Immunodeficiency, pulmonary lymphoreticular infiltration, paraproteinemia, and terminal lymphoma

Imm uno def icien cy, Pulmonary Lympho re tic ular Infiltration, Parapro tein em ia, and Terminal Lymphoma J. M. RICHMOND, MB, BS, FRACP,' R. L. DAWKINS, MD, MRCP, FRCPA,t D. W. HENDERSON, MB. BS, FRCPA,$ AND N. T. S. TAN, MB, BSP

A 64-year-old woman was found to have pulmonary lymphoreticular infiltration associated with a cryoprecipitate monoclonal paraprotein. History and investigation suggested that these features may have complicated long-standing immunodeficiency. Subsequent postmortem revealed a lymphocytic lymphoma of the lung and stomach. It is postulated that pulmonary lymphoreticular infiltration and monoclonal parapruteinemia might be a consequence of defective immunoregulation with excessive B cell proliferation. The eventual lymphoma is thought to represent malignant transformation. Cancer 47:2641-2647, 1981.

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has been increasing interest in the relationship b e t w e e n benign lymphorecticular infiltrations of t h e lung, lymphoid malignancy, and i m m u node fi cienc y . Various n e o p l a s m s may c o m p l i c a t e immune defects,' but it is not clear w h e t h e r pulmonary l y m p h o reticular infiltrations s h o u l d be considered in this

Case Heport

I N C E 1973, there

category A 64-year-old w o m a n had a c o m p l e x immune d e f e c t possibly a n t e c e d e n t t o t h e d e v e l o p m e n t o f p u l m o n a r y lymphoreticular infiltration and a s s o c i a t e d with a nionoclonal IgM k a p p a paraprotein. Subsequently, a p o s t m o r t e m revealed well-differentiated l y m p h o c y t i c l y m p h o m a involving the lung and s t o m a c h . We suggest that p u l m o n a r y lymphoreticular infiltration may c o m p l i c a t e long-standing immunodeficiency and that s u b s e q u e n t l y l y m p h o m a d e v e l o p e d in this patient. Registrar, Department of Clinical Immunology. Royal Perth Hospital. Perth. + Head. Department of Clinical Immunology. Royal Perth Hospital, and Head. Department of Clinical Immunology, Queen Elizabeth I1 Medical Centre, Perth. t Senior Lecturer. University Deparlment of Pathology. Perth Medical Centre. Perth. B Ixclurer. Hospital and University Pathology Services. Queen Elizabeth I I Medical Centre. Perth. D. W . Henderson's present address is Department of Pathology. Hinders University of South Australia. Sturt Road. Bedford Park. South Australia. Address for reprints: J . M. Richmond. MB, BS. FRACP. Departmen1 o f Medicine. Victoria Hospital Corporation. South Street Campus. 1.ondon. Ontario. Canada N 6 A 4G5. The authors [hank Dr. J . Elder for permission to study this patient and Professor Ronald F. Dorfmm, Laboratory of Surgical Pathology. Stanford University. California, for reviewing the pathological sections. They also thank Mr. P. Kay and Mr. T. Cobain for technical a\si\tance. Accepted for publication M a y 19. 1980.

