A n n a l s o f C l i n i c a l a n d L a b o r a t o r y S c i e n c e , Vol. 4, No. 3 Copyright © 1974, Institute for Clinical Science Experimental Plasmacytomas in Relation to Human Multiple Myeloma HENRY A. AZAR, M.D. Laboratory Service, VA Hospital, Tampa, FL 33612 and Department of Pathology, University of South Florida College of Medicine, Tampa, FL 33620 ABSTRACT Among animal models of plasma cell tumors, that induced in BALB/c mice by means of intraperitoneal injections of oils remains the most reproducible and the most intensively studied. The BALB/c oil-induced and transplantable plasmacytomas resemble hu­ man myeloma in their ability to produce a monoclonal immunoglobulin or Bence Jones protein. Bence Jones type nephrosis in BALB/c mice closely mimics its human counterpart. There are also similarities in background of immunodeficiency and in antigen-binding affinity of monoclonal immuno­ globulins, as well as in interesting interrelationships with malignant lympho­ mas. Unlike the BALB/c tumor model, human myeloma is, however, prin­ cipally a skeletal disease, not a gut-oriented or peritoneal plasmacytoma. The intriguing presence of intracistemal type A virus-like particles in BALB/c plasmacytoma cells and their absence in human myeloma is another major difference between the two forms of growth. The pathogenesis of human myeloma remains obscure but the availability of experimental plasmacytoma models offers a means of systematically analyz­ ing events leading to the neoplastic transformation of antibody-forming cells. Introduction other in a mesenteric lymph node.4 These In addition to man, several mammals spontaneous tumors constitute uncommon were observed to develop plasma cell tu­ though fascinating events. Plasma cell tu­ mors spontaneously. For example, the mul­ mors can be induced in a predictable tiple myeloma of the dog resembles human fashion in mice, particularly the BALB/c myeloma and features osteolytic lesions, strain. The reader is referred to Potters monoclonal gammapathy and Bence Jones comprehensive review of experimental type nephropathy.16 Multiple myeloma has plasma cell tumors of mice.18 been also observed in a cat.10 Two plasma­ The aim of this presentation is to outline cytomas have been described in the Syrian the characteristics of induced plasma cell hamster: one arose in the neck and the tumors of mice, particularly the BALB/c 1 5 8 AZAR Thelma Dunn6 reported in 1954 that sev­ TA BLE I eral mice had an inflammatory lesion of the P lasmacytomas o f M i c e cecum. In some of these lesions, plasma­ cytic neoplasms arise in the ileocecal region "Plasma Cell Leukemia" in Street and in relation to the cecitis. A later sur­ Strain Mice 1951 vey7 indicated that ileocecal plasmacyto­ Rask-Nielsen, R. and Gormsen, H. mas were commoner in C3H mice than in Ileocecal Plasmacytomas of C3H other strains and that they occurred more Mice 1954 frequently in old mice. Dunn, T .B . Murphy15 described in 1963 a new in- bred strain of mice (SJL/J) with a high Induced Peritoneal Plasmacytomas incidence of reticulum cell neoplasms. (BALB/c Mice) 1960 Fifty percent of these neoplasms were asso­ Potter, M. and Robertson, C.L. ciated with “paraproteinemia.” Unfortu­ Plasma Cell Tumors in NZB and nately, the production of monoclonal im­ NZBX BALB/c Mice 1966 munoglobulin has been unstable following Werner, N. et al transplantation of these tumors. Fujinaga et al11 transmitted “SJL/J disease” to Pleomorphic Lymphomas in SJL/J BALB/c mice with cell-free extracts. They Mice 1969 succeeded in producing reticulum cell neo­ Murphy, E.D. plasms but not plasmacytomas. Plasmacytomas are successfully induced by intraperitoneal injection of oily sub­ strain, and relate these to the problem of stances in BALB/c and NZB mice as well human myeloma. as in (BALB/c X NZB) FI hybrids.18 The NZB strain is also genetically susceptible Plasmacytomas of Mice to the development of nephritis and auto­ immune phenomena. The oil-induced plas­ The more important experimental plasma macytomas are by far the most widely cell tumor models of mice are listed in studied model of immunoglobulin-produc­ table I. Although the reader’s attention will ing experimental tumors. Primary and be drawn to the oil-induced peritoneal transplanted BALB/c plasmacytomas are plasmacytomas of BALB/c mice, a brief under active investigation in our labora­ outline of other models of plasmacytic and tory. They are considered to be a depend­ related lymphoreticular growths is in order. able and readily available source of tumor The “plasma cell leukemia” in Street that strikingly resembles human myeloma. strain mice described by Rask-Nielsen and and Gormsen20 in 1951 has the morphologic features of reticulum cell sarcoma with Oil-Induced Plasmacytomas