Lymphoproliferative disorders of the thorax

Lymphoproliferative E. R. Heitzman,

M.D., Bedros Markarian,

I

T IS POPULAR to state that the lung can respond to stimuli in only a limited number of ways. One such response is the infiltration of the interstitium with lymphocytes and plasma cells to produce a lymphoproliferative disorder. Those generalized conditions that are perhaps best grouped under this title include the dysgammaglobulinemias, the monoclonal gammopathies, and the plasma cell dyscrasias.” They affect the thorax uncommonly. Even so, these conditions have been attracting increased interest in recent years due to the fascinating array of clinical, pathologic, and radiologic findings that they present and because of their potential to evolve into frankly malignant forms. The rapidly proliferating body of information concerning the nature of immunologic responses in man has further heightened interest in the lymphoproliferative disorders. In the minds of almost all observers, these are mediated through abnormality of the immune response. This is not to imply that the exact nature of the immunologic background of the lymphoproliferative disorders is well understood. In fact, the nature of the abnormal immune response is at the present time poorly understood and highly controversial. The lymphoproliferative disorders are characterized by OssermanzO as follows: (1) Proliferation of plasma cells in the absence of an identifiable antigenic stimulus; (2) elaboration of monoclonal gammaglobulins; and (3) a commonly associated deficiency in the synthesis of normal immunoglobulins. Dysgammaglobulinemia is not invariably encountered, however. A classification of the lymphoproliferative disorders has been developed by Osserman and Isobe” and is given in Table 1. Recently, it has been suggested that several disorders of the lung that are similarly characterized by abnormal accumulations of lymphocytes and plasma cells in the pulmonary interstitium repreE. R. Heitzman, M.D.: Professor, Department

of RadiUpstate Medical Center, Syracuse, N. Y. Bedros of Markarian, M.D.: Assistant Professor, Department Pathology, Upstate Medical Center, Syracuse, N. Y. Charles T. DeLise, M.D.: Resident, Department of Radiology, Upstate Medical Center, Syracuse, N. Y. o I9 75 by Grane & Stratton, Inc. ology,

Seminars

in Roentgenology,

Vol.

Disorders of the Thorax

X, No. 1

(Januarv). 1975

M.D., and Charles T. DeLise, M.D.

sent variations in a spectrum of lymphoproliferative disease as it effects the thorax.12~‘4,15 These conditions are lymphocytic interstitial pneumonia (LIP), pseudolymphoma, Sjogren’s syndrome and primary (Waldenstrom) macroglobulinemia. It is probable that pulmonary amyloidosis should be included in this list, and it is likely that others will be added to the group as our knowledge grows. The lymphoproliferative disorders exist in a spectrum of benign to malignant forms in which lymphocytic interstitial pneumonia is the most benign and lymphocytic lymphoma the most malignant. This area of pulmonary medicine, therefore, is becoming another important interface between radiology and immunology. It is our purpose to review our experience with these disorders and to emphasize several facets of this continuum, including variations in radiographic and pathologic appearance, salivary gland involvement, immunoglobulin abnormalities, and clinical course. LYMPHOCYTIC

INTERSTITIAL

PNEUMONIA

Idiopathic chronic interstitial pneumonia has been divided into five types in a classification proposed by Liebow and Carrington.13 Included in this group is lymphocytic interstitial pneumonia. This condition has been defined by them as “exquisitely interstitial diffuse infiltrations of the lung predominantly by lymphocytes with varying admixtures of plasma cells and other elements.“14 This disorder affects primarily adults but has been reported in children as young as 15 mo.13 There is no sex predilection. The most common symptom is dyspnea, although many patients also complain of cough and fatigue. The clinical course usually is indolent (Fig. l), although at times the disease may demonstrate a more rapid progression or a sudden acceleration of a previously chronic course. Radiologically, the spectrum of pulmonary changes is extremely variable: One or more nodules (Figs. 2A and 2B), a fine reticular pattern consistent with interstitial disease (Fig. 2C), coarse flame-like shadows consistent with interstitial disease (Fig. 2D), and a diffuse confluent pattern frequently accompanied by an air bronchogram and therefore strongly simulating air space disease 73

HEITZMAN,

74

Table 1. Classification of the Lymphoproliferative Disorders Clinically overt forms Plasma cell myeloma (multiple myeloma) Primary (Waldenstrom) macroglobuI.i.nemia Heavy chain disease Amyloidosis Papular mucinosis Clinically occult forms Plasma cell dyscrasias of unknown significance Associated with chronic inflammatory and infectious processes Associated with nonreticular neoplasms Associated with lipodystrophies Transient olasma cell dvscrasias

