3IULTIPLE MYELOMA

A REPORTOF FIVECASES

ERNEST SCOTT, M.D., F. M. STANTON, M.D., AND MARY OLIVER, MA. (From the Department of Pathology, Ohio State University) In 1848 Sir Henry Bence-Jones aiid Sir James Watson pre- sented a paper entitled, “On a New substance Occurring in the Urine of a Patient with Mollitis-ossium,” a “substance” now known as the Bence-Jones bodies, frequeiitly found in the urine of patients with multiple myeloma. The clinical discussion of this same case mas presented in 1850 by McIntyre. In 1873 von Rustizky, in his histological studies of the disease, recognized its involvement of the bone marrow and gave it the name of multiple myeloma. IGililer, in 1889, ~lsopresented a clinical description of the disease and inasmuch as he, rather than McIntyre, has often been credited with the first clinical presentation, the term “Kahler ’s disease” is frequently encountered in the older litera- ture. In 1920 Wallgren reported 120 cases with histological verifica- tion. In 1928 Geschickter and Copeland (l), from the surgical pathological material of the Johns Hopkins Hospital, reported a series of 13 cases, together with a complete review of all available cases in the literature, making a total of 425 cases. Since the publication of this comprehensive article with its discussion of the clinical and structural characteristics of the disease, we have been able to collect from the more recent literature 30 cases of multiple myeloma. To these we add 5 cases from among about 4400 au- topsies in our own series. Grouped by years, the additional cases are : 1927 : Lewis (2), Meyeriling (3), Kleine (4) ; 1928: Battaglia (5), Hcilmann (6), Barr (7),Durman (8), Short iind Crawford (9) ; 1929: Hewitt (10) (5 cases), Stone (ll), Cappel1 (12) (2 cases), Rogers (13), Hub- bard and Case (14) ; 1930: Perla aiid Hutner (15) (2 cases), Cabot (16), Geschickter (17), Freund (18) ; 1931: Cabot (19), Porchownik (20), Jackson et a1 (21) (5 cases). ETIOLOGY Multiple myeloma is a disease of later life. Eighty per cent of all cases, according to Geschickter and Copeland, occur be- tween the ages of forty aiid seventy, with the peak of incidence at 682 MULTIPLE MYELOMA 683 fifty-fiveyears. These authors find but three histologically proved cases under thirty-five years of age; while in the more recent literature are reported 4 cases below thirty-five years (Durman, Hubbard and Case, Rogers, Cabot). The incidence is more than twice as great among males as females. Of the 35 more recent cases, 26 or ‘75 per cent were in males, 9 in females. Wallgren found 68 per cent males among 98 cases, and Geschickter and Copeland in their study of 425 cases, 70 per cent. The latter also itate that in the Johns Hopkins records they found multiple myeloma in 0.03 per cent of all malignancies. CLINICALFEATURES Pain.: Pain, rheumatic and often intermittent, is a frequent first symptom. It occurs most often in the lumbar and sacral regions, next in frequency over the ribs and sternum. Sudden onset of pain with tenderness in the lumbar or dorsal regions was found in all of the present series. The severity of the pain may subside for some months, only to return with the greatest intensity. In the later stages of the disease neurologic symptoms may ap- pear. Forty per cent of the cases report paraplegias and other neurologic disturbances due to compression of the cord (1). In cases 1 and 4 of our series there is record of complete paralysis from the waist down, almost total loss of sensation, and incon- tinence of urine and feces. Multiplicity: Multiple tumor involvement of the bone marrow is characteristic. The lesions vary in size from that of a pin-head to that of an orange. We found in the literature but two cases in which the lesion was single : (a) Geschickter ’s in 1930, a plasma- cell tumor occurring in the femur, and (b) Rogers’ in 1929, a plasma-cell myeloma of the femur with a history of successful amputation. The question of future multiple recurrence arises here, in consideration of the fact that Geschickter and Copeland’s case 10, with a history of amputation for myeloma of the femur, developed within two years multiple myeloma of several bones. In 90 per cent of the cases the ribs, sternum, clavicle or spine in some combination are involved (1). Forty per cent of these have in addition involvement either of the skull or of the ex- tremities about the shoulder or pelvic girdle. Subpleural nodules, as in case 1of our series, are not infrequent. Involving the spine alone, Cabot (16) (1930) reports a case of myeloma in the fourth dorsal vertebra. The lesions of multiple myeloma are to be distinguished from giant-cell sarcoma by the occurrence of the former in the shafts of the long bones, of the latter in their epiphyses. hfultiple myeloma is to be differentiated from endothelial myeloma (Ewing’s tumor) 684 ERNEST SCOTT, F. M. STANTON, AND MARY OLIVER by the frequent occurrence of the latter in childhood and by its existence as one nodule in a bone, in contrast to the adult-age incidence and multiple lesions of the former. Multiple myeloma, moreover, rarely infiltrates soft tissue. The roentgenogram reveals a characteristic, " punchecl-out '' appearance of tlic bonc-small (li scrcte arcas of rarefaction with ragged, moth-eaten outlines and little attempt at boiic repair. The vascularity is grcat and frequently produces a pulsation of tlie mass. -4s was markedly illustrated in case 5, a mere shell of bone may remain over the tumor mass, which can be very easily sliattcred giving rise to spoiitancous fracturcs on tlie slightest movement. Fmctuws : Fractures are very commoii. Among 425 cases tlicre were 62 per cent with pathologic fructnres (1). The most usual sites are in the trunk, first in the ribs, thcw in the clavicle and sternum. Several fractures may ocmr in the same bone. No other tumor of tlie bone or hone-marrow displays such a high pcr- centagc of fractures. Upon the basis of this clinical observation and the apparent bone-resorptive