plasmacytic differentiation. In later studies, of BALB/c Mice (CBA X DBA/2) FI hybrids, including In an experiment designed to test the mice injected with a variety of cell-free survival of allogeneic grafts as well as the material, developed a high incidence of behavior of M.T.A. virus, Merwin and Al- “plasma cell leukemia.”21 Several of the gire13 implanted estrogen-treated BALB/c transplanted reticular and plasmacytic neo­ mice with Millipore diffusion chambers plasms transplanted by Ebbesen and Rask- containing C3H mammary tumor. Six Nielsen9 were associated with “parapro­ months later, the BALB/c recipients de­ teinemia” and amyloidosis. veloped hemorrhagic ascites owing to per­ EXPERIMENTAL PLASMACYTOMAS 1 5 9 itoneal plasma cell tumor or fibrosarcoma.8 T A B L E II Empty chambers, leucite discs or borings N e o p l a s m s F o u n d i n B A L B / c M i c e F o l l o w i n g also caused the development of plasma cell I ntraperitoneal I n j e c t i o n o f A d j u v a n t tumors.14 Subsequently, Potter and Boyce19 reported that plasma cell tumors could be Con- induced by means of intraperitoneal injec­ Ex— v en - tions of mineral oil alone or adjuvant mix­ Germ- Germ- t i o n - tures. A variety of oils have been tested f r e e f r e e a l since. More recently, pristane (2,6,10,14- tetramethylpentadecane) was found to be Plasma cell 2 24 28 an extremely potent inducer of plasmacy­ tumor tomas in BALB/c mice.1 Pleomorphic 16 3 4 The experimental model of oil-induced reticulum plasmacytomas has been described in de­ cell sarcoma Monomorphic 7 1 1 tail elsewhere.18 This model has been ex­ reticulum tensively exploited to demonstrate the cell sarcoma chain of events leading to the synthesis of Mixed reticulum 2 specific classes and types of immunoglob­ cell sarcoma ulin. The same model has been used to Lymphocytic 1 study the effect of hereditary and hormonal ■ neoplasm Pulmonary 2 2 influences on the induction of plasma cell adenoma tumors. Since the majority of oil-induced Myoepithelioma 1 1 1 plasmacytomas are immunoglobulin-form­ Uterine adenoma 1 ing tumors, the role of intestinal bacteria R eticu lar 3 4 and bacterial antigens on the differentia­ hyperplasia tion of plasmacytomas has also been exten­ (no tumor) —— — sively investigated. T otal 33 31 40 M o r p h o l o g ic F e a t u r e s The sequence of events following the After Mclntire and Princler: intraperitoneal injections of mineral oil or Immunology 17:481, 1969. pristane starts with an acute inflammatory reaction which first covers the peritoneal readily transplanted. Primary or induced surfaces and surrounds oil droplets. No plasmacytomas may vary in size from one plasma cells or lymphocytes are noted at mm to two or three cm in greater diameter. this stage. At a later period, from one to Transplantable plasmacytomas grow into three months after the initial injection of BALB/c hosts or BALB/c hybrids to attain the oil, individual or small clusters of a size of two to three cm at which point plasma cells begin to form within the oil they frequently ulcerate or kill their host granulomas. From five months to eight as a result of bowel strangulation or of months following the injection of the oil, Bence Jones type nephrosis. larger clusters of plasma cell precursors are observed. Such aggregates are particularly Bence Jones type nephrosis with typical noted under the diaphragm and over the hard, fragmented or laminated casts are surface of the liver. Ultimately, these gran­ seen in animals bearing k or A polypeptide- ules grow into small tumors which become producing tumors. Metastases are not seen autonomous plasmacytomas that can be as a rule in primary or induced plasma- 1 6 0 AZAR cytomas but do develop in animals bearing ulum cells except for their basophilic and large transplanted plasmacytomas. pyroninophilic cytoplasm. Seldom do they Plasmacytoma cells often resemble retie- appear to be frankly plasmacytic. Trans- F i c u i i e 1. Electron micrograph of portion of Pristane-induced plasmacytoma cell illustrating a large number of intracisternal type A particles. Some of these appear to be budding from the endoplasmic reticulum lining the cisternae. Uranyl acetate and lead citrate, X 51,000. EXPERIMENTAL PLASMACYTOMAS 1 6 1 planted plasmacytomas are even more ana­ plastic looking than primary plasma cell tumors. On electron microscopy, plasma­ cytoma cells generally display an abun­ H0PC1 S dance of rough endoplasmic reticulin as well as free polyribosomes. RPC5 S T y p e A — I ntracisternal P a r t i c l e s Whereas the normal lymphoid tissue of TEPC183 S the BA LB/c mouse may contain type B or C RNA viruses with well-formed nucleoids, M0PC321 S one does not readily observe type A par­ ticles in either lymphocytes or plasma cells.