The patient, aged 64. was admitted to Sir Charles Gairdner Hospital in July 1975 for investigation of increasing respiratory difficulty. Symptoms had progressed over a period of at least six years and had been paralleled by radiologic evidence of increasing pulmonary infiltration predominantly in the upper zone (Figs. IA-C). In the year before admission a left pleural effusion had developed. Aspiration and culture were negative for tuberculosis, and treatment with prednisolone, 10 mg daily, was begun. There was a past history of recurrent rehpiratory infections and of four attacks of measles in childhood. Subsequently. frequent episodes of chest infection with purulent sputum developed, including pleurisy at age 25 and lobar pneumonia at age 42. Recent attacks were accompanied by wheezing. She was a nonsmoker, and there was no history of allergy. chest pain. fever, weight loss, or night sweats. Two brothers, both smokers. died of lung cancer, and the mother also died of cancer, type unknown. Rheumatoid arthritis and asthma were present in other family members. Examination revealed the absence of fever. a pulse rate of 84 beatshinute and blood pressure of 160190. Dyspnea was evident on minimal exertion. There were signs of a moderate left pleural effusion. and coarse inspiratory crepitations were present in both upper zones. The spleen was just palpable below the left costal margin. There was no significant lymphadenopathy or salivary gland enlargement. Initial investigations included a hemoglobin value of 115 &I, a leukocyte count of 5600/mm3. and erythrocyte sedimentation rate of 42 mm (Westergren). The chest x-ray on admission showed striking changes in both lung fields (Fig. IC) with infiltration of the parenchyma, bilateral upper zone patchy consolidation. and a left pleural effusion. Respiratory function assessment revealed reduced Iota1 lung capacity and uneveness of ventilation. which was attributed to parenchymal and obstructive airways disease. Progressive respiratory function tests demonstrated increasing obstruction and u n -

OOOX-543X/8l/0ho1/2641 $0.90CC American Cancer Society

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FIGS. 1A-C. Chest x-rays 1971 and 1975, demonstrating progressive pulmonary changes.

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PULMONARY LYMPHORETICULAR INFILTRATION . Richmond et rrl.

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TABLE1 . Clinical Course in Relation to Prednisolone Therapy

Prednisolone dosage mg/day Hemaglobin g/l Leukocyte count x 1OVl El ythrocyte sedimentation rate Total protein g/l Albumin g/l IgM g/l (0.96-2.80) IgC g/l (7.5- 15.0) IgA g/l (0.92-4.0)

Cryoprecipitate Vital capacity (Liters) FEVl Literdsec

July

August

September

October

November

10 149 9.1 25 75 38 5.2 4.2 0.9 - ve 1.70 1.11

10 115 5.6 42 67 34

60 123 8.1 45

40 129 6.8 55 58 33 4.4 5.6 0.8

40 130 17.6 54 33

+ve

+ ve

eveness of ventilation. The alkaline phosphatase was 510 unitsiliter (normal less than 350) and a liverlspleen scan demonstrated mild enlargement. Liver biopsy showed no abnormality by histopathology and immunofluorescence techniques. Bone marrow aspiration showed absent iron stores without evidence of plasmacytosis. The pleural effusion was aspirated (Table 1). Other studies included electrophoresis of serum, which revealed a sharp band in the gamma region but no other abnormalities. By densitometry scanning, the M component was found to have a concentration of approximately 6 gll. lmmunoelectrophoresis of serum showed a monoclonal IgM (Kappa) paraprotein. The urine contained free K light chains. Quantitation of serum immunoglobulins by the Mancini method (Oxford) revealed a distinctly elevated IgM with low IgG and IgA concentrations (Table I). On incubation of serum at 4 C for three days, a (dense)

FIG.2. Lung biopsy showing diffuse interstitial infiltration with mononuclear cells, predominantly lymphocytes. A mixture of plasma cells and large reticular cells is also present ( ~ 4 0 ) .

13.8 5.5 0.9

1.91 1.20

I .92

1.05

+ ve

1.95 1.38

2.20 1.36

cryoprecipitate appeared. On redissolving the cryoprecipitate at room temperature, immunoelectrophoresis revealed only ,uand K arcs. Serum rheumatoid factor titer was 1/1280 by latex agglutination (Hyland) and 1/16 by the Rheumaton assay (Denver). Following absorption with insolubilized human IgG, rheumatoid factor activity could no longer be detected. Subsequent examination of the pleural fluid confirmed the presence of IgM ( K ) paraprotein. Rheumatoid factor activity was also detected. Immune function testing revealed a combined defect of cell-mediated and humoral immunity. Skin tests with Candida (Bencard), Streptokinase-streptodornase (Eli-Lilly), and Tuberculin (Commonwealth Serum Laboratories) were negative. Lymphocyte transformations revealed a peak of only 2968 cpm/105 mononuclear cells on incubation with 200 pg PHA-P. (normal greater than 7000). T cell numbers ( E

