Primary macroglobulinemia

Reviews Primary Macroglobulinemia* Review with a Report on Thirp-One

Cases and Notes on the

Value of Continuous Chlorambucil BEN I).

MCCALLISTER,

M.D.,

EDWIN

D.

WARREN

BAYRD,

M.D.,

F. MCGUCKIN,

Rochester,

EDGAR

Therapy G.

HARRISON,

JR.,

M.D.

and

PH.D.

Minnesota

This paper presents a review of the recent literature on primary macroglobulinemia (Waldenstrom) and a report on thirty-one patients, including ten patients personally treated with chlorambucil over a period of seven years as well as three others followed closely. The course of the disease was categorized in several types: asymptomatic, delayed-progressive and progressive, and the life expectancies in each category compared. The most common symptoms noted in the present series were fatigue, weakness, adenopathy, hemorrhage and visual disturbances. Ocular abnormalities, lymphadenopathy and hepatosplenomegaly were the most common physical findings. In six patients personally examined, no abnormalities were found on physical examination. Five of the thirty-one patients had no symptoms and an additional three patients had long survival. The remaining twenty-three patients, however, had significant symptoms and complications early in the observed course of their disease. Histopathologic findings on lymph node biopsy in eight of the thirty-one cases and autopsy findings in two indicate that Waldenstrom’s macroglobulinemia represents a distinct variant of a neoplastic plasma-lymphoproliferative disorder with a characteristic plasmacytoid-lymphocytic composition. One patient has been treated successfully and continually with chlorambucil for five and a half years, the longest period yet observed. No patient has had a relapse so far while under treatment with chlorambucil, but all who discontinued such treatment have had relapses. After relapse, the response to therapy has been disappointing. The view is expressed that once an adequate remission is induced, treatment with chlorambucil should be continued indefinitely. man with failing vision, epistaxis, adenopathy and anemia. Bone marrow examination revealed 90 per cent “lymphocytes,” an erythrocyte sedimentation rate of 150 mm. and a serum globulin value of 10.2 gm. per 100 ml. The third patient was a sixty year old man with fatigue, adenopathy and anemia, with a serum globulin value of 7.3 gm. per 100 ml. and an erythrocyte sedimentation rate of 140 mm. [I]. Subsequent to this first report, approximately 300 cases of Waldenstrom’s macroglobulinemia have been recorded. Inasmuch as macroglobu-

NEW disease was introduced by Waldenin striim [ 71 as “incipient myelomatosis” 1944. On ultracentrifugation of the serum an abnormal globulin with a molecular weight of approximately 1 ,OOO,OOOwas found in three patients. The first patient was a sixty year old man with a six year history of epistaxis, anemia, rapid erythrocyte sedimentation rate (135 mm. in one hour), retinal hemorrhage, hypergammaglobulinemia (6.1 gm. per 100 ml. of serum) and 60 per cent “lymphocytes” in the bone marrow. The second patient was a sixty-two year old

A

* From the Sections of Medicine, Surgical Pathology and Biochemistry, Rochester, Minnesota. Manuscript received August 12, 1966.

394

AMERICAN

Mayo Clinic and Mayo Foundation,

JOURNAL

OF

MEDICINE

Primary

Macroglobulinemia-Md’allister

lins are present in normal serum, usually in amounts of less than 3 per cent of the total protein, it has become customary to regard only amounts in excess of 5 to 10 per cent as abnormal. However, the amount of macroglobulin present in the serum does not in itself distinguish the primary macroglobulinemia of Waldenstrijm from other macroglobulinemias. Various ingenious methods have been developed for distinguishing these abnormal proteins, with lessening dependence upon the ultracentrifuge for definitive identification, although this is still required. A distinct clinical entity, the macroglobulinemia of WaldenstrGm (MGW) exhibits qualities of both the lymphoproliferative and the plasmocytic diseases. Thirty-one cases of macroglobulinemia of WaldenstrGm, seen at the Mayo Clinic in the nine year period from 1955 through 1963, are here reviewed. Laboratory studies found helpful in its identification are related. The natural course of the disease, as observed among these patients, is noted, a successful method of treatment is described and a review of the now voluminous pertinent literature is reported [2-721. Progress reports on eight of our thirty-one cases, recorded in part previously [73,74], will also be presented. MGW is found most commonly in men more than fifty years of age who present with fatigue, weakness and weight loss. Epistaxis, gingival bleeding, blurring of vision and susceptibility to infection are also prominent. Generalized lymphadenopathy and hepatosplenomegaly reflect its lymphoreticuloproliferative nature, and the singular engorgement of retinal veins reflects its aberrant hyperglobulinemia. Normocytic, normochromic anemia, frequently associated with a monocytosis, is an ultimate development, as is extreme increase of the erythrocyte sedimentation rate. Finally hyperglobulinemia, associated with a sharp homogeneous peak on routine serum protein electrophoresis on paper, completes the salient features of the disease. AGE

AND

SEX

The early literature (114 cases) was well reviewed by Imhof and associates [3] in 1959. A review of the literature since that time (196 cases) reveals that the average age of affected patients is sixty years, 68 per cent of patients being men. The youngest patient was thirty-two years old [75], the oldest eighty-six, and 80 per cent of the patients were more than fifty years VOL.

43.

SEP?‘EMBER

1967

395

et al.

old. Three Negroes have been reported to have MGW [ 16-181. The average age of our patients was sixty years, with men making up 55 per cent of the total. Although MGW has rarely been recorded in persons less than forty years old, three of our patients (10 per cent) were thirtyeight, thirty-nine and forty years old, respectively. Our oldest patient was ninety-two years old. SYMPTOMS

The most common symptoms described by our patients and by those in the literature were fatigue and weakness (often associated with anemia), some form of bleeding, and weight loss (Table I). Although visual disturbances were infrequently mentioned (ten patients) in the literature, ten of our patients were notably bothered by impaired vision. This usually was referred to merely as blurred vision but it was disabling enough to two patients to be their main problem. It is noteworthy that adenopathy was the presenting complaint in three of our patients (Table II). Recurrent infections, usually of the respiratory tract, have been noted [79] and are a common terminal event. Congestive heart failure is also a relatively common and fatal complication. TABLE I INCIDENCE

OF PRESENTING

SYMPTOMS

No. of Cases

Symptom Fatigue, weakness Hemorrhage Multiple Epistaxis Gastrointestinal

Dental Hemoptysis Weight loss Visual disturbance Dyspnea Easy bruisability Adenopathy Abdominal pains Infection Arthralgias Anorexia Edema Neurologic disturbance Raynaud’s phenomenon Pruritus Mandibular swelling Psychosis Mouth ulcer None

Literature (196 cases)

Present Series (31 cases)

75 18

24 23 2

49 5

12 5

3 2 39 10 11 0 7 0 12 4 0 0 23 7 2 0 0 0 8

4 0 13 10 8 4 4 4 3 2 2 2 1 1 1 1 1 1 5

396

Primary

Macroglobulinemia--A1cCallister

TABLE II INCIDENCEOF CHIEF COMPLAINTS IN PRESENTSERIEY Chief Complaint __-.

No. of Cast-s

Fatigue, weakness Adenopathy Dyspnea Hemorrhage Menorrhagic Dental Visual disturbance Febrile episodes Pruritus Weight loss Vague abdominal pain Mandibular swelling Unresolved pneumonia None

11 3 2 2 1 1 2 1 1 1 1 1 1 5

Five of our patients had no symptoms and the disease was discovered during a routine examination. Increase of the erythrocyte sedimentation rate (three patients), slight anemia (one patient) and hyperglobulinemia (one patient) led to the diagnosis in others. None of these patients has manifested progression of disease. Seven of the twenty patients described by Kappeler and associates [B] were also asymptomatic. Pruritus was the sole symptom in one of our patients whose disease has also been nonprogressive. TABLE III INCIDENCEOF PHYSICALFINDINGS No. of Cases Physical Finding Ocular changes Lymphadenopathy Splenomegaly Hepatomegaly Edema Neurologic Cerebral vascular hemorrhage General Neuropathy Pulmonary Effusion Pneumonia Petechiae, purpura Mikulicz’s syndrome Sjiigren’s syndrome Congestive heart failure Cutaneous Mouth ulcer None

Literature (196 cases)

Present series (31 cas s)

66 49 71 77 13

18 13 8 7 0

8 19 7

0 0 2

8 8 35 6 4 8 4 0 17

2 1 0 1 0 1 0 1 6

et al.

Pruritus has been noted as a significant symptom in only two cases reported in the literature [X),27 1. Circulatory impairment may result from an increase in serum viscosity or a change in cold solubility of the circulating proteins. Carr and Henkind [ZZ] have indicated that the increase in serum I-iscosity that accompanies increase of serum macroglobulins may produce vascular stasis and, in turn, distention of the retinal vessels, hemorrhage and exudate formation. Fahey [23] also has expressed the view that retinopathy, congestive heart failure, bleeding diathesis and neurologic symptoms, as well as weakness and fatigue, are attributable to hyperviscosity. These symptoms have all been noted to be less evident after plasmapheresis, which lowers serum viscosity. Fahey [23] further describes a symptomatic threshold above which an increase in serum macroglobulin and viscosity causes symptoms, and uses the degree of serum viscosity as a guide to planning treatment. PHYSICAL FINDINGS

Both in our cases and in those recorded in the literature, hepatosplenomegaly, mild lymphadenopathy and ocular abnormalities were the most prominent physical findings (Table III). Hepatosplenic enlargement was usually mild, but both organs occasionally extended 5 to 6 cm. below the costal margin. Funduscopic findings reflect the severe hyperglobulinemia seen in this disease (Fig. 1). These findings were characteristic in eighteen of twenty-six of our patients who had funduscopic examination, and were mentioned in sixty-six of the 196 recorded cases. Retinal hemorrhages, microaneurysms, venous stasis and sausage-like segmentation of greatly dilated and tortuous retinal veins were the consistent abnormalities described. The term “fundus paraproteinaemicus” was originally used by Berneaud-K&z and Jahnke [24] in 1954 after they observed a patient with hyperglobulinemia and cryoglobulinemia who had the fundus picture described. The retinopathy of MGW (Fig. 1) is perhaps its most distinguishing physical feature, but similar findings have been noted occasionally in other conditions with high blood or serum viscosity, such as multiple myeloma, polycythemia vera and leukemia [22]. Occlusion of the central vein of the retina has been noted, and external segmentation, with clumping of red blood cells in the conjunctival vessels, has been reported [25]. The peripheral AMERICAN

JOURNAL

OF

MEDICINE

Primary

Macroglobulinemia~~-

McCullist~r et al.

~

FIG. 1.

A, normal ocular fundus. B, ocular fundus in patient with macroglobulinemia

systemic veins were grossly dilated in a case reported by Aarseth and associates [26] and in one of our cases (Case 8). Purpura has been reported but is not common. Enlargement of the parotid and other salivary glands has also been noted in MGW [7,8,27,28], and in one of our cases (Case 31) typical Mikulicz’s syndrome developed during her illness. Three cases of Sjijgren’s syndrome associated with an increase in macroglobulins were mentioned by Kappeler and associates [Cc]. We have observed this association, but have considered the macroglobulinemia to be associated with SjGgren’s syndrome, rather than with the primary macroglobulinemia of WaldenstrGm. Neurologic changes have been reported in 25 per cent of some series, with manifestations beginning from a few months to two years after diagnosis of the disease [29]. The association of hyperglobulinemia and neurologic manifestations has been referred to as the Bing-Neel syndrome, and the case of “hyperglobulinemia with affection of the central nervous system” reported by Bing in 1950 most likely represented MGW [30]. A cerebrovascular disturbance, presenting either as gross cerebral or as subarachnoid hemorrhage, is the most commonly reported neurologic manifestation. An encephalopathy or diffuse brain syndrome has been referred to as “coma paraproteinaemicum” [37]. A rarely occurring peripheral neuropathy may also develop late in the disease as a polyneuritis VOL.

43,

SEPTEMBER

1967

or polyradiculitis

of WaldenstrBm.

with an increase in spinal fluid protein [2.9,.?2,,33]. Polyneuropathy was found in seven reported cases [.?3,34]. The symptoms and findings in Darnley’s case were reminiscent of the type associated with systemic malignancies and bronchogenic carcinoma [,?J]. Two of our patients (Cases 17 and 30) had a severe polyneuropathy. In one (Case 17) this neuropathy developed in the terminal stages of his illness, but in the other (Case 30) the neuropathy was a prominent part of the disease from the onset. Schur and Appel [70] reported a case of MGW with pleural effusion and collected reports of seven such cases. They noted that pleural effusion was associated with congestive heart failure in two of these, but in the others the effusion seemed to be due to involvement of the pleura by the abnormal lymphocytes and reticulum cells. In one of our patients (Case 13) pleural effusion developed in association with pulmonary hypertension, idiopathic cardiomegaly and congestive heart failure. In another (Case 19) the pleural effusion itself contained 7.9 gm. of protein per 100 ml. Multiple, infiltrative, nodular, cutaneous lesions have been reported in two cases [35]. Ulcerations of the oral mucosa were noted in one of our cases and in one reported by Gamble and Driscoll [36]. In five of our cases the characteristic ophthalmoscopic findings were the sole physical findings, whereas adenopathy was the only abnormality

Primary

398

Macroglobulinemia-McCallister

found on physical examination in four other cases. Two patients (Cases 20 and 26) had symptoms but no physical findings, two patients (Cases 2 and 3) had no symptoms but some physical findings (mouth ulcerations and ocular abnormalities) and three patients (Cases 1, 4 and 5) had neither physical findings nor symptoms. LABORATORY

FINDINGS

normocytic aneAnemia. A normochromic, mia was present in 89 per cent of the reported cases. In twenty-three of our thirty-one cases the hemoglobin value ranged from 5.8 to 10.4 [gm. per cent]. A hemoglobin value of 1.1 [gm. per cent] was reported in a case by Imhof and associates [3]. In two of our ten patients with no anemia at the time of diagnosis, anemia developed later. Hemolytic anemia has been reported only occasionally [3,26,37,.?8], yet three of our patients (Cases 14, 28 and 29) had it and in two of these the Coombs’ test gave a positive result. Cline and associates [,?s], in studies of anemia in MGW, found a shortened life span of the red cells in six of eight cases and an absolute failure of erythropoiesis in the other two, alone or in a combination with an iron deficiency. In two cases serial studies showed that a decrease in serum viscosity and serum macroglobulin levels was accompanied by an increase in red cell survival [38]. Erythrocyte SedimentationRate and Rouleaux Formasedimentation rates reported tion. Erythrocyte in the recent literature (recorded in 101 cases) varied from 168 to 1 mm. in one hour and averaged 94 1nn1. (more than 100 mm. in fifty-six and less than 4 mm. in eight). These were essentially the same as those in previously reported series. Our experience was no different; the sedimentation rates varied from 1 to 145 mm. (twenty-eight patients tested) and averaged 80 mm. (greater than 100 mm. in thirteen and less than 4 mm. in three). Rouleaux formation, on the other hand, commented upon in only twenty-nine recorded cases, was exceedingly heavy in blood films in all our patients. In fact, intense rouleaux formation was often the first clue to the diagnosis. The presence of increased rouleaux formation became even more significant when it was associated with a low normal erythrocyte sedimentation rate. Leukocyte Count. The leukocyte count is usually normal, although a mild leukocytosis or leukopenia is occasionally seen. In our series the average leukocyte count was 7,243 per cu. mm.

et al.

Seventeen patients had normal counts, three had leukocytosis (12,000, 12,800 and 21,000 per CII. mm.), and seven had leukopenia (2,600 to 4,600 per cu. mm.). Mackay and associates [28] described a patient with a white blood count of 50,000 per cu. mm., as well as two patients with pancytopenia. Four of our seven patients with leukopenia also had pancytopenia. Imhof and co-workers [3] noted that in 37 per cent of 114 collected cases there was lymphocytosis. Only two patients in our series had absolute lymphocytosis (Cases 8 and 29). Of the 196 patients recorded in the recent literature, only twenty-five had leukocyte counts greater than 10,000 per cu. mm. and only five had counts greater than 20,000 per cu. mm. D$erential Leukocyte Count and Platelets. In twenty-one of twenty-five of our cases in which differential counts were made the monocyte count exceeded 5 per cent and in ten it exceeded 10 per cent. This has not been a frequent observation in reported cases [.?!)I, as in only twentynine has monocytosis been previously reported. Mild thrombocytopenia (count of less than 150,000 per cu. nun.) was observed in thirteen cases in our series and in eleven in the literature. One of our patients with a normal number of platelets had a qualitative deficiency in platelets (thrombasthenia) manifested by an abnormal prothrombin-consumption test which was corrected by adding normal platelets. The excellent work of Pachter and co-workers (401 concerning the hemorrhagic diathesis and, in particular, the platelets in MGW have added much to the understanding of this complication. When the plasma of patients with MGW was incubated with the platelets of normal patients, a prolonged prothrombin time was noted; however, when antimacroglobulin serum was added, the prothrombin time became normal. Macroglobulin platelets were then stained with fluorescent antimacroglobulin serum and a “halo” or coating was noted about the cells. This coating of the platelets by macroglobulin was thought to prevent the release of platelet factors. Schwab and Fahey [Jr] observed that after plasmapheresis and reduction of the amount of abnormal globulins present in a patient with MGW, the bleeding tendency disappeared. Prothrombin Time, Liver Function and Cholesterol. The prothrombin time has been observed to be slightly prolonged. A short prothrombin time and a prolonged bleeding time have also been mentioned [do]. In the 196 reported cases, the

Primary

Macroglobulinemia--McCallister

FIG. 2. Paper electrophoretic pattern ulinemia. Left panel, before treatment. ambucil.

prothrombin time was commented upon only seven times, and it was prolonged in four of these. In nine of our fourteen patients in whom the prothrombin time was determined, it was between twenty and twenty-four seconds (normal seventeen to nineteen seconds). The results of liver function tests were usually normal despite moderate hepatomegaly. Hyperuricemia has been noted in a few cases [42], which may be coincidence; however, hyperuricemia sometimes has also been associated with lymphosarcoma, reticulum cell sarcoma, chronic myelogenous leukemia and multiple myeloma. Five of seven patients described by Olmer and associates [43] had a low value for plasma cholesterol (50 to 135 mg. per 100 ml.). Quattrin et al. [Z] also noted a low cholesterol value in six of twenty-seven cases (two of their own and four reported cases). The concentration of plasma cholesterol was determined in only eight of our patients, in all but one (Case 11) of whom it was low (values of 72, 80, 98, 118, 128, 134 and 137 mg. per 100 ml., respectively). The low value for plasma cholesterol has been attributed to a limitation in the amount of protein available for the synthesis of normal quantities of lipoprotein [&I, but with plasmapheresis the plasma level has been noted to rise [41]. The apparently low incidence of coronary artery disease in elderly men with MGW may have some relation to the plasma cholesterol. Proteins. Bence Jones proteinuria has been found in one third to one half of the reported “Or..

43,

SEPTEMBER

1967

et al.

of serum protein in primary R&ht panel, after treatment

399

macroglobwith chlor-

cases [JZ,J5,S]. Of the 196 cases reviewed, Bence Jones protein was looked for in fifty-five and found in nineteen. The Bence Jones reaction was positive in eight of thirty-one cases in our series. The value for serum total proteins varied from 6.45 to 11.9 gm. per 100 ml. in our thirty-one cases, and averaged 9.3 gm. The value for serum “gamma globulin” averaged 4.15 gm. Serum albumin was usually decreased (to a low of 1.6 gm.) and always varied inversely with the amount of abnormal protein present. Cryoglobulins were found in Cryoglobulins. only two of our ten patients in whom they were sought (Cases 16 and 18), although reported in twenty-two of fifty-five cases in a recent review of the literature. Some patients with cryomacroglobulinemia manifest cold intolerance [47]. All patients with MGW who have had Raynaud’s phenomenon have had cryoglobulins, but some patients have had cryoglobulins with no clinical symptoms of Raynaud’s phenomenon. It has been stated that macroglobulins with the physical properties of cryoglobulins or macrocryogelglobulins are responsible for the low erythrocyte sedimentation rates occasionally noted in MGW [4]. On the other hand, none of the recently reported fifty-five patients with cryoglobulins had unusually low sedimentation rates; and of nine with cryoglobulinemia in the present series who had both tests, six had sedimentation rates of more than 100 mm. in one hour. In our series three patients had erythrocyte sedimentation rates of 4 mm. or below. Of the two patients with

400

Primary

Macroglobulinemia-;VKal/ister

et al.

FIG. 3. A, Case 11. Bone marrow typical of m;lcroglobulinemia. Smear is hypoccllular and rcxals a preponderance of cytoplasm-poor lymphoid cells, and a slight increase in plasma cells and plasmoidal lymphocytes. \Vright’s stain; original magnification X 850. B, Case 8. Biopsy specimen from axillary lymph node showing lymphocytic character of abnormal cells. Eicmatoxylin and eosin stain, original magnification X 700.

