* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Reactive Plasmacytic Lesions of the Bone Marrow
Survey
Document related concepts
Monoclonal antibody wikipedia , lookup
Molecular mimicry wikipedia , lookup
Osteochondritis dissecans wikipedia , lookup
Adaptive immune system wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Innate immune system wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
X-linked severe combined immunodeficiency wikipedia , lookup
Transcript
Reactive Plasmacytic Lesions of the Bone Marrow BONG HAK HYUN, M.D., D.Sc, DANIEL KWA, M.D., AND J O H N K. ASHTON, HERMINIA GABALDON, M.D., M.D. From the Departments of Pathology, Muhlenberg Hospital, Plainfield, New Jersey, and Rutgers Medical School, Piscataway, New Jersey ABSTRACT Hyun, Bong Hak, Kwa, Daniel, Gabaldon, Herminia, and Ashton, John K.: Reactive plasmacytic lesions of the bone marrow. Am J Clin Pathol 65: 921 — 928, 1976. A consecutive series of 1,000 bone marrow aspirates was analyzed for percentage of plasma cells, incidence of plasmacytic satellitosis, associated clinical disease states, lymphoid follicles, lipid granulomas, hemosiderin content, and various combinations thereof. Plasmacytosis was a common finding, and tended to parallel the presence of lymphoid follicles, lipid granulomas and plasmacytic satellitosis. The latter is emphasized as a normal phenomenon, may reflect morphologically a physiologic response of the B cell system to antigenic stimulation, and is conspicuously absent in plasmacytic neoplasia. Various secretory forms of plasma cells are illustrated. (Key words: Plasma cells; Bone marrow; Plasmacytosis; Plasmacytic satellitosis; B cells; Immune response.) MUCH HAS BEEN LEARNED in recent years concerning the functional relationships of plasma cells to the immune reaction and about the biochemistry of the immunoglobulins, their secretory products. Less is known about the morphologic aspects of the steps in the immune response. An increase in the number of plasma cells (plasmacytosis) in the bone marrow is of some clinical importance, as it is found both in malignant plasmacytic diseases and in benign and malignant diseases other than plasmacytic neoplasms. Morphologic evaluation of the bone marrow is still probably Received September 2, 1975; accepted for publication September 2, 1975. Address reprint requests to Dr. Hyun: Department of Pathology, Muhlenberg Hospital, Plainfield, New Jersey 07061. Presented in part as a scientific exhibit at the annual convention of the American Medical Association, New York, J u n e 1973, and at the joint fall meeting of the American Society of Clinical Pathologists and the College of American Pathologists, Chicago, October 1973. the most important step in the differentiation between reactive and neoplastic plasmacytic proliferations. The present study was undertaken to analyze the morphologic aspects of reactive plasmacytosis of the bone marrow and to correlate their incidences with underlying diseases and other bone marrow alterations, such as lipid granulomas, lymphoid follicles and hemosiderosis. Plasmacytic satellitosis, a morphologic unit consisting of a central histiocyte surrounded by three or more plasma cells, was of particular interest to us, and was systematically evaluated. Materials and Methods The analysis is based on a series of 1,000 consecutive bone marrow aspirates. T h e specimens were obtained from the iliac crest, sternum or tibia (in the case of infants). Films and sections were prepared in all instances, by previously reported tech- 921 922 Table 1. Normal Values for Plasma Cells in the Bone Marrow Differential Count 7 Berman (1949) Custer6 (1974) Diggs(1948) Israels (1955) Leitner (1945) Lucia and Hunt (1947) McDonald et al.a (1970) Vaughan and Brockmyre (1947) Whitby and Britton4 (1969) Wintrobe20(1974) A.J.C.P.