate fixation. The predominance of immunoblastic lymphoma among the NHLs of the brain found in our study has also been reported by others5, 6, 14, 16. Among the low grade malignant eNS lymphomas we found, one was classified as centroblastic-centrocytic, all the others as LPimmunocytomas. Differential diagnosis of primitive neuroectodermal tumor ll or of a metastatic tumor such as small cell bronchogenic carcinoma could be excluded in these cases by cytologic and histologic criteria. The single case of centroblastic-centrocytic lymphoma contained a relatively large number of centroblasts within sheets of centrocytes. The growth pattern was diffuse with marked fibrosis. We encountered no histiocytic tumor of the CNS. One case had many lysozyme positive large cells with small, round, regular nuclei showing no atypia. These cells were interpreted as reactive histiocytes. The smalllymphocytes found between these histiocytes were larger, lay close together, and showed occasional lymphoplasmacytoid differentiation. Hence the tumor was classified as an LP-immunocytoma with a pronounced histiocytic reaction. No case of primary Hodgkin's disease was found in our series. NHL in the eNS occurs in all age groups, most often, however, during the fourth and fifth decades. On the whole, high grade malignant lymphomas of the CNS seem to affect an older age group than their low grade malignant counterparts. Acknowledgments We thank Prof. Dr. K. Lennert for his constructive criticism of the manuscript.
The study was presented in part at the 6th Annual Meeting of the American Association of Neuropathologists, June 14-17, 1984, Holiday Inn at the Embarcadero San Diego, California
References 1 Barnett LB, Schwartz E (1974) Cerebral reticulum cell sarcoma after multiple renal transplants. J Neurol Neurosurg Psrchiatry 37: 966-970 Henry JM, Heffner RR JR, Dillard SH, Earl KM, Davis RL (1974) Primary malignant lymphomas of the central nervous system. Cancer 34: 1295-1302 3 Hoover R, Fraument JF Jr (1973) Risk of cancer in renal transplant recipients. Lancet 2: 55-57 4 Houthoff HJ, Poppema S, Ebels EJ, Elema JD (1978) Intracranial malignant lymphomas. A morphologic and immunocytologic study of twenty cases. Acta neuropathol (Berl) 44: 203-210 5 Jellinger K, Radaskiewicz TH, Slowik F (1975) Primary malignant lymphomas of the central nervous system in man. Acta neuropathol (Berl) Suppl VI: 95-102 6 Jellinger K (1983) Maligne Lymphome und Leukiimien im Zentralnervensystem. Verh dtsch Ges Path 67: 556-573 7 Kersey JH, Spector BD (1975) Immunodeficiency diseases. In: Fraument JF JR, (Ed.7 Persons at High Risk of Cancer: An Approach in Cancer Etiology and Control. (p. 55-67) Academic Press, New York 8 Lennert K (1975) Morphology and classification of malignant lymphomas and so-called reticuloses. Acta neuropathol (Bed) Suppl VI: 1-16 9 Lennert K (1978) Malignant lymphomas other than Hodgkin's disease. In: Uelinger E (Ed.) (Handbuch der speziellen pathologischen Anatomie und Histologie Bd.1) Teil 3, Lymph Nodes; Part B, Malignant Lymphomas. (Springer, Berlin) 10 Mepham BL, Frater W, Mitchell BS (1979) The use of proteolytic enzymes to improve immunoglobulin staining by the PAP technique. Histochem J 11: 345-357 11 Rubinstein LJ (1971) Cytogenesis and differentiation of primitive central neuroepithelial tumors. J Neuropathol Exp Neurol 30: 7-26 12 Schaumburg HH, Planck CR, Adams RD (1972) The reticulum cell sarcoma-micro glioma group of brain tumors. A consideration of their clinical features and therapy. Brain 95: 199-212 13 Schneck SA, Penn I (1971) De-novo tumors in renal transplant recipients. Lancet 1: 983-6 14 Taylor CR, Russell R, Lukes RJ, Davis RL (1978) An immunohistological study of immunoglobulin content of primary central nervous system lymphomas. Cancer 41: 2197-2205 15 Ulrich J, Wiithrich R (1974) Multiple sclerosis: reticulum cell sarcoma of the nervous system in a patient treated with immunosuppressive drugs. Eur Nerol 12: 65-78 16 Varadachari Ch, Palutke M, Climie ARW, Weise RW, Chason JL (1978) Immunoblastic sarcoma (histiocytic lymphoma) of the brain with B cell markers. J Neurosurg: 49: (887-892
Received October 21, 1985 . Accepted December 11, 1985
Key words: Non Hodgkin's lymphomas - Kiel classification - Central nervous system - B-ceillymphoma PD Dr. K. H. H. Merkel, Department of Pathology, Hospital Am Urban, Dieffenbachstr. 1, D-1000 Berlin 61, Federal Republic of Germany