Document eYbZaX16Kq9LKyV59Jp9kegy

FILE NAME Brakes BRK DATE 1983 July DOC BRK085 DOCUMENT DESCRIPTION Article - Lymphoid and Plasma Cell Malignancies Disorders and Long Latency Feakeaninnh nace Lymphoid and Plasma Cell Malignancies Asbestos Disorders of Long Latency ELLIOTT KAGAN M.D. AND ROBERT J. JACOBSON M.D. F.A.C.P. We have identified 13 asbestos workers with lymphoplasmacytic neoplasms six with chronic lymphocytic leukemia four with IgG myeloma two with IgA myeloma and one with histiocytic lymphoma The subjects occupations were varied but all had experienced protracted asbestos exposure ranging from 3-37 years Tumor latency periods were similar to other known asbestos malignancies and ranged from 16-41 years Stigmata of asbestos pulmonary disease were evident in 12 subjects Malignant pleural mesotheliomas coexisted with IgG myelomas in two individuals an association which seems unlikely to be fortuitous It has been speculated previously that asbestos may be a lymphoid system carcinogen Our findings strongly support this view and indicate that patients presenting de novo with lymphoproliferative neoplasms should be investigated for previous occupational or environmental exposure to asbestos Key words Asbestos Asbestosis Mesothelioma Pleural plaques Lymphoma Myeloma Chronic lymphocytic leukemia Am J Clin Pathol 1983 80 14-20 THE CARCINOGENIC POTENTIAL of asbestos is now recognized and there is little doubt about the Departments of Pathology and Medicine Hematology Division Georgetown University School of Medicine . Washington D.C. due either to a paucity of clinical information or to other possible etiologic cofactors We previously documented three instances of asbes- associated neoplasms of cell lineage The num- ber of cases however was inadequate to derive definitive conclusions concerning the latency periods of such tumors after initial asbestos exposure and the types of occupational settings associated with the development of these neoplasms The present study was undertaken in order to address these specific issues We now report an enlarged series of 13 cases in which lymphoplasmacytic neoplasms were detected in asbestos workers six instances of myeloma six of chronic lymphocytic leuke- mia and one of histiocytic lymphoma relationship between asbestos exposure and malignant mesotheliomas of the pleura and peritoneum An Materials and Methods issue that is however receiving considerable current attention is the association of asbestos exposure with the development of other neoplasms The latter include bronchogenic carcinomas gastrointestinal malignancies oropharyngeal cancers laryngeal carcinomas and ovarian neoplasms Several reports of associated lymphocytic and plasma cell dyscrasias have appeared in the 3.4.7-11,13,18 20 22.23.33.34.36.40 These have however mainly been anecdotal single case reports encompassing a variety of lymphoproliferative disorders in which no specific tumor category has predominated Two recent epidemiologic studies have provided tentative support for the role of asbestos as a possible lymphoid carcinogen but definitive conclusions could not be reached in this regard Selection of Cases Three cases were reported previously patients , 2 and .18 Ten patients seen initially by other physicians were referred to us for hematologic appraisal because of our interest in associated hematologic disor- ders A definite history of occupational asbestos exposure was elicited in all instances Each patient had been evaluated previously for the presence of asbestos pulmonary disease as evidenced by parenchymal fibrosis pleural plaques bronchogenic carcinoma or malignant mesothelioma The diagnosis of pulmonary disease was established by chest radiography patients 1-3 59 11 and 13 computerized tomography patients 2 5 and 13 thoracotomy patients 2 4 12 and 13 and or necropsy examination patients 3 and 4 Received October 11 1982 received revised manuscript and ac- cepted for publication December 6 Presented at the ASCP Fall October 1982 1982 Meeting Miami Beach Florida Supported by US Environmental Protection Agency Grant R80825201 Address reprint requests to Dr. Kagan Department of Pathology Georgetown University Medical Center 3900 Reservoir Road N W. Washington DC 20007 Hematologic Evaluation The diagnosis of chronic lymphocytic leukemia was based on the presence of a persistent lymphocytosis in the peripheral