MGW checked, one had cryogelglobulins and one did not; in one case in our series of MGW with cryoglobulinemia, no sedimentation rate was recorded. The serum of patients with MGW may be quite viscous [4,48,49], and one case has been reported in which no blood would flow through a venipuncture needle without first warming the arm of the patient to 37”~. [50]. Serum Protein Electrofihoresis on Paper. Serum protein electrophoresis on paper in this disease always shows a sharp homogeneous peak or spot in the globulin fraction (Fig. 2), usually in the intermediate or slow gamma position, as was true of all our patients. The proteins in the pleural effusion of four of the eight patients with MGW reported to have such effusion were similar to those of the serum [/O]. Intense periodic acid-Schiff staining of the paper electrophoretic strip in the area of the abnormal protein reflects its high carbohydrate content [5/,52], in contrast to the faint stain of myeloma proteins of similar mobility [.5.3]. On paper electrophoresis

a distinct shift of the macroglobulin peak to\vard the albumin end of the strip is noted after the serum is incubated in D-1-penicillamine [5,3]. This effect has not been produced with either normal or myeloma serum. Roentgenographic Findings. Roentgenologic examination may be helpful in distinguishing MGW from myeloma. Osteolytic lesions are rare in MGW, if they occur at all, in contrast to myeloma, although isolated instances have been reported in the foreign literature [8,55]. None of our patients with MGW had lytic skeletal lesions. Generalized osteoporosis, however, is not uncommon. Bone Marrow. Bone marrow examination was reported in 144 of 196 of the cases in the recent literature. Differential counts showed 10 to 90 per cent plasmacytoid lymphocytes in 43 per cent of these cases, 10 to 80 per cent small lymphocytes in another 31 per cent, a 2 to 15 per cent increase in plasma cells in 21 per cent, and a normal marrow in 5 per cent. In all patients with normal marrow the hemoglobin value was AMERICAN

JOURNAL

OF

MEDICINE

FIG. 4. Case 27. Biopsy specimen from supraclavicular lymph node showing diffuse intiltration of cells, which vary from recognizable plasma cells to plasmacytoid lymphocytes to lymphocytic cells. Anna-Papprnheirn stain, original ma~nilication X 1 .lOO.

lnore than 10.5 gm. per cent. Of our ten patients with a hemoglobin value of 10.5 gm. per cent or more who had a marrow examination, only one had a normal marrow (Case 1). Bone marrow examination readily distinguished MGW from multiple myeloma in all our thirty-one cases (Fig. 3A). The state of the marrow corresponds to the degree of anemia ; that is, the more anemic the patient, the more typical are the marrow findings. The characteristic “myelonla cell” is not seen, although lnyeloma is almost invariably one of the suggested diagnoses. The usual yield of cells on sternal aspiration is poor. However. the number of slnall atypical “plasmacytoid lymphocytes” and plasma cells is increased. On electron microscopic examination the number of cells containing an endoplasmic reticulum appears to be far greater than would seem to be accounted for by typical, light-visible plasma cells? thus suggesting that a significant number of the “lymphocytes” may really be plasma cells functionally [56]. When changes are well developed in the marrow, tissue mast cells ma)- be seen [57,58]. In contrast to the poor yield of the aspirate and the hypocellularity of bone marrow smears, Inarrow sections are hypercellular and may suggest lymphoma. The marrow picture is often confused with that in lym““I..

43,

SEPTEMBER

1967

phocytic le(lkelnia, lymphosarcoma and multiple myeloma. In reported instances in which “lymphocytes” constitrkted up to 95 per cent of marrow cells, differentiation from lymphatic leukemia by light microscopy would be difficult [3.9]. Periodic acid-Schiff (PAS) staining material has been found in the form of intracellular globules (“grape cells”) in the bone marrow [.59]. A significant number of atypical plasmacytoid lymphocytes which contain intranuclear PAS-positive staining material have been reported only in MGW [!/I. Histopathology. Lymph node biopsy was performed in nine of our cases. In three the original interpretation was nonspecific or “inflammatory” changes, in one the tissue was suggestive of lymphoma and in five a diagnosis of “lymphoma” was made. In no case was the underlying diagnosis of macroglobulinemia suspected from the original histopathologic examination. All lymph node sections were reviewed and additional tissue sections were stained and examined (hematoxylin and eosin, Vnna-Pappenheim, Gomori’s reticulum, Giemsa, periodic acid-Schiff [before and after diastase digestion] and methyl violet stains). The histopathologic features were essentially silnilar in the lymph nodes in eight cases. There was a diffrlse, pre-

402

Primary

Macroglobulinemia-McCallis~er

et al.

FIG. 5. Case 8. Biopsy specimen from axillary lymph node showing marked extracapsular is indistinguishable from lymphoma. Hematoxylin and eosin stain, original magnilication FIG. 6. Case 12. Intranuclear periodic acid-Schiff positive material is demonstrated Periodic acid-Schiff stain after diastase digestion, original magnification X 1,300.

dominantly atypical lymphocytic replacement of most of the nodal architecture which infiltrated the perinodal fat and was almost indistinguishable from lymphoma (Fig. 3B and 4). In two cases the architecture was discernible and several patent sinusoids were seen, yet the perinodal fat was extensively infiltrated (Fig. 5). Lymphoid follicles were not evident. The atypical lymphocytic component varied from cells indistinguishable from mature lymphocytes to larger, lymphoblastic-type cells. In all these cases the atypical lymphocytes blended into small scattered foci of plasmacytoid lymphocytes and mature plasma cells. These could be identified particularly in the Unna-Pappenheim stain which disclosed their moderate cytoplasmic pyroninophilia. Although the plasmacytoid lymphocytes usually had eccentric nuclei and a moderate amount of cytoplasm, their chromatin was not clumped in the usual configuration of mature plasma cells. A few scattered reticulum cells were noted in the background in addition to histiocytes with engulfed hemosiderin. Intracellular, diastase resistant, PAS-positive

infiltration X 40.

of fat which

near center of field (arroz~).

material was noted either as rare, intrantlclear, droplet-like, brightly pink deposits in scattered plasmacytoid lymphocytic or reticulum cells (Fig. 6) or more frequently as a diffuse cytoplasmic positivity in similar scattered cells (Fig. 7). Much more abundant were the intercelllllar collections of proteinaceous material either in small pools or in a lace-like pattern in the stroma. In one case a stromal hyalin-like deposit stained positively for amyloid. The one “inflammatory” node observed in our series had the appearance of nonspecific subacute lymphadenitis with preservation of the architecture. There were scattered infiltrations of plasma cells and neutrophils and follicles with germinal centers. Some PAS-positive material was seen intranuclearly in a few reticulum-type cells and intracytoplasmically in a few scattered lymphocytes, reticulum cells or plasma cells. This node biopsy was performed very early in the course of the disease, and was associated at that time with erythema multiforme. Biochemically, the diagnosis of macroglobulinemia was not established until ten years later. AMERICAN

JOURNAL

OF

MEDlClNE

Primary

Macroglobulinemia-McCaZiister

et al.

403

FIG. 8. CASE 11. Lymph node, reticulum cell sarcoma. There are scattered pleomorphic and multinucleated reticulum cells which simulate Sternberg-Reed cells. In the background, plasmacytoid forms and a few plasma cells arc noted. Hematoxylin and eosin stain, original magniIication X 350.

In one case (Case ll), somewhat like that recently reported by Wanebo and Clarkson [60], the appearance had become that of disseminated reticulum cell sarcoma when seen at autopsy (Fig. 8). There were only a few plasma cells and minimal cytoplasmic PAS-positive material in tumor cells. Rarely, intranuclear diastase-resistant PAS-positive material was found in a few reticulum cells. Autopsy in another patient (Case 27) disclosed some scattered lymphocytic and plasmacytoid infiltration in perinodal fat which had minimal PAS-positive intranuclear and cytoplasmic material similar to that in the cases mentioned. A comparative study of tissue sections from patients with nonspecific lymphadenitis (six cases), sarcoidosis (three cases) and lymphomas of various types (nine cases), including Hodgkin’s disease, was made and similarly stained sections were prepared. A few plasma cells were encountered in two of the nine cases of lymphomas, in all three cases of sarcoidosis and in two cases of nonspecific lymphadenitis. Some of these sections exhibited cytoplasrnic pyroninophilia; however, none had foci of associated plasmacytoid cells VOI..

43.

SEP=TEM*IBER

1967

such as those seen in some cases of macroglobulinenlia. Some PAS-positive cytoplasmic reaction was seen in all eighteen cases in which it was sought, and was observed particularly in histiocytes, in the epithelioid cells of Boeck’s sarcoid and in some of the tumor cells in reticulum cell sarcoma. Comment on pathology: Martin [12] has described histopathologic variations which ranged from diffuse infiltration by plasma cells of an otherwise normal reticuloendothelial system to a cellular picture which resembled that of a lymphoma of low grade malignancy. Zollinger [61] studied eight cases at autopsy and noted focal and diffuse infiltrations which consisted of reticular lymphoid cells and plasmocytes. The bone marrow was affected in all cases. There was also involvement of lymph nodes and, in some cases, the liver and spleen. Occasionally, infiltrates into nonlymphoid tissues have been observed and are similar to those seen in the liver (671. Larnm [62] reported an autopsy case of macroglobulinemia associated with polymyositis in which plasma cell infiltration of the muscles was found. The central nervous system and pe-

404

Primary

Macroglobulinemia-~~lV&u~/ister

ripheral nerves have been found to have endoneural and perivascular infiltrations with plasma cells and lymphocytes [26,.?.9,.X&?J], and Hines [63] reported perineural cufing by lymphocytes in a case of MGW with peripheral neuritis. An intracytoplasmic and intranuclear PASstaining material has been observed in lymph nodes in macroglobulinemia [!1,.?2,32,62], and it has been suggested that this material is chemically identical with the circulating 18s hexoserich macroglobulin. In support of this suggestion, Argani and Kipkie [64] have observed, by electron microscopy, crystalline bodies within the premature reticulum cells of the bone marrow of two patients with MGW. These bodies were thought to represent lnacroglobulins which were synthesized by the abnormally differentiated reticulum cells. Le Beux and Ganter [6.5] and Kok and associates [66], respectively, reviewed tissue in six and four cases of MGW at autopsy and expressed the view that there is a clearly defined histopathologic picture which should permit a diagnosis from lymph node biopsy or sternal puncture. Le Beux and Ganter [65] presented the view that, in addition to infiltration of the reticuloendothelial system by lymphocytes and plasma cells, an “asynchronous nucleocytoplasmic maturation in the plasma cell series and an increase in the number of mast cells in the infiltrate” are the most characteristic features. Kok and associates [66] as well as Dutcher and Fahey [.9] further stated that the infiltrations in the nodes are too pleomorphic to suggest a diagnosis of chronic lymphatic leukemia or lymphosarcoma and that the plasma cells are not increased enough to support a diagnosis of myeloma. Kok and associates [66] also stated that, contrary to observations in lymphoma, lymphosarcoma and chronic lymphatic leukemia, the reticulum structure of the nodes is well preserved and the reticulum pattern of the bone marrow is said to be normal. Zubrod and co-workers [&_‘I, however, have commented on the disorganized architecture of the lymph nodes in MGW, as we have observed. Amyloid deposits have been found on occasion [8,27,63,67] in the tissues of patients with increased serum macroglobulins, but the usual clinical history was not characteristic of MGW. There is probably no sharp line of demarcation for cells classified as “plasmacytoid” lymphocytes seen in these cases. As Wanebo and Clarkson [60] pointed out in their electron microscopic observations, many of the cells which had

el al.

a conspicuous endoplasmic reticulum (1 per cent of the total in splenic aspirates) had a morphologic appearance that was intermediate between that of an “atypical” lymphocyte and that of a mature plasma cell. These cells may be o\.erlooked in routine biopsies of lymph nodes and only knowledge of the clinical problem may alert one to search for them and thus recognize this entity as distinct from ordinary lymphoma. Histopathologically, it seems that MGW represents a clinical syndrome which is an unusual but distinct variant of a lympho- or plasmoproliferative disorder with a characteristic plasmacytoid-lymphocytic type of cell. In most of our cases this was essentially a malignant neoplastic process akin to that of lymphocytic or lymphoblastic lymphoma, as judged by the infiltrative character of the lymphoidal component and the almost uniformly fatal course of the disease. However, specimens obtained in these cases also varied from an “inflammatory” node to a frankly anaplastic reticulum cell sarcoma, as illustrated by our Cases 11 and 17. THE

PROTEIN OF

AND

STUDY

SPECIAL (TABLE

TECHNICS Iv)

Sia Tfrst. This is the simplest but least reliable and least specific method of detecting the abnormal serum protein. When a drop of abnormal serum is added to a column of distilled water, a white flocculant cloud may form. The Sia test gave a positive result in sixteen of twenty-one of our patients and in eighty-one of ninety of the patients in whom the test was recorded in the literature. Strict criteria to avoid false positive reactions have been stressed [ 72,681. On the other hand, 26 per cent of the patients in the review by Schur and Appel [ 701 had a false negative Sia reaction. A positive Sia reaction has also been noted in hepatic cirrhosis, kala-azar, chronic malaria, tuberculosis and systemic lupus erythematosus. It has been reported that in all serums with a positive Sia reaction the abnormal globulin has a gamma-2 mobility, whereas the euglobulin (Sia) reaction will be negative if the protein demonstrates beta mobility [57]. However, all the abnormal proteins in our series had the mobility of a gamma-2 protein, and both positive and negative Sia reactions were noted. Hexose Content. Many of the characteristics of MGW have gradually emerged, making it more readily distinguishable from multiple myeloma and the other dysproteinemias. The high hexose content of the abnormal protein is onr of these

Primary

40s

et al.

Macroglobulinemia-_UL’a//istPr 'I'ABLE IV RESU1;TS

0): SERUM

PROTEIN

STUDIES

Macroglobulin

(%a) 19.8s 19.7s 16.5s 27s 16.5s 18.8s 7s = 14s = 20s = 23s =

1 2 3 4 5 6

7 8

+t 18s = 25s = 30s = 18s = 25s = 32s = 17s 16.8s + 16.5s 17s 15.5s

9

10 11 12 13 14 15 16 17 18 19 20 21

Mobility

‘l’otal Protein ~gm./lOO ml.)

Globulin (gm./lOO ml.)

7.2 9.4

2.04 4.95

4?,

7.5 8.0 7.3

2.06 2.87 2.28

42 40

10.1 10.4

5.26 5.51

65

12.1

8.23

8.8 6.6 10.1 9.9 9.9 6.8 9.1 11.9 11.2 10.2 11 ,l 6.5 9.6

4.68 2.77 5.18 4.59 5.12 2.05 4.98 7.5 7.4 6.26 6.44 2.76 5.22

8.0

< .50

Y

< 259;

of

‘rotill Protein

i25 Y

6% 5% 23’j;, 37; 5oyi 12c/, 3% 38:/G 6% 1.5’;;

...

47 “1 high” -‘High“ 31

Y Y ?,

Y

Slow y 75

14.5s.. 18s 18s 17.6s 15.6s 22.3s 18s 17-18s

24 25

17s 19s 20s 20s 18.6s 18s

26 27 28 29 30 31

= positive result; = macroglobulins

“Considerablc“

50

SlowYB 01

fast y Slow y Slow y Slow y Slow y

61

Y)

Slo’, y

43,

SEPTEMBER

Hexosc Content

Sia

(%)

rest *

‘4’

4.2 4.8

_ +

T +

5.2 4.8 4.6

1 +

.

.

i ‘3’8

T +

6.5 6.7 5.2 4.0 4.6

: +

5’.2 5.1 “High“ 5.3

3.47

+

4.4

10.0 9.2 8.5

6.1 4.06 4.4

‘+’ +

5.1 5.9 5.4

8.8 9.2 7.6 6.4 7.0 8.9

3.3 4.23 2.4 2.38 2.12 3.8

5 4.7 7.0 4.8 3.88 5.2

t+i -

1 ‘i’

I: 1 + -_ ‘i’ :

- = negative. increased.

characteristics, and its estimation assists in distinguishing this condition from multiple myeloma. The pathologic protein fraction of R1GW has been found to have a hexose content of 4.6 to 6.7 per cent as compared to 0.15 to 2.42 per cent for the proteins of multiple myeloma of the same mobility (slow gamma) [53]. In our series the average hexose content was 5.1 per cent and varied from 4.0 to 6.7 per cent in the twenty-four VOL.

Gel Penetration*

Y

T

22 23

* + t +

ci,c,

Sedimentation Constant

Case No.

1967

patients in whom the test was performed. Increased amounts of polysaccharide have also been noted in the urine of one patient with MGW 1691. Gel Electrophoresis. Starch and acrylamide gel electrophoresis has been helpful in the diagnosis of MGW. The abnormal protein has failed in all instances of such tests to penetrate the gel [46,70-741, but when an active sulfhydryl corn-

406

Primary

Fro. 9. Serum ultracentrifugation macroglobulinemia.

Macroglobulinemia-MCallisler

pattern

in primary

pound, such as 2-mercaptocthanol, is added to the buffer the macroglobulins are depolymerized and an abnormal protein zone of penetrance can then be seen [46]. In all eighteen cases in our series in which gel electrophoresis was performed, it was positive for MGW. Thus the combination of a compact homogeneous globulin, noted on paper electrophoresis of serum and taking a rich PAS-stain, and failure to penetrate a gel is a reliable indication of significant macroglobulinemia. Serum Viscosity. Increased serum viscosity, which can be correlated with the amount of macroglobulins present [23,75,76], has led Shearn and co-workers [75] and Fahey [23] to‘ advocate the use of a serum viscometer as an additional screening device for the diagnosis of the dysproteinemias. The serum viscosity of patients with MGW has been found to average five times that of normal serum and three times that of serum from myeloma patients [23]. Ultracentrifugation. The ultimate diagnosis of MGW depends upon analytic ultracentrifuge determination of the sedimentation constant and demonstration of the characteristic “self-sharpening” macroglobulin peak (Fig. 9). DeLalla [77] studied the serum of 143 healthy men by means of the ultracentrifuge and found that the macroglobulin 19s content accounted for 2.5 f 1 per cent of the total protein (about 300 mg. per

et al.

100 ml. of serum). The S values in MGW differ from patient to patient, with a scattering of results that has led to disagreement concerning the sedimentation properties of the MGW protein. Kunkel 1781 observed the serum of four patients with MGW and found that 71 to 81 per cent of the abnormal macroglobulins occurred in the 19s range and 12 to 21 per cent occurred in the 27 to 31s range. Smaller quantities of other components are also found. The mean sedimentation constant (Svedberg units) was 19.6s in eighty cases in which ultracentrifugation was performed, as reported in the recent literature. The abnormal macroglobulin accounted for an average of 36 per cent of the total protein and for 62 per cent in one case. In all but one (Case 18) of our thirty-one cases the diagnosis of MGW was confirmed by analytic ultracentrifugation, and all these serums demonstrated the “self-sharpening” peak characteristic of MGW. Ultracentrifugation studies in two of seven patients with MGW and pleural effusion revealed that the characteristic macroglobulin was present in the pleural fluid as well as in the serum [IO]. Adner and colleagues [55] noted a macroglobulin in the cerebrospinal fluid of a patient with myeloma and an increase in serum macroglobulin. The cerebrospinal fluid of a comatose patient with cryoglobulinemia and macroglobulinemia was found to contain high concentrations of the abnormal globulins [79]. Immunoelectrophoresis. Immunoelectrophoresis may be used to detect the IgM globulin of MGW [80]. Since the macroglobulin of Waldenstrijm is primarily related to the IgM fraction, immunoelectrophoresis has been used as a substitute for ultracentrifugation in the diagnosis of MGW [80]. In multiple myeloma there is a decrease in the normal immunologic constituents, but this is presumed not to occur in MGW [80]. Since a “monoclonal” type low molecular weight has been noted to react immunoprotein logically as IgM globulin, the results of immunoelectrophoresis alone cannot be regarded as diagnostic [87]. Habich and Hassig [82,83] deAntiserums. veloped a specific immune antiserum against the macroglobulin of Waldenstrom. The serum of twenty-one patients reported by Kappeler and associates [8] all showed positive reactions with a specific MGW antiserum which was prepared according to their methods. Since the macroglobulin protein develops well defined precipitation lines against rabbit IgM antiserum whereas AMERlCAN

JOURNAL

OF

MEDICINE

Primary

Macroglobulinemia-_c(:nlLister

et al.