—Vol. HYUN, ETAL. 1% 0.1-1.2% 0-1% 0-2% 1.2% 0-4.1% 0.1-3.5% 0-1.5% 0-1% 0-3.5% 65 1+, normal; 2 + , slightly increased; 3 + , moderately increased; 4 + , markedly increased. Results Figure 1 summarizes the incidences of plasmacytosis and plasmacytic satellitosis in the various clinical conditions encountered. Of 1,000 consecutive bone marrows, there were 35 cases of multiple myeloma. Of the remaining 965 cases, 28.6% showed reactive plasmacytosis. This finding was comnics.11 Films were stained by Wright- mon in association with infections and inGiemsa, Prussian blue and periodic acid- flammatory conditions, diabetes mellitus, Schiff technics. Marrow particles were epithelial malignancies, cardiovascular disfixed in Zenker or B-5 solution, processed eases, and Hodgkin's disease, the highest in the Autotechnicon, and embedded in incidence being found in association with paraffin. Sections were cut at 6 ixm. and hepatic cirrhosis. Of interest is the relastained by hematoxylin and eosin, Giemsa, tively high incidence in Hodgkin's disease and Prussian blue technics. T h e percentage compared with leukemias and other of plasma cells was determined by a differ- lymphomas. In the majority of cases there were also parallel increases in the inciential count of 500 cells on films. dences of plasmacytic satellitosis except in Plasmacytosis was defined for our purHodgkin's disease, hemolytic anemias and poses as 2% or more plasma cells. A rather diabetes mellitus, where the percentages of wide range of normal values has been used plasmacytic satellitosis exceeded the perby various investigators, as shown in centages of reactive plasmacytosis. Table 1. Perivascular distribution of plasma cells The numbers of examples of plasmacytic satellitosis in at least eight films, the num- is a normal finding, and was seen occabers of lipid granulomas and lymphoid sionally in sections of bone marrows withfollicles in the sections, and the hemo- out plasmacytosis. Diffuse plasmacytosis, siderin content as judged from both films when present in sections, was invariably and sections were also recorded. T h e associated with an elevated percentage of incidences of plasmacytosis and plasma- plasma cells in films. cytic satellitosis in the different disease T h e incidences of plasmacytic satellitosis states were tabulated. The incidences of when the percentage of plasma cells was plasmacytic satellitosis in cases where the normal and in reactive plasmacytosis are percentage of plasma cells was normal and shown in Table 2. When the percentage of in reactive plasmacytosis were compared. plasma cells was normal, the incidence of The incidences of lymphoid follicles and plasmacytic satellitosis was 10%. A siglipid granulomas in aspirates with and with- nificant increase in incidence of plasmacytic out reactive plasmacytosis were also com- satellitosis was found when there was repared. Last, hemosiderin content was active plasmacytosis. Plasmacytic satellitosis evaluated in aspirates without plasma- was not encountered in sections, with one cytosis, with plasmacytosis, and with mul- exception. tiple myeloma. Hemosiderin content was Figure 2 shows the correlation between graded as follows: 0, absent or decreased; lymphoid follicles and lipid granulomas in June 1976 PLASMACYTIC LESIONS OF BONE MARROW Clinical NOOf Situations cases 0 A. Neoplastic diseases 296 [ 91 Carcinoma Leukemia/ lymphoma lexc. Hodgkin'sJ 10 20 30 Percent 40 50 923 60 70 151 Hodgkin's disease 24 Myeloproliferative disorders lexc.PV, C G U 21 rnninniinnnTniiti 9 Polycythemia vera B. Nonneoplastic hematologic diseases 221 Iron deficiency anemia 113 Megaloblastic anemia 39 Marrow hypoplasia 21 Hemolytic anemia 12 Thalassemia and sideroblastic anemia 11 Idiopathic thrombocytopenic purpura 25 C. Infectious and inflammatory 309 conditions 32 Fever of unknown origin 17 Viral infections 37 Bacterial infections 57 Cirrhosis 30 Granulomatous diseases 26 Collagen disorders Nonspecific inflammatory conditions 110 18 D. Diabetes mellitus 14 E. Cardiovascular diseases 107 F. Miscellaneous conditions 35 G. Plasma cell neoplasia IOTAL •IUOO PLASMACYTOSIS PLASMACYTIC SATELLITOSIS MM FIG. 1. Incidences of bone marrow plasmacytosis and plasmacytic satellitosis. aspirates with and without reactive plasmacytosis. Clearly there were higher incidences of lymphoid follicles and lipid granulomas in cases of reactive plasmacytosis. The hemosiderin contents of the bone marrow in aspirates with and without plasmacytosis and in multiple myeloma are shown in Table 3. A significant number of aspirates with plasmacytosis also showed slight to moderate hemosiderosis. Cases of multiple myeloma showed a similar incidence of hemosiderosis. Aspirates without plasmacytosis showed most commonly either absent or decreased iron or a normal amount of iron. Figure 3 illustrates their graphic relationships. In keeping with the secretory function of plasma cells, a variety of cell forms was found. Structures such as Russell bodies, grape cells, thesaurocytes and intracellular crystals were demonstrated. Binucleated and multinucleated plasma cells were also encountered. These are illustrated in Figure 4, along with a typical example of plasmacytic satellitosis. 