blood and bone marrow Myeloma was diagnosed on the basis of an abnormal marrow plasmacytosis exceeding 15 of nucleated cells in associ- 0002-9173 0700 01.15 'American Society of Clinical Pathologists 14 ASBESTOS LYMPHOID MALIGNANCIES 15 Vol No 1 ation with a persistent serum monoclonal gammopathy having an component concentration in excess of 2 dL and free immunoglobulin light chains in the urine The identity of serum components and urinary immunoglobulin light chains was established by immunoelectrophoresis The diagnosis of histiocytic lymphoma patient 13 was determined by histopathologic examination occupational settings associated with the mining milling or handling of asbestos fibers These occupations all are considered to be potentially at risk for the de- velopment of asbestos diseases.It is noteworthy that stigmata of asbestos pulmonary disease were detected in all but one individual Table ) Parenchymal asbestosis was evident in nine subjects localized pleural plaques were noted in four instances bronchogenic adenocarcinoma was detected in one case and two Tissue Analysis for Ferruginous Bodies individuals developed malignant pleural mesotheliomas There was considerable variation in the length of time PME The embedded tissue block of a biopsy from subjects were exposed to asbestos ranging from 3-37 a the lingular region of patient 13 was submitted to Dr. years mean 22.8 years Prolonged asbestos exposure Victor L. Roggley for quantitation of ferruginous bodies however was the general rule Five individuals also were an The tissue which contained tumor was deparaffinized exposed occupationally to materials other than asbestos and then digested in 5.25 sodium hypochlorite and 8.0 oxalic acid Ferruginous bodies were quantitated by light microscopy Two patients 1 and 7 were exposed to quartz dust one patient ) to coal dust two patients 3 and 8 had worked with fiberglass and one patient 11 had inhaled Results General Clinical Features All the subjects were male Their occupations cir- cumstances of asbestos exposure and hematologic diare listed in Table 1. They had all worked in agnoses organic solvents No single type of asbestos emerged as a common de- nominator of exposure Thus one subject patient ) was exposed exclusively to amosite another patient 2 was exposed exclusively to chrysotile while yet another patient 8 sustained mixed exposure to chrysotile crocidolite and amosite It is probable that the majority of Table 1. General Clinical Features of Cases Studied Case 1 2 3 4 5 67 67 88 88 10 11 12 Length of Asbestos Exposure Years 3 25 24 5 2 28 28 22 22 63 63 35 Asbestos Occupation Amosite miner Instillation of auto brake linings Shipyard insulator Shipyard electrical technician Insulator Pipe lagger Asbestos mill supervisor Insulator Fireproofing insulator Shipyard boilermaker Brake lining machinist Shipyard insulator and pipe lagger 13 29 Shipfitter and construction site carpenter * Indicates chronic lymphocytic leukemia Evidence of Prior Asbestos Exposure Parenchymal silicoasbestosis Right malignant mesothelioma Parenchymal asbestosis and pleural plaques Bilateral malignant mesotheliomas Parenchymal asbestosis and pleural plaques Parenchymal asbestosis Parenchymal asbestosis and pleural plaques Parenchymal asbestosis Parenchymal asbestosis _ Parenchymal asbestosis and pleural plaques Parenchymal asbestosis associated with bronchogenic adenocarcinoma Pleural plaques Cigarette Smoker Status Unknown Smoker smoker smoker Smoker smoker Smoker Smoker Smoker smoker Smoker Smoker smoker Hematologic Diagnosis Myeloma Myeloma Myeloma Myeloma Myeloma Myeloma CLL CLL CLL CLL CLL CLL Histiocytic lymphoma KAGAN AND JACOBSON AJCP AJCP July 1983 Table 2. Hematologic Features of Myeloma Cases aU Age at Diagnosis Nature of Serum Proportion of Marrow Bence Tumor Latency Case Years Component Plasma Cells Proteinuria Period Years ee COMT 54 COMT 178826 COMT 178826 COMT 60 no 178826 6 65 IgA IgG kappa IgA kappa IgG IgG kappa IgG lambda 20 60 70 50 30 70 Negative 833332 Negative 25 Positive 35 Negative 37 Not tested 35 Positive 21 * Indicates the period between initial exposure to asbestos and the date the neoplasm was hrst diagnosed the remaining individuals also had experienced mixed asbestos exposure when the nature of their occupations is considered opsy was performed when the subject was 61 years old Microscopic examination showed extensive