407

none develops when this antiserum is added to 7S gamma globulin fractions [84], Walton and co-workers [85] have suggested the use of a specific anti-IgM globulin antiserum to screen MGW from other forms of hyperglobulinemia. Roulet and associates [X6] found no false positive precipitin reactions in twenty-four cases of MGW in which he used rabbit antihuman IgM globulin. Although immunoelectroImmunoglohulins. phoresis has revealed functional resemblances between 7s globulin and 19s globulin with immunologic crossover [6X], the relationship between normal IgM (19s) globulin and the pathologic macroglobulin of Waldenstriirn renlains uncertain. One opinion is that the macroglobulin of WaldenstrGm represents a quantitative increase of a protein that is present in normal serum in minute quantities [X7]. Evidence for this is the fact that rabbit antibody to the macroglobulin of WaldenstrGm combined in toto with the normal macroglobulin fraction of normal serum [X8]. Korngold and others [X9,90], on the other hand, found specific antigenic materials in the macroglobulin of WaldenstrGm that are absent from normal serum. In addition, although abnormal macroglobulins customarily have the same high carbohydrate content and are made of the same hexose and hexosamine components as are normal IgM globulins, they are also said

macroglobulin, suggesting that two clones of malignant cells produced either type I or type II immunoproteins, but not both. Rosen [95] has reviewed extensively the various normal and pathologic human macroglobulins. A number of IgM (1%) antibodies are found in normal human serum. These include the constituents of the rheumatoid factor, the heterophil antibody, the Wassermann antibody, the 0 antibodies of gram-negative bacteria, the anti-A and anti-B isohemagglutinins, cold agglutinins, insulin antibodies and thyroid autoantibodies [95,96]. Properdin is also a normally occurring high molecular weight protein [97]. Extreme increase of certain antibodies of 1% sedimentation constants, such as that of the rheumatoid factor, can produce a serum picture somewhat suggestive of MGW [7X]. Conversely, Kritzman and co-workers [9X] observed that the macroglobulins of three patients with MGW had rheumatoid factor-like properties. One of our patients (Case 19) also had such a positive rheumatoid factor. Mouse Lymphocyte-Stimulating Factor. ,4 mouse lymphocyte-stimulating factor, not present in myeloma, has been observed in the serum of patients with MGW as well as in the serum of patients with chronic lymphatic leukemia, lymphosarcoma and myelofibrosis [6,2X]. Size of Molecule. The shortest diameter of the macroglobulin paraprotein molecule is 140 to

to be deficient in some antigenic groupings that are present in normal proteins [78,85,X9-!12]. Although all pathologic macroglobulins have general group determinants, the antigenic structure seems to be specific for each individual patient [92,93]. In further support of this, Mackay and associates [28] found that anaphylaxis occurred when the macroglobulin of Waldenstriim was given as an injection to a rabbit previously specifically sensitized to it, but challenge with the macroglobulin of Waldenstrijm from another patient elicited no response. Still, it does not appear to be possible, with present technics, to isolate normal individual immunoglobulins in significant or sufficient quantity to permit their characterization as individual and specific proteins, and thus resolve this controversy. Fahey and Solomon [94] were able to divide the serum of ten patients with macroglobulinemia into two specific groups according to antigenic determinants. Five of these patients also had Bence Jones protein, all of which were of the same antigenic type as the associated serum

220 Angstrijm (A) units, compared to 30 to 70 A for normal 7s protein and 110 to 200 A for myeloma protein [99]. Chromomatographic Behavior, Amino Acid Composition and Protein Synthesis. The macroglobulin of Waldenstram has a chromatographic behavior distinct from that of myeloma proteins with identical paper electrophoretic mobility [ 1001. The amino acid composition of the macroglobulin of WaldenstrGm also differs from that of normal gamma globulin [ 107,702], and Putnam [ 7031 has suggested that the protein abnormality may be analogous to that of the abnormal hemoglobins. Studies [704] of 1311-labeled protein have indicated an increased rate of synthesis of the abnormal paraprotein. In six patients Solomon and associates [ 70.51 noted a decrease in the synthetic rates of normal gamma globulin also. Special Features of MG W Protein. The addition of a sulfhydryl compound, such as mercaptoethanol, cystamine (beta-mercaptoethylamine) or penicillamine, will dissociate the macroglobu-

VOL.

43,

SEPTEMBER

1967

408

Primary

~~acroglobulinemia-.~ll.~ff~/istpr

lin into molecules the size of normal 7s gamma globulin [20,88,706]. Macroglobulins thus are polymers of gamma globulin units which are held together by disulfide bonds. Although the monomers obtained following dissociation were 7s globulins, they had different antigenic determinants from those of normal 7s globulin [ 707,708]. Following reaggregation of the polymers, after dialyzing out the excess reagent-sulfhydryl groups, the antigenic determinants were again found to be like those of the original macroglobulin [ /08]. Of interest is the observation that the concentration of sulfhydryl groups was normal in the serum of four patients with MGW studied by Bloch and associates [ 7091, and of three patients studied by Lorber and coworkers [I 701. The blood of some patients with MGW has been noted to be more viscous after the addition of heparin [ 7771. Although the reaggregated polymer and the original pure MGW protein had heparin precipitability, the depolymerized lllonomer did not. A secondary increase in macroglobulins has been noted in a number of diseases. These include (1) neoplastic diseases such as multiple myeloma, primary amyloidosis, iymphoma, carcinoma, sarcoma and leukemia; (2) the various “collagen” disorders such as lupus erythematosus, rheumatoid arthritis and SjGgren’s syndrome; (3) infections such as hepatitis and syphilis; and (4) other chronic diseases that disturb protein synthesis such as cirrhosis and nephrosis [68,95]. In secondary macroglobulinemia the macroglobulins rarely account for more than 15 per cent of the serum total protein [4] and usually have a S-20 value of less than 16s. Fessel [67], however, has reported three cases of chronic leukemia, three of lymphoma, one of chronic renal disease and one of metastatic carcinoma in all of which the serum macroglobulins accounted for more than 30 per cent of the total protein. In MGW, with rare exceptions, macroglobulins make up 20 per cent or more of the total protein on ultracentrifugation. Perhaps with earlier detection more exceptions will be noted. Fluorescent antibody studies have localized the abnormal macroglobulins to both the nucleus and the cytoplasm of plasmoblasts, plasma cells and lymphocytoid plasma cells from the bone Inarrow of patients with MGW [ 7 12,713], and to the cytoplasm of the lymphocytoid plasma cells seen in spleen and lymph node aspirates [98].

et al.

Tisstlc crllture studies of lymph nodes of three patients with MGW gave indirect evidence that the cells synthesized 19s macroglobulin [ 1 IJ]. \t-hen imprints of lymph nodes and smears of the huffy coat of bone marrow were stained with a fluorescein-conjugated antiserum to the macroglobulin of Waldenstrtim, large and mediumsized lymphocytes and lymphoblasts rather than mature lymphocytes were found to be fluorescein-positive [ 7741. Brittin and colleagues [ 7751 have presented evidence that the nuclear inclusion bodies seen in plasma cells with the electron microscope may well represent nuclear elaboration of an abnormal protein. Three cases have been reported in which an abnormally long chromosome was identified [15,1 ls,i17]. Possibly there may be an identity between the population of cells with an abnormal chromosome complement and the population of cells that produce excessive quantities of high molecular weight protein [ 7181. DIAGNOSIS

Serum protein electrophoresis on paper is a simple screening test. Abnormal “spots” may then be elucidated further with PAS-staining for hexose content, acrylamide gel electrophoresis as a macromolecule filter and qualitative immunologic testing. If such tests are indicative of MGW, analytic ultracentrifugation of serum proteins is then performed to confirm the diagnosis. Since the development of these special laboratory procedures, the diagnosis of MGW, once suspected, can be made with relative ease. Multiple myeloma with or without clinical symptoms is most frequently confused with MGW, as indeed it should be, for myeloma produces the same gross protein picture far more commonly than does MGW. Bone marrow examination will usually confirm the presence of myeloma, whereas attempts to demonstrate 19s macroglobulins will almost always be negative in myeloma. In rare instances, a macroglobulin may be found in the serum of a patient with myeloma and may then present some diagnostic difficulties. In the one instance we have observed, the macroglobulin was atypical. Purpura hypergammaglobulinemia of WaldenstrBm is distinguished by the characteristic dependent purpura, the broad-based tented elevation representing gamma globulin on serum protein electrophoresis on paper, the lack of AMERICAN

JOURNAL

OF

MEDICINE

Primary

Macroglobulinemia-McCallister

anetllia, the benign course. the frequent association of SjGgren’s syndrome and the absence of macroglobulinemia. The bone marrow and clinical findings of MGW may be reminiscent of lymphosarcoma, and lymph node biopsy is almost invariably confusing. More commonly in lymphosarcoma there is a hypogammaglobulinemla, and when there is an increase in serum globltlins a homogeneous peak is distinctly unusual [77.9]. In our experience, encompassing more than 6,000 serum electrophoretic patterns, an occasional lymphoma was found to be associated with a hyperglobulinemia, but almost never with the homogeneity seen in MGW. In a survey of these 6,051 serum electrophoretic patterns by Kyle and colleagues [ 720] only fifteen were grossly indistinguishable from myeloma. Of these fifteen, seven were in cases of MGW, one was in a probable case of MGW, two were in cases of systematized amyloidosis and one was in a case of lymphoma. Only three of the thirty-three urinary electrophoretic patterns from nonmyeloma patients had a tall, sharp, globulin component and ail were in cases of MGW. Differentiation from systematized amyloidosis rarely offers difficulty; however, since amyloidosis may occur in conjunction with MGW, this possibility must be borne in mind [27,63,66,72?]. The blood and particularly the bone marrow may also suggest chronic lymphatic leukemia. However, an increase in serum macroglobulins in the latter is seldom if ever seen in lymphocytic leukemia. Fairley and Scott [ 7221 noted an increase of macroglobulins in the electrophoretic pattern of only one of 110 patients regarded as having chronic lymphatic leukemia. On the other hand, 50 per cent of patients with chronic lymphatic leukemia have hypogammaglobulinemia [ 7 791. MGW might also be considered in evaluating a patient with pancytopenia and greatly increased rouleaux formation, since pancytopenia occasionally may be a part of the presenting clinical picture in MGW. Finally, the large group of diseases characterized by signal increases in the serum globulins will also be brought to mind. These include the “collagen” diseases, kala-azar, lymphogranuloma venereum, “lupoid” hepatitis, Laennec’s cirrhosis, nephrosis, sarcoidosis and certain chronic infections. Almost always these diseases are associated with a broader based and less VOL.

43.

SEPTEMBER

1967

marked MGW.

409

Pt al.

hyperglobulinemia

than

that

seen

in

COMMENTS

MGW is not a common disease, but in the city of Malmo, Sweden, with a population of 220,000, WaldenstrGm found seventy cases in a ten year period [723]. In Heremans and associates’ [68] study of 296 abnormal serum proteins, which were found to have an obvious abnormality on paper electrophoresis, 132 of the 296 patients had multiple myeloma and twenty-two MGW. At the Mayo Clinic in the years 1956 and 1957, 165 patients were seen with multiple myeloma. During that period MGW was diagnosed in only seven patients [ 7201. In 1961 at the Mayo Clinic, five patients were found to have MGW compared to seventy-five with myeloma. There has been some reluctance to recognize MGW as a definite entity, and Waldenstrijm [I] himself has been critical in accepting the syndrome. Establishment of MGW as a specific disease has been complicated by variability in the clinical course, by disparity in the reports of histologic findings and by differences in the physicochemical properties of the macroglobulin. However, the clinical diagnosis alone was correct and usually obvious in thirty-four of thirty-nine cases observed by Heremans and associates [68]. It would seem that the plasmacytoid-lymphocytic cells and their occasional transition to more malignant forms, the unusually high molecular weight of the protein and its immunologic characteristics, the lack of osteolytic lesions, the recently noted chromosomal abnormalities and the clinical picture justify acceptance of MGW as a distinct neoplastic entity, separate from chronic lymphatic leukemia, lymphosarcoma and myeloma. The original controversy whether MGW is but a form of multiple myeloma seems to have been settled. Macroglobulins in multiple myeloma are rare and, when present, the molecular size is usually less than 15s and the macroglobulins make up only a minor portion of the total protein [706]. Heremans and colleagues have reported two cases of clinical myeloma with a significant increase of serum macroglobulin [68], but this is exceptional in their experience. Adner and co-workers 1551 found reports of only twelve cases of coexisting multiple myeloma and macroglobulinemia in the literature and described a sixty-eight year old woman with skeletal lesions and a myelomatous bone marrow.

410

Primary

Macroglobulinemia-McCallister

et al.

TABLE v PATIENTSWITH ATYPICALM‘4CRoGL.oBIJLINEMI.A

Case No.

Primary Diagnosis

Cholesterol (gm./lOO ml.)

32 33 34 35

Rheumatoid arthritis Multiple myeloma Multiple myeloma SjGgren’s syndrome

122 500

NOTE:

;sk

Sedimentation Constant (S,)

Gel Penetration

Hexose content

19

ND ND f ND

ND 23 5.2 4.1

17.8 14

(%)

Globulin (gm./lOO ml.)

Ocular Fundi

3.46 3.8 2.26 1.61

+ ND ND ND

ND = not determined.

They further noted that 47 per cent of the total protein was 19s macroglobulin. None of these patients had the typical clinical picture of MGW. Kappeler and associates [8] have reported on patients with MGW who had rare osteolytic lesions evident in roentgenograms of the skull, mandible, femur, vertebrae and humerus, and have observed at autopsy rare osseous changes of myeloma that were too insignificant to have been seen roentgenographically. It is, of course, possible that transitional forms between myeloma and MGW do exist. We have observed two patients (Table v) with an increase of serum macroglobulins associated with multiple myeloma (during this period we observed 1,087 patients with multiple myeloma). Mackay and colleagues [28] have expressed the opinion that MGW may be a phenomenon which develops in the course of lymphosarcoma, for it resembles lymphosarcoma in its clinical features, in invasion of the bone marrow by lymphocytes and in the presence of a mouse lymphocyte-stimulating factor. They further postulated that malignant lymphoma tissue may acquire the capacity to synthesize paraproteins after a somatic mutation, and Abrams and colleagues [ 7.241 suggested that macroglobulins may be synthesized by lymphosarcoma tissue in vitro. MGW does indeed resemble lymphosarcoma, as well as myeloma, and is no doubt closely related to them. Probably many early cases of MGW appeared in the literature as nothing more than lymphosarcoma before advances in diagnosis allowed a further distinction. Histologically the lesion is usually regarded as a lymphosarcoma [7]. Prasad and Bloch [ 7251 described a sixty-three year old woman with clinical MGW of three years’ duration who was found to have a “lymphosarcoma” of the brain. Dawborn [ 126] excised a bleeding lesion from the small bowel in a patient with longstanding

MGW; the lesion was regarded histologically as lymphosarcoma. He pointed out that one must consider excision of specific bleeding sites in MGW despite the frequent association of a bleeding diathesis. One of our patients (Case 31) had a “lymphosarcoma” removed from the stomach five years before the clinical and laboratory diagnosis of MGW was made. A second patient (Case 19) also had a neoplasm in the fundus of the stomach, which at gastroscopy was thought to be a “lymphosarcoma.” Although possibly a coincidence, since MGW generally occurs in the cancer age group, in up to 10 per cent of the reported cases it has been associated with carcinoma [67]. Kappeler and colleagues [8] reported three cases of MGW with various forms of cancer and reviewed the data in eighteen recorded cases. Imhof and colleagues [3] also noticed that nine of the 107 cases of MGW that he reviewed were associated with malignancy. In contrast, none of our cases were associated with other malignant neoplasms. Three cases of systematized amyloidosis with MGW have been reported, with macroglobulins accounting for 10.9 per cent of the total protein in one [27] and 43 per cent in another [67]; the amount was not reported in the third case [ 1271. In a critical review of these cases, it was most difficult to be sure that they did not represent primary amyloidosis with a secondary increase in macroglobulins. Sirridge [ 7271 found sixteen cases in which cryoglobulinemia occurred in association with MGW and reported one case in which rheumatoid arthritis also was present. A diffuse polymyositis was noted at autopsy in a patient with unequivocal clinical and laboratory evidence for MGW [ 771. A few cases of note in the literature have been described in association with Sjogren’s syndrome [8] but these seem most likely to represent secondary rather than primary macroglobulinemia. Other, less common conditions

Primary

Macroglobulinemia-McCallister

associated with MGW have been hemolytic anemia [26] and Mikulicz’s syndrome [27]. In addition to our 31 patients with “typical” MGW, four patients had large amounts of macroglobulins in their serum but did not have the characteristic clinical or biochemical characteristics of MGW (Table v). One patient had Sjogren’s syndrome, two had multiple myeloma with macroglobulinemia and one had severe rheumatoid arthritis. None of the four demonstrated the “self-sharpening” peak of MGW on ultracentrifugation of the serum. The patient with Sjogren’s syndrome received a nine month course of chlorambucil (Leukeran@) therapy with little change in symptoms, although the value for gamma globulin decreased from 1.36 to 0.98 gm. per cent during treatment. Primary macroglobulinemia was considered in each of these patients, but the laboratory data and the clinical findings were incompatible. Three theories of the pathogenesis of macroglobulinemia of Waldenstrom have been offered : (1) production of an abnormal protein by a neoplastic cell; (2) neoplastic proliferation of a cell that ordinarily produces the protein in very small amounts, that is, in response to some unknown antigenic stimulus there is an increase in high molecular weight antibodies [89]; and (3) proliferation of a cell, following somatic mutation, with subsequent production of the abnormal protein. Present evidence seems to favor the first theory, but perhaps the separation of the first and third formulations is more apparent than real. Dutcher and Fahey [9] have expressed the view that MGW is a distinct neoplastic proliferative disease of reticuloendothelial origin. There seems to be a family relationship between the “plasmocytic diseases,” namely, MGW, myeloma, lymphomatous myeloma,, primary systemic amyloidosis and possibly lichen myxWaldenstrom has explained the edematosus. overlapping and rare coexistence of chronic myelogenous leukemia, multiple myeloma, lymphosarcoma, reticulum cell sarcoma and chronic lymphatic leukemia as all derivatives from a common cell stem [72,?]. Dameshek [728] has postulated that the vast number of related varieties of the lymphoproliferative disorders may be due to malignant aberrations of the immunecompetent cells at various maturation levels. Although proliferations of. the plasma cell or lymphoreticular series, such as those occurring in multiple myeloma or MGW, are usually associated with an excessive formation of antibody “01..

43.

SEPTEMBER

1967

et al.

411

globulins, abnormalities of the lymphocytic series are rarely so associated [ 7281. Whether the myeloma and MGW proteins are truly qualitatively unique or are just increases of normal protein has yet to be completely established, but the preponderance of evidence favors the former. Osserman and Lawlor [8O] noted the contrast between the diffuse hypergammaglobulinemia of chronic infection, collagen diseases and sarcoidosis (thought to be due to a polystimulation of many immunoglobulin-forming cells [ 7291, and the sharp homogeneous electrophoretic peak in the serum of patients with MGW and myeloma. They expressed the view that MGW and multiple myeloma, with their accompanying protein abnormalities, represent malignant transformation of a single clone of cells, capable of synthesizing only one specific immunoglobulin [80]. Ritzmann and colleagues [ 730,737] also have expressed the opinion that MGW is an example of primary or monoclonal malignant proliferation, with the formation of a specific abnormal immunoglobulin. Evidence that MGW is a neoplastic disease is also provided by some experimental work in animals. Fahey et al. [ 7.321 have described a plasma cell tumor in mice which, as it enlarges, produces proteins of 9S, 11 S and 13s sedimentation constants not present in normal mouse serum. Isotope studies showed that the abnormal proteins were formed in the tumor. In addition, Clausen and colleagues [ 73,?] have noted a 16s macroglobulin in mouse transplantation lines which makes up 27.5 per cent of the total protein. They observed pathologic changes that correspond to those of MGW in man. On the other hand, Cohen and associates [ 7341 studied the liver of a patient with MGW and homologous serum jaundice by means of immunofluorescent technics. They found macroglobulins to be distributed in location corresponding to those of 7S globulins in similar cases of hepatitis without macroglobulinemia. They interpreted this evidence to indicate that the macroglobulin-producing cells in the liver were reactive, immunologically competent cells rather than neoplastic in nature [734]. Mackay and colleagues [28] suggested that roentgen therapy might produce a somatic mutation which could result in a genetic difference in the cells that synthetize protein. However, a history of previous radiation has been infrequent in MGW, and this factor seems to be unrelated to the pathogenesis of the disease.

Primary

412

Macroglobulinemia-McCalliste~

et al.

TABLE VI ASYMPTOMATIC PATIENTS

HemoCase globin No. (gm. %)

Years Since Diagnosis

Erythrocyte Sedimentation Rate (mm./hr.)

Bone Marrow Normal

1

13.0

3

106

2

11.0

3

5

3

12.0

3

87

Slight increase of plasma cells, few cytoplasm-poor lymphocytes Small increase of plasma cells

4

13.4

9

106

Slight increase of plasma cells

5

13.2

2

85

Physical Signs

Globulin (gm./lOO ml.)

