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Bone marrow involvement by B-cell non-Hodgkin's lymphoma
ABSTRACTS
their reflection in the peripheral blood and though the rate of evolution may be influenced by therapy this has little effect on the type of transformation the cMPD may undergo.
The pattern of marrow fibrosis J. te Velde, MD, PhD and Spaarne Ziekenhuis, Department of Clinical Pathology, Handellaan 2, 2102 CW Heemstede, The Netherlands Myelofibrosis is a misnomer. Previously it was thought that due to a malignant proliferation of fibroblasts within the bone marrow, haematopoietic cells were evicted and migrated to the spleen. Today it is still seen as a distinct myeloproliferative disorder, although mostly encountered as an endstage of another MPD. As such, it is better to compare it to liver cirrhosis and endstage nephrosclerosis: it is the histological picture of scarring and not a malignant or dysplastic disease in itself. However, it is possible to recognise various patterns or scarring, which correspond to different primary bone marrow diseases. This pattern of stromal fibre formulation can be very useful even in the early diagnosis of bone marrow disorders. Marrow fibrosis is associated with increased megakaryopoiesis. Even in the absence of thrombopoiesis excessive fibrosis can also be found in monocytosis, lymphoma or malignant mastocytosis. Osteoid in collagenous fibrosis (osteomyelosclerosis) is correlated with pathological megakaryopoiesis. Selective fibrosis of the wall of the venous sinuses is seen only in systemic disease originating outside the marrow. Reticulin fibres within the haematopoietic area and not as part of the capillary or arteriolar wall are indicative of the presence of a myelodysplastic or myeloproliferative process. For example, a hypocellular bone marrow with an extensive inflammatory like infiltrate and interstitial fibre formation can be found in extremely pancytopenic patients, who eventually develop leukaemia.
Myelodysplastic syndromes versus chronic myeloproliferative disorders J-G. van den Tweel (See Mini-symposium: bone marrow Current Diagnostic Pathology 1994; l(4): 198-202)
Acute leukaemia and transient myeloproliferative disorder in down syndrome Richard D. Brunning, MD and Craig E. Litz, MD, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA Individuals with Down syndrome are at increased risk for developing acute leukaemia; the incidence in children and adolescents with trisomy 21 has been estimated at IO-30 times higher than in normal children. In addition, neonates with Down syndrome may develop a
24 I
transient myeloproliferative disorder which is morphologically indistinguishable from acute myeloid leukaemia. This study consists of 30 patients with Down syndrome and acute leukaemia or transient myeloproliferative disorder. Three morphologic groups were identified: (1) acute lymphoblastic leukaemia (ALL, 6 cases), (2) acute myeloid leukaemia (AML. 3 cases), (3) 21 cases with a morphologically distinctive form of AML. The age at diagnosis of the patients with ALL was l-9 years and l-34 years for the AML cases in group 2. The age at diagnosis of the 21 patients in group 3 was 1 day to 6 years; 9 patients in group 3 were less than 1 year of age. The blasts in group 1 were morphologically and immunologically typical of ALL, Ll or L2, and Tdt positive. The group 2 cases were morphologically and cytochemically Ml, M2, and M5. The major blast population in the group 3 cases had basophilic cytoplasm, frequently containing basophilic granules. These blasts were myeloperoxidase, non-specific esterase, Tdt and lymphoid antigen negative. The blasts frequently expressed CD7, CD34, and CD36. A minor population of blasts in most patients in group 3 had megakaryocytic features and some expressed platelet glycoproteins IIW IIIa (CD41) and IIIa (CD 61). The most common cytogenetic abnormality in the hematopoietic cells in the group 3 patients was a + 8 in addition to trisomy 2 1. The survival of the patients in group 3 appeared to be related to the age at time of diagnosis. 66% of the patients less than one year of age and 14% of patients more than 1 year of age were alive at 5 years. There were no recognizable differences in the clinical or morphologic findings between the patients less than 1 year of age or older than 1 year. 9 of the 21 patients in group 3 were not treated; 4 of the untreated patients underwent spontaneous remissions which have lasted 12+, 8+, 7+, and 7+ years. All 4 patients were neonates at diagnosis. 2 other patients had spontaneous remissions but relapsed within 6 months. There were no haematologic or morphologic features which distinguished the group of patients who underwent spontaneous remission from those with progressive disease.