power of tlie tumor cell, Wil- liams (35) in 1932 advanced the theory that the myeloma tumor cell is derived from the osteoblast ratlicr than from tlie plasma cell or myeloblast. If this be the case, however, we should expect to find some attempt at bone repair, whicli we failed to see in any of our cases and which authors state is characteristically absent. Beuzce-Jones Bodies: Tlie clemonstration of the Bence-Jones bodies, a protein distiiict from albumin and globulin, depends 011 the appearance, between 45" C. and 60" C., of a white precipitate in the urine and its disappearance upon further heating to 90'- 100" C. During thc course of the disease its appearance may be iiitermittcnt. It w'as fo~indin the wine of 16 of the 30 cases u7c collected from the literature and iii oiic of our own associated with c~lironicnephritis. It was not tested for in three of onr cases. On the other hand, Bencc-Jones bodies are found in a number of otlicr diseases involving the bone marrow (Boggs :uid Guthrie, 22) such as osteomalacia, mysedcma with bone clianges, lymphatic leukemia, aiid carcinoma of tlie stomach with bone metastases. Some authors consider it an intermediary metabolic substance wliicli may be due to a toxin from the tumor. Pcrlzwcig, Delruc, aiid Gescliickter (23) found a liypcrproteinuria associated with multiple myeloma, which they explain as a systemic respoiisc to tlie foreign-body proteins prescnt in tlie Bence-Jones bodies. Perla and Hutiier (15) found in their studies an association of Hence-Jones proteinuria and arteriosclerotic nephritis. They cx- plain the variable occurrence of Bence-Jones bodies in tlie urine as dependent on the presence of kidney lesions which may mist in MULTIPLE MYELOMA 685 the older age groups independently of tlie myeloma. It is not yet certainly known wlietlier Rcnce-Jones proteins can pass through the normal kidney. Metastases: Metastases are said to be rare in multiple myeloma. Hemopoietic tissues, as tlic spleen, liver, and lymph glands, are the most frequent sites, but metastases have been reported in other organs. Several authors have taken the position tliat these arc not true metastases, but evidences of a systemic disease of the hemopoietic organs, as Syrnmers (24), Hoffman, Heilmann, Barr, Jackson et al. In the hlood vessels of many of the bone-marrow growths, however, and in tlie liver sinusoids and kicliiey capillaries of Case 4, free tumor cells were found. It is to be expected that, if the tumor cell is a derivative of licmopoietic tissue and multiple myeloma is, therefore, a specific tumor of the bone marrow and general hemopoietic tissues in which the plasma cell is the neo- plastic element, the neoplasm will display a predilection for the marrow rather tlian for the epipliyses of tlic bones and will occur in multiple foci in tlie same aiid other bones through clircct ex- tension in the vascular tissue and through metastases. In view of the occurrence of tumor cells in kidney capillaries aiid liver sinusoids as well as in the marrow blood vessels, it seems to us that genuine metastasis is uiidoubteclly one method of dissemina- tion, and that by this means and by direct extension the multiple occurrence of tliese growths can be explained. On the contrary, it cannot be denied that the theory of a generalized hemopoietic origin has as yet not been entirely disproved. Bow Defornzities: Skeletal deformities were found in GO per cent of the cases (1). They are chiefly confined to the thorax and rarely involve the extremities, in this respect differing from the deformities of Paget’s disease aiid osteomalacia. There may be shortening of the spine, as in Case 5, lipping of the vertebrae, as in Case 3, or Iryphosis, “parasternal rosary,” and sunken sternum, as in Case 2. Tlie deformities of the thorax may lcad to elironic bronchitis, pleurisy, and emphysema. Blood Pictzcre: A secondary anemia often occurs ; occasionally it simulates tlic primary type. 111 our 5 cases the red blood count and hemoglobin were iiormal. The differential count may show an increase in the lymphocytic aiid mycloid series, evidence of ail irritative response, but there is not the extreme picture of the leukemias. AZrcnosco~~cCHARACTERISTICS The typical tumor cell of multiple myeloma is oval or angular, 9-11 microns in diameter, with basopliilic cytoplasm, a ceiitral vacuole, aiid ail ecwiit rically placed, round iiucleus in whicli the 686 ERNEST SCOTT, F. M. STANTON, AND MARY OLIVER chromatin is arranged peripherally in coarse masses like the spokes of a wheel. This is the mature plasma cell of the Mar- shalk6 type which, in our opinion, stands at the peak of a series of cells developiiiq from the reticular tissue cell of the marrow and general connective tissues under a specific stimulus as a differen- tiated series closely related to tlic lymphocytes. The close re- semblaiice of these cells to tlie lymphocytes is seen in certain fields of Cases 2 and 3, in which the chromatin arrangement in the lym- pliocytic nucleus is similar to that of the plasma cell, but in which the cytoplasm is very sliglit. It is well known, fnrthermore, that in certain chronic inflammatory processes, such as tuberculosis or as a response to neoplastic irritations, both lymphocytes aiid plasma cells are abundant. We do not agree, however, with the view that tlie plasma cell is an old lymphocyte ; typical plasma cells are to be found in such rapidly growing tumors as C”me4, in which no lymphocytes were present. The reticular framework of these growths may be conspicuous aiid show cells in tlie process of rounding up to form free cells. These young plasma cells or plasmoblasts are large cells of vari- able shape, wit 11 basopliilic cytoplasm and rouiid or bean-shaped vesicular nuclei, as yet not ecceiitrically placed and containing chromatin scattered irregularly throughout or largely collected in one or two ‘nucleoli.” The plasmoblasts are not easily clistin- guislicd by routine staiiiiii~methods from any early