How Disease was Discovered

.

2.04

Erythrocyte sedimentation rate high Mild anemia

Ocular veins distended Mouth ulcers

.

NATURAL COURSE OF THE DISEASE

Asymptomatic Type. In five of our cases the disease is, at the present writing, seemingly limited to a biochemical abnormality (Cases 1, 2, 3, 4 and 5, Tables VI and VII). Similar cases have been observed by others [8,45,735], and eight were noted in our recent review of 196 reported cases. We suspect that if these patients are observed long enough the clinical picture will eventually appear, as it did in one of our cases ten years after the chemical abnormality was first noted. Three of our patients (Cases 1, 2 and 3) have been observed for three years, one (Case 4) for nine years and one (Case 5) for two years since the diagnosis was made, and in none have clinical symptoms developed. Although the erythrocyte sedimentation rate decreased from 106 to 70 in one patient over a nine year period, and from 87 to 40 over a three year period in another, the gamma globulin levels have remained unchanged. CASE 4. A fifty-six year old man who came to the Mayo Clinic in December 1956 for a general physical examination had no specific complaints. An increased erythrocyte sedimentation rate (108 mm. in one hour [Westergren]) led to further investigation. In 1947 his sedimentation rate had been 34 mm. The physical findings were not remarkable. Urinalysis revealed grade 1 proteinuria and a negative

2.06 2.28 2.28

Typical

The neoplastic nature of the process is further emphasized by the occasional transformation to a reticulum cell or undifferentiated sarcoma as in our Cases 10 and 11 and in the case of Wanebo and Clarkson [CO].

4.59

Erythrocyte sedimentation rate high Erythrocyte sedimentation rate high Gout; hyperglobulinemia

Bence Jones reaction. The value for hemoglobin was 13.9 gm. per 100 ml. and the leukocyte count was 5,300 per cu. mm. with a differential count of 69 per cent neutrophils, 24 per cent lymphocytes, 6 per cent monocytes and 1 per cent eosinophils. Blood smears showed moderate (grade 2) rouleaux formation. The serum proteins totaled 7.9 gm. per 100 ml., of which 3.9 gm. was albumin and 2.3 gm. was gamma globulin. The gamma globulin appeared on paper electrophoresis as a narrow band. Sternal aspiration yielded marrow smears showing a slight increase in myelopoiesis and some increase in plasma cells. The patient has returned periodically and has continued to be asymptomatic. The erythrocyte sedimentation rate was 88 mm. in 1957, 89 in 1958, 94 in 1959 and 57 in 1960. The serum protein values have remained essentially unchanged. The abnormal protein had a hexose content of 4.8 per cent, a mobility in the gamma region and no migration in acrylamide gel. Analytic ultracentrifugation of the serum revealed that a significant fraction of the serum proteins consisted of macroglobulins with a sedimentation constant of 16.5S, and with a migration characteristic of primary macroglobulinemia.* Sternal aspiration in 1960 showed an increase in cytoplasmpoor atypical lymphocytes. No treatment has been prescribed. On reevaluation of the patient in December 1962 there was no change in either the clinical or the laboratory findings. When last seen in February 1965, more than nine years after the first objective evidence of a dysproteinemia was discovered, he indicated that he had remained symptom-free. The value for serum total protein in 1964 was 8.2 gm. per cent of which 2.4 gm. per cent was gamma globulin. * Ultracentrifngation was performed in the Department of Biochemistry, University of Minnesota, through the courtesy of Dr. D. R. Briggs. AMERICAN

,JOuRNAL

OF

MEDICINE

Primary

Macroglobulinemia-McCallister TABLE

THIRTY-ONE

Duration

Symptoms to Now or Death

Diagnosis to Now or Death

9t

8$

5 3 6 6

MACROGLOBULINEMIA*

Y

Treatment Years of Chlorambucil

.4gent

Before Treatment

After Treatment (mar )*

Serum Globulin (gm./lOO ml.) ~ Brfore After TreatTreatmen, menl

2.04 4.95 2.06 2.87 2.34 2.28

13.0 11.0 12.0 13.9 13.2

3.5

6 3.5 7

VII

PRIMARY

Hemoglobin (em./100 ml.)

3.2 3 4 9

6 7 8

WITH

of Disease (y=. 1

Case No.

PATIENTS

.

First Four Symptom&

Pa&nts

11.4 8.0 7.0 11.6 9.8

:::

Steroids, BT, HNt HNr, steroids HN,, steroids BT

413

et al.

(1943) (1958)

..

Comment

High ESR Mild anemia Increased ESR High ESR Gout;

5.26 5.51 8.23 5.0 4.68

.

increased

Dead, Dead Dead, Dead

globulin

blurred

vision

massive

hepatosplenomegaly

(chief complaint)

1961 GIOUP T,catcd With Chlorambucil 10

5

4

BT,

chlorambucil

11 12

7 7.5

5.5 6.5

Chlorambucil BT, HNz, chlorambucil

13

4.3

5.5

Urethane,

14

16

2.5

Steroids,

15 16

2.5 3.3 13

0.5 1.3 5

BT BT,

17t

6.0

13.2

2.77

1.50

2.6 10.6 2 On, 9.3 3 off 1.8”“, 8.5 0.4 off, 3.3 on

13.0 12.8

5.18 4.59

1.80 2.23

Dead, on chlorambucil 1 mo. after off Dead, ocular symptoms Doing well

12.3

5.12

1.12

Doing

2.55

chlorambucil

x-ray t” spleen

..’ steroids, HNr,

nP

7.411

2.05

8.8 5.8 5.0

4.98 7.50 7.40

18 19

3.2 1

0.2 0.75

No chlorambucil No chlorambucil

7.4 8.5

6.26 6.44

20

2

0.6

No chlorambucil

8.8

2.76

2’ll 22 23~ 247

6.5 7.5 4.5 1.6

5.5 7 4 4

Steroids, chlorambucil HNz, chlorambucil BT, cblorambucil# Chlorambucil

25 26 27**

3.5 4.5 6.0

2.5 2.7 3.5

Chlorambucil Chlorambucil Chlorambucil

28 29

1.5 4.0

1.0 3.0

Cblorambucil, steroids BT, chlorambucil, steroids

5 4

Chlorambucil Chlorambucil

3Oli 3’lI

8 10

2.5 2.8 1 1 on, ‘/a off, 1 on 1.2 1.5 3

12.7 10.0 9.2 9.8

. 11.4 10.1 10.4

5.22 3.47 6.10 4.06

9.0 8.0 9.6

12.0 12.3 10.8lt

4.44 3.3 4.23

12.4 11.9

2.41 2.38

0.3 6.4 l.Oon, 6.2 l.O”li, 0.20 on 0.622 11.8 0.1gg 9.6

*Abbreviations: max. = maximal; BT = blood transfusion; HNz = nitrogen sedimentation rate. t Long survivor. $ Biochemical macroglobulinemia for ten years prior t” onset of sympt”ms. Q Died five months after stopping of chlorambucil therapy. 11Hemolytic anemia. T Treated elsewhere. # Treated by home physician; advised t” increase dosage of chlorambucil. ** Partial treatment elsewhere. ti Advised t” stop chlorambucil therapy temporarily owing to cytopenia. $$ Chlorambucil therapy stopped elsewhere owing to “low platelets.” $8 Chlorambucil therapy stopped by home physician owing t” “chills, fever.” VOL.

43.

SEPTEMBER

1967

2.12 3.8

mustard;

aP

well, pulmonary

21/z yr., severe

died

at onset

hypertension

Doing well, hemolytic anemia, Coombs’ test positive Dead Dead, cryoglobulins Dead, peripheral neuropathy, diagnosed Hodgkin’s in 1947 Dead, susceptible to infection Malignant IILBSE, gastric funduslymphoma? Dead at age 92; weak, fatigue 2 yr.

1.9

1.49 2.2 2.09 2.78 1.26

.

Severe pruritus Doing well Doing well Doing well

Doing well Doing well Dead, severe bleeding after dental extraction, died 4 m”. after off chlorambucil, oral infection Doing well, hemolytic anemia Doing well, Coombs’ test positive, hemolytic anemia Severe peripheral neuropathy? 1956: lymphosarcoma (stomach), Mikulicz’s?

= radioactive

phosphorus;

ESR

=

erythrocyte

414

Primary

Macroglobulinemia-McCallister

Delayed-Progressive Type. A few cases illustrate the fact that patients with MGW may have a long survival (Table VII). One of our patients (Case 17)* lived for thirteen years from onset of symptoms. Imhof and colleagues [3] noted a similar patient who survived sixteen years after diagnosis. A second patient in our series (Case 14) was found to have monocytosis and mild anemia in 1948 during examination at the Mayo Clinic and was said to have been anemic for ten years previously. However, the erythrocyte sedimentation rate was 37 mm. in the first hour and there was no rouleaux formation. She required no treatment until 1958, when hemolysis developed. Since 1958 she has had roentgen and corticosteroid therapy elsewhere, and is still alive. Another of our patients (Case 9) lived for ten years without symptoms and was at first suspected of having incipient multiple myeloma. No treatment was required until eight years before death when severe anemia became manifest and he required repeated blood transfusions. In all, the patient lived for eighteen years without specific treatment, but death finally resulted from macroglobulinemia. CASE 9. A seventy-six year old man t was examined in December 1955 because of swelling of his legs of two months’ duration. He had been examined here on four other occasions since his initial examination in 1943 for hoarseness. At that time idiopathic paralysis of the left vocal cord was discovered. Urinalysis revealed grade 3 “albuminuria” with Bence Jones proteinuria. The erythrocyte sedimentation rate was 35 mm. in the first hour and the differential leukocyte count revealed 17 per cent monocytes. Multiple myeloma was suspected, but a study of the sternal bone marrow did not confirm this. Marrow smears revealed an increase in lymphocytes and plasma cells, but “typical” myeloma cells were not seen. When examined six, nine and ten years later (in 1949, 1952 and 1953), Bence Jones proteinuria and “albuminuria” were persistently present and the marrow pattern remained unchanged. There were no visual complaints, but ophthalmologic examination in 1952 revealed engorgement of the retinal veins of both eyes. Diffuse osteoporosis was apparent in roentgenograms of the skull and spinal column, but focal osseous lesions were absent. The value for serum globulins was 6.6 gm. per cent. Cryoglobulins were absent. In 1952 the patient had a massive gastrointestinal for which ten blood transfusions of hemorrhage, * Also previously reported by Hines [63]. t Previously described in part by Hanlon, Kearns 1741 in 1958.

Bayrd and

et al.

500 ml. each were given. A second episode of hematemesis and melena occurred in 1955. Examination in 1955 revealed marked pitting edema of the lower extremities. No hepatospleno-

megaly or significant lymphadenopathy was detected. Urinalysis revealed grade 3 “albuminuria” and Bence Jones proteinuria. The value for blood urea was 42 mg. per cent. The hemoglobin measured 9.2 gm. per cent, the erythrocyte count was 2,650,OOO per cu. mm. and leukocytes numbered 5,300 per cu. mm. A differential blood count revealed 35.5 per cent lymphocytes, 15 per cent monocytes, 47.5 per cent neutrophils and 2 per cent eosinophils. Blood smears showed grade 3 rouleaux formation. The platelet count was 173,000 per cu. mm. The erythrocyte sedimentation rate was 136 mm. in the first hour. The value for serum total protein was 8.9 gm. per cent with 2.8 gm. of albumin and 3.9 gm. of gamma globulin. Bone marrow examination again showed an increased number of lymphocytes, plasma cells and occasional immature forms of plasma cells. The Sia test gave a negative result. Ultracentrifugation revealed that 47 per cent of the serum proteins consisted of macroglobulins (18s = 38.0 per cent, 25s = 6.0 per cent and 32s = 1.5 per cent).* The patient returned in 1958 with no symptoms but gave a history of minor episodes of epistaxis and some dyspnea on exertion. There was again nothing remarkable in the physical findings except for increased engorgement of the retinal veins. The hemoglobin value was 9.8 gm. per cent, the erythrocyte sedimentation rate 121 mm. and the serum gamma globulin value 4.68 gm. A gastric polyp was excised without complications. The patient was seen elsewhere in 1959 and was given blood transfusions for anemia (hemoglobin 6 gm. per cent). His family wrote that he died in September 1961, eighteen years after objective laboratory evidence of his macroglobulinemia was first obtained.

Progressive Type. In contrast to the five asymptomatic patients and the three with long surthe remaining twenty-three patients vival, (Table VII) had significant symptoms and complications early in the known course of their disease. Twelve of these have died, the average survival time being 5.3 years from the onset of symptoms and 3.2 years from the time of diagnosis. When death occurs, sepsis, pneumonia, exsanguination, cachexia, congestive heart failure and coma are common terminal events. The fifteen patients who have had significant symptoms and are still alive have lived an average of * This investigation was performed in the Department of Physicochemistry, University of Wisconsin, through the courtesy of Dr. H. F. Deutsch. AMERICAN

JOURNA’.

OF

MEDICINE

Primary

Macroglobulinemia-McCallister

6.1 years from the onset of symptoms and 3.9 years from the time of diagnosis. All but two of these patients have been treated with chlorambucil. Pertinent data on special protein studies in our twenty-six symptomatic patients with MGW are included in Table IV. European observers have divided MGW into benign and malignant forms [8]. The average duration from onset of symptoms to death has been said to be 2.5 years in the malignant type and 5.5 years in the benign type [ 7 71. Heremans and colleagues [SS] have suggested that patients with MGW who have a low concentration of serum macroglobulin and a normal concentration of serum albumin have a better prognosis than others. In our series, four of five asymptomatic patients had serum gamma globulin fractions of less than 2.3 gm., whereas six of the more seriously ill patients had a gamma globulin level of 2.4 gm. or less (Case 10, 1.67; Case 14, 2.05; Case 19, 1.24; Case 28, 2.4; Case 29, 2.38 and Case 30, 2.12). All five asymptomatic patients had serum albumin fractions of more than 3.0 gm. per cent, but eight patients with more severe disease also had an albumin fraction of more than 3.0 gm. per cent. Two of eight had a long survival, five are alive and under treatment with chlorambucil and one with a low value for serum albumin died three years after diagnosis. Thus, although higher levels of serum albumin and lower levels of serum globulin do not guarantee a good prognosis, they make it more likely. It is also likely that such findings indicate that the patient was observed early in the course of his disease. The degree of anemia has also been said to have a bearing on prognosis [40]. Generally, it has been observed that anemia will develop if the disease is progressive, and not if it is benign. This has been true in our cases; three of the asymptomatic patients have had no anemia at all, whereas the other two have had only negligible anemia. Thus there appears to be little question that in at least some cases MGW may be benign or indolent for years, whereas in others it is progressive from the time the diagnosis is first made. For the latter, treatment is of value. TREATMENT

OF

MACROGLOBULINEMIA

(WALDENSTR~)

The treatment of macroglobulinemia (Waldenstrijm) has been unpredictable, inconsistent, and generally disappointing until relatively reVOL.

43,

SEPTEMBER

1967

et al.

415

cently [a]. Transitory, inconlplete remission and failure have resulted from the use of roentgen radiation, 32P corticosteroids, corticotropin, cytotoxic age& (urethane, nitrogen mustard, diamidine, triethylene melamine, chlorambucil) and splenectomy. Somewhat greater hope was raised by observation of the depolymerization effect on the macroglobulin of low molecular weight thiols (mercaptoethanol [ 7361, penicillamine [25,97,737]) and by the more consistent clinical benefits resulting from removal of large quantities of the abnormal protein by plasmapheresis (18,600 ml. in fifty-one days, 14,400 ml. in thirty days and 8,700 ml. in twenty-six days [47,738]). Despite the generally bleak results of treatment, an occasional better than expected remission was obtained. Thus a twenty-one month remission has been reported with the use of prednisone and nitrogen mustard [20], a year’s remission with cortisone [42,69], and biochemical improvement with splenectomy [78,7391. Recently Bouroncle and associates (7401 have reported improvement in the clinical and laboratory expressions of MGW in two patients treated with continuously administered cyclophosphamide and prednisone and in a third patient treated with cyclophosphamide (Cytoxan@) alone. Plasmapheresis affords predictably reproducible clinical benefits which result from reduction of the total circulating macroglobulin with consequent changes in plasma volume, viscosity and coating effects of the abnormal protein [47,738]. Plasmapheresis does not, of course, affect the underlying neoplastic disease. It must be repeated as often as weekly, since relapse can occur within days, and does pose some problem for a community without a well established blood bank that can perform the plasmapheresis. Five years ago one of us (E.D.B.) [73] reported our first experiences with the prolonged use of chlorambucil (over a period of two and a half years) in the treatment of these patients. Since then similar benefits have been reported [60,75,747-7431. ,4 review of the present cases provides a follow-up of the first four patients so treated, with observations now extending over more than seven years, and incorporates our subsequent personal experience with an additional four patients (Table VII). The usual starting daily dose ranged from 6 to 12 mg. of chlorambucil, and the maintenance dose from 2 to 8 mg. per day. In general, small doses are effective, given sufficient time. Ten milligrams a

Primary

416

Chlorambucll,

Macroglobulinemia-McCallister

et al.

mg.,‘day 60gmJday

Prednisone

0 7 6 k L$ B 9

5 4

:

:

t

1

FIG. 10. globulin,

Case 12. Correlation

of chlorambucil

therapy

day for three weeks produced appreciable cytopenia in one patient, and 3 mg. per day has been an excessive maintenance dose in others. CASE 12. Our first personally treated patient was given chlorambucil continually from July 1958 until March 1960, when she discontinued medication. Under treatment the hemoglobin increased from 7 to 11.8 gm. per 100 ml. in four months and later to 12.6 gm. Macrogammaglobulins decreased from 4.6 to 2.2 gm. per 100 ml. and the patient became

Chlorambucil

and gamma

symptomatically well. The remission was sustained throughout the nineteen to twenty months of treatment and for approximately two and a half years thereafter. When she returned in October 1963, sixty-two months after treatment was first started, relapse was complete; the hemoglobin value was 7.8 gm. per cent and gamma globulin 7 gm. per cent. All treatment over the next forty-six months was ineffective. The hemoglobin value remained at 7 to 8 gm. per cent and the gamma globulin value at 5.0 to 6.0 gm. per cent despite the varied use of chlor-

,mg./doy

2-56 -

FIG. 11.

with values for hemoglobin

Case 11. Correlation

c---‘6~-c-‘61-c--‘62--‘63-c’64-

of chlorambucil

therapy

with values for hemoglobin AMERICAN

and gamma

JOURNAL

OF

globulin. YEDIClNE

Primary

Macroglobulinemia-IMc(:allister

el al.

417

Chlorombucil,mg./doy Blood transfusions A4 WJkC 7.c1. 6.c1 ))))-

I-

P

6.0 5.0 4.0 I

7-49

I

7-50

1

10-59

I

9-60

,I

11-613

It

7

6

YiiiT

FIG. 12. Case 10. Correlation of chlorambucit therapy with values for gamma globulin. ambucil and corticosteroid therapy during the last eighteen months (Fig. 10). CASE 11. Our second patient was treated from August 1959 until March 1962, some thirty-one months, with sustained complete hematologic and clinical remission and substantial diminution in abnormal proteins. Treatment was then stopped. Nine months later indications of relapse were noted, and fourteen months later (May 1963) hematologic relapse was complete (incomplete protein). Treatment for the subsequent nineteen months did not induce a second remission, although some improvement was observed fourteen months after therapy was reinstated (July 1964). From that time, however, the course of the illness was progressive, and complicated by bleeding, severe anemia (4.8’ gm. per cent of hemoglobin), and infection. The patient finally died with malignant transformation of his disease in February 1965 (Fig. 11).

CASE 10. Our third patient was treated with chlorambucil from October 1959 to March 1962 (eighteen months), during which time the hemoglobin value increased from 4.5 to 13.2 gm. per cent and was sustained. Three months after discontinuation of medication the patient became anemic and two months later she was dead of malignant lymphosarcomatous transformation (Fig. 12). VOL.

43,

SEPTEMBER

1967

hemoglobin

and

Thus relapse occurred in all three patients in whom treatment was stopped. One of these patients is living, but still in relapse, at this writing, despite prolonged and continuing efforts to induce a second remission, and the other two are dead of their disease. It is conjectured that the death of the third patient was coincidental and not related to cessation of treatment. There are some interesting similarities between the terminal courses in our Cases 11 and 10 and that in a case reported by Wanebo and Clarkson [SO]. Their patient also had a complete biochemical, symptomatic and hematologic remission while receiving chlorambucil therapy. Nine months after chlorambucil treatment was discontinued relapse occurred which was not responsive to the reinstitution of chlorambucil therapy and the patient’s condition deteriorated rapidly. The findings on lymph node biopsy before death were reported to be compatible with reticulum cell sarcoma [60]. Of note is Argani and Kipkie’s [64] observation of abnormally differentiated protein-secreting reticulum cells in the bone marrow of two patients with MGW. These cells were in various stages of maturation and appeared to form a distinct cell series.