Bone marrow involvement by B-cell non-Hodgkin’s lymphoma D. Anagnostou, Department of Hematopathology, Evangelisimos Hospital, Athens, Greece The incidence of bone marrow (BM) involvement by non-Hodgkin’s lymphomas (NHL), at the time of diagnosis, is 35-75%. B-cell lymphomas represent 80-85% of all lymphomas. Low grade NHLs involve BM more frequently than do the high grade ones. We identify 5 patterns of BM involvement by NHLs: nodular, focal, paratrabecular, interstitial, diffuse. The paratrabecular mode of spread has been considered indicative of malignancy. However, reactive conditions (tuberculosis, autoimmune diseases etc) may also present the same pattern. Classification of B-NHL cannot be made accurately on BM sections alone due to: (a) the expansion of the
242 CURRENT DIAGNOSTIC PATHOLOGY
spectrum of differential diagnosis after the incorporation of new histological subtypes (mantle, marginal) in the group of small lymphocytic lymphomas, (b) the limitations of applying immunohistochernistry on BM frozen sections and (c) the detection of discrepancies in histology and malignancy grade in l/3 of NHL (discordant NHL). The existing histological guidelines in favour of morphologically benign lymphoid infiltrates (BLI) are no longer completely reliable. 22% of patients with BLI in BM were latter proven to have lymphoproliferative disorders. According to our immunophenotypical data, morphologically BLI consisting mainly or exclusively of B-lymphocytes appeared to be neoplastic in nature. In contrast, a mixed population of B and T or of T-lymphocytes was in favour of a reactive process. Patients with marrow involvement by B-NHL experience longer survival than patients with T-NHL. The presence of large cell NHL in the BM predict a short survival.
Bone marrow involvement in T cell malignant lymphoma J. Diebold, Department of Pathology, Hdtel-Dieu, Paris, France
Bone marrow (BM) involvement can occur in T cell malignant lymphoma (TML) as in B-cell ML. The architectural patterns which can be seen are the following: (1) interstitial infiltrate minimal or dense, with or without focal reinforcement, localized or diffuse; (2) patchy infiltrate, more or less nodular; (3) paratrabecular nodules; (4) massive infiltrate (packed marrow); (5) monocellular dispersion sometimes intra-sinusal, particularly in anapIastic large cell ML. Fibrosis systemized or destructive, localized or diffuse can be present as well as vascular hyperplasia and sinusal distension. Reactive lesions of the 3 normal cell series can be observed with dysmaturation and either hyperplasia or hypoplasia. Hypereosinophilia is frequent, as is a polyclonal plasmacytosis. Reactive lymphoid nodules can also be seen. Diffuse hyperplasia of histiocytes sometimes with erythrophagocytosis can obscure some TML, particularly large pleomorphic or anaplastic large cell ML. Clusters of epitheliod cells or granulomas can be observed. The updated Kiel classification allows classiftcation of the majority of the TML. The frequency of BM involvement is reported as between 20-70% of the cases in the majority of TML. In anaplastic large cell lymphoma, the overall frequency is not over 10% to 15%. BM involvement should be regarded as a factor of bad prognosis. In our series, the median survival rate was 9 months in patients with BM involvement, and 41 months in patients without. The main diseases which should be considered in the differential diagnosis are the following: reactive lymphoid nodules, reactive T cell aggregates particularly with hypereosinophilia, and malignant diseases such as Hodgkin’s disease, and ‘I’ cell rich or histiocyte rich B cell high grade lymphomas. Some B cell ML with irregular nuclei should also be considered (centrocytic or mantle zone ML, centroblastic-centrocytic or multi-
lobated centroblastic) as well as systemic mastocytosis and sometimes acute myeloblastic or monoblastic leukaemia. Immunohistochemistry on paraffin sections can be useful in establishing the diagnosis of TML.