924 HYUN, A.J.C.P. —Vol. 65 ETAL. Discussion B cells, a major component of the immune system, are concerned with the production of antibodies (immune globulins, immunoglobulins), in response to appropriate antigenic stimulation. Plasma cells are now widely accepted as the secretory form of B lymphocytes, differing principally by the presence of abundant protein-synthesizing equipment in the cytoplasm. Patients who have the Bruton form of inherited agammaglobulinemia show an absence of plasma cells in their tissues, in keeping with their inability to form antibodies. Plasmacytosis of the bone marrow occurs often, and is considered to be a reflection of systemic antigenic stimulation. 3 ' 5 ' 8,12 Our series of consecutive bone marrow examinations, analyzed for plasma cell percentage and several other features, is sufficiently large to permit observation of common trends in incidence and extent of plasmacytosis in various clinical settings. Diseases of infectious and inflammatory nature were commonly accompanied by plasmacytosis of the bone marrow. T h e highest incidence and greatest extent were found in cirrhosis, a chronic inflammatory state with hypergammaglobulinemia in which the sustained high level of exposure to antigen has been ascribed to gutderived bacteria or, in certain cases, to autoantigens. Certain malignant diseases are associated with plasmacytosis, perhaps as a response to new surface antigens of the I With Plasmacytosis 1 Without Plasmacytosis 30% 20% 10%" Lymphoid follicles Lymphoid Follicles Lipid Granulomas 276 with plasmacytosis 689 without plasmacytosis 71(25.7%) 94(13.6%) Lipid granulomas 34(12.3%) 25(3.6%) FIG. 2. Incidences of lymphoid follicles and lipid granulomas in bone marrow aspirates with and without reactive plasmacytosis. neoplastic cell clones. The association of other diseases with plasmacytosis is interesting but more obscure, as in the cases of diabetes mellitus and iron-deficiency anemia, but may be related to complications of the underlying disease state. Lymphoid follicles and lipid granulomas in the bone marrows were simultaneously searched for and recorded. They were found more commonly in those marrows with plasmacytosis. This correlation suggests that they are reactive phenomena to similar stimuli. Lymphoid follicles may be Table 2. Incidences of Plasmacytic Satellitooccasionally found in small numbers in sis in Bone Marrows without and normal bone marrows. 15 It is not known with Plasmacytosis whether they are composed of B cells or T Aspirates with cells. The exact significance of lipid granuPercentage of Number of Plasmacytic lomas has not been determined. 14 Plasmacytes Aspirates Satellitosis Plasmacytic satellitosis has been deNormal, < ! 689 69 (10%) scribed under several names. 1 6 - 1 9 In 1950, 2-4% 239 111 (46.4%) Undritz, 19 in a study of histiocytes (mono5-10% 37 17 (45.9%) cytes), observed that they were frequently June 1976 PLASMACYTIC LESIONS OF BONE MARROW surrounded by plasma cells. He referred to these groupings as plasmacytic islets. In the 1960's, Thiery 17,18 confirmed Undritz's observations on lymph node suspensions and spleen by phase contrast and electron microscopy, and postulated a functional cooperation of these two cellular systems in the immune response. He suggested that the configuration reflected a physiologic role, but did not analyze the incidence and significance of this interesting phenomenon in clinical material. We have called this finding "plasmacytic satellitosis" and have defined it as a morphologic unit consisting of a central histiocyte surrounded by three or more plasma cells. It appears to be a normally occurring entity and was found in a small percentage of bone marrows without plasmacytosis. It was present in almost half of those bone marrows with plasmacytosis, suggesting that its appearance is attributable to a response to similar stimuli. Extensive studies in recent years have shown that macrophages play an important role in humoral antibody formation. 