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FIG.3. Magnification of inset of Figure 2. Imrnunofluorescence of lung tissue with monospecific antiIgM demonstrating plasma cell staining ( ~ 2 5 0 ) .

rosette formation) were determined on a number of occasions with results between 0.4 and 0.8 x 10’ cells/l (normal greater than 1 x 10y/l). Humoral immune function was assessed by estimating resting titers to commensal E . coli and isohemagglutinin titers. The latter were normal but E . coli titers were persistently low (114) suggesting that functional humoral immunity was defective. Immunization with tetanus toxoid revealed an inadequate response with titers rising by only one tube dilution (from undetectable to 1/40). HLA typing demonstrated antigens, A l , A2, B8, W15. Screening for antinuclear, antismooth muscle, antiparietal cell, and antimitochondrial antibodies was negative. An open lung biopsy was performed, and a biopsy of the macroscopically most abnormal tissue was performed. This showed diffuse expansion of interstitial tissues by an infiltrate of lymphoreticular cells composed of mature lymphocytes. with moderate numbers of plasmacytoid cells and a few large lymphoid cells (Figs. 2 , 3 , and 4). Accompanying the infiltrate was an increase in agyrophilic fibers within the interstitiurn together with moderate deposition of interstitial collagen. The lymphoid infiltrate extended to the subpleural tissues, but nodular pleural infiltrates were absent. No overt features of malignancy were present, but atypical plasmacytoid cells were present in the pleural fluid. This suggested a guarded prognosis. Immunofluorescence of the lung tissue with polyvalent antihuman immunoglobulin and monospecific anti-IgM demonstrated interstitial staining together with focal areas of bright staining related to single cells, which had the features of plasma cells (Fig. 3). Staining with anti-IgG was absent, and with anti-lgA there were broad bands of staining dividing the tissue. A lip biopsy for Sjogren’s syndrome was negative.

Following the diagnosis of lymphoreticular pulmonary infiltration, the prednisolone dosage was increased to 60 mg daily. Prednisolone therapy was monitored with ventilatory function studies and serial paraprotein quantitation. The IgM paraprotein initially increased to 13.8 gil, but then decreased to 4.8 g/l. The erythrocyte sedimentation rate fell in parallel. Marked symptomatic respiratory improvement was accompanied by minimal objective change only (Table 1). Cellmediated immunity, humoral immunity, and complement component C4 remained unchanged. Epigastric discomfort developed two weeks after commencing the higher prednisolone dosage. A barium meal did not demonstrate a gross mucosal defect, and antacids gave symptomatic relief. The patient’s final admission was in November 1975, when she had fever and severe dyspnea. Streptococcits pneunronitre was grown from sputum and blood. Despite intensive therapy, the patient died. The significant postmortem findings were confined to the thorax and abdomen. There was extensive fibrosis throughout both lungs with a honeycomb appearance and patchy consolidation in both upper lobes. Histologically, the perihilar regions demonstrated intense cellular infiltration with lymphoreticular cells, predominantly lymphocytes. Scattered mitoses were present (Fig. 4). and in some sections, there was invasion of small bronchioles and blood vessels. Towards the periphery of the lung, the infiltrate was more polymorphous with mature lymphocytes, plasma cells, and larger plasmacytic cells. Hilar nodes were discrete and slightly enlarged. Histologically, they revealed atypical hyperplasia and infiltration with well-differentiated lymphocytic cells. The stomach was distended with a uniformly thickened wall. There was a gastric ulcer 2.5 cm in diameter in the fundus. Histologically, the gastric wall was infiltrated with well-differentiated lymphocytic lymphoma (Fig. 5 ) .

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FIG. 4. High power view of predominantly lymphocytic cells with a mixture of plasma cells and large reticular cells ( ~ 6 4 0 ) .