Reactive lymphoid aggregates in the bone marrow H. K. Miller-Hermelink, Ch. Kessler and A. Marx, Pathologisches Institut der Universitiit Wiirzburg, JosefSchneider-Str. 2, 97080 Wiirzburg, Germany
Reactive lymphoid aggregates in the bone marrow (BM) are found in 3-50% of ‘normal’ trephines. The number of BM lymphocytes is highest up to the age of 2, declines until the age of 20 and increase thereafter. Lymphocytes in adults make up 10-U% of BM cells, 90% of which are T cells. No definite criteria defining reactive infiltrates can be given. The following features favour a reactive process: (1) size < 1 mm; (2) well defined borders of aggregates in a perivascular location; (3) random distribution in the marrow; (4) prominent vascularity; (5) germinal centers; (6) plasma cells, histiocytic cells and eosinophils accompanying lymphocytes. Reactive lymphoid aggregates need to be distinguished from diffuse lymphocytosis, lymphofollicular hyperplasia, granulomatous reactions and histiocytic infiltrates. Diffuse BM lymphocytosis occurs in acute immunological diseases and probably is the precursor of lymphofollicular hyperplasia. However, since there is a wide range in numbers of lymphocyte in and around BM, we diagnose ‘diffuse reactive lymphocytosis’ rarely. Lymphofollicular hyperplasia: while small lymphoid aggregates are frequent in apparently healthy persons, a larger number and size of lymphoid aggregates with germinal centers qualifies as ‘lymphofollicular hyperplasia’. It is typical of chronic immunodysregulation, autoimmune diseases, ARC/AIDS, chronic drug exposure, IL-2-therapy and following splenectomy or chemotherapy. Granulomatous reactions in the BM remain etiologically unexplained in 80% of cases. On the other hand, the possible causes of granuloma formation are numerous; they include drug reactions; sarcoidosis; infection due to tuberculosis, atypical mycobacteriosis, Q-fever, Brucellosis, fungi, EBV, CMV or mycoplasma; Hodgkin’s disease, T cell lymphomas and mast cell disease. Histiocytic infiltrates in the BM are quite frequent due to chemotherapy and intravenous infusions; accumulation of cell debris or infusion additives may be seen in the BM histiocytes. Endogenous storage diseases due to inherited metabolic deficiencies or hemophagocytic syndromes also had to be considered. In the differential diagnosis of reactive BM lymphoid aggregates, low grade B and T cell lymphomas and Hodgkin’s disease need to be considered. Diffculties in diagnosis arise with minimal lymphoma infiltrations. Peritrabecular localization, cytology, B cell phenotype or light chain restriction favour a lymphoma.
their reflection in the peripheral blood and though the rate of evolution may be influenced by therapy this has little effect on the type of transformation the cMPD may undergo.
The pattern of marrow fibrosis J. te Velde, MD, PhD and Spaarne Ziekenhuis, Department of Clinical Pathology, Handellaan 2, 2102 CW Heemstede, The Netherlands Myelofibrosis is a misnomer. Previously it was thought that due to a malignant proliferation of fibroblasts within the bone marrow, haematopoietic cells were evicted and migrated to the spleen. Today it is still seen as a distinct myeloproliferative disorder, although mostly encountered as an endstage of another MPD. As such, it is better to compare it to liver cirrhosis and endstage nephrosclerosis: it is the histological picture of scarring and not a malignant or dysplastic disease in itself. However, it is possible to recognise various patterns or scarring, which correspond to different primary bone marrow diseases. This pattern of stromal fibre formulation can be very useful even in the early diagnosis of bone marrow disorders. Marrow fibrosis is associated with increased megakaryopoiesis. Even in the absence of thrombopoiesis excessive fibrosis can also be found in monocytosis, lymphoma or malignant mastocytosis. Osteoid in collagenous fibrosis (osteomyelosclerosis) is correlated with pathological megakaryopoiesis. Selective fibrosis of the wall of the venous sinuses is seen only in systemic disease originating outside the marrow. Reticulin fibres within the haematopoietic area and not as part of the capillary or arteriolar wall are indicative of the presence of a myelodysplastic or myeloproliferative process. For example, a hypocellular bone marrow with an extensive inflammatory like infiltrate and interstitial fibre formation can be found in extremely pancytopenic patients, who eventually develop leukaemia.