form of the P myeloid or erythrocyte series ; this is probably the cause of many of the errors made by the early workers in interpreting them as myeloblasts and erythrohlasts. In a tumor, however, in which tlie plasma cell is the conspicuous or only element, we feel justified in terming the young forms plasmoblasts, especially when we are able to trace their development into older types. Evidence of the maturation of the tumor plasma cell is likewise seen in the mitotic figures and in the binucleate aiid multinucleate forms. These multiiiuclcate cells differ from t lie megakaryocyte in tlie lion-granular cytoplasm mid compound rather tliaii lobulated nucleus. In our series the more rapidly growing and malignant the tumor and the shorter the clinical course, the more numerous were these early cell forms. In slower growing tumors tlie mature plasma cell is more numerous, usually smaller, more acidophilic, and possessed of a more characteristic arrangement of chromatin. Still older degenerative forms with cytoplasmic granules aiid vacuoles were to be distinguished in all growths. These stages appear structurally similar to the series of plasma cells derived experimentally in Miller’s work from tlie reticular mother-cell of tlie rabbit omentum. The plasma cell usually appears to be crowding out the iiormal MULTIPLE MPELOMA 687 cells of the bone marrow, or, as in Case 2, there may be evidence in the increased lymphocytic forms that these cells are likewise pro- liferating as a secondary response to the irritative action of the tumor growth. The proportions in which the bone-marrow and plasma cells apparently occurred in different tumors led to the use of a mixed nomenclature by the earlier workers ; as myeloblastic, lympho- blastic, erythroblastic, and plasma-cell myelomas. Some, in their reliance upon tlie specific staining reactions as a means of differen- tiating myeloid and plasma cells, included plasma cells in the mye- loid series because these forms sometimes gave the oxidase reac- tion. In recent years, on the other hand, Rfenten (36), having shou7n that the intensity of the oxidase reaction depends on the susceptibility of the tissue to the reducing action of the a-naphthol and paraplieiiy~endiamine,found that certain tumor tissues, such as spindle-celled sarcomas and stratified squamous epitheliomas, also give the osidase reaction. Wood and Luck6 (37) state that the reaction is not sufficiently diagnostic of the myelocytic series to serve as a means of determining the histogenesis of the myeloma cells. Similarly, the plasma-cell stain of Hitchcock and Ehrich has been found non-specific for these cells. These facts, together with the variability of the myeloma cells in giving a positive reaction to either test, iiiclicate that neither of these reactions can be relied on as a means of determining the relationship of the tumor cell either to the plasma cell or myelocyte. More recent workers as Christian (25), Symmers (24), and MacCallnm (26), however, take the position that all varieties of cells are diff erentiatioiis of a primitive reticular bone-marrow cell under the abnormal conditions of tumor formation. HISTOGENESIS We must at present depend for our interpretation of the origin of the tumor cell upon (1) experimeiital studies on the histogenesis of cells which resemble the tumor cells, aiid (2) upon the study of developmental stages in growing tumor tissues. Cunningham, Sabin, and Doaii (27) regard the reticulum cell of the blood-forming organs as the mother cell, not only of the marrow stroma, but also of the myeloid series, the lymphocyte series, aiid tlie monocaytes. Doan, in a personal interview, states that he regards the myeloma plasma cell, which under normal con- ditions is not a coiistitucnt of bone marrow, as a derivative of the reticular cell of the bone marrow aid general connective tissues, developing under abnormal stimulation as a differentiated cell closely related to the lymphocytic series. 688 ERNEST SCOTT, F. M. STANTON, AND MARY OLIVER Williams (35), in a recent study (1932), in view of the apparent bone-resorptive action of the mycloma cell and its histologic re- semblance to the osteoblast, is inclined to relate tlie myeloma cell to the osteoblast rather than to tlie plasma cell. We disagree with this view because (1) the ostcoblast very early appears as a dis- tinct cell type; (2) in the tumor tissue the early tumor cell stages more closely resemble the other carly blood cells than the osteo- blast; (3) no bonc-repairing properties of the ccll were obscrvcd. Of special interest in the consideration of the histogenesis of the tumor cell is Miller’s experimental work (29) inducing the cle- velopmcnt of plasma cells in the omcntum of rabbits through iiitra- peritoneal injections of tuberculoprotein. He finds that the pre- cursor of the plasma cell is the reticular cell and is able to trace its stages through tlic early plasmoblast forms to the typical mature Alarslialk6 type and filially into tlic degenerative 12usscll-body-cell stage. Tliesc forms we have seen duplicated in the tissues of our cases. From tlie litcratnrc TVC find confirmatory support for our posi- tion in the case of Clappell (12), who demonstrated traiisitional forms betwecii “m~eloblast”and plasma cells, aiicl who further states : “It might he considered that tlie abnormal myeloma cells arc dcrivcd originally from the primitive reticulum cells. Some have diffcrciitiatcd through a myeloblast-like stage into the rounded mycloma ccll of the common type or have even been fur- ther transformed into the plasma cell type. . . .” Cappell’s “myeloblast” corresponds to our plasmoblast. Jackson et a1 (21) studied plasmocytomata of extraosseous origin involving first tlie lymphoid tissues and later, in certain cases, the bone marrow. These plasmocytomata were interpreted as part of a neoplastic disease of the hemopoietic tissues, appear- ing in the lymph glands some years before the multiple involve- ment of the bone marrow.