Primary

418

Macroglobulinemia-McCallistpr

et al.

Chlorembucil, mg./day Urethone,l.Sgm./doy I5.0 I 4.0 13.0 $a

3.0 -

L$ 3

2.0 -

*

F’ cn .sQ ,o 3F

12.0

11.0

T .95 ;2

-

.90 1.0 I

I

I

10.0 9.5 9.0 8.5 0.0 I

d I

I

3

10

-‘60-v’

I’

I

4

10

I

4

I

I

I

10

4

10

1

I

4

10

61~‘62~e-63---+264+

FIG. 13. Case 13. Correlation of chlorambucil hemoglobin and gamma globulin.

CASE 13. Our fourth patient had been treated for only six months at the time of the initial report. She has now been treated with chlorambucil virtually continually for five and a half years and remains on treatment. When she was first seen, her hemoglobin value was 8.5 gm. per cent; it is now 12.0 gm. per cent. The initial value for the gamma-migrating protein was 5.12 gm. per cent; it is now 0.95 gm. per cent. This patient was in congestive heart failure, from unknown causes, associated with apparent pulmonary hypertension and pleural effusion when first seen five and a half years ago. Since then, after conventional therapy for congestive heart failure and treatment for the macroglobulinemia, she has been working regularly and has remained in cardiac compensation (Fig. 13). In the four years since these cases were reported, we have personally treated six additional patients (Cases 22, 25, 26, 27, 28 and 29) and followed closely another three (Cases 21, 23 and 24). In addition, chlorambucil treatment was started in two patients with MGW but discontinued by their home physicians because of chills and fever in one (Case 31) and thrombocytopenia (platelet count 75,000 per cu. mm.) in the other (Case 30). Summary data on these cases and on the four originally reported are given in Table VII. In addition to the three patients who had an excellent remission with chlorambucil therapy initially and a relapse

and urethane

therapy

with values for

after cessation of therapy, five patients had excellent results (Cases 13, 24, 25 and 26) and are clinically well. Two patients treated by us (Cases 27 and 28) and one followed by us (Case 23) had a good response and all three benefited from therapy in some objective manner. One or perhaps two of those with a good response were actually overtreated, as they showed even greater improvement with adjustment in the dose of chlorambucil, for example, one patient (Case 13) (Fig. 13) after two and a half years of continuous treatment. One patient (Case 27) (Fig. 14) died six years after the onset of symptoms from a terminal oropharyngeal infection. He had remained in hematologic and biochemical remission for 3.5 years after therapy with chlorambucil was started and there was no evidence of relapse in these respects until the last few days before death. Treatment with chlorambucil was discontinued four months before death on the advice of his consulting physician. Whether or not this was related to the patient’s death is conjectural. The average survival time after diagnosis in the nonchlorambucil-treated group, including the asymptomatic patients, is 2.9 years. The average survival time in the chlorambuciltreated group is at present 3.5 years. Since we have found thus far that chlorambucil alone, properly administered, represents

Primary

et al.

Macroglobulinemia-McCallister

419

4

Chlorombucil, mgJW

Prednisone mgJdoy 40 --

i5

12.5 12.05.0 -

11.5-

4.5 -

ll.O-

4.0 3.5 3.0 2.5 2.0 -

,.ot ,

1.5-

(

810

,

,

(

2

0

3

Case 27. Correlation

of treatment

adequate therapy, we are unable to statewhether or not combined use of corticosteroids and chlorambucil or another cytotoxic agent would constitute superior treatment. The infrequency of the disease and the time needed to effect and maintain a desirable remission are obstacles in making such an assessment. APPENDIX* CASE 10. (Fig. 12). This patient was first seen at this institution in July 1949, at the age of thirty, for mild menometrorrhagia. The value for hemoglobin was 12.2 gm. per cent, the erythrocyte and leukocyte counts were normal and the results of urinalysis were negative. The patient was next seen in July 1958, at the age of thirty-nine, with a vesicovaginal fistula which followed hysterectomy performed elsewhere for menorrhagia and anemia. Prior to hysterectomy the patient had received 6 units (3,000 ml.) of blood and subsequently an unknown number of units. She appeared emaciated and chronically ill. There was no adenopathy and the liver and spleen were not palpable. Pelvic examination revealed a vesico-

* Report on personally treated patients. Cases through 13 were previously reported in part [ 131. VOL.

43,

SEPTEMBER

1967

8

,, 121

,

(

1-4

2-l

, 4-5

4-12

----+c'64~-'65-

t'6l--+-'62--'63

FIG. 14. ulin.

,

10

with values for hemoglobin

and gamma glob-

vaginal fistula 1 to 2 cm. in diameter, and the vaginal vault was entirely open into the pelvis. Urinalysis revealed grade 3 proteinuria, a positive reaction for Bence Jones protein, grade 2 microhematuria and grade 4 pyuria. The value for hemoglobin was 13.8 gm. per cent and the erythrocyte count was 3,900,OOO per cu. mm. on admission. Leukocytes numbered 5,100 per cu. mm., with 28 per cent lymphocytes, 2 per cent monocytes, 69 per cent neutrophils, 0.5 per cent eosinophils and 0.5 per cent basophils. The erythrocyte sedimentation rate was 122 mm. in the first hour. Electrophoresis revealed 6.6 gm. of serum protein, of which 1.67 gm. was albumin, 0.45 gm. alphat-globulin, 0.83 gm. alphaz-globulin, 0.90 gm. beta globulin and 2.77 gm. gamma globulin. In addition, gamma globulin presented, on paper electrophoresis, as a sharp peak (narrow band). A smear obtained on sternal aspiration was hypocellular and showed a background of marked rouleaux formation and some pale blue amorphous material suggestive of increased protein. Erythropoiesis was normoblastic, and myelopoiesis was moderately active, with some shift to the left. Megakaryocytes were present. The prominent feature, however, was an increase in small lymphocytes with scanty cytoplasm. There was also an associated but smaller increase in plasma cells. Sections of marrow

420

Primary

Macroglobulinemia-McCallister

units obtained at the same time showed very cellular units composed for the most part of small round cells which appeared to be lymphocytes and plasma cells. The result of the Sia test was positive. The abnormal protein had gamma mobility and a hexose content of 6.4 per cent. Ultracentrifugation of the serum revealed that 30 per cent of the proteins consisted of a with a sedimentation constant of macroglobulin, 19.7S, migrating in a manner characteristic of primary macroglobulinemia; there was also a second heavier component in lesser amount. During the period of observation the value for hemoglobin decreased to 6 gm. per cent. Four units (2,000 ml.) of blood again increased the hemoglobin value to the range of 10 to 11 gm. per cent. During this time the patient’s condition improved but not to the extent that surgical repair of the vesicovaginal fistula was considered wise. She was then dismissed to return two months later for repair of the fistula, which was performed in October 1958. The hemoglobin value was 13.2 gm. per cent prior to operation, 7.8 gm. per cent after operation and 11.7 gm. per cent after transfusion of 2 units of blood. The erythrocyte sedimentation rate was 134 mm. The patient convalesced satisfactorily after repair of the fistula, and had no recurrence. No treatment was prescribed for the macroglobulinemia. She returned in October 1959 because of weakness Physical exand faintness of one month’s duration. amination was not remarkable except that funduscopic examination showed huge distended veins typical of macroglobulinemia, edema of both disks and scattered small hemorrhages in each eye. There had been marked deterioration in the fundus picture since July 1958. The urine was normal except for grade 2 proteinuria. The hemoglobin value was 4.8 gm. per cent, erythrocytes 1,460,OOO per cu. mm., and leukocytes 2,000 per cu. mm., with 45 per cent lymphocytes, 10 per cent monocytes, 44.5 per cent neutrophils and 0.5 per cent eosinophils. Platelets numbered 18,000 per cu. mm. The erythrocyte sedimentation rate was 168 mm. in the first hour. Reticulocytes numbered 2.8 per cent. Blood smears contained so few red cells and distortion was so great because of much protein background that it was not possible to evaluate the type of anemia morphologically. Leukopenia, without immaturity, and thrombocytopenia were evident. A sulfobromophthalein test of hepatic function showed no retention of dye after one hour. The findings on sternal aspiration were much as they had been the year previously except that now there was little evidence of normal marrow activity, almost all the cells being small lymphocytes or plasma cells with the characteristics noted on the initial examination of the marrow. Serum protein electrophoresis showed 2.27 gm. per cent albumin, 0.35 gm. alphai-globulin, 0.67 gm. of alphaz-globulin, 1 .Ol gm. of beta globulin

et al.

and 5.56 gm. of gamma globulin, for a total of 9.86 gm. per cent. The patient was given 2 units of blood, which increased her hemoglobin value to 6.5 gm. per cent and treatment with chlorambucil, 6 mg. per day, was started (Fig. 12). During the next several months she continued to take chlorambucil, and she was given several transfusions by her home physician, the last one in early January 1960. In March the hemoglobin value was 11.2 gm. per cent. The patient returned again in September 1960. She was still taking 6 mg. of chlorambucil a day, as directed eleven months previously. She now felt well, had a good appetite, was not fatigued, considered her strength and endurance normal, had gained 10 pounds and had no blurring of vision. The results of physical examination were negative. Funduscopic examination was interpreted by the ophthalmologist as revealing amazing improvement. The disks were both flat, although blurred nasally. The veins in both eyes were only mildly distended. No sludging of the venous column could be demonstrated with application of ocular pressure. Urinalysis gave negative results now except for grade 1 proteinuria (sulfosalicylic method) ; the reaction for Bence Jones protein was negative. The hemoglobin value was 13.2 gm. per cent, the erythrocyte count 3,810,OOO per cu. mm. and the leukocyte count 3,800 per cu. mm., with 10 per cent lymphocytes, 7.5 per cent monocytes, 79 per cent neutrophils, 2.5 per cent eosinophils and 1 per cent basophils. Platelets numbered 41,000 per cu. mm. The erythrocyte sedimentation rate was 74 mm. Serum protein electrophoresis showed 3.43 gm. per cent albumin, 0.35 gm. alphai-globulin, 0.61 gm. alphaz-globulin, 0.71 gm. beta globulin and 1.50 gm. gamma globulin for a total protein value of 6.6 gm. per cent. Sternal aspiration revealed normal cellularity. Marrow smears were interpreted as showing remarkable improvement over previous ones, with very few or no abnormalities. In touch preparations there appeared to be a relative increase in erythropoiesis, which was normoblastic, and some’ small, mature lymphocytes and plasma cells were noted. It was not regarded as a diagnostic marrow. Sections showed a hypercellular marrow with scattered foci of lymphocytes and plasma cells surrounded by eosinophils. The patient continued to take chlorambucil, 6 mg. per day, for the next eighteen months. She remained free of symptoms. The use of the drug was discontinued elsewhere in March 1962. Three months later the hemoglobin value had decreased from 65 to 45 per cent and purpura had developed. She was given 6 mg. of chlorambucil daily for two weeks and received six transfusions. By August 3, 1962, the hemoglobin value was 4.0 gm. per cent and the leukocyte count was 750 per cu. mm. The patient AMERICAN

JOURNAL

OF

MEDIClNE

Primary

Macroglobulinemia-McCallister

died on August 18, 1962. Autopsy elsewhere showed multiple intestinal hemorrhages with generalized petechiae. Marrow preparations, obtained at that time and reviewed here, were regarded as showing an extensive, malignant sarcomatous transformation. A two and a half year remission of symptoms and of hematologic abnormalities was obtained with continuous chlorambucil therapy. Within three months after cessation of therapy the hemoglobin value dropped precipitously, and within fi1.e months the patient was dead. Whether or not a patient who once requires chlorambucil therapy must continue use of the drug indefinitely remains to be determined. Whether the acute sarcomatous transformation that ultimately caused the third patient’s death was related to either the administration or withdrawal of chlorambucil or was coincidental is conjectural, but it is to be noted that this patient is one of two in this small group in whom death occurred in this manner. CASE 11. (Fig. 11). A fifty-two year old man was referred to the Mayo Clinic in August 1959 because of “cloudy vision” in the right eye of two weeks’ duration. On a previous visit, in 1956, he had a hemoglobin value of 12.6 gm. per cent and 10 per cent of the leukocytes were monocytes. During the years 1957 and 1958 he had had frequent small nosebleeds. One year before the present admission prostatectomy performed elsewhere had been followed by hemorrhages that required his hospitalization for forty-six days. Physical findings on admission were not remarkable. Ophthalmoscopic examination showed markedly distended retinal veins with sausage-shaped segmentation, microaneurysms and round and flame hemorrhages. There was no adenopathy and the spleen was not palpable. Urinalysis gave negative results. The hemoglobin value was 10.6 gm. per cent, the erythrocyte count 3.180,OOO per cu. mm. and the leukocyte count 5,100 10 per per cu. mm., with 26.5 per cent lymphocytes, cent monocytes, 63 per cent neutrophils and 0.5 per cent eosinophils. Platelets numbered 111,000 per cu. mm. The erythrocyte sedimentation rate was 49 mm. in the first hour. Reticulocytes numbered 0.1 per cent. The peripheral blood smear showed marked rouleaux formation. The concentration of blood urea was 38 mg. per 100 ml. Serum protein electrophoresis showed 3.01 gm. of albumin, 0.38 gm. alphaiglobulin, 0.68 gm. alphaz-globulin, 0.85 gm. of beta globulin and 5.18 gm. of gamma globulin, for a total of 10.10 gm. per cent. The clinical impression of primary macroglobulinemia was strengthened by bone marrow examination which revealed, on smears, a relatively acellular marrow: with about half the VOL.

43,

SEPTEMBER

1967

et al.

421

cells small cytoplasm-poor lymphocytes, and an increase in plasma cells. The diagnosis was confirmed by ultracentrifugation, which revealed very little normal gamma globulin, a sharp major macroglobulin peak with a sedimentation constant of 16.858 and two smaller peaks with sedimentation constants of 24.5 and 29.5s. The result of the Sia test was negative and the abnormal protein demonstrated a gamma mobility with a hexose content of 6.5 per cent. Treatment with chlorambucil, 8 mg. per day, was given continuously from August to December 1959 (Fig. 11). At that time the patient felt well, was working regularly and had had no further deterioration in his vision. Physical findings were not remarkable and the retinal hemorrhages had disappeared. The hemoglobin value was 11.5 gm. per cent, the erythrocyte sedimentation rate 114 mm. and the gamma globulin 4.6 gm. per cent. The patient continued to take 8 mg. of chlorambucil daily and was still symptom-free when seen in July 1960. The hemoglobin value was 12 gm. per cent and the leukocyte count 5,500 per cu. mm., with 12 per cent lymphocytes, 10.5 per cent monocytes, 76.5 per cent neutrophils and 1 per cent eosinophils. Platelets numbered 169,000 per cu. mm. The erythrocyte sedimentation rate was 14 mm. Serum protein electrophoresis showed 4.21 gm. per cent albumin, 0.39 gm. alphai-globulin, 0.55 gm. alphazglobulin, 0.65 gm. beta globulin and 2.68 gm. gamma globulin for a total of 8.48 gm. per cent of protein. The patient was next seen in early January 1961, seventeen months after starting treatment. The hemoglobin value was then 13.0 gm. per cent and the globulins was only 2.33 gm. value for “gamma” per cent. The patient was maintained on a regimen of 8 mg. of chlorambucil daily. In March 1962 the hemoglobin value was 13.0 gm. per cent, the leukocyte count 5,900 per cu. mm., with 7 per cent monocytes, the erythrocyte sedimentation rate 90 mm. and the value for gamma globulin 1.80 gm. per cent. Chlorambucil therapy was then discontinued, after thirty-one months of treatment. Nine months later the patient still felt well. The hemoglobin value was 12.0 gm. per cent, the leukocyte count 4,000 per cu mm., with 12 per cent monocytes, the erythrocyte sedimentation rate 90 mm. and the value for gamma globulin 2.4 gm. per cent. In May 1963, four months later (and thirteen to fourteen months after stopping therapy), the patient had two episodes of rectal bleeding and involvement of small nodes in the axilla. The value for hemoglobin was 9.8 gm. per cent, the leukocyte count 3,500 per cu. mm., the erythrocyte sedimentation rate 124 mm. and the value for gamma globulin 2.3 gm. per cent. Chlorambucil therapy was reinstituted (8 mg. per day). One month later the leukocyte count was 2,900 per cu. mm. The dose of chlorambucil was decreased to 6 mg. per day. Two weeks later the value for

422

Primary

et al.

Macroglobulinemia-McCallister

hemoglobin was 8.4 gm. per cent, the leukocyte count 2,600 per cu. mm. and the platelet count 50,600 per cu. mm. Therapy was then discontinued for one week and reinstituted at a dosage of 4 mg. per day. One month later, the physical findings were normal, the value for hemoglobin was 8.7 gm. per cent, the leukocyte count 2,900 per cu. mm. and the platelet count 76,000 per cu. mm. Treatment was discontinued for three weeks. In October 1963 the patient returned with no complaints except mild fatigue. The weight had remained stable. The hemoglobin value was 8.6 gm. per cent, the leukocyte count 2,500 per cu. mm., and the platelet count 41,000 per cu. mm. Chlorambucil therapy was restarted at 6 mg. per day. One month later the hemoglobin value was 6.8 gm. per cent and the leukocyte count 2,000 per cu. mm. The dose of chlorambucil was decreased to 4 mg. per day. When the patient was next seen in December 1963 the hemoglobin value was 7.7 gm. per cent, the leukocyte count 3,500 per cu. mm., the platelet count 39,000 per cu. mm., the gamma globulin value 2.37 gm. per cent and the plasma cholesterol value 170 mg. per 100 ml. He was advised to continue treatment with chlorambucil, 4 mg. and 2 mg. on alternate days. When he was next seen in July 1964 the hemoglobin value had increased to 10.6 gm. per cent and he was feeling well. On a return visit in November 1964 he complained of inguinal adenopathy. A bone marrow section revealed an active, packed marrow with nests of plasmocytoid-lymphoid cells. This was thought to represent a regression in the marrow findings since the previous examination on October 26, 1963. Therefore, the dose of chlorambucil was doubled. The patient returned in two weeks complaining of night sweats and an increase in the inguinal adenopathy. The hemoglobin value was 6.0 gm. per cent. He was hospitalized for further management of his MGW in relapse, but died of the disease in February 1965, unresponsive to treatment, which included the use of antibiotics, corticosteroids, blood transfusions, chlorambucil and vincristine. Autopsy demonstrated 30 to 40 groups of lymph nodes in the pelvic and right external iliac regions; the dimensions of the groups averaged 2 by 2.5 cm. The liver weighed 2,190 gm. and there were four white tumor nodules, 3 by 3 cm., on its surface. A solitary enlarged lymph node was found in the region of the head of the pancreas. Generalized hemorrhagic gastritis and moderate bronchopneumonia were also demonstrated. Microscopic examination of the lymph nodes revealed complete replacement by an anaplastic reticulum cell infiltrate (Fig. 8). Some of the cells formed bizarre structures, but there were no true Reed-Sternberg cells. Scattered lymphocytes and plasma cells were seen in the nodes, and extranodal

and capsular extension \vas evident. Focal deposits of hemosiderin were noted. The liver was involved by similar tumor nodules, and scattered foci were seen in the spleen, dorsal root ganglion, thoracic spinal marrow and meninges. Figure

11 illustrates

therapy

on

hemoglobin A steady

two and

decrease

continuance

the effect

parameters serum

of chlorambucil

of the

gamma

disease:

globulin

in hemoglobin

of the use of the drug

the levels.

followed

dis-

and there

was

a poorer response to the second course of therapy after relapse of the disease. The markedly anaplastic

character

autopsy

is of note.

ventional

MGW

of the

abnormal

cells

found

This

transition

from

the con-

picture

was clearly

depicted

at in

bone marrow aspirates antemortem. Of interest is the fact that the plasma cholesterol value was 236 mg. per cent during the remission in 1962, whereas with relapse it decreased to 106 mg. per cent. serial