Myelodysplastic syndromes versus chronic myeloproliferative disorders J-G. van den Tweel (See Mini-symposium: bone marrow Current Diagnostic Pathology 1994; l(4): 198-202)
Acute leukaemia and transient myeloproliferative disorder in down syndrome Richard D. Brunning, MD and Craig E. Litz, MD, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA Individuals with Down syndrome are at increased risk for developing acute leukaemia; the incidence in children and adolescents with trisomy 21 has been estimated at IO-30 times higher than in normal children. In addition, neonates with Down syndrome may develop a
24 I
transient myeloproliferative disorder which is morphologically indistinguishable from acute myeloid leukaemia. This study consists of 30 patients with Down syndrome and acute leukaemia or transient myeloproliferative disorder. Three morphologic groups were identified: (1) acute lymphoblastic leukaemia (ALL, 6 cases), (2) acute myeloid leukaemia (AML. 3 cases), (3) 21 cases with a morphologically distinctive form of AML. The age at diagnosis of the patients with ALL was l-9 years and l-34 years for the AML cases in group 2. The age at diagnosis of the 21 patients in group 3 was 1 day to 6 years; 9 patients in group 3 were less than 1 year of age. The blasts in group 1 were morphologically and immunologically typical of ALL, Ll or L2, and Tdt positive. The group 2 cases were morphologically and cytochemically Ml, M2, and M5. The major blast population in the group 3 cases had basophilic cytoplasm, frequently containing basophilic granules. These blasts were myeloperoxidase, non-specific esterase, Tdt and lymphoid antigen negative. The blasts frequently expressed CD7, CD34, and CD36. A minor population of blasts in most patients in group 3 had megakaryocytic features and some expressed platelet glycoproteins IIW IIIa (CD41) and IIIa (CD 61). The most common cytogenetic abnormality in the hematopoietic cells in the group 3 patients was a + 8 in addition to trisomy 2 1. The survival of the patients in group 3 appeared to be related to the age at time of diagnosis. 66% of the patients less than one year of age and 14% of patients more than 1 year of age were alive at 5 years. There were no recognizable differences in the clinical or morphologic findings between the patients less than 1 year of age or older than 1 year. 9 of the 21 patients in group 3 were not treated; 4 of the untreated patients underwent spontaneous remissions which have lasted 12+, 8+, 7+, and 7+ years. All 4 patients were neonates at diagnosis. 2 other patients had spontaneous remissions but relapsed within 6 months. There were no haematologic or morphologic features which distinguished the group of patients who underwent spontaneous remission from those with progressive disease.
Bone marrow involvement by B-cell non-Hodgkin’s lymphoma D. Anagnostou, Department of Hematopathology, Evangelisimos Hospital, Athens, Greece The incidence of bone marrow (BM) involvement by non-Hodgkin’s lymphomas (NHL), at the time of diagnosis, is 35-75%. B-cell lymphomas represent 80-85% of all lymphomas. Low grade NHLs involve BM more frequently than do the high grade ones. We identify 5 patterns of BM involvement by NHLs: nodular, focal, paratrabecular, interstitial, diffuse. The paratrabecular mode of spread has been considered indicative of malignancy. However, reactive conditions (tuberculosis, autoimmune diseases etc) may also present the same pattern. Classification of B-NHL cannot be made accurately on BM sections alone due to: (a) the expansion of the
242 CURRENT DIAGNOSTIC PATHOLOGY
spectrum of differential diagnosis after the incorporation of new histological subtypes (mantle, marginal) in the group of small lymphocytic lymphomas, (b) the limitations of applying immunohistochernistry on BM frozen sections and (c) the detection of discrepancies in histology and malignancy grade in l/3 of NHL (discordant NHL). The existing histological guidelines in favour of morphologically benign lymphoid infiltrates (BLI) are no longer completely reliable. 22% of patients with BLI in BM were latter proven to have lymphoproliferative disorders. According to our immunophenotypical data, morphologically BLI consisting mainly or exclusively of B-lymphocytes appeared to be neoplastic in nature. In contrast, a mixed population of B and T or of T-lymphocytes was in favour of a reactive process. Patients with marrow involvement by B-NHL experience longer survival than patients with T-NHL. The presence of large cell NHL in the BM predict a short survival.