There was local spread to celiac and paraaortic nodes and into the capsule of the left kidney. The liver, spleen, adrenal glands, and pelvic organs were not involved. Bone marrow examination did not reveal lymphomatous involvement.

Discussion

This case demonstrates the spectrum of lymphoproliferative disease from paraproteinemia to lymphoma. The difficulty of distinguishing benign from malignant involvement in lymphoid pulmonary in-

FIG. 5 . Section of the stomach showing diffuse infiltration with well-differentiated lymphocytic lymphoma ( ~ 4 0 ) .

filtration has been alluded to by Liewbow and Carrington.* They suggested that the presence of multiple isolated nodules, numerous mitose5, and destructive involvement of large air passages indicated lymphomatous involvement, whereas diffuse infiltrative lesions of polymorphous character, having plasma cells with an admixture of mononuclear elements, indicate benign lymphoid interstitial infiltration. From these criteria and from the clinical features of slowly progressive disease, the present case was initially con-

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sidered benign lymphoreticular pulmonary infiltration. At necropsy , the lung demonstrated diffuse lymphoreticular infiltration. There was also well-differentiated lymphocytic lymphoma diffusely infiltrating the stomach and involving perigastric tissues. This had been asymptomatic before death. When studied, the patient had an extensive defect in immune responsiveness affecting both humoral and cell-mediated elements. A history of recurrent infections in childhood and repeated attacks of measles suggested that a primary immunodeficiency state may have existed before the development of pulmonary lymphoreticular infiltration. A cryoprecipitable IgM K paraprotein was detected in the patient's serum, and immunofluorescence studies (Fig. 5 ) confirmed that this was being produced by plasma cells in the pulmonary infiltrate. IgM paraproteins have been described previously in association with lymphoreticular pulmonary infiltration,2~4~x~Y though in these cases, the paraprotein-secreting plasma cells were not detected in the pulmonary infiltrate. In the presence of IgM paraproteinemia and low IgG and IgA concentrations, Waldenstron's macroglobulinemia was considered, but other clinical features were absent, and bone marrow studies were not suggestive. The lung biopsy in association with the immunologic abnormalities suggested Sjogrens syndrome as a possible diagnosis. However, antisalivary duct antibodies were not detected, and a lip biopsy showed no abnormality. One possible explanation for the presence of paraproteinemia in this patient with demonstrable T cell dysfunction is a deficiency of suppressor T cell activity, resulting in p B cell proliferation and paraproteinemia. Radl et rrl. I" have recently suggested this as a mechanism for transient paraproteinemia occurring in patients with Wiskott-Aldrich syndrome. The association of lymphoreticular disorders and hypogammaglobulinemia is well recognized. Kersey et ~ 1 have . ~collected a large number of case reports in their registry of malignancy associated with immunodeficiency. Of 450 cases of ataxia telangiectasia reported in the literature, 32 were lymphoreticular in type. Of 41 cases of common variable immunodeficiency in which malignancy developed, 23 had had lymphoreticular neoplasms. Further evidence of this association has been demonstrated in patients with Sjogren's syndrome by Anderson et al.' An association between T cell dysfunction and lymphoreticular neoplasms has been demonstrated in patients with the Wiskott-Aldrich syndrome. Malignancy develops in approximately 10% of these in-

