Document 9moR3KkMm0nrOweykzjJe1Yq

:UM THE NEW ENGLAND JOURNAL OF MEDICINE Juiv I. 1943 CASE RECORDS or THE MASSACHUSETTS GENERAL HOSPITAL Weekly Clinicopathological Exercises rouxots v micxAU e. casot Robert E. Scully, M.D., Edut Eucene J. Mask, M.D., Aiaaau Edim Betty U. McNezly, Ahum Edam Case 27-1982 Presentation or Case A 64-vcar-old man was admitted to the hospital because of a right pleural abnormality. He was in his usual state ofbealth until one month before admission, when microscopic hematuria was found in a routine urinalysis. A culture of urine was negative, and cvtologic examination ofurine was nega tive on three occasions. An intravenous urographic examination with nephrotomograms showed a normal appearance of the kidneys; there was slight trabeculation of the bladder, with a small post-voiding residu um. Five days before admission cvtoscopic examina tion revealed that the prostatic urethra appeared erythematous and friable. Routine x-ray films of the chest (Fig. I) disclosed considerable loss of volume and pleural thickening at the right-lung base, which had appeared since films obtained one year earlier no calcification or associated rib abnormality was seen: the pleural spaces and lungs were otherwise normal, and the heart was at the upper limit of normal in size; there was slight ectasia of the thoracic aorta. Three davs before admission another x-ray film of the chest, with bilateral decubitus views, disclosed no evidence of free pleural fluid. The padent recalled nonpleuridc right subscapular pain lor one day shortly before the cvtoscopic examination but denied all other chest pain. A dry cough and mild fever were noted on phys ical examination, and a course of erythromycin was prescribed, without improvement. On the day of ad mission the coueh and fever persisted, with occasional sweats. There w as a history of dyspepsia since the age of 18 years. Thirr.-seven years before entry a duodenal ulcer was found on an upper gastrointestinal series, and a Billroth 11 gastrectomy was performed. He had worked in a ship\ arc for six months during World War II; thereafter he -vas employed in the upholstery busi ness. He had smoked two packs of cigarettes daily in the past but stopped smoking 28 years before entry. There was a 20-year history ofseropositive rheumatoid arthritis and a 10-year history of hypertension, which was controlled with hydrochlorothiazide and triamter ene. For several years before entry he experienced re peated bouts.of upper gastrointestinal bleeding from a marginal ulcer. There was no history of sputum pro duction. hemoptysis, or dyspnea. The temperature was 37.3*C, the pulse 80, and the respirations 24. The blood pressure was 140/80 mm Hg. On examination the patient appeared well. No rash or Ivmphadenopathy was found. The lungs were clear except for diminished breath sounds at the right base and reduced excursion of the right hemidiaphragm. The heart was normal. Abdominal examination was negative. There was synovial thickening in the proxi mal interphalangea! joints bilaterally; no digital club bing was observed. The urine gave a + test for protein: the sediment contained rare granular casts. The hematocrit was 41.2 per cent; the white-cell count was 10,300, with 69 per cent neutrophils, 1 per cent band forms, 15 per cent lymphocytes. 13 per cent monocytes, and 2 per cent eosinophils. The platelet count was 189.000, and the erythrocyte sedimentation rate 63 mm per hour. The urea nitrogen was 23 mg per 100 ml (8.2 mmol per liter), the glucose 119 mg per 100 ml (6.61 mmol per liter), the bilirubin 0.4 mg per 100 ml (7 jimoi per liter), the uric acid 10.4 mg per 100 ml (0.619 mmol per liter), the calcium 9 mg per. 100 ml (2 mmol per liter), the phosphorus 3.5 mg per 100 ml (1.1 mmol per liter), and the protein 7.2 g (the albumin 3.5 g. and the globulin 3.7 g) per 100 ml. The sodium was 140 mmol, the potassium 4.4 mmol, the chloride 98 mmol, and the carbon dioxide 30 mmol per liter. An electrocardio gram demonstrated a normal rhythm at a rate of 67, with nonspecific ST-segment and T-wave abnormali- Figuie 1. Roentgenogram ofthe Chest Taken Five Days before Admission, Showing a Right Pleural Abnormality with Biuntmg of the fiijht Costopnremc Angle. ifl^ n n n is DOW 06676 Vat. 307 No. 2 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL 103 figura 2. CT Scan of the Cheat. Showing breguiar and Nodular Plaurai ThteMfang and Possibly Locutatsd EJtuswt The undadymg tag normal. ties. X-ray films of the chest were unchanged. A com puted tomographic (CT) scan of the chest (Fig. 2) disclosed diffuse nodular thickening and possibly a Joculated effusion of the pleura on the right side, with loss of volume in the underlying lung; no pulmonary mass was observed; there was a suggestion of a pleural plaque on the left side. A test for antinuclear anti bodies was positive in a titer of 1:32, with a homoge neous pattern. A culture of sputum yielded a normal throat flora; cytologic examination was negative for tumor cells. A diagnostic procedure was performed. DimacNTiAL Diagnosis Dr. Edward A. Gaensler*: In summary, this 64* ycar-old man was found to have a right pleural abnor mality dune a routine radiologic