PllOGNOSIS AND TREATMENT The average duration of multiple myeloma from tlie timc of recognition is about two years. Our cases pursued a shorter clini- cal course, the longest under observation being one year and the shortest three months. Most authors regard the disease as incurable; but Coley (34) in 1931 stated that in a iiumber of his cases use of the toxins of erysipelas and B. prorligioszis combined with irradiation resulted in apparent complete recovery. Geschickter, however, found such treatment unavailing to prevent eventual recurrence. MULTIPLE MYELOMA 689

CASEREPORTS CASE I (No. 2738) : J. Y., a white male, aged thirty-seven years, a car-repair man, while helping his men push a car, on Feb. 15, heard a sudden snap in his back which sounded like the breaking of a bone. This was followed by a dull aching pain in the lumbar region. The patient continued work until August, when the pain became so severe that he was forced to give up. He was unable to walk alone by this time. Physical Examiizatioiz : The spinal lumbar region was estremely tender to the touch. The lower extrrmities were paralyzed from the hips down, with a total loqs of sensation in the feet. Tests for reflexes showed Babinsky negative, ankle clonus negative, patellar reflexes grmtly diminished. On Sept. 1 there was com- plete loss of motor control in the legs; on Oct. 26, incontinence of urine and feces. Expansion of the chest was liniited on one side. The temperature was 9S.S" F. ; pulse 110. The blood count was normal except for a leukocytosis of 10,500. The blood Wassermann mas negative ; spinal fluid Wassermann one plus.

FIG.1. CASE I: SECTIONTIIROUQH THE TUMORMASS IN THE BONEMARROW OF A RIB. x 300 Note the prcdominance of plasma cells and numerous plaumoblasts. A few lympho- cytes and noriuohlasts are scattered throughout.