pulmonary infiltration by large lymphoid cells many of which had The cigarette status of each individual also prominent nucleoli Mitoses were numerous Fig 2 is given in Table 1. Four subjects were smokers The features were consistent with a histiocytic lym- seven were regular cigarette smokers and one was an phoma Occasional ferruginous bodies were evident in sind cigarette smoker areas infiltrated by the neoplasm Fig 2 Analysis of the Ct Lymphoplasmacytic neoplasms were detected in all tumor tissue block revealed 521 ferruginous bodies of detain 4 cases studied A preponderance of myelomas six cases wet lung The tumor was diagnosed 35 years after the and chronic lymphocytic leukemias six cases were subject's initial exposure to asbestos noted Histiocytic lymphoma was diagnosed in one sub- ject Discussion Hematologic Features Exposure to asbestos has been documented infrequently in association with neoplasms of the hemato- The hematologic features of the myeloma cases are poietic system However when this association has been summarized in Table 2. When myeloma was diagnosed observed lymphoid and plasma cell dyscrasias have pre- HET the subjects ages ranged from 54-72 years mean 65.0 dominated The latter include chronic lymphocytic leu- ate years The serum component was of the IgG variety kemia 9,13,18,20,33,40 malignant lym- MAie in four instances and IgA in two Bence protein- phoma 10,11,13,19,20,23,34 Waldenstr^m's macroglobulin- anes uria was detected in two cases The tumor latency pe- emia immunoblastic lymphadenopathy alpha chain riods after initial asbestos exposure were lengthy ranging disease amyloidosis and giant lymph node hyper- from 21-37 years mean 30.2 years A striking finding plasia Nearly all have been single case reports In most was the coexistence of malignant pleural mesotheliomal instances the subjects occupations were not stated and with IgG myeloma in two individuals The histologic few details were provided concerning the circumstances features of these neoplasms in patient 4 are illustrated in Figure 1 Table 3 summarizes the hematologic features of the cases of chronic lymphocytic leukemia The subjects ages ranged from 50-62 years mean 57.7 years at the time ofdiagnosis The tumor latency periods were similar to those noted in the myeloma cases ranging from 16-41 years mean 30.2 years One individual patient 13 had been investigated of asbestos exposure In the present study we have identified 13 individuals with associated neoplasms of the lympho ular system six cases of myeloma six of chronic lym- phocytic leukemia and one of histiocytic lymphoma - A definite history of occupational asbestos exposure was elicited in each instance There were however no un- usual features of our cases which clearly distinguished them from the spectrum of clinical and pathologic pat- elsewhere for progressive effort dyspnea and interstitial terns seen when the same lymphoplasmacytic neoplasms pulmonary roentgenographic infiltrates A lingular bi- occur within the general population Nevertheless our yy o eta FIG 1 upper Coexistence of malignant pleural mesothelioma panel A and myeloma panel B in Case 4 Panel A left shows features of a papillary epithelial neoplasm stained with hematoxylin and eosin original 100 Panel B right shows marrow replacement by numerous bizarre plasma cells with prominent nucleoli Hematoxylin and eosin original 400 FIG 2 lower Histiocytic lymphoma of lung in Case 13 composed of lymphoid cells with numerous mitotic figures Hematoxylin and eosin original 300 Arrow indicates a ferruginous body in inset panel Vol No 1 ASBESTOS LYMPHOID MALIGNANCIES 17 tt $s. oePad a? + fa bd AGE se ae ie @ rears ats , Re oe og Cott * ae % Poh ToewR,2 b OY. Rr Rare Su CL * ase ise 18 Case 7 8 031 031 031 12 KAGAN AND JACOBSON Table 3. Hematologic Features of Chronic Lymphocytic Leukemia Cases Age at Diagnosis Years Total Leukocytes 10fl Proportion of Lymphocytes Presence of Organomegaly 79 None 61 30.4 90 Lymphadenopathy and 76.0 50 hepatomegaly 26.6 78 None Ann 155.0 94 Hepatosplenomegaly Ann 20.0 75 Lymphadenopathy and 62 hepatomegaly 19.0 65 None 59 CP July 1983 Tumor Latency Period Years 28 24 267 16 41 40 * For explanation see able 2 leukemia are of special sequently studied 1,334 autopsy specimens in patients AED hematologic malig- Six cases of chronic lymphocytic 50 or older noted five since no other occupational