examination. The past historv%,,s of interest with respect to duodenalulcer problems for over 37 years, a 20-year history of seropositive rheumatoid arthritis, and treated hyper tension. The occupational history, although scanty, is noteworthy with respect to shipyard work during World War II and upholstery work since that time. In regard to the latter, it may be ofhistorical interest that some of the earliest descriptions of asbestosis in Great Britain concerned mattress workers. The patient stopped smoking 28 years ago and in terms of cancer statistics must be regarded as a nonsmoker. The initial admission to the hospital was prompted b\ microscop ic hrmaiuria, but culture and cytologic examination of urine and an intravenous urographic study of the kidneys were negative. Radiologic examination of the bladder and cystoscopic examination suggested *frafuor ot urftty and ptoruototr. Bono* Uaiwnoy School of Mtriictat: WnnrM uirfffy. Horvvri Morin! School, iocaritr m moriica*. Tofu Uaawrw) School t Mariana. changes probably due to benign prostatic hyper trophy, although we are not told about examination of the prostate gland. Abnormalities were found in the chest and the interphalangealjoints. The further work up was prompted by the findings on roentgenograms of the chest. May we see the films at this time? Dr. Theresa C. McLous: The intravenous uro grams show normal renal contours, with no evidence ofa mass. Slight, irregular trabeculation ofthe bladder and slight elevation of the bladder floor are demon strated, with a small post-voiding residuum, consistent with benign prostatic hypertrophy. Tomograms of the kidneys are also normal. A roentgenogram of the chest obtained one year before admission reveals slight unfolding ofthe thorac ic aorta. The pleural spaces, including the costophrenic angles, are normal, with no evidence of pleural thickening or plaques. A film obtained five days before admission (Fig. 1) shows blunting of the right costophrenic angle and a pleural abnormality laterally ex tending about a fourth of the way up the chest. A lateral view reveals minimal blunting of the right pos terior costophrenic angle. A decubitus film taken two days later discloses no evidence of a free pleural effu sion. The appearance is consistent with either pleural thickening or possibly loculated pleural fluid. A section from the CT scan (Fig. 2) at the level ofthe great vessels demonstrates irregular, nodular pleural thickening on the right side, which extends caudad to the level of the diaphragm. There is no evidence of a mass in the lung, hilus. or mediastinum. A small pleu ral plaque is visible on the left side. In summary, the radiologic studies show evidence of diffuse nodular pleural thickening on the right side, with loss ofvolume ofthe underlying lung. In addition, a loculated effusion is suggested. Dk. Gaensler: The radiologic findings may be ex plained in two ways. The patient had a right pleural effusion. It is possible that the fluid became loculated and after its resorption a somewhat uneven fibrotic pleura remained. An alternative explanation is a tumor. The last time that I was invited to discuss a case at one of these conferences the diagnosis seemed obvious, and I had difficulty in manufacturing a differential discussion. This time the opposite is true: the differen tial diagnosis is large, and no diagnosis fits very well. In the end we shall have to rely on a biopsy, and even after a biopsy the diagnosis may remain in doubt. I shall discuss the various possibilities by excluding the unlikely ones first. If the effusion was benign we can rule out a transudate because the patient appeared entirely well when the effusion was discovered: he was not in left ventricular failure and did not have nephrosis or ascites. Fur thermore, transudates rarely leave a fibrotic residuum. Therefore, the fluid was an exudate. There is nothing in the history to suggest pulmonary infarction or a subphrenic lesion. A pulmonary infection, the most common cause of a pleural exudate, cannot be exeluded entirely. The serial roentgenograms ofthe chest , > * | j f * snisfiooisj DOW 06677 il S I U U O j ' U I. 106 THE NEK ENGLAND JOURNAL MEDICINE July , 19*2 and the dinical course during the weeks before admis sion are not suggestive of a bacterial or viral pneumo nia. However, we must always consider the possibility of tuberculosis. Certain impressions from medical school are never forgotten. When Or. Henry Jackson, Jr., lectured on pleural effusion in 1943 he wrote on the blackboard the most common cause, which was tuber culosis, and then for 35 minutes he listed 14 additional causes, all of them tuberculosis. Only during the last five minutes did he suggest that there were also other, more unusual causes. In this case we are not even told the results of a tuberculin test. How times have changed! Nevertheless, we must consider tuberculosis, especially in view of the low-grade fever, the elevated sedimentation rate, the occasional sweats, and the his tory ofa gastrectomy. One might add the finding ofred cells in the urine. Tuberculosis is a distant possibility, even though tuberculous effusions rarely become loculatcd and rarely leave a fibrotic