The urine was positive for iilbumin ; the Rewe-Jones test was not made. Granu- lar and cpithclial casts and a f~mergthrocytrs n'ere found. Piis was present in in- creasing quantities, about 2 to 4 ounces at the beginning and end of each urina- tion. Bacteriologic examination revraled streptococci, staphylococci, and B. coli. Death occurred Nov. 16, after a clinical course of nine months. Gross Pathology: The lining of the bladder was found to be dark in color and showed numerous areas of erosion. It contained about 800 C.C. of a very dark, foul- smrlling urine. The pelvis of the left kidney contained a small quantity of turbid fluid and numerous small hemorrhagic areas in the mucous membrane. The right kidney resembled the left eserpt for the absence of hemorrhagic areas in the pelvic wall. In making the incision for the removal of the spinal cord, it was noted that the muscles in the lumbar region were degenerated and edematous. The vertebral column lacked rigidity and, on prj-ing out the spinous processes of the lumbar vertebrae, the laminae were severed from the bodies of the vertebrae with great ease. In cutting across the cord in the lower lunibar region, the knife entered a cavity filled with a soft, srmifluid matrrial in which small particles of bony sub- stance were detected. Upon the removal of the cord, there was evidence of a slight 690 ERNEST SCOTT, F. M. STANTON, AND MARY OLIVER liemorrhage in the canal, in the mid-dorsal region. No areas of softening nor of apparent compression were found. From the ventral aspect, nothing abnormal in the appearance of the vertebral column was observed. It was found, howevei; that the knife coultl be thrust easily into the bodies of the lumbar vertebrae, and that thry existed only as a mass of a somewhat gelatinous substance surrounded by a thin shell of bone. The interverte- bra1 discs had maintained their integrity and appeared normal. Anatomical Diagmsis: Sarcomatous degeneration of the bodies of the lumbar tincl lower dorsal vertebrae ; gangrene of tlie urinary bladder ; peritonitis. Jficroscopdc Pathology: The sections through the bone marrow show a closely packed cellular growth in which the predom,inant eel1 type is the typical plasma cell. A few trabrculae of bone remain. The normal constituents of bone marrow have been largely replaced by the tumor growth, except in a few areas. Mixed with the mature plasma cells are some early forms with round or bean-shaped nuclei, occasional binucleate and multinucleate cells and mitotic figures, and, in some of the fields, numerous lymphocytic cells. The vascularity of the section is conspicuous. Forman and Warren (28), in 1917, tested tlie e~llsof this tumor for their oxidase reaction. Obtaining a positive test in most of the myeloblasts and myelo- cytes and in some of the plasma crlls, they were inclined at that time to placc the tumor cell in the myeloid series. Microscopic Diagnosis: A fairly active plasma-cell multiple myeloma involving the lumbar and dorsal vertebrae and ribs.

CASE I1 (No. 3035) : A. If., a white male, aged sixty years, a laborer, had complained of pains in his back for snme time. He attributed the onset of his illnrss to a blow between the scapulae recrived from an iron bolt. Physical Emniiaafion: There were marked loss of weight and weakness with some tenderness over the thoracic and upper lumbar vertebrae. The skin had become hypersensitive. A markrd depression had drveloped in the region of the junction of the manubrium and gladiolus, the sternum having collapsed inwardly and left a depression 4 em. in depth. On prrssurr the sternum was found to be soft and spongy. Kyphosis developed gradually and became quite marked. The patient complained of pleuritic pains and devrloprd a persistent cough. The blood Wassermann test was nrgative. Death was tluc lo terminal pneumonia. The clinical course wa4 probably more than nne year. Clinical Diagnosis: Osteomalacia. Gross Patholog?/ : The ribs were found to be decalcificcl and degenerated to such a degree that it was rasirr to cut through the substance of the ribs than through the costal cartilages. Upon the removal of the sternum, the severed rnds of the ribs showed the medullary cnvity to br greatly rnlarged and filled with a ratlirr homogeneous gelatinous substance in which bony tissue was entirely ab- sent. At the juncture of the ribs and the sternal cartilage there were small yrl- lowish enlargements protruding henrath the parietal layer of the pleura. The nodnles varied somewhat in size; the largest was 10 cm. x 5 em. Similar nod- ules of larger size were found along the course of the ribs of the left side, with the exception of the seventh, roughly arranged in thc anterior axillaly line. At these nodular areas the ribs were very soft and fractured with great ease. Similar nodules were found on the eighth and ninth ribs in the posterior axillary line. Likewise, in the right thorax nodules of the same nature mere found on each of the ribs, the largest being on the first, srcond, and fourth. The ribs on this side were also extremely fragile. The vertebral column showed two rather distinct nodules on the lateral sur- MULTIPLE MYELOMA 69 1 face of the seventh and eighth thoracic vertebrae. Upon further examination it was found that the bodies of the vertebrae were very soft and that the knife could be thrust easily into their substance. The medullary substance of these vertebrae was seen to consist of a dark reddish material which contained small spicules of bone ; the general appearance was that of the homogeneous gelatinous mass seen in the medullary cavities of the ribs. Examination of the bones of the pelvis and of the long bones of the body failed to reveal any softening or abnormal condition. Anatomical Diagnosis : Multiple myeloma involving the sternum, each of the ribs, and the thoracic and lumbar vertebrae. Microscopic I’athology : Sections from a vertebra show a microscopic picture representative of those from all the affected bones. Remnants of bone spicules and portions of cartilage are to be seen. Several sections show an increase in the amount of the connective-tissue stroma with cells ranging from reticular forms to plasmoblasts and mature plasma cells. There are foci of plasma cells in which the cells are rather smaller and apparently more mature than in the preceding case and with them many lymphocytic cells with nuclei resembling the plasma- cell’s arrangement of chromatin but with less cytoplasm. Outside these foci are scattered plasma cells and bone marrow cells of all forms. Microscopic Diagnosis : Multiple myeloma of the mature plasma-cell type, probably of fairly slow development.