MARKARIAN,

AND

DeLlSE

(Figs. 1B and 1C). Examples of the latter type point out the now well-established fact that many disease processes that are purely interstitial in origin, when extensive, may present all the radio’ graphic features usually attributed to air space disease. In these cases, the abnormal process has replaced so much pulmonary tissue that no underlying architecture, alveolar or interstitial, can be identified grossly or microscopically. Lymphocytic interstitial pneumonia is rarely associated with lymphadenopathy. Pleural fluid has not been encountered. Since the roentgen presentations of lymphocytic interstitial pneumonia are so diverse, it is unfortunately true that the diagnosis cannot be made with any degree of certainty from the radiographs alone. PSEUDOLYMPHOMA

Pseudolymphoma is characterized histologically by Saltzstein as “an infiltrate of mature lymphocytes and other inflammatory cells, true germinal centers and lymph nodes free of lymphoma.“25 According to Liebow and Carrington, the appear-

Fig. 1. Lymphocytic interstitial pneumonia histologically verified. This 58yrold woman had an indolent course, with progression over a lo-yr period (A and 5) to extensive, poorly marginated shadows accompanied by an air brochogram, simulating air space disease. Note the rapid resolution (Cl following the administration of steroids. The patient’s IgM elevation returned to normal with the improvement in the radiographic appearance.

76

HEITZMAN,

MARKARIAN,

AND

DeLlSE

(A) Poorly defined Fig. 3. Pseudolymphoma. shadow of increased density in the right lower lobe, simulating air space disease; and (BI microscopic section from the excised lesion. The exquisitely interstitial nature of the lymphocytic infiltration is apparent. A diagnosis of pseudolymphoma was rendered. (C) biopsy material from the chest wall 4 yr later shows infiltration of muscle fibers (arrow) by lymphocytes, indicating lymphosarcoma.

ante of the individual microscopic field in pseudolymphoma is identical to that of lymphocytic interstitial pneumonia.14 The two terms therefore can be used interchangeably; however, it is more common parlance to use the term lymphocytic interstitial pneumonia for a diffuse process in lung, while pulmonary pseudolymphoma is reserved for a localized, although conceivably extensive, lesion. Based on this distinction, the localized lesion of pseudolymphoma can be expected to appear radiographically as a homogenous, poorly defined localized pulmonary lesion often accompanied by an air bronchogram (Fig. 3).

SJijGREN’S

SYNDROME

Sjogren’s syndrome is a chronic autoimmune disease characterized by keratoconjunctivitis sicca, xerostomia, and a connective tissue disease.7 About half the patients have rheumatoid arthritis, but systemic lupus erythematosus, polyarteritis, dermatomyositis, and scleroderma also have been described.397 The disease is primarily one of middle-aged women. It has been pointed out that “a broad spectrum of lymphoproliferation exists in Sjogren’s syndrome from benign to frankly malignant disease with a group of diseases termed

LYMPHOPROLIFERATIVE

DISORDERS

77

pseudolymphoma occupying the middle portion of the spectrum. The basic histopathology of these lesions is the same; namely, lymphoid infiltration.“’ Thus, the histologic picture presented in lung or thoracic lymph nodes may be identical to that seen in lymphocytic interstitial pneumonia and pseudolymphoma. The radiologic diagnosis of the thoracic lesions of Sjogren’s syndrome present relatively little problem. Chronic parenchymal densities, appearing either alveolar or interstitial in nature, associated with mediastinal adenopathy in a patient with the classic clinical syndrome should be considered a manifestation of lymphocytic infiltration until proven otherwise (Fig. 4). Although obviously other intercurrent disease processes may appear similar, the diagnosis of the pulmonary lesions usually can be established with more certainty on the basis of response to radiation therapy or steroids. WALDENSTR6M

MACROGLOBULINEMIA

Primary (Waldenstrom) macroglobulinemia is characterized by “an abnormal bone marrow proliferation in which lymphocytes or lymphocytelike cells predominate, a striking narrow band increase in serum globulins which can be shown to be IgM by immunoelectrophoresis and a macroglobulin by ultracentrifugal analysis, and a clinical pic-

Fig. 4. SjSgren’s syndrome. This patient “sicca” syndrome shows mediastinal typical hilar adenopathy with a diffuse, poorly parenchymal infiltrate.