environmental aged years 35 interest in the cause of this nancies four of which were lymphoid among cases agent has been implicated previously of asbestosis The incidence of these asbestos lymphoid neoplasm The subjects occupations were varied but each in- dividual had worked with containing materials in jobs potentially at risk for developing asbestos diseases Exposure to asbestos had been prolonged in every instance ranging from 3-37 years Since the airborne asbestos concentrations were not monitored at the workplace at the time of exposure there is no reliable means of assessing the severity of asbestos exposure in these subjects However it is likely that those individuals who had worked in United States shipyards during World War II patients 3 4 6 10 12 and 13 and those who were employed in the mining patient ) and milling patient 7 of asbestos had sustained heavy asbes- tos exposure The detection of stigmata of asbestos- related pulmonary disease in 12 cases provides additional objective evidence of prior asbestos exposure in these individuals In all instances the lymphoid and plasma cell dyscrasias manifested clinically a consider- able time after the initial asbestos exposure occurred in the workplace Comparable latency periods have been noted previously with respect to mesotheliomas and bronchogenic carcinomas in asbestos popula- tions A key question posed by this study is whether asbestos exposure is indeed causally linked to the development of lymphoproliferative malignancies Because our cases ciated hematopoietic neoplasms 14.3 was significantly higher than the 2.8 overall incidence of such tumors in the total autopsy population of comparable age More recently Robinson and workers reviewed death certificates from a cohort of 3,276 white male as- bestos workers employed in a manufacturing facility The authors reported four deaths resulting from lym- phosarcoma and three from malignant lymphoma whereas only 3.28 deaths were expected on the basis of specific rates for this tumor category They suggested that male asbestos workers had an increased risk of de- veloping lymphoid cancers A similar mortality excess for lymphoid neoplasms during the period 1950-1960 was observed in a study of shipyard workers and ship- fitters in the state of Washington.25 In the latter study however no mention was made of possible asbestos ex- posure in these occupational settings Of particular interest is a recent preliminary epide- miologic control study of Hodgkin's large cell lymphomas primary to the gastrointestinal tract In that study Dworsky and associates documented previous heavy asbestos exposure in 11 of 22 cases but in only two of matched neighborhood controls The interpretation of their data however is clouded by a prior history of malaria a disease characterized by immu- nologic stimulation in many of the cases having prior were mainly referrals from widely differing geographic regions within the United States it is not possible to determine whether these cases reflect an increase of lym- phoid and plasma cell malignancies over those expected in the general population There is however a consid- erable body of circumstantial evidence that supports a effect relationship between asbestos exposure and lymphoid system neoplasia In a study of 68 asbestos workers Lieben documented 21 malignancies Among the latter a disproportionate number 19 were lymphoid cancers Gerber who sub- asbestos exposure There are reports of asbestos lymphoid and plasma cell dyscrasias produced in experimental animals In one study injection of asbestos into the air sacs of White Leghorn fowls induced one tumor consistent with a plasmacytoma and another classed as a reticulo- sarcoma In another study the intraperitoneal instil- lation of chrysotile asbestos in mice evoked considerable amyloid deposition in the livers and spleens of these animals.42 The nature of the amyloid however was not defined Vol 80 No. 1 ASBESTOS LYMPHOID MALIGNANCIES 19 The development of lymphoproliferative neoplasms in exposed individuals may result from an un- derlying abnormality of immunologic homeostasis in these people since striking alterations of immunologic function have been described in asbestos workers.17 These abnormalities reflect an imbalance between de- fective mediated immunity and hyperactive cell function which may relate to deficient suppressor cell function in these