CASEI11 (No. 3694) : This case occurred in the service of one of the authors (F. M. S.). G. V., a white male, aged fifty-five years, an electrician, began to complain of severe lumbar pain in December. For some years he had suffered from rheumatic pains in the back and legs. The pain in the lumbar region gradu- ally grew worse. He was admitted to the hospital on Feb. 11 as a bed-patient. He was later removed to his home, somewhat improved. Physical Examination: The chief feature was a sharp, non-transmitted pain localized at the third lumbar vertebra, and aggravated by sudden movements. There was no tenderness in this area nor rigidity of the lumbar muscles. The patient moved with great difficulty due to the pain arising from any movement of the spine. . The blood count was normal except for increase of lymphocytes to 35 per cent. The Wassermann test was negative. Blood chemistry : non-protein nitrogen 59.0 mg., creatinine 3.2 mg. per 100 C.C. of blood. Examination of the urine showed: specific gravity 1.023; no sugar; albumin and casts varying in amount. The Bence-Jones test was strongly positive. Roentgenographically a marked osteoporosis of the entire lumbar spine was demonstrable. There was some evidence of hypertrophic arthritis, lipping of the vertebrae, and bone-bridging between the twelfth thoracic and first lumbar, first and second lumbar, and second and third lumbar vertebrae. Death occurred July 4 from lobar pneumonia. The clinical course was six to seven months. Gross Pathology : All the lumbar vertebrae showed distinct areas of softening. Only the thin shell of the anterior portions of the third, fourth, and fifth lumbar vertebrae remained. Inspection of the ribs revealed a marked softening of the marrow spaces and a distinct darkening of this substance. The spleen was en- larged to twice its normal size. Anatomical Diagnosis : Myeloid degeneration of the bodies of the lumbar verte- brae and of the marrow spaces of the ribs; lobar pneumonia; chronic splenitis; chronic nephritis. Xicroscopic Pathology: The sections show rather nodular, plasma-cell growths with areas of nearly normal bone marrow intervening. The mature plasma cell is predominant, but it is a somewhat larger cell than in Case 11, with less pyknotic 692 ERNEST SCOTT, F. M. STANTON, AND MARY OLIVER

nuclei. A few multinucleated arid other plasrnoblasts together with some small lymphocytes are to be seen, the latter being also found in the foci with the plasma cells. Microscopic Diaglaosis : Multiple niyeloma of the mature plasma-cell type.

CASE IV (No. 5309) : M. T., a white, unmarried femalr, aged fifty-one years, was admitted to the hospital May 3, complaining of pain in the fifth iintl sixth

FIG. 2 FIG.3 I"1QS. 2 AND 3. CASE 11': SECTION TIIROIiGII EXTRADIJRAL TLJMOR. X 630 Note the several cells in the field shown iu Fig. 2 eoutaiiiiiig iiiorc tlinii oiic nucleus. 111 tlie eeiiter are typical mature plauiiia cells, Marslialkd type. I'1:isnioblast or youiig form is indicated by arrow. A = inultiiiucleate pl:wiiolilast. Note typical plasma cells in Fig. 3, reprrseiitiiig varying ages up to aiid iiicludiiig the Itussell-body degcucr:itiiig cnil st:igr. The arrow iiiiirks :I typical Russell-body erll. Again uote teiideirry to u~oretlieu one iiurlrus 1wr ccll vliirli, togvtlicr with tliu nu- ~iicrnusmitotic figures prcseiit iii the iiuw tissue iii this case, indiratus a rapidly growiiig tumor.