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dividuals.6 Of the 24 cases with malignancy in this condition, 19 have been lymphoreticular in type. The presence of altered immune status has been described, but not emphasized, in lymphoid pulmonary infiltration. Hypogammaglobulinemia was present in five of the original cases reviewed by Liebow and Carrington.* In the case of the plasma cell interstitial pneumonia and macroglobulinemia reported by Essig et ~ i l . there , ~ was a significant T cell defect as assessed by negative skin tests to Candida, mumps, and histoplasma antigens, by failure of sensitization to DNCB and by poor responses to phytohemagglutinin. In contrast, Levinson et id.' have reported a case of lymphoid interstitial pneumonia, co-existent with pernicious anemia and hypogammaglobulinemia. Because of previous work:' suggesting a role for T cells in the pathogenesis of the gastric lesion in pernicious anemia, they suggested that T cells may have a similar role in the pathogenesis of benign lymphoid pulmonary infiltration. However, they were unable to demonstrate T cells specifically sensitized to gastric antigens. The presence of hypogammaglobulinemia in this case may have been of particular significance. In contrast with this case, our patient had a significant defect in T cell function. From a clinical history spanning at least five years, from radiologic evidence of slowly progressive pulmonary infiltration, and from histologic features consistent with the criteria of Liebow and Carrington,R the patient was considered to have benign lymphoid pulmonary infiltration. At postmortem, the patient was also found to have a well-differentiated lymphocytic lymphoma diffusely involving the stomach. There are several possible explanations for these pathologic findings. First, the pulmonary infiltrate may have represented slow spread from a primary gastric lymphoma, or second, both lesions may be manifestations of a multifocal lymphoma. In this context, the immunodeficiency may have been a secondary immunodeficiency state. These diagnoses, however, would seem unlikely in view of the length of history of respiratory symptoms, the initial lung biopsy findings, the paucity of gastrointestinal symptoms, and the absence of hepatic involvement with lymphoma. A more satisfactory explanation, we believe, is the development of lymphoma in the presence of long-standing immunodeficiency and lymphoid pulmonary infiltration. One previous report5 has described lymphoma developing in a patient with benign lymphoid pulmonary infiltration, and a parallel to this process has been described with lymphomas occurring in a patient with Sjogren's syndrome.

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There is strong circumstantial evidence from this and other cases of disturbances of immune function in association with benign lymphoid pulmonary infiltration. Congenital immunologic defects are known to be associated with a very high frequency of lymphoproliferative disorders, and it is compelling to believe that immunologic defects may be causative factors in pulmonary lymphoid infiltration. REFERENCES I . Anderson LG, Tatal N . Spectrum of benign to malignant proliferation in Sjogrens syndrome. Clin E.rp Immunol 1972: 10: 199-221. 2. Essig LT. Timms ES, Hancock D E , Sharpe GC. Plasma cell interstitial pneumonia and macroglobulinaemia. A m J M P 1974; ~ 56:398-405. 3 . Finlayson NDC. Fanconnet M H , Krohn K. In vitro demon-

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stration of delayed hypersensitivity to gastric antigens in pernicious anaemia. A m J DiRe.\r Diu 1972; 17:631-638. 4. Greenberg SD, Haley MD, Jenkins D E , Fisher SP. Lymphoplasmacytic pneumonia with accompanying dysproteinaemia. Arc,h Puthol 1973; 96:73-80. 5 . Halprin GM, Ramirez RJ, Pratt PC. Lymphoid interstitial pneumonia. CIws/ 1972; 62:418-427. 6. Kersey J H , Spector BD. Good RA. Primary inimunodeficiency disease and cancer. The immunodeficiency cancer registry. I t i t J Conctzr 1973; 12:333-347. 7. Levinson AI, Hopewell PC, Stites DP, Spitler L E , Fudenbrrg HH. Co-existent lymphoid interstitial pneumonia, pernicious anaemia and agammaglobulinaemia. Arch Intern Mrd 1976; 136:213-216. 8. Liewbow AA, Carrington CB. Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinaernia. M r t l C/in North Am 1973; 57:809-843. 9. Moran TJ, Totten RS. Lymphoid interstitial pneumonia with dysproteinaemia. Am J Clin Puthol 1970; 54:747-756. 10. Radl J , Dooren LJ, Morrell A, Skvalil F , Vossen JMJJ, Uiteenbogaart CH. Immunoglobulins and transient paraproteins in sera of patients with the Wiskott-Aldrich syndrome: a follow-up study. Clin E,Y,DImmunol 1976; 25:256-263.