with the and right marginated

ture which largely reflects a ‘hyperviscosity synsyndrome is drome’.“22 The hyperviscosity secondary to the macroglobulins that are apparently manufactured by the abnormal cells. The disease is recognized by most observers as a more malignant process in the lymphoproliferative spectrum. Pulmonary parenchymal involvement in primary macroglobulinemia is rare but, when present, is characterized by a lymphocytic and plasma cell interstitial infiltration that is histologically indistinguishable from the cellular infiltrations produced by the other lymphoproliferative disorders.79’4 Radiographs may show a broad range of pulmonary abnormalities including nodules, reticular changes consistent with interstitial disease (Fig. 6), and diffuse, confluent, and poorly marginated shadows consistent with air space disease. Pleural effusion in Waldenstrom’s macroglobulinemia is not uncommon” and extramedullary hematopoesis may be seen.22 Radiographic patterns in the lung produced by Waldenstrom’s macroglobulinemia again should present relatively little problem in differential diagnosis if they are associated with a classical clinical syndrome. LYMPHOCYTIC

LYMPHOMA

Lymphocytic lymphoma of the lung clearly represents lymphoproliferative pulmonary disorder at the most malignant end of the spectrum. Primary lymphocytic lymphoma of the lung is an extremely rare entity, although the lung is not infrequently involved in systemic lymphosarcoma,24 predominantly between the ages of 30 and 70 yr.8 The course is not uncommonly indolent. Histologically, lymphocytic lymphoma may be difficult to distinguish from the nonmalignant conditions in the lymphoproliferative spectrum, particularly early in its course. Liebow and Carrington state that “lymphocytic interstitial pneumonia may be difficult to distinguish from lymphoma as it involves the lung since the criteria are not yet well defined or tested by the necessarily long period of observation. The presence of numerous mitoses favors lymphoma. In localized lesions, it has been stated that the presence of germinal centers favors the diagnosis of pseudolymphoma. However, when the lesions are diffuse, these can occur both in LIP and lymphoma. Lymphoma also is favored by the destructive involvement of the

HEITZMAN,

78

MARKARIAN,

AND

DeLlSE

Fig. 5. Primary (WaldenstrGm) macroglobulinemia. Diffuse reticular pattern. This radiographic appearance in the face of the typical syndrome should be considered to be due to this lymphoproliferative disorder until proven otherwise. Proved by biopsy. (Courtesy of R. G. Fraser, M.D., Montreal, Canada.)

larger air spaces.” The diagnosis of lymphoma is substantiated “when symphysis with the parietal pleura has taken place and invasion of the extrapleural fat and endothoracic fascia has occurred” (Fig. 4C).14 The most common radiographic appearance is that of diffuse poorly marginated shadows of increased density consistent with air space disease; an air bronchogram may be encountered. Lymph node enlargement in the mediastinum is commonly but not invariably associated. DIFFERENTIAL

DIAGNOSIS

Since the five conditions just discussed produce very similar and occasionally identical gross and microscopic pathologic changes, it is clear that their radiographic appearances often will be indistinguishable from one another. Furthermore, since the roentgen findings are so varied, distinction from other pulmonary processesis frequently impossible prior to lung biopsy. If the clinical features in the patient are those of Sjogren’s syndrome or primary macroglobulinemia, it is reason-

able to assume that the changes identified on radiographs of the thorax are the result of lymphoproliferative changes occurring in these conditions. Response to appropriate therapy is confirmatory. How does one suggest the diagnosis of lymphocytic interstitial pneumonia or pseudolymphoma, the most common entities in the lymphoproliferative group? Two important clues may be encountered that suggest a lymphoproliferative disorder: salivary gland enlargement and immunoglobulin abnormalities. Salivary gland enlargement is an important feature of the lymphoproliferative disorders. It is, of course, one of the classical findings in Sjbgren’s syndrome and has been reported in primary macroglobulinemia. Perhaps more important from the standpoint of differential diagnosis is the fact that the salivary gland involvement was found in four of 18 patients with lymphocytic interstitial pneumonia reported by Liebow and Carrington and was also encountered in our series. When an obscure chronic pulmonary process is accompanied by clinical evidence of salivary gland enlargement,