CASE 12. (Fig. 10). A fifty-two year old housewife was first seen in August 1957 because of anemia, weakness and dyspnea. Six months previously her hemoglobin value had been 68 per cent. During the next six months she received six blood transfusions as well as multiple hematinics for progressive anemia. Physical examination on admission was significant primarily for pallor and bilateral palpable cervical lymph nodes. Ophthalmoscopic examination revealed small microaneurysms in the retina. Urinalysis showed proteinuria, grade 2, but gave an equivocal reaction for Bence Jones protein. The hemoglobin value was 9.3 gm. per 100 ml. of blood. Erythrocytes numbered 2,870,OOO per cu. mm. and the leukocytes 4,600 per cu. mm., of which 33 per cent were lymphocytes, 11 per cent monocytes, 51.5 per cent neutrophils, 1 per cent eosinophils, 0.5 per cent basophils, 1 per cent metamyelocytes, 1.5 per cent myelocytes and 0.5 per cent blast cells. Platelets numbered 60,000 per cu. mm. The erythrocyte sedimentation rate was 139 mm. in one hour (Westergren). Blood smears showed considerable rouleaux formation and myeloid immaturity to the myeloblast. Serum proteins totaled 9.9 per 100 ml., of which 2.9 gm. was albumin, 0.44 gm. alphalglobulin, 0.78 gm. alpharglobulin, 1.14 gm. beta globulin and 4.6 gm. gamma globulin. X-ray examination of the esophagus, stomach and duodenum showed a duodenal ulcer. The appearance of the supraclavicular lymph nodes as seen at biopsy was not diagnostic. Sternal aspiration yielded hypocellular smears with marked rouleaux formation. Erythrogenesis was relatively conspicuous, megakaryocytes were present, the myeloid line was somewhat shifted to the left and an occasional mast cell was seen. The possibility of lymphosarcoma was AMERICAN

JOURNAL

OF

MEDICINE

Primary

Macroglobulinemia-McCallister

considered clinically, and the patient was given a trial of treatment with nitrogen mustard (HN2) before being dismissed. About a year later (July 1958) the patient returned, still suffering from easy fatigability. She had had no transfusions since her dismissal. However, she was still pale and the cervical lymph nodes were still palpable. The hemoglobin value was now 7 gm. per cent. The leukocyte count was 4,100 per cu. mm., of which 25 per cent were lymphocytes, 12.5 per cent monocytes and 62.5 per cent neutrophils. Platelets numbered 185,000 per cu. mm. Serum protein electrophoresis revealed 3.26 gm. per cent albumin, 0.57 gm. alphar-globulin, 1.01 gm. alphazglobulin, 1.40 gm. beta globulin and 4.60 gm. gamma globulin (total protein 10.84 gm. per cent). Bone marrow examination showed marked rouleaux formation and lymphocytosis, with many lymphocytes containing basophilic cytoplasm and showing plasma cell characteristics. Many of the lymphocytes had scant cytoplasm. The clinical impression of primary macroglobulinemia was confirmed by ultrarevealed that 42.5 centrifugation studies, * which per cent of the serum total protein was macroglobulins. The result of the Sia test was positive, and the abnormal protein had a hexose content of 6.7 per cent. Treatment with 12 mg. of chlorambucil (Leukeran) a day was started (Fig. 10). Two months later the hemoglobin value was 10.4 gm. per cent, the erythrocyte count 3,820,OOO per cu. mm., the leukocyte count 3,300 per cu. mm. and the platelet count 156,000 per cu. mm. She had had no transfusions in the interim. The dose of chlorambucil was reduced to 6 mg. daily and continued at this level for the next two months. At the end of the two months the hemoglobin value was 11.8 gm. per cent, the erythrocyte count 4,460,OOO per cu. mm. and the leukocyte count 4,800 per cu. mm. The differential count showed 15.5 per cent lymphocytes, 12.5 per cent monocytes, 70 per cent neutrophils, 1.5 per cent eosinophils and 0.5 per cent basophils. Platelets numbered 153,000 per cu. mm. The dose of chlorambucil was then reduced to 4 mg. daily and two months later to 2 mg. per day. The patient returned in April 1959 feeling well. She had had no transfusions. The hemoglobin value was 12.6 gm. per cent, the erythrocyte count 4,440,OOO per cu. mm., the leukocyte count 4,600 per cu. mm. and the platelet count 153,000 per cu. mm. Of 7.7 gm. of serum total protein, 3.6 gm. was albumin and 2.2 gm. gamma globulin as determined by electrophoresis. Urinalysis now gave negative results. The erythrocyte sedimentation rate was 94 mm. in one hour. The patient continued to take 2 mg. of chlorambucil daily until March 1960. * Courtesy of Dr. D. R. Briggs, Department chemistry, University of Minnesota. VOL.

43,

SEPTEMBER

1967

of Bio-

et al.

423

The remission persisted thereafter for about two and a half years, when the patient again began to tire and feel weak. Anemia recurred and the patient was treated at home with iron and vitamin Br2, without improvement. She returned to the Mayo Clinic in October 1963, about six years after her first visit, five years after the initiation and three and a half years after the discontinuation of chlorambucil therapy. Physical examination revealed a palpable spleen tip, left supraclavicular adenopathy and a sixth cranial nerve palsy attributed to her disease. Funduscopic examination disclosed grossly dilated retinal veins and scattered retinal hemorrhages and exudates. The hemoglobin value was 7.8 gm. per cent, the leukocyte count 5,700 per cu. mm. (9 per cent monocytes), the platelet count 153,000 per cu. mm. and the erythrocyte sedimentation rate 5 mm. per hour. Urinalysis revealed grade 2 proteinuria. The value for serum total protein was 12.5 gm., of which 7.0 gm. was gamma globulin and 3.0 gm. albumin. X-ray examination of the head and spinal column showed some generalized osteoporosis. The patient was hospitalized and given a transfusion of 3 units of packed cells. Chlorambucil therapy was resumed and in the subsequent twelve months negligible improvement was noted. The value for hemoglobin decreased to 7.1 gm. per cent and for serum gamma globulin to 5.75 gm. per cent. Neither approximated the value obtained after her initial treatment. For the past sixteen months she has also received corticosteroid and androgen therapy with dubious results. Except for fatigue and occasional problems with bleeding gums, she is symptomatically well despite persistent anemia.

In this patient an excellent symptomatic and hematologic remission was induced with chlorambucil given over a period of nineteen months. The remission continued thereafter for almost three more years. Relapse occurred five years after treatment with chlorambucil was begun and three and a half years after it was stopped. Since then continued efforts to induce another remission have failed. (Fig. 13). A fifty-six year old woman CASE 13. came to the Mayo Clinic in the latter part of March 1960 with a history of having had “double pneuin January which necessitated hospitalizamonia” tion until early February. Continued follow-up at home had revealed residual pulmonary findings, and there had been some loss of weight, mild anorexia and continued dry cough. The results of physical examination were not remarkable, except for mild enlargement of retinal veins. Urinalysis revealed grade 2 proteinuria. The hemoglobin value was 8.5 gm. per cent and the leukocyte count 6,800 per cu. mm., with 31 per cent lymphocytes, 11.5 per cent monocytes, 53.5 per cent

424

Primary

Macroglobulinemia-McCallister

neutrophils, 1 per cent metamyelocytes and 3 per cent myelocytes. Platelets numbered 136,000 per cu. mm. The reticulocyte count was 5 per cent. The bleeding time was two minutes and the erythrocyte sedimentation rate 139 mm. per hour. Blood smears showed rouleaux formation, grade 4, with myeloid immaturity, and an occasional plasma cell. The coagulation time was five and a half minutes; clot retraction was complete in two hours. Stereoroentgenograms of the chest showed a loculated pleural effusion in the region of the right lower lobe laterally. An electrocardiogram was normal except for a sinus tachycardia with a rate of 120. Serum protein electrophoresis showed 2.64 gm. per cent albumin, 0.53 gm. alphat-globulin, 0.62 gm. alphas-globulin, 0.99 gm. beta globulin and 5.12 gm. gamma globulin, for a total protein value of 9.9 gm. per cent. Electrophoresis revealed that 84 per cent of the urinary protein migrated in a single beta-gamma globulin peak. The Sia test gave a positive result. Sternal aspiration yielded smears of poor cellularity which showed only a scattering of bone marrow elements made up of normoblasts, small lymphocytes and occasional plasma cells. Marrow sections were hypercellular, showing heavy infiltration with small, mature, lymphoid-appearing plasma cells. The pleural fluid on the right was aspirated and penicillin was instilled. The patient was given a transfusion of 2 units (1,000 ml.) of blood. A provisional diagnosis of primary macroglobulinemia was made and confirmed by ultracentrifugation studies, which revealed macroglobulinemia with a sedimentation constant of 16.5s. The abnormal protein demonstrated gamma mobility, no penetrance into acrylamide gel and a hexose content of 5.2 per cent. Treatment with 1.5 gm. of urethane and 4 mg. of chlorambucil daily was started (Fig. 13). The patient returned for reevaluation in October 1960. She had done well until three weeks previously, when she had begun to have exertional dyspnea and bilateral ankle edema. The blood pressure was 130/95 mm. Hg and the pulse rate was 110 per minute. She had an intermittent gallop rhythm and grade 2 pitting edema of the legs. The results of urinalysis were negative except for grade 1 proteinuria. The value for hemoglobin was 10.6 gm. per cent and the leukocyte count 2,600 per cu. mm., with 4 per cent lymphocytes, 2 per cent monocytes, 91 per cent neutrophils and 3 per cent eosinophils. Platelets numbered 38,000 per cu. mm. Blood smears showed rouleaux formation, grade 4, some polychromasia and decrease in platelet count. The erythrocyte sedimentation rate was 93 mm. per hour. The blood urea value was normal. The sulfobromophthalein test of hepatic function gave normal results, and estimations of bilirubin were within normal limits. A Paunz test for amyloid gave results. Serum protein electrophoresis negative

et al.

showed 2.93 gm. albumin, 0.38 gm. alphai-globulin, 0.55 gm. alpha*-globulin, 0.82 gm. beta globulin and 2.97 gm. gamma globulin, for a total protein value of 7.65 gm. per cent. Stereoroentgenograms of the chest disclosed that there had been considerable clearing of the density in the base of the right lung since April 7, 1960. There now appeared to be cardiac enlargement and only minimal residual pleural thickening. The value for protein-bound iodine was normal at 4.9 pg. per 100 ml. of serum. The urinary protein now showed no significant peak on electrophoresis, although 58 per cent of it was in the beta-gamma zone. On interruption of the urethane-chlorambuci treatment for five days, the leukocyte count increased from 2,700 to 5,700 per cu. mm. and the platelet count from 38,000 to 111,000 per cu. mm. On treatment for congestive heart failure in the hospital the patient lost 10 pounds and the gallop rhythm disappeared. She was dismissed with advice to follow the usual program for congestive heart failure and to take 6 mg. of chlorambucil each morning. Treatment with urethane was discontinued. The patient returned in April 1961 and was feeling better. The hemoglobin value was 10.5 gm. per cent, the leukocyte count 4,200 per cu. mm. and the gamma globulin value 2.9 gm. per cent. Chlorambucil was increased to 8 mg. daily. Six months later the patient had no symptoms. Xray examination of the chest revealed some cardiomegaly. The hemoglobin value was 9.0 gm. per cent, the leukocyte count 5,800 per cu. mm., the erythrocyte sedimentation rate 125 mm. per hour, the gamma globulin value 1.8 gm. per cent and the platelet count 66,000 per cu. mm. Treatment with chlorambucil was discontinued for two weeks and then reinstituted at 6 mg. daily. In April 1962 the patient noted ankle edema and mild dyspnea. Physical examination revealed an increased pulmonary second sound and an apical systolic murmur. The electrocardiogram showed right axis deviation, right atria1 hypertrophy and right ventricular hypertrophy. Chlorambucil therapy was discontinued because of cytopenia with a hemoglobin value of 9.9 gm. per cent, a leukocyte count of 3,000 per cu. mm. and a platelet count of 75,000 per cu. mm. After three weeks, use of the drug was again started at a dosage of 4 mg. per day. The patient returned in October 1962 with ankle edema. She was treated with digitalis and chlorothiazide (Diuril@) for right ventricular failure and pulmonary hypertension. The hemoglobin value was 9.6 gm. per cent, the leukocyte count 3,300 per cu. mm., with 5 per cent monocytes, the erythrocyte sedimentation rate 124 mm. per hour and the gamma globulin value 1.5 gm per cent. Chlorambucil treatment, 4 mg. and 2 mg. on alternate days, was continued after a rest of four weeks. The patient felt stronger when she returned in AMERICAN

JOURNAL

OF

MEDICINE

Primary

Macroglobulinemia-McCallister

425

et al.

8 Chlorombucll, mgJdoy Blood transfusion 3.6 3.4 3.2 $

3.0-

3*

2.8-

x 2

2.6 -

;

2.4 -

9.0 t

2.2 2.0 1.84

7

12

!

I

,

I

4

8

1

63

I

1

I

2

6

1

_,

10

-‘6l--‘62--‘63-+-‘64+

FIG. 15. Case 22. Correlation gamma globulin.

of chlorambucil

April 1963. The hemoglobin value had risen to 10.9 gm. per cent and the leukocyte count was 5,400 per cu. mm. Chlorambucil therapy was continued. In October 1963 the patient had less ankle edema, was no longer dyspneic and felt much stronger. The hemoglobin value was 11.5 gm. per cent, the leukocyte count 3,100 per cu. mm., with 4 per cent monocytes. The platelet count was 50,000 per cu. mm., the erythrocyte sedimentation rate 9.5 mm. per hour and the gamma globulin value 1.2 gm. per cent. She was advised to continue taking chlorambucil, but to decrease the dose to 18 mg. per week. In April 1964 the patient was feeling stronger. The hemoglobin value was 12.1 gm. per cent, the erythrocyte sedimentation rate had dropped to 59 mm. per hour and the gamma globulin value was 0.97 gm. per cent. When last seen in October 1965 the patient had only mild pedal edema and was free of symptoms. The hemoglobin value was stable, the erythrocyte sedimentation rate and serum gamma globulin value had fallen slightly. She was advised to continue the same dosage of chlorambucil. The hemoglobin value increased and the abnormal protein levels decreased to normal with continuous chlorambucil therapy over a five and a half year period. Brief rest periods from use of the drug were required on three occasions for cytopenia, until an optimal maintenance dose of 18 to 21 mg. per week was reached. This dose has been used for two and a quarter years with susVOL.

43,

SEPTEMBER

1967

therapy

with values for hemoglobin

and

tained hematologic and clinical well-being. The relationship of the pulmonary hypertension to the primary disease process, MGW, is not known,

although one may speculate that it is related to the disease and its abnormal protein. CASE 22. (Fig. 15.) A forty-six year old housewife was referred to the Mayo Clinic in October 1957 because of easy fatigability, listlessness and slight loss in weight. Mild anemia, slight cervical adenopathy and increased erythrocyte sedimentation rate had been observed by her home physician. Physical examination revealed only moderate cervical adenopathy. Funduscopic findings were normal. Urinalysis disclosed grade 1 proteinuria. The Bence Jones reaction was negative. The hemoglobin value was 10.0 gm. per cent and the leukocyte count 6,900 per cu. mm., with 12 per cent monocytes, 19 per cent lymphocytes, 67 per cent neutrophils, 1 per cent myelocytes and 1 per cent normoblasts. Blood smears revealed marked rouleaux formation and adequate numbers of platelets. The erythrocyte sedimentation rate was 130 mm. per hour. Sternal aspiration of the bone marrow showed one conspicuous aggregation of lymphocytes and toxic granulocytes. Lymph node biopsy sections were interpreted as showing lymphosarcoma, lymphocytic type. Twenty-five milligrams of nitrogen mustard was given and the patient was advised to return in two months. In January 1958 the patient returned with complaints of general malaise and night sweats. Because visible adenopathy did not seem to account

Primary

426

Macroglobulinemia-McCallister

et al.

Chlorombucil, mgJdov

11.c1 . $

3 2

.

2

10.8I -

9.6 -

$

10.6

9.4

,o $

10.4

zF

10.2

-

9.0 -

IO.0

8.8 -

Q

3

8.6 -

9.6

8.4 -

9.4 F

82

9.2

c.. 2

-

L

809.0 t

I

3

+---I6 FIG. 16. Case 25. Correlation total protein and hemoglobin.

I

I

I

!

I

I

10

11

3

5

7

9

I

11

2-t---63-+-%

of chlorambucil

for the degree of the systemic illness, roentgen therapy was given to the abdomen. She felt better for six weeks thereafter. The patient was seen about every four months ovet the next six years, during which she continued to have moderate fatigue and some weakness. The hemoglobin value varied from 13.1 to 9.4 gm. per cent, the leukocyte count varied from 4,600 to 9,500 per cu. mm., with 7 to 21 per cent monocytes, and the erythrocyte sedimentation rate remained increased (93 to 126 mm. per hour). The patient was given another course of nitrogen mustard in May 1959 and blood transfusions on three occasions. The patient complained of progressive weakness on her return in April 1961. The hemoglobin value was then 9.2 gm. per cent, the leukocyte count 4,500 per cu. mm., with 17 per cent monocytes, and the platelet count 121,000 per cu. mm. The erythrocyte sedimentation rate was 105 mm. per hour. The blood smear revealed such a high grade of rouleaux formation that MGW was suspected. Serum protein electrophoresis showed 2.16 gm. albumin, 0.56 gm. alpharglobulin, 0.82 gm. alphaz-globulin, 0.98 gm. beta globulin and 3.47 gm. gamma globulin, for a total protein value of 8.0 gm. per cent. The result of the

5

10

4-a

therapy

with values for serum

Sia test was positive. Sternal aspiration showed increased cellularity and some moderate-stied plasmacytoid lymphocytes. The diagnosis of primary macroglobulinemia was confirmed by ultracentrifugation, which revealed a sharp macroglobulin peak with a sedimentation constant of 17.6s. The abnormal protein demonstrated gamma mobility, no migration into acrylamide gel and a hexose content of 4.4 per cent. Treatment with chlorambucil (8 mg. per day) was started (Fig. 15). Three months later (July 1961) the dose was decreased to 6 mg. daily, as the leukocyte count had fallen to 2,800 per cu. mm. The hemoglobin value was 9.9 gm. per cent and the patient was given 1 unit of blood. When she returned in December 1961 she felt stronger and more vigorous. The hemoglobin value was 11.3 gm. per cent, the leukocyte count 4,900 per cu. mm. and the platelet count 90,000 per cu. mm. The erythrocyte sedimentation rate was 117 mm. per hour and the gamma globulin measured 2.70 gm. per cent. The patient was advised to continue taking chlorambucil (6 mg. daily). She returned in April 1962, a year after the institution of chlorambucil therapy, feeling well. The hemoglobin measured 11 .O gm. per cent, the leukoAMERICAN

JOURNAL

OF

MEDICINE

Primary

Macroglobulinemia-L~!cCallister

cyte count was 2,700 per cu. mm., with 21 per cent monocytes, and the platelets numbered 136,000 per cu. mm. The erythrocyte sedimentation rate was 118 mm. per hour and the gamma globulin measured 2.35 gm. per cent. Sternal aspiration revealed a nondiagnostic normocellular marrow. The patient continued to take chlorambucil (6 mg. daily) and was seen at four month intervals. In June 1964 she had no symptoms, the hemoglobin value was 10.1 gm. per cent, the leukocyte count 4,000 per cu. mm., the platelet count 46,000 per cu. mm., the erythrocyte sedimentation rate 123 mm. per hour and the serum gamma globulin value 2.28 gm. per cent. A blood smear revealed grade 2 rouleaux formation. Chlorambucil treatment was continued at reduced dosage (4 mg. per day). When the patient was last seen in October 1964 laboratory findings were essentially the same. She had no symptoms except easy bruisability. Short-lived nitrogen

periods

mustard

of improvement

therapy

in this

followed

case. A lasting

which has been maintained for more than two years, has been achieved with continuous chlorambucil therapy. When the patient was last seen the hemoglobin value had dropped 1.0 gm. per cent from its previous level and this was accompanied by thrombocytopenia and leukopenia. At the same time the abnormal globulin had decreased further. We thought that this late decrease in hemoglobin was due to the drug. remission,

CASE 25. (Fig. 16.) A fifty-seven year old farmer was first seen at the Mayo Clinic in 1947. His hemoglobin value was 13.7 gm. per cent and leukocyte count 6,300 per cu. mm., with 38 per cent lymphocytes, 52 per cent neutrophils and 8 per cent monocytes. Urinalysis gave normal results. He returned in July 1962 because of weakness and fatigue of one year’s duration. He also noted vague epigastric pains, slight weight loss, occasional bouts of epistaxis and occasional melena. Physical findings were not remarkable except for slight bilateral epitrochlear and axillary lymphadenopathy. Urinalysis revealed grade 1 proteinuria and a Bence Jones reaction. The hemoglobin negative value was 9.9 gm. per cent and the leukocyte count 6,600 per cu. mm., with 43 per cent lymphocytes, 56.5 per cent neutrophils, 2.5 per cent eosinophils and 5.5 per cent monocytes. Platelets numbered 154,000 per cu. mm. The blood smear revealed marked rouleaux formation. The erythrocyte sedimentation rate was 70 mm. per hour. Serum protein electrophoresis showed 3.14 gm. per cent albumin, 0.32 gm. alphai-globulin, 0.60 gm. alphaz-globulin and 4.4 gm. gamma globulin, with a total protein value of 8.5 gm. per cent. Findings on sternal aspiration initially suggested lymphocytic lymphoma-it revealed many small immature lymphocytes. The VOL,

43,

SEPTEMBER

1967

et al.