2,10 ' 16 An initial step in the production of antibody involves the phagocytosis and degradation of antigen in macrophages. The antigen processed by the macrophages or an active fraction thereof, perhaps messenger RNA or an RNA-antigen complex, when transferred to antibody-forming cells, results in the production of antibody. 2 Schoenberg and associates16 demonstrated by electron microscopy direct cyto- 40* 925 •••••••Without plasmacytosis — x — W i t h plasmacytosis —<*— Multiple myeloma *.._ "•••._ x-—____^ 30V a \ A 20%- •»•••• \ \ 10%- 0 0 1' V 2' 3' Hemosiderin Content 4 Absent or decreased 2# Slight increase Normal 3* Moderate increase 4* Marked increase FIG. 3. Hemosiderin contents of bone marrows with reactive plasmacytosis and multiple myeloma. plasmic communications between macrophages and surrounding lymphocytes and plasma cells in lymph nodes and splenic tissue from immunized rabbits, and observed small particles of the size of ribosomes in these cytoplasmic "bridges." Andre-Schwartz 1 studied the cellular changes in the regional lymph nodes following homografts in rabbits. By electron microscopy an extensive interdigitation between the cytoplasmic membranes of both young and mature plasma cells and adjacent "reticulum cells" was ob- Table 3. Hemosiderin Content in Bone Marrow 276 Aspirates with Plasmacytosis 689 Aspirates without Plas macytosis 3 : Aspirates Multiple Myeloma Fe Content No. % No. ft No. ft Decreased or absent Normal Slight increase Moderate increase Marked increase 76 82 39 72 7 27.5 29.7 14.1 26.1 2.5 267 237 79 93 13 38.8 34.4 11.5 13.5 1.9 11 10 5 8 1 31.4 28.6 14.3 22.9 2.9 926 HYUN, ETAL. A.J.C.P.—Vol. 65 FIG. 4. A (upper, left). Bone marrow film. Plasmacytic satellitosis. Six plasma cells surround a central histiocyte, from a patient with chronic pelvic inflammatory disease. Wright-Giemsa. X 1,500. B (upper, right). Bone marrow section. Plasmacytosis with three Russell bodies, from a patient with alcoholic cirrhosis. Hematoxylin and eosin. X 1,500. C (middle, left). Bone marrow film. Grape cell, a giant plasma cell filled with protein globules, from a patient with anemia of chronic renal failure. Wright-Giemsa. x 1,500. D (middle, right). Bone marrow film. Thesaurocyte, a large plasma cell with finely vacuolated cytoplasm, from a patient with iron-deficiency anemia associated with carcinoma of the colon. Wright-Giemsa. x 1,500. E (lower, left). Bone marrow film. Intracellular crystal in a plasma cell, from a patient with iron-deficiency anemia, without bone marrow plasmacytosis. Wright-Giemsa. x 1,500. F (lower, right). Bone marrow film. A multinucleated plasma cell, from a patient with bronchopneumonia and refractory anemia. Wright-Giemsa. x 1,500. June 1976 PLASMACYTIC LESIONS OF BONE MARROW 927 served, a picture of active pinocytosis. The cyte surrounded by three or more plasma appearance of plasma cells was a distinct cells, appears to be a normally occurring entity, and was seen in 10% of our bone feature of the second-set reaction. On the basis of these considerations, we marrows without plasmacytosis. Its incisuggest that plasmacytic satellitosis repre- dence increased to 46.4% in those marrows sents the morphologic manifestation of with plasmacytosis, suggesting that it reantigen processing by the macrophage and flects a reaction to similar stimuli. We have transfer of information required for anti- not observed this phenomenon in any of body production to the effector cells, the our 35 cases of plasmacytic neoplasia. plasma cells. It is interesting that satellitosis Plasmacytic satellitosis may represent a by lymphocytes was a rare finding in our stage in antigen handling; the configuraexperience, although theoretically this tion raises speculation that information or might be expected to occur commonly. Per- coding destined for antibody production is haps plasmacytic satellitosis represents the being transferred from the histiocyte to anamnestic