LYMPHOPROLIFERATIVE

DISORDERS

79

a lymphoproliferative disorder should be considered a likely diagnosis. Abnormalities of immunoglobulin synthesis in the lymphoproliferative disorders constitute one of their most interesting aspects. Monoclonal elevation of IgM is a constant feature of primary macroglobulinemia, and immunoglobulin abnormalities also are frequent findings in Sjogren’s syndrome.’ It has been well established that lymphocytes of the B cell type are responsible for the production of immunoglobulins.” It might be reasonable to postulate, therefore, that the abnormal accumulations of lymphocytes in the lymphoproliferative disorders cause the immunoglobulin abnormalities. Indeed, the abnormal lymphoid tissue that infiltrates the salivary glands in Sjogren’s syndrome has been shown to synthesize immunoglobulin in much larger amounts than one finds in the salivary glands of normal individuals.7 Liebow and Carrington have reported 17 patients in whom lymphocytic interstitial pneumonia was associated with a dysproteinemia. In 12, gammaglobulins were elevated, while in five they were reduced. The incidence of dysproteinemia in lymphocytic interstitial pneumonia is still uncertain, but the fact that they were able to collect 17 cases suggests that the association must be frequent. In the seven patients with lymphocytic interstitial pneumonia in our series (Table 2), immunoglobulins were elevated in six and were normal in only one patient whose immunoglobulin determinations

Table

2. Dysgammaglobulinemia in the Lymphoproliferative Disorders

CXXS

7 8 9

10

Diagnosis L.I.P. L.I.P. L.I.P. L.I.P. L.I.P. L.I.P. Initial Post Rx L.I.P. Primary Macroglobulinemia Sjiigren’s syndrome Initial Late Sjbgren’s Initial Late

IN

Ii@

IgM

N N t t N

N t N N N

N N N N t

N N t N

N N N N

t N N t

N

N Hypogammaglobulinemia

N

N

t Hypogammaglobulinemia

N

syndrome

were made several months after treatment was instituted. The likelihood that the abnormal lymphocyte collections in lymphocytic interstitial pneumonia produce excess immunoglobulins is supported by observations made on one patient in our series in whom marked IgM elevation was associated with extensive pulmonary lymphocytic infiltration (Fig. 1). Following steroid therapy, the pulmonary changes improved and the IgM level returned to normal, only to rise with the recrudescence of the pulmonary lesion following reduction in steroids. Immunoglobulin elevations with lymphocytic lymphoma is uncommon.23 It is interesting to conjecture that lymphocytes at the malignant end of the lymphoproliferative spectrum are less differentiated and therefore less capable of carrying out a complicated cell function, such as immunoglobulin synthesis. In support of this idea is the report of a case of primary macroglobulinemia in which the IgM elevation disappeared when the disease process passed into a frankly malignant phase.“8 The determination of immunoglobulin levels, therefore, is often worthwhile in the evaluation of an obscure chronic pulmonary abnormality. If dysgammaglobulinemia is present, one of the benign lymphoproliferative disorders should become a major consideration. MALIGNANT POTENTIAL LYMPHOPROLIFERATIVE

OF BENIGN DISORDERS

As already implied, it is generally conceded that the lymphoproliferative diseases manifest themselves in a spectrum of benign to malignant forms. Lymphocytic interstitial pneumonia and pseudolymphoma, the more benign variants, apparently rarely degenerate into malignant lymphoma. One example in the present series (Fig. 3) seems to demonstrate this transformation, although it might be contended that he really had low-grade lymphosarcoma from the onset. Sjogren’s syndrome apparently exists in benign and malignant variants. Appearance of malignant lymphoma in a patient with Sjogren’s syndrome is not uncommon and occurred twice in our series. Each of these patients developed reticulum cell sarcoma, the most common form of malignant degeneration in this disease.‘,’ It has been noted that the development of hypogammaglobulinemia is a poor prognostic sign in Sjogren’s syndrome, sometimes heralding malignant degeneration.1,26

HEITZMAN,

80

This occurred in both of our malignant cases. Primary macroglobulinemia, usually considered at the more malignant end of the lymphoproliferative spectrum, frequently terminates fatally. In some cases, frank transformation to lymphosarcoma occurs.28 RELATIONSHIP LYMPHOPROLIFERATIVE OTHER THORACIC