427

result of the Sia test was positive and ultracentrifugation of the serum revealed a sharp macroglobulin peak with a sedimentation constant of 17 to 18s. The abnormal protein demonstrated a fast gamma mobility, no penetrance into acrylamide gel and a hexose. content of 5.4 per cent. The patient was returned to his home physician who has kindly supplied the following information.* In September 1962 chlorambucil therapy was begun (8 mg. per day for six weeks) (Fig. 16). In the first part of October the patient was feeling stronger and had no lymphadenopathy. The hemoglobin value was 9.2 gm. per cent, the leukocyte count 4,200 per cu. mm., the platelet count 366,000 per cu. mm. and the gamma globulin value was 45 per cent of the 9.2 gm. per cent of total protein. The dose of chlorambucil was decreased to 4 mg. daily. In March 1963 the patient stated that he continued to feel better and had had no further nosebleeds. The hemoglobin value was 9.4 gm. per cent, the leukocyte count 4,900 per cu. mm., with 4 per cent monocytes. The erythrocyte sedimentation rate was 86 mm. per hour and the gamma globulin value 46 per cent of the total protein content of 9.3 gm. per cent. The patient’s condition continued to improve over the next eight months and when seen in November 1963 he was asymptomatic and working hard. The hemoglobin value was 10.6 gm. percent and the leukocyte count 4,500 per cu. mm., with 3 per cent monocytes. The platelet count was 280,000 per cu. mm., the erythrocyte sedimentation rate 106 mm. per hour and the total protein value 8.9 gm. per cent. In May 1964 the patient stated that he had stopped taking chlorambucil one month previously. The hemoglobin value was 12.0 gm. per cent, the erythrocyte sedimentation rate 80 mm. per hour and the value for serum total protein was 7.9 gm. per cent, with a serum gamma globulin value of 4.1 gm. per cent. When last seen in October 1964 the patient was free of symptoms and performing his farming normally. There was no essential change in laboratory data. He was advised to continue taking chlorambucil (4 mg. daily).

This patient obtained a satisfactory remission after two years of therapy and has been able to return to his normal activities as a farmer. CASE 26. (Fig. 17.) A sixty-two year old housewife was first seen in May 1962 because of fatigue of two years’ duration, progressive anemia of one year’s duration and easy bruisability of six months’ duration. She had also noted mild ankle edema, dyspnea on exertion and some blurring of vision.

* J. L. University

Marciniak, M.D., Saskatoon Cancer Clinic, Hospital, Saskatoon, Saskatchewan, Canada.

Primary

428

Macroglobulinemia--hrirCallister

et al.

10

,;“

f ,’

mg./day

4

2

1

9r

8

t

--xc-~x--_

Lyglobulin --

--

--X

6 5’ 5-7

17. globulin.

III, 5-20 6-61118

< Case 26. Correlation

I 27

I 7-23

I

I 8-20

1962 of chlorambucil

Physical findings were not remarkable except for a questionably palpable liver. Ophthalmoscopic examination revealed normal findings. Urinalysis gave negative results. The hemoglobin value was 8.0 gm. per cent and the leukocyte count 3,400 per cu. mm., with 43 per cent neutrophils, 43 per cent lymphocytes, 8 per cent monocytes, 2 per cent metamyelocytes and 2 per cent myelocytes. Platelets numbered 54,000 per cu. mm. The erythrocyte sedimentation rate was 130 mm. per hour. The peripheral blood showed moderate rouleaux formation. The blood urea value was 30 mg. per cent. Stereoroentgenograms of the chest did not disclose any abnormality. Serum protein electrophoresis showed 3.43 gm. per cent albumin, 0.42 gm. alphai-globulin, 0.88 gm. alphaz-globulin, 0.79 gm. beta globulin and 3.3 gm. gamma globulin, for a total protein value of 8.82 gm. per cent. Sternal aspiration of the bone marrow gave a poor yield composed of lymphocytes with a scattering of plasma cells. The clinical impression of primary macroglobulinemia was confirmed by ultracentrifugation of the patient’s serum, which showed a typical selfsharpening peak of 17s globulin. The abnormal protein, which had a slow gamma mobility, did not migrate into acrylamide gel and the hexose content of the protein was 5.0 per cent. On May 7, 1962, treatment with 10 mg. of chlorambucil a day was started (Fig. 17). After three weeks drug therapy was temporarily discontinued because of cytopenia. The hemoglobin value at that time was 7.1 gm. per cent, the leukocyte count 1,900 per cu. mm. and the platelet count 39,000 per cu. mm. Three weeks later, with a hemoglobin value of 7.5 gm. per cent, a leukocyte count of 1,500 per cu.

9-29

therapy

lo-26

4-22

10-10

>a1963with values for hemoglobin

and gamma

mm. and a platelet count of 79,000 per cu. mm., chlorambucil therapy (4 mg. per day) was reinstituted. After five weeks of continued therapy the hemoglobin value had increased to 10.4 gm. per cent, the leukocyte count was 2,500 per cu. mm. and platelets numbered 69,000 per cu. mm. The patient felt well now and had no symptoms. Two months later, and still during treatment with chlorambucil (4 mg. daily), the hemoglobin value had risen only 0.4 gm. to 10.8 gm. per cent. Leukocytes numbered 2,000 per cu. mm. and platelets 230,000 per cu. mm. The dose of chlorambucil was then decreased to 2 mg. per day. Within a month thereafter the hemoglobin value rose to 11.8 gm. per cent, and when the patient returned in April 1963, a year after her first visit, she was feeling well and her hemoglobin value was 12 gm. per cent. Leukocytes numbered 3,800 per cu. mm. and platelets 83,000 per cu. mm. Six months later the patient again returned, having continued taking 2 mg. of chlorambucil a day; she felt well except for mild angina. The hemoglobin value was 12.3 gm. per cent and the leukocytes numbered 4,600 per cu. mm., with 23 per cent lymphocytes, 8 per cent monocytes, 66 per cent neutrophils, 2 per cent eosinophils and 1 per cent basophils. Platelets numbered 150,000 per cu. mm. The erythrocyte sedimentation rate was 64 mm. per hour and gamma globulin measured only 1.49 gm. per cent whereas total proteins measured 7.01 gm. per cent. The patient was advised to continue taking chlorambucil at a dosage of 2 mg. daily. Initial

treatment

per day) penia.

with

chlorambucil

was accompanied

After

three

AMERICAN

weeks

(10

by appreciable without

JOURNAL

treatment OF

MEDICINE

mg. cytocyto-

Primary

Macroglobulinemia-McCallister

et al.

429

penia, although persistent, became moderate and the thrombocytopenia was no longer severe. Use of the drug was then resumed at only 4 mg. per day. Within five weeks the hematologic findings were markedly- improved over those noted on admission. However, the hemoglobin value remained almost constant in the vicinity of 10.5 gm. per cent and leukocytes remained deficient in the two months that followed on the same dosage. The dose of chlorambucil was then reduced from 4 to 2 mg. per day and there was a prompt increase in hemoglobin value to 11.8 gm. per cent and a return of the leukocyte levels to normal. The therapeutic effect on the macroglobulin level was also maintained and improved. The patient has continued under treatment for more than two years and has sustained a complete hematologic and symptomatic remission of her disease.

Roentgen therapy was given to the involved lymph nodes and the patient returned in two months for reevaluation. The nodes had decreased markedly in size, and the patient felt essentially well. The hemoglobin value was 8.7 gm. per cent, the erythrocyte sedimentation rate 132 mm. per hour and the gamma globulin value 2.4 gm. per cent. In February 1962 the patient was seen again and had no symptoms. The lymphadenopathy had disappeared. The hemoglobin value was 10.1 gm. per cent, the leukocyte count 5,700 per cu. mm., the erythrocyte sedimentation rate 118 mm. per hour, and the gamma globulin value 4.4 gm. per cent. Proteinuria was graded 3. Chlorambucil therapy (4 mg. per day) was started. Six months later the patient was asymptomatic. Physical findings were not remarkable. The hemoglobin value was unchanged but the abnormal gamma globulin was half its previous value, 2.2 gm. per cent (Fig. 14). The dose of chlorambucil was reduced to 2 mg. per day.

CASE 27. (Fig. 14). A sixty-one year old man was referred to the Mayo Clinic in August 1961 because of anemia and lymphadenopathy discovered in April 1961 after dental extraction with excessive postoperative bleeding. Until that time the patient had been in apparent good health except for mild fatigue. Physical examination revealed moderate inguinal and supraclavicular lymphadenopathy. Ophthalmoscopic examination showed a slight increase in size of the retinal veins. Urinalysis disclosed grade 2 proteinuria and a positive Bence Jones reaction. The hemoglobin value was 9.6 gm. per cent and the leukocyte count 10,000 per cu. mm., with 55.5 per cent neutrophils, 21 per cent lymphocytes, 21 per cent monocytes, 2 per cent eosinophils and 0.5 per cent myelocytes. The platelets numbered 148,000 per cu. mm. The erythrocyte sedimentation rate was 15 mm. per hour. The peripheral blood smear showed marked rouleaux formation. Serum protein electrophoresis showed 2.77 gm. albumin, 0.54 gm. alphalglobulin, 0.89 gm. alphaz-globulin, 0.73 gm. beta globulin and 4.23 gm. gamma globulin, with a total protein value of 9.16 gm. per cent. The result of the Sia test was positive, but no cryoglobulins were found in the serum. Sternal aspiration revealed a hypocellular marrow with a slight increase in monocytes and plasma cells. Histologic sections of a lymph node removed elsewhere were suggestive, on initial review, of lymphosarcoma, lymphocytic type (Fig. 4). The clinical impression of MGW was confirmed by ultracentrifugation of the patient’s serum, which revealed that 61 per cent of the serum proteins appeared as a sharp macroglobulin peak with a sedimentation constant of 19s. The abnormal protein demonstrated a slow gamma mobility, no penetrance into acrylamide gel and a hexose content of 4.7 per cent.

The patient returned in March 1963, still feeling well. The erythrocyte sedimentation rate was 17 mm. per hour, the gamma globulin value 2.3 gm. per cent and the hemoglobin value 10.8 gm. per cent. The dose of chlorambucil was increased to 6 mg. daily.

VOL.

43,

SEPTEMBER

1967

In August 1963 the patient was hospitalized for a dental extraction. Two units of blood were required for this procedure. Prior to operation the hemoglobin value was 10.3 gm. per cent, the leukocyte count 3,700 per cu. mm., with 27 per cent monocytes, and the platelet count 107,000 per cu. mm. The erythrocyte sedimentation rate was 133 mm. per hour and the gamma globulin measured 2.1 gm. per cent. Postoperatively, herpes zoster developed involving the right trigeminal nerve. Chlorambucil therapy was continued at a dosage of 6 mg. daily. The patient was next seen in December 1963 because of postherpetic neuralgia and otitis media on the right. The leukocyte count was 3,600 per cu. mm., and the platelets numbered 88,000 per cu. mm. Treatment consisted of an alcohol nerve block for the neuralgia, and the dose of chlorambucil was decreased to 4 mg. per day. The patient’s home physician wrote in January 1964 that the leukocyte count had fallen to 1,500 per cu. mm. and that the hemoglobin value was 8.4 gm. per cent. Temporary discontinuance of chlorambucil therapy was advised. The patient continued to take chlorambucil (4 mg. per day) and did well except for postherpetic pain until January 1965. Then stomatitis, anorexia and increased fatigability developed. Chlorambucil therapy was discontinued by his home physician and prednisone was given (40 mg. per day for one month and then 15 mg. per day). The stomatitis subsided after one month of therapy. The hemoglobin value was 10.6 gm. per cent and the leukocyte count 4,400 per cu. mm., with 14 per cent lymphocytes, 40 per

430

Primary

Macroglobulinemia-McCallister

cent neutrophils,

24 per cent eosinophils and 21 per cent monocytes. The patient returned in April 1965 because the stomatitis had recurred. The oral lesions were associated with severe pain and temperatures to 104”~. The hemoglobin value was 13.0 gm. per cent, the leukocyte count 4,000 per cu. mm., and the gamma globulin value 1.77 gm. per cent, with a total protein value of 7.0 gm. per cent. Cultures for pathogenic bacteria and fungi in the mouth and blood were

negative, but penicillin, streptomycin and methicillin were administered empirically. The patient continued a febrile course and died in coma seven days after hospitalization. Autopsy disclosed changes that were less striking than those seen in Case 11. Grossly there were enlarged yellowish white periaortic and peripancreatic lymph nodes and the pericardium was thickened and yellow. The liver was studded with minute whitish yellow areas and weighed 1,725 gm. Similar small nodules were present on the surface of the kidneys. Bilateral bronchopneumonia and diffuse purulent bronchitis were evident. Microscopic examination revealed a slight lymphocytic infiltration in the portal triads and the kidneys. The pericardium was diffusely involved and the periaortic and pancreatic nodes were moderately infiltrated by lymphocytic cells, but most striking was the presence of many lymphocytes surrounding fairly normal appearing nodes. Pyroninophiha was noted. Acute membranous glomerulonephritis was evident. Within six months of therapy with chlorambucil a marked decrease in abnormal protein and an increase in hemoglobin occurred. After two years of treatment increasing leukopenia and anemia developed. Since the amount of abnormal protein produced remained well controlled and the hemoglobin value rose to 13.0 gm. per cent after treatment was stopped, the leulcopenia and anemia would appear to have been due to excessive medication. The patient died of a recalcitrant oral infection four months after chlorambucil therapy was discontinued. However, he remained in hematologic and biochemical remission until the last few days of his life. REFERENCES 1. WALDENSTR~M,J. Incipient myelomatosis or “essential” hyperglobulinemia with fibrinogenopenla: a new syndrome? Acta med. scondinnu., 117: 216, 1944. 2. QUATTRIN,N., DINI, E. and PICCOLI,P. On the differential diagnosis and pathogenesis of the purpuras with hypergammaglobulinemia or macroglobulinemia. Acta med. scandinav., 156: 25, 1956. 3. IMHOF,J. W., BAARS, H. and VERLOOP, M. C. Clinical and haematological aspects of macroglobulinaemia of Waldenstrom. Acta med. scandinav., 163: 349, 1959.

et al.

4. RITZMANN,S. E., THURM, R. H., TRUAX, W. E. and LEVIN, W. C. The syndrome of macroglobulinemia: review of the literature and a report of two cases of macryogelglobulinemia. Arch. Int. Med., 105: 939, 1960. 5. OSSERMAN, E. F. The plasmocytic dyscrasias: plasma cell myeloma and primary macroglobulinemia. Am. J. Med., 31: 671, 1961. Australasian 6. MACKAY, I. R. Macroglobulinemia. Ann. Med., 5: 244, 1956. 7. MACKAY, I. R. Macroglobulins and macroglobulinaemia. Australasian Ann. Med., 8: 158, 1959. 8. KAPPELER, R., KREBS, A. and RIVA, G. Klinik der Makroglobulin&nie~WaldenstrBm. Beschreibung von 21 Fallen und Ubersicht der Literatur. Helvet. med. acta, 25: 54, 1958. 9. DUTCHER, T. F. and FAHEY, J. L. The histopathology of the macroglobulinemia of WaldenStrom. J. Nat. Cancer Inrt., 22: 887, 1959. 10. SCHUR, P. H. and APPEL, L. WaldenstrEm’s macroglobulinemia with pleural effusion. New York J. Med., 61: 2431, 1961. 11. PACHTER, M. R. Macroglobulinemia of Waldenstrijm: clinical, laboratory and anatomic features. Postgrad. M. J., 26: 815, 1959. 12. MARTIN, N. H. Macroglobulinaemia: a clinical pathological study. Qumt. J. Med., 29: 179, 1960. 13. BAYRD, E. D. Continuous chlorambucil therapy in primary macroglobulinemia of Waldenstrom: report of four cases. Proc. Staff Meet. Mayo Clin., 36: 135, 1961. 14. HANLON, D. G., BAYRD, E. D. and KEARNS, T. P. Macroglobulinemia-report of four cases. J.A.M.A., 167: 1817, 1958. 15. GERMAN, J. L., BIRO, C. E. and BEARN, A. G. Chromosomal abnormalities in Waldenstrom’s macroglobulinaemia. Lancet, 2: 48, 1961. 16. COYLE, J. T., FRANK, P. E., LEONARD, A. L. and WEINER, A. Macroglobulinemia and its effect on the eye. Arch. Ophth., 65: 75, 1961. report of two 17. LAMM, M. E. Macroglobulinemia: cases. Am. J. Clin. Path., 35: 53, 1961. 18. CONRAD, M. E., JR., RAMOS, H. S., HOWIE, D. L. and CROSBY, W. H., JR. Waldenstrom’s macroglobulinemia. M. Ann. District of Columbia, 28: 193,1959. 19 FAHEY, J. L., SCOQGINS, R., UTZ, J. P. and SZWED, C. F. Infection, antibody response and gamma globulin components in multiple myeloma and macroglobulinemia. Am. J. Med., 35: 698, 1963. 20. GLENCHUR.H.. ZINNEMAN.H. H. and BRIGCS,D. R. Macroglobulinemia: report of two cases. Ann. Int. Med., 48: 1055, 1958. 21. GASSNER, C., BITTAR, E. E., and PARRISH, A. E. Macroglobulinemia and amyloid nephrosis: report of a case. M. Ann. District of Columbia, 30: 342, 1961. 22. CARR, R. E. and HENKIND, P. Retinal findings associated with serum hyperviscosity. Am. J. Ophth., 56: 23, 1963. 23. FAHEY, J. L. Serum protein disorders causing clinical symptoms in malignant neoplastic disease. J. Chron. Dis., 16: 703, 1963. 24. BERNEAUD-KATZ, G. and JAHNKE, K. cber einen Fall von ungewiihnlicher Dys- und Paraproteinlmie mit auffallenden AugenhintergrundAMERICAN

JOURNAL

OF

MEDICINE

Primary

25.

26.

27.

28.

29.

30.

31.

32. 33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

VOL.

Macroglobulinemia-McCallister

veranderungen (Fundus paraproteinaemicus). Klin. Monatsbl. Ayenh., 125: 160, 1954. ACKERMAN, A. L. The ocular manifestations of Waldenstrom’s macroglobulinemia and its treatment. Arch. Ophth., 67: 701, 1962. AARSETH, S., OFSTAD, E. and TORVIK, A. Macroglobulinaemia Waldenstrom: a case with haemolytic syndrome and involvement of the nervous system. Ac6a med. scandinav., 169: 691, 1961. CURTAIN, C. C. and O’DEA, J. F. Possible sites of macroglobulin synthesis: a study made with fluorescent antibody. Australasian Ann. Med., 8: 143,1959. MACKAY, I. R., TAFT, L. I. and WOODS, E. F. Clinical features and pathogenesis of macroglobulinaemia. Brit. M. J., 1: 561, 1957. LOGOTHETIS, J., SILVERSTEIN, P. and COE, J. Neurologic aspects of Waldemtr8m’s macroglobulinemia: report of a case. Arch. Neural., 3: 564, 1960. BICHEL, J., BING, J. and HARBOE, N. Another case of hyperglobulinemia and affection of the central nervous system_:Acta med. scandinav., 138: 1, 1950. WUHRMANN,F. Uber das Coma paraproteinaemicum bei Myelomen und Makroglobulin%mien. S&J&. med. Wchnschr., 86: 623, 1956. Clinicopathologic Conference. Macroglobulinemia. Am. J. Med., 28: 951, 1960. GARCIN, R., MALLARM& J., ROUDOT,P. and ENDTZ, L. J. Forme nevritique de la macroglobulintmie de Waldenstrom (a propos d’une nouvelle observation). Sang, 31: 441, 1960. DARNLEY, J. D. Polyneuropathy in Waldenstrom’s macroglobulinemia: case report and discussion. Neurology, 12: 617, 1962. BOTHIER,F., MOREL, P., CREYSSEL,R., REVOL, L. and CROIZAT, P. Considtrations cliniques et cytologiques a propos de vingt observations de macroglobulintmie. Sang, 31: 405, 1960. GAMBLE,J. W. and DRISCOLL,E. J. Oral manifestations of macroglobulinemia of Waldenstrom: report of a case. Oral Surg., 13 : 104, 1960. WINDRUM, G. M., FREEMAN,Z. and OWEN, J. A. A case of anaemia associated with macroglobulinaemia. M. J. AuFtralia, 1: 655, 1960. CLINE, M. J., SOLOMON, A., BERLIN, N. I. and FAHEY, J. L. Anemia in macroglobulinemia. Am. J. Med., 34: 213, 1963. DREYFUS, B., NENNA, A., SAMARCQ, P. R. and FRAN~OIS,P. l&de cytologique de la maladie de Waldenstrom. Sang, 31: 387, 1960. PACHTER, M. R., JOHNSON,S. A., NEBLETT, T. R. and TRUANT, J. P. Bleeding, platelets, and macroglobulinemia. Am. J. Clinlpath., 31: 467, 1959. SCHWAB, P. J. and FAHEY. J. L. Treatment of WalddnstrBm’s macroglodulinemia by plasmapheresis. New England j. Med., 263: 574, i960. ZUBROD, C. G.. HILBISH. T. F.. FAHEY. J. L.. DUTC~ER, T. k., Fox, F: A. and~OSSERI&N,E. F: Waldenstrom’s Clinical macroglobulinemia. pathological conference at the National Institutes of Health. Ann. znt. Med., 50: 1010, 1959. OLMER, J., MONOIN, M., MURATORE, R. and DENIzet, D. fitude de sept cas personnels de macroglobulinCmie de Waldenstrom. Sang, 31: 415, 1960. 43,

SEPTEMBER

1967

et al.