residuum. A more important due is the 20-year history ofsero positive rheumatoid arthritis. Involvement ofthe pleu ra by granulomatous lesions ofrheumatoid origin, first documented by Baggenstoss and Rosenberg,1 is the most common manifestation of rheumatoid lung dis ease. Some investigators have found pleurisy to be slightly more frequent in patients with rheumatoid ar thritis than in persons without this disease,1 and others have demonstrated an unexpectedly high frequency of otherwise unexplained effusions both in patients with rheumatoid arthritis3 and in series of cases of that disease with post-mortem examination.4 In this con nection it has been pointed out that conclusions about the relation of any two conditions must be made with caution and that the more common the conditions are the greater is the likelihood oferror.3 Although there is still some controversy, the results of controlled studies by Walker and Wright6 appear convincing; pleural effusions were 10 times more prevalent in a group of patients with rheumatoid arthritis than in a control group of patients with degenerative arthritis. This pa tient had synovial thickening in the proximal interphalangeal joints bilaterally, and a test for antinuclear antibodies was weakly positive, with a relatively lowtiter of 1:32 and a homogeneous pattern. Furthermore, rheumatoid effusions occur predominantly in middleaged men.7 and residual pleural thickening is occa sionally extensive and may require decortication.'** However, the patient under discussion apparently had no complaints suggestive ofsevere rheumatoid ar thritis, there were no subcutaneous nodules, and the disease seems to have been fairly inactive, where as rheumatoid elusions are generally seen during ex acerbations and in patients with active and progressive disease.:*9-10 Therefore, a rheumatoid cause for the effusion is possible but not very likely. The last and probable explanation fur this patient's pleural abnormality is what we have called "benign asbestos effusion."11 There is a convincing history of asbestos exposure, with work in a shipyard for s:\ months during World War II. During that period the work force at the shipyards increased rapidly, and there was little time or interest in the control of asbes tos dust. Furthermore, many yards in this area were largely engaged in the refitting of old ships, a proce dure that was dangerous not only to pipe coverers and (aggers but also to members of the related trades who worked below deck in poorly ventilated holds, walking on the asbestos material that had been removed from the pipes before refitting could, take place. At the Thorndike Memorial Laboratory at the Boston City Hospital in the 1950s virtually all our cases of severe asbestosis were seen in members of a variety of trades engaged in ship refitting. At that time the dangers of asbestos exposure in the asbestos industry itself were recognized, but the dangers to secondary users were not appreciated. Indeed, shortly after World War II investigators from the Harvard School of Public Health issued a very reassuring report indicating that there was no danger to shipyard workers,12 and it was not until 25 years later that the generally accepted threshold limit value of 5.000,000 panicles per cubic foot was found to be excessive.13 Bilateral recurrent effusions were first described in an insulation worker in 1962,14 and nine years later we reported the findings in a series of 12 patients with historical and histologic evidence ofexposure to asbes tos who had pleural efTusions, which were often: bloody, sometimes bilateral, and sometimes recur rent.1 Subsequently, we became interested in the prevalence of benign asbestos efTusion. We defined this disorder by four criteria: direct or indirect exposure to asbestos; the presence ofan efTusion confirmed by tho racentesis or by the finding of a transient pleural change on serial x-ray films; lack of evidence of any other disease related to a pleural effusion; and failure to detea a malignant tumor within three years after the effusion. We followed prospectively 1135 employ ees of the asbestos industry and shipyards for 10 to 15 years, and retrospectively we reviewed roentgeno grams of the chest and records for up to 35 years. The results were compared with those in 717 unexposed control patients who had serial roentgenograms for three to 35 years (Table l}.13 In the entire survey group there was a prevalence of 3.1 per cent of asbes tos effusions, with a frequency of 5.2 per thousand prrsnn-years. Among the 717 controls there were no otherwise unexplained efTusions during the observa tion period. The prevalence of asbestos effusions was related to the severin' of the exposure: among persons directly exposed to asbestos, such as pipe coverers, laggers, and asbestos paper-pulp mixers, the preva lence was 7 per cent; among indirectly exposed persons who worked nearby in the plant the prevalence was 3.7 per cent; and among 511 distantly exposed persons, mostly executives, draftsmen, and secretaries, the prevalence was 0.2 per cent. We are all familiar with the concept of the latent period between the initial exposure and the manifesta tions of asbestos-related