OF THE DISORDERS DISEASES

TO

Our observations lead us to concur with Talal et a1.,26 who stated “we conclude that patients with Sjogren’s syndrome, macroglobulinemia, and pseudolymphoma have a disorder that lies somewhere between hyperplasia and neoplasia. It seems likely that other pulmonary diseases may be similarly, although probably less directly, related to these lymphoproliferative disorders.” The microscopic findings in one case (Fig. 3) in our series strongly supports this point of view. This patient, originally considered to have pseudolymphoma, eventually died of pulmonary lymphosarcoma. In addition to these diagnoses, the microscopic material obtained from pulmonary resections performed during his protracted clinical course presents features typical of three other pulmonary diseases, rheumatoid lung, lymphomatoid granulomatosis, and necrotizing sarcoid angiitis and granulomatosis. What if lung biopsy only had been performed? Depending on the site of the biopsy, it is conceivable that a diagnosis of one of these three different diseases,usually considered to be distinct entities, would have been made, rather than a lymphoproliferative disorder. This observation suggests that these conditions are related to the lymphoproliferative disorders in some as yet undefined way. Some other interesting associations are worthy of comment. Recently, the association of Sjiigren’s syndrome and amyloidosis has been reported. Evidence is accumulating that strongly supports the view that amyloidosis is likewise a disease of altered immune response.4’5Y16 Recent observations suggest that the basic constituent of amyloid is a portion of the immunoglobulin light chain produced by cells in the lymphocytic series.’ Idiopathic interstitial fibrosis14 and plasma cell granuloma’ (still another disease characterized by proliferation of cells in the lymphocyte-plasma cell series) may have elevated serum immunoglobulins, in common with the lymphoproliferative

MARKARIAN,

AND

DeLlSE

disorders. Rheumatoid lung commonly is associated with elevated rheumatoid factor in serum; this finding may also be encountered in chronic interstitial pneumonia27 and is frequent in such lymphoproliferative disorders as Sjogren’s syndrome7 and lymphocytic interstitial pneumonia.14 At the moment, the significance of these associations is obscure, but they certainly reinforce the often suggested possibility that interstitial pneumonia and the so-called collagen diseases.in common with the lymphoproliferative disorders, are diseasesof altered immunity. DISCUSSION

What, then, is the nature of the abnormal immunologic response that leads to the development of a lymphoproliferative disorder? Unfortunately, the answer to this question is unknown. Anderson and Talal state that “at this point in our knowledge, there is no adequate explanation for the lymphoproliferation in glandular tissue and its spread to extraglandular sites, the autoimmune phenomena or the tendency for lymphoreticular malignancy in Sjogren’s syndrome.“’ A similar statement could be made for all of the lymphoproliferative disorders. Coombs and Gel1 define a type IV immunologic reaction or response as “initiated essentially by the reaction of specifically modified mononuclear cells containing a substance or mechanism capable of responding specifically to allergen deposited at a local site. The exact mechanism of this type of reaction is still uncertain, but it is manifested by the infiltration of cells at the site where the antigen is.“6 Since the lymphoproliferative disorders are characterized by proliferation of reticuloendothelial cells, and since this type of cellular response is not characteristic of the other three classic types of immunologic response, it is attractive to postulate that the lymphoproliferative disorders are mediated through a type IV response as are diseasesproduced by certain viruses and by most fungi and parasites. The fact that the lymphoproliferative disorders exist in malignant forms and apparently can undergo malignant transformation also suggests that they may be mediated through a type IV response, since it is generally conceded that this type of immunologic reaction is responsible for tumor surveillance and immunity. However, the type IV or cell-mediated type of immune response involves thymic lymphocytes or

LYMPHOPROLIFERATIVE

DISORDERS

81

so-called T cells. These cells apparently are not responsible for immunoglobulin synthesis, abnormalities of which are so characteristic of the lymphoproliferative disorders. This function is carried out by B cells that are the mediators of humoral immunity. Furthermore, the lymphoproliferative disorders seem to be allied in many ways to the so-called collagen diseases that are generally considered to be mediated through a type III immune complex response.ls,lg It may

well be that the lymphoproliferative disorders are the result of abnormality of more than one type of immune response mediated by both T and B lymphocytes. Holborow states: “The hypothesis that lymphocytes cooperate in the production of antibodies has received experimental support from many different quarters. This has laid new emphasis on the interrelationship between T and B lymphocytes, distinct though their provenances and effector roles have seemed to be.“”