subjects There is also evidence from animal experiments that asbestos exposure can stimu- late the immune system Alveolar macrophages from asbestos rats have been shown to induce splenic lymphocyte proliferation an event preceded by enhanced attachment of these lymphocytes to the mac- rophages Moreover the repeated intratracheal instil- lation of chrysotile in sheep has been associated with enhanced proliferative responses of bronchoalveolar lymphocytes to certain mitogens These phenomena may relate to the enhanced production of interleukin- a potent lymphoid mitogen noted after asbestos ex- posure 14 other It has been shown in other situations that lymphoid neoplasia may result from persistent immunologic stimulation in a mileu deprived of normal immunoregulatory influences Such neoplasms have been mainly histiocytic lymphomas immunoblastic sarcomas There is evidence however that myelomas can under certain circumstances occur excessively with diseases characterized by chronic antigenic stimulation or altered immunoregulation It is therefore conceivable that asbestos exposure may similarly provide a host environ- ment that predisposes to the development of neoplastic immunocytes The finding of ferruginous bodies in the digest of the tumor tissue block from our case of pulmonary lym- phoma patient 13 is of interest since the neoplasm occurred in the organ of primary asbestos insult The number of ferruginous bodies identified in this case is especially noteworthy Although the development of a second cancer in myeloma patients is not uncommon this particular tumor combination has only been documented twice by others In each instance a his- tory of asbestos exposure was either known or inferred The coexistence of mesothelioma and chronic lymphocytic leukemia also has been reported in an asbestos worker The probability of myeloma and mesothelioma occurring by chance in an individual not exposed to asbestos is however remote since only one instance of this tumor combination was found in a survey of a seg- ment of the general population of the United States in- volving 20 million individuals who were followed for three consecutive years Young JC National Cancer Institute personal communication The coexistence of these two neoplasms in two of our patients thus seems unlikely to be a fortuitous occurrence It is conceivable that the lymphoplasmacytic neo- plasms we have observed may be a consequence of oc- cupational exposure to materials other than asbestos Exposure to asbestos was however the only factor common to all our cases Since seven subjects were cigarette smokers and one was an smoker it is possible that cigarette smoking also could be a cofactor although the number of cases is too small to draw specific conclusions in this regard Although our observations are based on selected case material they clearly underscore the need for scale epidemiologic studies to determine whether asbestos exposure can definitely be linked causally to lymphoid and plasma cell dyscrasias Such studies should not only be performed on different categories of asbestos workers but they also should include patients presenting de novo with lymphoplasmacytic neoplasms 4h Acknowledgments We are indebted to Dr. Victor L. Roggley for ferruginous body analysis and to Dr. Thomas V. Colby for histologic material from patient 13. We thank Miss Eileen Rusnock for preparing the illustrations and Mrs. Marilyn Davis for typing the manuscript 521 of wet lung was within the range obtained for asbestos workers with mesothelioma or bronchogenic carcinoma Roggley VL personal communication We have no information regarding the ferruginous body or asbestos content of the affected hemopoietic organs in our cases of myeloma and chronic lymphocytic leukemia There is however evidence that inhaled asbestos can translocate from the lung to other viscera Thus Auerbach and workers have identified ferruginous bodies in the spleen and other organs anatomically remote from the lungs in asbestos workers The observation by Brody and associates that chrysotile asbestos can breach alveolar capillary walls within five hours of inhalation also is pertinent in this regard The coexistence of IgG myeloma with malignant mesothelioma in two of our patients patients 2 and 4 References 1. 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LIPPINCOTT COMPANY a a oy oR OE OR AJCPAI ISSN 0002-9173