Bone marrow involvement in T cell malignant lymphoma J. Diebold, Department of Pathology, Hdtel-Dieu, Paris, France
Bone marrow (BM) involvement can occur in T cell malignant lymphoma (TML) as in B-cell ML. The architectural patterns which can be seen are the following: (1) interstitial infiltrate minimal or dense, with or without focal reinforcement, localized or diffuse; (2) patchy infiltrate, more or less nodular; (3) paratrabecular nodules; (4) massive infiltrate (packed marrow); (5) monocellular dispersion sometimes intra-sinusal, particularly in anapIastic large cell ML. Fibrosis systemized or destructive, localized or diffuse can be present as well as vascular hyperplasia and sinusal distension. Reactive lesions of the 3 normal cell series can be observed with dysmaturation and either hyperplasia or hypoplasia. Hypereosinophilia is frequent, as is a polyclonal plasmacytosis. Reactive lymphoid nodules can also be seen. Diffuse hyperplasia of histiocytes sometimes with erythrophagocytosis can obscure some TML, particularly large pleomorphic or anaplastic large cell ML. Clusters of epitheliod cells or granulomas can be observed. The updated Kiel classification allows classiftcation of the majority of the TML. The frequency of BM involvement is reported as between 20-70% of the cases in the majority of TML. In anaplastic large cell lymphoma, the overall frequency is not over 10% to 15%. BM involvement should be regarded as a factor of bad prognosis. In our series, the median survival rate was 9 months in patients with BM involvement, and 41 months in patients without. The main diseases which should be considered in the differential diagnosis are the following: reactive lymphoid nodules, reactive T cell aggregates particularly with hypereosinophilia, and malignant diseases such as Hodgkin’s disease, and ‘I’ cell rich or histiocyte rich B cell high grade lymphomas. Some B cell ML with irregular nuclei should also be considered (centrocytic or mantle zone ML, centroblastic-centrocytic or multi-
lobated centroblastic) as well as systemic mastocytosis and sometimes acute myeloblastic or monoblastic leukaemia. Immunohistochemistry on paraffin sections can be useful in establishing the diagnosis of TML.
Reactive lymphoid aggregates in the bone marrow H. K. Miller-Hermelink, Ch. Kessler and A. Marx, Pathologisches Institut der Universitiit Wiirzburg, JosefSchneider-Str. 2, 97080 Wiirzburg, Germany
Reactive lymphoid aggregates in the bone marrow (BM) are found in 3-50% of ‘normal’ trephines. The number of BM lymphocytes is highest up to the age of 2, declines until the age of 20 and increase thereafter. Lymphocytes in adults make up 10-U% of BM cells, 90% of which are T cells. No definite criteria defining reactive infiltrates can be given. The following features favour a reactive process: (1) size < 1 mm; (2) well defined borders of aggregates in a perivascular location; (3) random distribution in the marrow; (4) prominent vascularity; (5) germinal centers; (6) plasma cells, histiocytic cells and eosinophils accompanying lymphocytes. Reactive lymphoid aggregates need to be distinguished from diffuse lymphocytosis, lymphofollicular hyperplasia, granulomatous reactions and histiocytic infiltrates. Diffuse BM lymphocytosis occurs in acute immunological diseases and probably is the precursor of lymphofollicular hyperplasia. However, since there is a wide range in numbers of lymphocyte in and around BM, we diagnose ‘diffuse reactive lymphocytosis’ rarely. Lymphofollicular hyperplasia: while small lymphoid aggregates are frequent in apparently healthy persons, a larger number and size of lymphoid aggregates with germinal centers qualifies as ‘lymphofollicular hyperplasia’. It is typical of chronic immunodysregulation, autoimmune diseases, ARC/AIDS, chronic drug exposure, IL-2-therapy and following splenectomy or chemotherapy. Granulomatous reactions in the BM remain etiologically unexplained in 80% of cases. On the other hand, the possible causes of granuloma formation are numerous; they include drug reactions; sarcoidosis; infection due to tuberculosis, atypical mycobacteriosis, Q-fever, Brucellosis, fungi, EBV, CMV or mycoplasma; Hodgkin’s disease, T cell lymphomas and mast cell disease. Histiocytic infiltrates in the BM are quite frequent due to chemotherapy and intravenous infusions; accumulation of cell debris or infusion additives may be seen in the BM histiocytes. Endogenous storage diseases due to inherited metabolic deficiencies or hemophagocytic syndromes also had to be considered. In the differential diagnosis of reactive BM lymphoid aggregates, low grade B and T cell lymphomas and Hodgkin’s disease need to be considered. Diffculties in diagnosis arise with minimal lymphoma infiltrations. Peritrabecular localization, cytology, B cell phenotype or light chain restriction favour a lymphoma.