REFERENCES 1. Anderson LG, Talal N: The spectrum of benign to malignant lymphoproliferation in Sjogren’s syndrome. Clin Exp Immunol10:199-221,1972 2. Bahadori M, Liebow AA: Plasma cell granulomas of the lung. Cancer 31:191-208, 1973 3. Bloch KJ, Buchanan WW, Wohl MJ, et al: Sjogren’s syndrome. A clinical, pathological, and serological study of 62 cases.Medicine (Baltimore) 44: 187-231, 1965 4. Bomrer H Jr, Ennis RS, Geelhoed GW, et al: Lymphoid infiltration and amyloidosis of lung in Sjogren’s syndrome. Arch Path01 95:42-44, 1973 5. Calkins E: Relationship of amyloidosis to immunologic mechanisms in amyloidosis, in Mandema E, Ruinem L, Scholten JH, et al (eds): Amsterdam, Excerpta Medica, 1968, pp 87-99 6. Coombs RRA, Gell PGH: The classification of allergic reactions underlying disease,in Gel1 PGH, Coombs RRA (eds): Clinical Aspects of Immunology (ed 2). Philadelphia, SA Davis, 1968, pp 575-596 7. Cummings NA, Schall GL, Asofsky R,et al: Sjogren’s syndrome-newer aspects of research, diagnosis, and therapy. Ann Intern Med 75:937-950, 1971 8. Fraser RG, Pare JAP: Diagnosis of Diseases of The Chest. Philadelphia, WB Saunders, 1970 9. Glenner GG, Terry W, Harada M, et al: Amyloid tibril proteins: Proof of homology with immunoglobulin light chains by sequence analyses. Science 172: 1150-1151,197l 10. Good RA: Disorders of the immune system, in Good RA, Fisher DW (eds): Immunobiology. Stamford, Sinauer, 1971, pp 3-17 11. Holborow EJ: An ABC of Modern Immunology (ed 2). Boston, Little Brown, 1973 12. Liebow AA: Pulmonary angiitis andgranulomatosis. The J Burns Amberson Lecture. Am Rev Respir Dis 108:1-18,1973 13. Liebow AA, Carrington CB: The interstitial pneumonias, in Simon M, Potchen EJ, LeMay M (eds): Frontiers of Pulmonary Radiology. New York, Grune and Stratton, 1969 14. Liebow AA, Carrington CB: Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia. Med Clin North Am 57:809-843,1973

15. Liebow AA, Carrington CB, Friedman PJ: Lymphomatoid granulomatosis. Hum Path01 3:457-588, 1972 16. Mandema E, Ruinen L, Scholten JH, et al (eds): Amyloidosis. Proceedings of the Symposium on Amy. loidosis, University of Groningen, The Netherlands, September 24-28, 1967. Amsterdam, Excerpta Medica, 1968 17. McCallister BD, Bayrd ED, Harrison EG Jr, et al: Primary macroglobulinemia. Am J Med 43:394-434, 1967 18. McCombs RP: Diseases due to immunologic reactions in the lung. I. N Engl J Med 286:1186-1194, 1972 19. McCombs RP: Diseases due to immunologic reactions in the lung. II. N Engl J Med 286:1245-1252, 1972 20. Osserman EF: Plasma cell dyscrasias, in Belson PB, McDermott W (eds): Cecil Textbook of Medicine (ed 13). Philadelphia, WB Saunders, 1971, pp. 1574-1589. 21. Osserman EF, Isobe T: Lymphoreticular disordersmalignant proliferative response and/or abnormal immunoglobulin synthesis-plasma cell dyscrasias, in Williams W, Beutler E, Erslev A, et al (eds): Hematology. New York, McGraw-Hill, 1972 22. Renner RR, Nelson DA, Lozner EL: Roentgenologic manifestations of primary macroglobulinemia (Waldenstrom). Am J Roentgen01 113:499-508, 1971 23. Ritzmann SE, Staufflet EJ, Houston EW, et al: Coexistent chronic myelocytic leukemia, monoclonal gammopathy, and multiple chromosomal abnormalities. Am J Med 41:981-989,1966 24. Rosenberg SA, Diamond HD, Jaslowitz B, Craver LF: Lymphosarcoma: A review of 1269 cases. Medicine (Baltimore) 40:31-84, 1961 25. Sal&stein SL: Pulmonary malignant lymphomas and pseudolymphomas: Classification, therapy, and prognosis. Cancer 16:928-955, 1963 26. Talal N, Sokoloff L, Barth WF: Extrasalivary lymphoid abnormalities in Sjogren’s syndrome (reticulum cell sarcoma, “pseudolymphoma,” macroglobulinemia). Am J Med 43:5065, 1967 27. Tomasi TB Jr, Fudenberg HH, Finby N: Possible relationship of rheumatoid factors and pulmonary disease. Am J Med 33:243-248, 1962 28. Williams RC Jr, Bailly RC, Howe RB: Studies of “benign” serum M-components. Am J Med Sci 257: 275-293, 1969