431

44. STRISOWER, E. H. and GALLETO, A. T. WaldenStrom’s macroglobulinemia: differential diagnosis, lipoprotein study, and case report. Am. J. Med., 32: 304, 1962. 45. MARTIN, N. H. and CLOSE, H. G. Macroglobulinaemia. Lancet, 2: 8, 1957. 46. BUTLER, E. A., FLYNN, F. V., HARRIS, 1-I. and ROBSON, E. B. The laboratory diagnosis of macroglobulinaemia with special reference to starch-gel electrophoresis. Lancet, 2: 289, 1961. a 47. RITZMANN,S. E. and LEVIN, W. C. Cryopathies: review. Classification; diagnostic and therapeutic considerations. Arch. Znt. Med., 107: 754, 1961. 48. JAHNKE,K., SCHOLTAN,W. and HEINZLER, F. Die Viskositlt von Seren und isolierten Serunproteinen bei Makroglobulin~mien und anderen Dys- und Paraproteinlmien. H&x6. med. acta, 25 : 2, 1958. 49. WALDENSTR~M,J. Abnormal proteins in myeloma. In: Advances in Internal Medicine, vol. 5, p. 398. Edited by Dock, W. and Snapper, I. Chicago, 1952. The Year Book Publishers, Inc. 50. DONDERS,P. C., IMHOF, J. W. and BAARS, H. Clinical demonstrations: ophthalmological phenomena in Waldenstrom’s disease with cryoglobulinaemia. Ophthalmologica, 135: 324, 1958. 51. LAURELL, C. B., LAURELL, H. and WALDENSTR~DI, J. Glycoproteins in serum from patients with myeloma, macroglobulinemia and related conditions. Am. J. Med., 22: 24, 1957. 52. SEHON, A. H., GYENES, L., GORDON, J., RICHTER, M. and ROSE, B. Physico-chemical and immunologic studies on macroglobulins. J. Clin. Znvest., 36: 456, 1957. 53. EVENSON, D. J., MCGUCKIN, W. F., MCKENZIE, B. F. and HAGEDORN, A. B. An electrophoretic study of serum protein-bound carbohydrate in dysproteinemia. Clin. Chem., 10: 824, 1964. 54. LEDER, P. Simple paper electrophoretic method of detecting Nature, 193: macroglobulinaemia. 1087, 1962. 55. ADNER, P. L., WALLENIUS, G. and WERNER, I. Macroglobulinemia and myelomatosis. Actn med. scandinav., 168: 431, 1960 56. MALDONADO, J. and BAYRD, E. D. Personal communication. 57. WALDENSTR~M,J. Macroglobulinemia. Acta haemat., 20: 33, 1958. 58. TISCHENDORF,W. and HARTMANN, F. Makroglobulinaemia (Waldenstrom) mit gleichzeitiger Hyperplasie der Gewebsmastzellen. Acta haemat., 4: 374,195o. 59. ZLOTNICK, A. Macroglobulinemia of WaldenStrom. Am. J. Med., 24: 461, 1958. 60. WANEBO, H. J. and CLARKSON, B. D. Essential macroglobulinemia: report of a case including immunofluorescent and electron microscopic studies. Ann. Znt. Med., 62: 1025, 1965. 61. ZOLLINGER,H. U. Die pathologische Anatomie der Makroglobulin~ie WaldenstrBm. Helvet. med. acta, 25: 153, 1958. 62. LAMM, M. E. Macroglobulinemia: report of two cases. Am. J. Clin. Path., 35: 53, 1961. 63. HINES, D. R. Macroglobulinemia: report of ten cases. Henry Ford Hosp. M. Bull., 10: 297, 1962. 64. ARGANI, I. and KIPKIE, G. F. The cellular origin of

432

65.

66.

67.

68.

69. 70.

71.

72.

73.

74.

75.

76.

77. 78.

79.

80.

81.

Primary

Macroglobulinemia-McCallister

macroglobulins: a study of the protein-secreting cells in WaldenstrGm’s disease. Lab. Invest., 14: 720, 1965. LE BEUX, Y. and GANTER, P. fitude histopathologique et cytologique de la maladie de Waldenstrijm: A propos de 8 cas de macroglobulintmie. Ann. Amt. Path., 8: 377, 1963. KOK, D. A., WHITMORE, D. N. and AINSWORTH, R. W. Four cases of Waldenstrijm’s macroglobulinaemia. J. Clin. Path., 16: 351, 1963. FESSEL, W. J. Clinical analysis of 142 cases with high molecular weight serum proteins. Acta med. scandinnr., 173 (supp. 391): 1, 1962. HEREMANS,J. F., LAURELL, A. H. MARTENSSON,L., HEREMANS,M. T., LAURELL, C. B., SJOQUIST,J. and WALDENSTR~M, J. Studies on “abnormal” serum globulins (M-components) in myeloma, macroglobulinemia and related diseases. Acta med. scandinau., 170 (supp. 367): 1, 1961. Dr GUOLIELMO,R. Clinical and biochemical aspects of macroglobulinemia. Acta haemat., 24: 92, 1960. ENGLE, R. L., WOODS, K. R., CASTILLO, G. B. and PERT, J. H. Starch gel electrophoresis of serum proteins and urinary proteins from patients with multiple myeloma, macroglobulinemia, and other forms of dysproteinemia. J. Lab. B Clin. Med., 58: 1, 1961. FINE, J. M. and CREYSSEL, R. Starch gel electrophoresis studies on abnormal proteins in myeloma and macroglobulinemia. Nature, 183: 392, 1959. SILBERMAN, H. J. Multiple myelomatosis and macroglobulinaemia: differentiation by starchgel electrophoresis. Lancet, 2: 26, 1957. OLIVER, I. T. and RUBINSTEIN,H. J. Studies on macroglobulins by starch gel electrophoresis and ultracentrifugation. Clin. Chem., 7: 73, 1962. ZINGALE, S. B., MATTIOLI, C. A., BOHNER, H. D. and BUENO, M. P. Disc electrophoresis study of serum proteins from patients with multiple myeloma and macroglobulinemia. Blood, 22: 152, 1963. SHEARN, M. A., EPSTEIN,W. V. and ENGLEMAN,E. Serum viscosity in rheumatic diseases and macroglobulinemia. Arch. Int. Med., 112: 684, 1963. STEEL, A. E. The laboratory diagnosis of macroglobulinaemia by viscometry. Chim. Acta, 8: 86, 1963. DELALLA, 0. F. Cited by Strisower, E. H. and Galleto, A. T. [&I. KUNKEL,H. G. Macroglobulins and high molecular weight antibodies. In: The Plasma Proteins, vol. 1, p. 279. Edited by Putnam, F. W. New York, 1960. Academic Press, Inc. MACKAY, I. R., ERIKSEN,N., MOTULSKY,A. G. and VOLWILER, W. Cryo- and macroglobulinemia: ultracentrifugal and clinical electrophoretic, studies. Am. J. Med., 20: 564, 1956. OSSERMAN,E. F. and LA~LOR, D. Immunoelectrophoretic characterization of the serum and urinary proteins in plasma cell myeloma and WaldenstrBm’s macroglobulinemia. Ann. New York Acad. SC., 94: 93, 1961. SOLOMON, A. and KUNKE~, H. G. A “monoclonal” type low-molecular weight protein related to yM macroglobulins. (Abstract.) Blood, 26: 880-1, 1965.

et al.

82. HABICH, H. and Hb;ssrc, .4. Essai d’analyse antigenique des paraprotides dam la macroglobulin&nie de WaldenstrGm. VOX Sang., 3: 99, 1953. 83. HABICH, H. Zur Antigenanalyze der Paraproteine bei Makroglobulin8mien. Schwci:. med. Wchnschr., 83: 1253, 1953. 84. ALBERT, A. and JOHNSON, P. Macroglobulins. I Studies on the isolation and physical properties of pathological macroglobulins. 11. Immunochemical studies on isolated pathological macroglobulins. B&hem. J., 81: 658, 1961. 85. WALTON, K. W.,RO~E,D.S., SOOTHILL,J.F.~~~ STANWORTH, D. R. An investigation of methods of isolation of @2M, globulin (syn.: iota protein, 19s y globulin, y1 macroglobulin, B2M globulin) and its association with isoagglutinin activity, together with preliminary observations on other macroglobulins of slow electrophoretic mobility in normal human serum. fmmunolopy, 6: 305, 1963. 86. ROULET, D. L. .4., SPENGLER,G. A. and HXSSIG,.A. Immunoelectrophoretical studies on paraproteins. VOX Sang., 7: 281, 1962. 87. (a) DEUTSCH, H. F. and MORTON, J. I. Human serum macroglobulins and dissociation units. I. Physiochemical properties. J. Biol. Chem., 231: 1107, 1958. (b) Ibid. II. Immunochemical properties. Idem, p. 1119. 88. KRATOCHVIL,C. H. and DEUTSCH,H. F. A crystalline macroglobulin from human serum. J. Biol. Chem., 222: 31, 1956. 89. KORNGOLD, L. and VAN LEEU~EN, G. Macroglobulinemia. II. Antisera specific for pathological macroglobulins. J. Exper. Med., 106: 477, 1957. 90. KORNGOLD, L. and VAN LEEUWEN, G. Macroglobulinemia. I. The antigenic relationship of pathological macroglobulins to normal r-globulins. J. Exper. Med., 106: 467, 1957. 91. KORNGOLD, L. and VAN LEEU~EN, G. Macroglobulinemia. III. The effect of mercaptoethanol on the antigenic structure of macroglobulins. J. Exper. Med., 110: 1. 1959. 92. SCHEIDEGGER,J. J., WEBER, R. and H;iss~c, A. Zur Antigenstruktur der Makroglobuline beim Morbus WaldenstrGm. H&et. med. acta, 25: 25, 1958. 93. PUTNAM,F. W. Abnormal human serum globulins. I. The nonidentity of macroglobulins. Arch. Biothem., 79: 67, 1959. 94. FAHEY, J. L. and SOLOMON,A. Two types of ymyeloma proteins, /3a-myeloma proteins, ylmacroglobulins, and Bence Jones proteins identified by two groups of common antigenic determinants. J. Clin. Invest., 42: 811, 1963. 95. ROSEN, F. S. The macroglobulins. New England J. Med., 267: 491, 546, 1962. 96. KUNKEL, H. G., FUDENBERG,H. and OVARY, Z. High molecular weight antibodies. Ann. New York Acnd. SC., 86: 966, 1960. 97. RITZMANN,S. E., COLEMAN,S. L. and LEVIN, W. C. The effect of some mercaptanes upon a macrocryogel-globulin; modifications induced by cysteamine, penicillamine and penicillin. J. Clin. Invest., 39: 1320, 1960. 98. KRITZMAN, J., KUNKEL, H. G., MCCARTHY, J. and AMERICAN

JOURNAL

OF

MEDICINE

Primary

Macroglobulinemia--1ZfcCallister

M~~LL~Rs, R. C. Studies of a Waldenstrom-type macroglobulin with rheumatoid factor properties. J. Lab. & Clin. Med., 57: 905, 1961.

99. &RDA, J. and \TIEDERMANN, D. Ultrafiltration measurement of paraprotein particles in four cases of macroglobulinemia. Experientza (Base/), 13: 397,1957. 100. FAHE’I., J. L. Chromatographic studies of anomalous y-, BII-, and macroglobulins and normal yglobulins in myeloma and macroglobulinemic sera. J. Biol. Chem., 237: 440, 1962. 101. PERNIS, B., WUHRMANN, F. and WUNDERLY, C Aminoacid composition of macroglobulins in four cases of macroglobulinemia. Acta haemat., 11: 309, 1954. 102. MANDEMA, E., VAN DER SCHAAF, P. C. and HUIS MAN, T. H. J. Investigations on the amino acid composition of a macroglobulin and a cryoglobulin. J. Lab. @ Clvz. Med., 45: 261, 1855. 103. PUTNAM, F. W. Plasma-cell myeloma and macroglobulinemia. I. Physicochemical, immunochemical and isotopic turnover studies of the abnormal serum and urinary proteins. New England J. Med., 261: 902, 1959. 104. GABUZDA, T. G. The turnover and distribution of I-i3’-labeled myeloma and macroglobulin proteins. J. Lab. & Clin. Med., 59: 65, 1962. 105. SOLOMON, A., WALDMANN,‘1’. A. and FAHEY, J. L. Metabolism of normal 6.6-S -y-globulin in normal subjects and in patients with macroglobulinemia and multiple myeloma. J. Lab. & Clin. Med., 62: 1, 1963. 106. DEUTSCH, H. F. and MORTON, J. I. Dissociation of human serum macroglobulins. Science, 125: 600, 1957. 107. REISNER, C. A. and FRANKLIN, E. C. Studies of mercaptoethanol-dissociated normal human 19s r-globulin and pathologic macroglobulins from patients with macroglobulinemia. J. Zmmunol., 87: 654, 1961. 108. KORNGOLD, L. and VAN LEEUWEN, G. Macroglobulinemia. III. The effect of mercaptoethanol on the antigenic structure of macroglobulins. J. Exper. Med., 110: I, 1959. 109. BLOCH, H. S., PRASAD, A., ANASTASI, A. and BRIGGS, D. R. Serum protein changes in WaldenStrom’s macroglobulinemia during administration of a low molecular weight thiol (penicillamine). J. Lab. & Clin. Med., 56: 212, 1960. 110. LORBER, A., PEARSON, C. M., MEREDITH, W. L. and GANTZ-MANDELL, L. E. Serum sulfhydryl determinations and significance in connective tissue disease. dnn. Znt. Med., 61 : 423, 1964. 111. MILLER, D. Heparin precipitability of the macroglobulin in a patient with Waldenstrijm’s macroglobulinemia. Blood, 16: 1313, 1960. 112. DUTCHER, J. F. and FAHEY, J. L. Immunocytochemical demonstration of intranuclear localization of 18s gamma macroglobulin in macroglobulinemia of Waldenstt%m. Proc. Sot. Exper. Biol. & Med., 103: 452, 1960. 113. CURTAIN, C. C. Localization of 18s gammamacroglobulin in plasmacytoid cells of the bone marrow of a case of macroglobulinaemia. Australian J. Exper. Biol. & M. SC., 39: 391, 1961. 114. ZUCKER-FRANKLIN, D., FRANKLIN, E. C. and VOL.

43,

SEPTEMBER

1967

115.

116.

117.

118. 119.

120.

121. 122.

123.

124.

125.

126.

127.

128. 129.

130.

131.

132.

133.

et al.

433

COOPER, N. S. Production of macroglobulins in vitro and a study of their cellular origin. Blood, 20: 56, 1962. BRITXN, G. M., TANAKA, Y. and BRECHER, G. Intranuclear inclusions in multiple myeloma and macroglobulinemia. Blood, 21: 335, 1963. BOTTURA, C. and FERRARI, I. Chromosome abnormalities in Waldenstrom’s macroglobulinemia. Lancet, 1: 1170, 1961. BENIRSCHKE, K., BROWNHILL, L. and EBAUCH, F. G. Chromosomal abnormalities in WaldenstrGm’s macroglobulinaemia. Lancet, 1: 594, 1962. PATAU, K. Chromosomal abnormalities in WaldenStrom’s macroglobulinemia. Lancer, 2: 600, 1961. WALL, R. L. The use of serum protein electrophoresis in clinical medicine. Arch. Znt. Med., 102: 618, 1958. KYLE, R. A., BAYRD, E. D., MCKENZIE, B. F. and HECK, F. J. Diagnostic criteria for electrophoretie patterns of serum and urinary proteins in muliple myeloma: study of one-hundred and sixty-five multiple myeloma patients and of seventy-seven nonmyeloma patients with similar electrophoretic patterns. J.A.M.A., 174: 245, 1960. Weekly Clinicopathological Exercises. New England J. Med., 264: 504, 1961. FAIRLEY, G. H. and SCOTT, R. B. Hypogammaglobulinaemia in chronic lymphatic leukaemia. Brit. M. J., 2: 920, 1961. WALDENSTR~M, J. Diseases associated with abnormal plasma proteins. Proc. Roy. Sac. Med., 53: 789, 1960. ABRAMS, A., COHEN, P. P. and MEYER, 0. 0. The physical properties of a cryoglobulin obtained from lymph nodes and serum of a case of lymphosarcoma. J. Biol. Chem., 181: 237, 1949. PRASAD, A. S. and BLOCH, H. S. Macroglobulinemia secondary to a lymphosarcoma of the brain. Arch. Znt. Med., 105: 316, 1960. DAWBORN, J. K. Macroglobulinaemia and severe intestinal haemorrhage in lymphosarcoma. M. J. Australia, 2: 515, 1961. SIRRIDGE, M. J. WaldenstrBm’s macroglobulinemia with cryoglobulinemia. Ann. Znt. Med., 53: 380, 1960. DAMESHEK, W. Cited by Ritzmann, S. E., Lang, P. A. and Levin, W. C. [730]. BURNET, F. M. The Clonal Selection Theory of Acquired Immunity. Nashville, Tenn., 1959. Vanderbilt University Press. RITZMANN, S. E., LANG, P. A. and LEVIN, W. C. Multiple paraproteinemia with cold agglutinin syndrome in malignant lymphoma. Texas Rep. Biol. & Med., 20: 251, 1962. RITZMANN,S. E. and LEVIN, W. C. Cold agglutinin disease. A type of primary macroglobulinemia: a new concept. Texas Rep. Biol. & Med., 20: 236, 1962. FAHEY, J. L., POTTER, M. and NATHANS, D. Myeloma proteins and macroglobulins associated with plasma cell tumors in experimental animals. Acta Univ. internat. contra cancrum, 16: 1137, 1960. CLAUSEN, J., RASK-NIELSEN, R., CHRISTENSEN, H. E., LONTIE, R. and HEREMANS, J. Macroglobulinemia in a transplantable mouse leu-

434

134.

135.

136. 137.

138.

139.

Primary

Macroglobulinemia--McCallister

kemia. I’roc. Sac. Exper. Biol. H Med., 103: 802, 1960. COHEN, S., SOLOMON, A., PARONETTO, F. and POPPER, H. Subacute hepatitis in WaldenstrGm’s macroglobulinemia. Am. J. Med., 34: 256, 1963. KOUGH, R. H. Macroglobulinemia of Waldenstriim: report of a case with few symptoms: brief review of the literature. J. Am. Geriatrics Sot., 11 : 323, 1963. LEVIN, W. C. and RITZMANN, S. E. Treatment of macroglobulinaemia. &it. M. J., 1: 1160, 1963. BLOCH, H. S., PRASAD, A. and ANASTASI, A. Serum macroprotein changes in WaldenstrBm’s globulinemia during penicillamine administration. J. Lab. & Clin. Med., 52: 793, 1958. SOLOMON, A. and FAHEY, J. L. Plasmapheresis therapy in macroglobulinemia. Ann. Znt. Med., 58: 789, 1963. LONG, L. A., RIOPELLE, J. L., FRANCOEUK, M.,

140.

141.

142.

143.

et al.

PARE, A., POIRIER, P., GEORGESCO, M. and COLPRON, G. Macroglobulinaemia: effect of macroglobulins on prothrombin conversion accelerators. Canad. M. A. J., 73: 726, 1955. BOURONCLE,B. A., DATA, P. and FRAJOLA, W. J. Waldenstram’s macroglobulinemia: report of three patients treated with cyclophosphamide. J.A.M.A., 189: 729, 1964. CLATANOFF, D. V. and MEYER, 0. 0. Response to chlorambucil in macroglobulinemia. J.A.M.A., 183: 40, 1963. KOK, D’A. Response to chlorambucil therapy in two cases of Waldenstrlim’s macroglobulinemia. In: Proceedings of the Eighth Congress of the European Society of Haematology, vol. 1, p. 161. New York, 1962. S. Karger AG. PHELPS, M. D., JR. and GEOKAS,M. C. Circulatory problems in dysproteinemia. M. Clin. North America, 47: 353, 1963.

AMERICAN

JOURNAL

OF

MEDICINE