intcrcostnl spaces (luring thr last month niitl increasing mrnkness. The previous history was negative rxc.el)t tor :ill attack of influenza, followed by onset of the cord symptoms in three or four days. 1'7ryaiccil Eeai~iv~tion: Physical rxtiniination showed : hyprresthesia over the body arid legs and a rriai*ked hyperrrflexin in the arms; clonus in both ankles; Babiiiski positive ; ahdominal reflexes ahscAiit ; rrtention of urine and anal relasa- tion. On May 22 motor paralysis occurred, with absolute sensory loss hchw the level of the tenth thoracic, except for a tingling sensation and deep pain in tho left leg. The blood count was normal. Urinalysis showed : albumin four plus; hyaline and granular casts; rcd hlootl cells present on the day of death. The spinal fluid wiis clcvir ; cell count 6 ; glolnilin and colloidal curve normal ; Wasserinunn test negative ; piwsure 6 mg. Hg, rising slowly to 20 nig. on com- pression of the juguhrs, indicating a partial hlock. Roentgenograms revcalrd a distinct shadow in the right chest nt thc hilum. MULTIPLE MYELOMA 693

Several ribs showed a peculiar decalcified or ‘‘ washrd-out ” appearance on the right side. No x-rays were made of the vertebral column. The patient died June 23 after a clinical course of three months. Clinical Diagnosis: Acute infectious myelitis. Gross Pathology: In the region of the fourth and fifth thoracic vertebrae was found a longitudinal thickening on the posterior and lateral aspect of the dura mater, measuring 0.5 em. at its mid-portion and tapering at each end. This miass

FIQS.4 AND 5. CASE Iv: SECTION THROUGH DURALTIJNOR. X630 In FIG. 4 (above) A = plavmoblast; B = Russell-body cell; C = recently divided plasma cells in the lnaturntive phase where rapid cell division occurs; D = binucleate plasmoblast. Fig. 5 shows a focus of plasma cells with younger forms in the cciitral portion. was firm in texture and of a dark reddish color. The inner surface of the dura was smooth and apparently not penetrated by the mass on the outer surface. The cord was of approximately normal appearance except for a slight swelling in the mid-dorsal region at the level of the extradural tumor. Sections through this area revealed a marked softening, with obliteration of all anatomical structure. 694 ERNEST SCOTT, F. M. STANTON, AND MARY OLIVER

Microscopic Pathology : Sections through the spinal cord, stained by the hema- toxylin-eosin and Pal-Weigert methods, revealed a diffuse type of degeneration. The mid-dorsal region had undergone almost complete degeneration of both white and gray matter, the cervical and lumhar regions a diffuse degeneration not con- fined to definite coliimns or tracts. There mas no evidence of infection or of in- flammatory infiltration in any section. The tumor mass from the dura was found to consist of plasma cells in various stages of development. In addition to a co~ispicuousreticular tissue cell, the pic- ture was one of numerous plasmoblasts, mature plasma cells of the Marshalkc5 type, and the older rlegenerative forms with granules and vacuoles, the Russell- body-cell forms. Mitotic figures and many binueleate and multinucleate plasmo- blasts were present, indicating the rapid growth of this tumor. Sections from the bone marrow of the ribs, stained by the Maximow stain, revealed a growth similar to that of the dural tumor but of somewhat more im- mature character. The plasmoblasts predominated over the rather young plasma cells of the Marshalk6 type.

PIC+. 6. CASE Iv: SECTIOS THROUGH LIVERSIIOWINC4 SINUSOIDS FILLEDWITII M.\TURE PLASMACELLS. xG65

Sections from the liver showed an increase in fibrous tissue and the accunn- lation in the sinusoids of a considerable number of mature plasma cells. Similar cells were found in the capillaries of the kidney. The occurrence of these myr- loma tumor cells in the circulation is rather rare and offers evidence of genuine metastasis in multiple myeloma. ikficroscopic Diagnosis: Plasma-cell multiple myelonia of rapid growth, involv- ing at least the ribs, with extrnsion or metastasis of tlie disrase to the externiil surface of the dura, resulting in necrosis of the mid-dorsal region of the cord. Occurrence of diffusely distributed myeloma plasma crlls in the sinusoids of tlie liver and the capillaries of the kidney.