response of sensitized B cells, the plasma cells. although no direct evidence is available to In keeping with the secretory function of clarify this point. plasma cells, a variety of cell forms is found. We did not observe plasmacytic satellito- Structures such as Russell bodies, grape sis in any of the 35 cases of plasmacytic cells, thesaurocytes and intracellular crysneoplasia encountered in this series of bone tals are illustrated. marrow examinations, and this negative feature may prove to be a differential Note: Fifteen additional cases of multiple myeloma point of some usefulness. This failure of were reviewed following completion of this study. Plasmacytic satellitosis was found in one case. physiologic responsiveness may correlate with the fact that patients with multiple myeloma have impairment of antibody Acknowledgments: Dr. Joon Seuck Lee helped in the production 9 (apart from the monoclonal accumulation of data. immunoglobulin) with resulting increased susceptibility to infection. References Conclusions Plasmacytosis, defined as 2% plasma cells or more in the differential count, occurred in 28.6% of a series of 1,000 bone marrow aspirates, apart from 35 cases of multiple myeloma. This finding was particularly common in association with inflammatory and infectious diseases, diabetes mellitus, epithelial malignancies, Hodgkin's disease, and iron-deficiency anemia. T h e highest incidence was in cirrhosis. Bone marrows with plasmacytosis showed increased lymphoid follicles and lipid granulomas more commonly than did marrows without plasmacytosis. These findings are probably reactive phenomena in a general sense. Plasmacytic satellitosis, defined as a morphologic unit consisting of a central histio- 1. Andre-SchwartzJ: T h e morphologic responses of the lymphoid system to homografts. III. Electron microscopy study. Blood 24:113-133, 1964 2. Askonas BA, Rhodes JM: Immunogenicity of antigen-containing ribonucleic acid preparations from macrophages. Nature 205:470-474, 1965 3. Azar HA: Diffuse (nonmyelomatous) plasmacytosis with dysproteinemia. Am J Clin Pathol 50:302-312, 1968 4. Britton CJC: Whitby and Britton Disorders of the Blood. Tenth edition. New York, Grune and Stratton, 1969, p 8 5. Clark H, Muirhead EE: Plasmacytosis of bone marrow. Arch Intern Med 94:425-432, 1955 6. Custer RP: An Atlas of the Blood and Bone Marrow. Second edition. Philadelphia, W. B. Saunders, 1974, p 42 7. Dittmer DS (editor): Blood and Other Body Fluids. Washington, D. C , Federation of American Societies for Experimental Biology, 1961, pp 138-139 8. Fadem RS, McBirnieJE: Plasmacytosis in diseases other than the primary plasmacytic diseases: A report of six cases. Blood 5:191-200, 1950 9. Fahey JL, Scoggins R, Utz JP, et al: Infection, antibody response and gamma globulin com- 928 10. 11. 12. 13. 14. 15. HYVN,ETAL. ponents in multiple myeloma and macroglobulinemia. Am J Med 35:698-707, 1963 Fishman M: Antibody formation in vitro. J Exp Med 114:837-856, 1961 Hyun BH, Ashton JK, Dolan K: Bone marrow examination, Practical Hematology: A Laboratory Guide with Accompanying Filmstrips. Philadelphia, W. B. Saunders, 1975, pp 300313 Klein H, Block M: Bone marrow plasmocytosis: A review of sixty cases. Blood 8:1034-1041, 1953 McDonald GA, Dodds TC, Cruickshank B: Atlas of Haematology. Third edition. Baltimore, Williams and Wilkins, 1970, p 12 Rywlin AM, Ortega R: Lipid granulomas of the bone marrow. Am J Clin Pathol 57:457-462, 1972 Rywlin AM, Ortega RS, Dominguez CJ: Lym- 16. 17. 18. 19. 20. A.J.C.P.—Vol. 65 phoid nodules of bone marrow: Normal and abnormal. Blood 43:389-400, 1974 Schoenberg MD, Mumaw VR, Moore RD, et al: Cytoplasmic interaction between macrophages and lymphocytic cells in antibody synthesis. Science 143:964-965, 1964 Thiery JP: Microcinematographic contributions to the study of plasma cells, CIBA Foundation Symposium on Cellular Aspects of Immunity. Edited by GEW Wolstenholme, M O'Connor. Boston, Little, Brown, 1960, pp 59-91 Thiery JP: Etude au microscope electronique de l'ilot plasmocytaire. J Microscopie 1:275286, 1962 Undritz E: Die regionaren Monocyten der Blutkorperchennester. Folia Haematol 70: 32-42, 1950 Wintrobe MM: Clinical Hematology. Seventh edition. Philadelphia, Lea and Febiger, p 1796