CASE V (No. 4663) : C. P., a white male, aged sixty-one, was admitted April 10, complaining of pain in the back and lateral thorax. The past history was negative. The present illness began in July 1929, with the onset of severe painh in the ribs and back, necessitating the use of hypodermics. There was some fever. Phglskcul Exuminrctiolz: The patient was poorly nourished. The spinr wns hrltl absolutely rigid, and there was myasthenia. Blood pressure was normal. ICnrc jerks were absent. MULTIPLE MYELOMA 695

The blood count was normal; the color index .98; sedimentation rate 34 per cent in one hour. The Kalin test mas negative. The urine was positive for albumin. No Bence-Jones bodies were found. Roentgenograms of the lumhar and dorsal spine showed a degenerative process with disappearance of the calcium. The femur showed one or two lighter, ‘‘ punched-out ” areas suggestive of malignancy. In the mid-dorsal region there were apparently some crushing and fusing of several of the bodies. Death occurred July 13, 1930, after a clinical course of one year. Clinical Diagmosis : Osteomalacia. GTOSSPatholog?j: The chest was irregular in outline and somewhat sunken in the sternal region. In removing the muscles from the ribs, the latter were found to be quite soft and friable. After the removal of the sternum, the mere passing of the hand into the pleural cavity in an enileavor to examine the lungs caused a fracture of one or more of the ribs. The sternum was soft and easily fractured, the knife being pushed through its body without effort. In passing through the bone, the knife blade sremrd to come into rontact with a slightly calcified area or

FIQ. 7. CASE IV: SECTIONTIIROUOII DURALTUMOR. x 900 Note the mitotic figures iiidiratiiig pliases of cell division. with bong spiculrs nrar the periosteum, but the central portion of the bone was entirely devoid of calcium. The interverlehml discs were somewhat more con- spicuous than usual, and the periosteum over the bodies of the vertebrae was com- pressible. In passing through the periostrum, there mas a slight gritting of the knife resrmbling somewhat the crackling of an egg-shell, but the interior of the bodies of the vertel)riie c.onttiinrd no calcium nor bony spirules. This decalcified condition extendtd throughout the entire column. The bodies of the vertebrae were severed easily from the anterior laminae hy passing the knife down either side of the column and lifting off the bodies of the vertebrae, exposing the spinal cord. It was found that the pelvic bone could he punctured with the same ease as the ribs and vertebrae. Examination of the other honrs revealed no evidence of enlargement, nodules, or tumor formation. Anatomicat Diagnosis: Decalcification or softwing of the sternum, ribs, verte- brae, and pelvic bones. M~CTOSCO~~CPathology : The spleen presented a marked congestion with an ap- parent increase in the crlls of the pulp substance. A few scattered plasma cells were seen among the cells of the pulp. 696 ERNEST SCOTT, F. M. STANTON, AND MARY OLIVER

The mesenteric nodes presented evidence of irritation, witli the accumulation of a large number of mononuclear cells within the sinuses. The bone marrow taken from several of the vertebrae, from the sternum, and from the ribs presented an identical picture. The sxiialler blood vessels: were greatly congested. The stroma was not conspicuous. The nornial bone marrow was still represented by myeloblasts, myelocytes, normoblasts, and lymphocytes. The predominant cell, however, was the mature plasma cell, but its vatious stages of development, the plasmoblasts, the niultinucleate forms, and the degeueriitive Russell-body cell, were present. A few plasma cells were to be found in some of the larger blood vessels, suggesting possibilities of metastasis.

FIG.8. CASE V: SECTIONTHROUGH TUMORTISSUE OF THE BONEMARBOW. x 270 Note plasma cells, plasmoblasts, and iiumerous normoblasts.

Microscopic Diagwosis : Multiple myeloma involving the bodies of the verte- brae, the ribs, and the sternum. CONCLUSIONS 1. To the 425 cases of multiple myeloma already collected from the literature by Geschickter and Copeland, we have added 30 cases from the recent literature and 5 cases of plasma-cell multiple myeloma occurring in our autopsy series. 2. The clinical features of multiple myeloma are briefly re- viewed. 3. Theories of the histogencsis of the myeloma cell are dis- cussed. 4. From a study of maturation stages in fast-growing myelomas and their similarity io experimentally produced plasma cells, we consider it probable that the tumor plasma cell is a derivative of MULTIPLE MYELOMA 697 the reticular cell of the hemopoietic and general connective tissues, and closely related to the lymphocyte series. NOTE: We are indebted for the opportunity of studying Case I to Dr. C. S. Lott of Columbus, Ohio; Case I1 to Dr. H. H. Snively; Case IV to Drs. Ralph Taylor and G. T. Harding, Jr.; Case V to Drs. J. A. McClure and C. W. Mc- Gavran. We wish to express our appreciation to Dr. Charles A. Doan for his helpful suggestions regarding the cell types studied in these tumors.

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