disease. In our series the la tent period for all asbestos-related diseases, including DOLI 06678 Vol. 30* No. 2 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL 107 asbestosis, pleural plaques, lung cancer, and mesothe lioma. was usually 20 yean or more, whereas a benign effusion was the only asbestos-related disorder ob served during the first 10 yean after exposure and was the most common manifestation during the lint 20 yean (Fig. 3). The possibility of a mesothelioma was the principal differential diagnostic problem, but that tumor was always seen more than 20 and usually 30 to 40 yean after the initial exposure. Radiographic signs of other asbestos-related disease, such as plaques or pulmonary fibrosis, were not helpful in differentiating between a benign effusion and a mesothelioma. It has been estimated that between 2.000,000 and 6.000.000 penons have received appreciable exposure to asbes tos in the United States/6 A prevalence of 3.7 to 7.0 per cent of benign efTusions should alert us to the im portance of this disorder in the differential diagnosis of idiopathic effusions. Indeed, in-our ambulatory chest referral clinic exposure to asbestos was the most com mon cause of all effusions seen during the past 30 years. Therefore, we must consider the possibility of a benign asbestos effusion in this case, but it is not very likely for two reasons. Virtually all our patients with this disorder were seen during the first 20 years after exposure, with only a few at 30 to 39 years and none thereafter (Fig. 3). This patient's effusion, in contrast, probably occurred about 38 years after the initial ex posure. .Also, most asbestos effusions leave in their wake nothing but a blunted costophrenic angle or, at most, a smooth pleural residue, whereas this man had a rather thick, nodular residual shadow. The pleural lesion in this case was described as nod ular, suggesting the likelihood of a tumor with a sec ondary effusion. Primary benign and malignant tu mors may arise from any of the tissue components between the ribs and the lungs, but most such tumors are so rare that, except for a mesothelioma, they are not even mentioned in standard textbooks.17 Carcino- Taoie T. Pleural Effusions in Asbestos-Exposed Employees and Control Radiograpnic and Clinical Obaervations from Three to 35 Year*. fewm Owmnoi TOTAL mem tUUtAt OnrtMWB m. % AcbctiovopOMd Hapi0)1 AlltfTiwoni Du* to known imam Benign ubwoi tfTuuom * Dirootv ripend tndimlv cipoMd hnpbortlly apw* UnpowOeomiot* AUtffuMW Du* to known rfimi* Effusion* of unknown cans* 1133 34 4.1 tt 1.7 1133 33 3.1 32t 23 7.0 2*3 It 3.7 311 1 03 717 7 1.0 7 1.0 00 *D>AH to a Inaaary *r Man iiagun. iffm* mrnfntm to maaaai pmi total aa aaial ra*a|ra*a ar > marina. U* at !"*' at aaa wkar Wain Riatas la adaaMa. aM lack at Sataauaa a( a aiaieaoM um anan Una raan altar toaiaa. Years Since First Caposure Figure 3. Aabestos-Reiaied Manifestations in Employees Directly and indirectly Exposed." The prevalences are grouped according to years smee me first exposure. The numoers above me columns indicate the numbers of employees. Benign asbestos effusion was seen earlier man other disorders. It was ms only manifestation during me fast 10 years and was mo most common disorder during me first 20 years. ma metastatic to the pleura, on the other hand, is the most common form of localized pleura-based tumor with an effusion. The most frequent primary sites are the lung and the breast, which together account for more than half the cases.1* In this case we can vtnually exclude a bronchogenic carcinoma on two grounds. Neither the conventional roentgenograms of the chest nor the CT scan showed a pulmonary lesion. Further more, for practical purposes the patient was a nonsmoker. Other relatively common primary sites in clude the stomach, pancreas, colon, and prostate gland. There is no indication of disease in any of these organs in this patient except for the prostate gland, and nothing suggests metastatic tumor arising from it. Renal-cell carcinoma brings to mind "cannon-ball" metastascs to the lungs. It is not usually considered in connection with pleura-based tumors, although there are occasional cases with pleural metastases. We have seen an enlarging pleural tumor with an efTusion in a shipyard pipe coverer who was followed with a clinical diagnosis of mesothelioma for about three years: at autopsy the tumor encased the lung like a mesotheli oma, but microscopical examination revealed that it was a metastatic renal-cell carcinoma. In the case under discussion the early finding of microscopic hematuria suggested initially a renal-cell carcinoma metastatic to the pleura, but I had to abandon that diagnosis when Or. McLoud assured me that the nor mal intravenous pyriograms and nephrotomograms excluded the presence of a renal tumor. We are thus left with the problem of an elderly, nonsmoking former shipyard worker in whom a nodu lar pleura-based mass with an effusion developed 33 to 40 years after the initial exposure to asbestos. I sup pose that most second-year medical students and vir- b CO i1 ii DOW 06679 IOS THE NEW ENGLANDJOURNAL OF MEDICINE July 8. I9C tuallv every lawyer would make a diagnosis ofa malig nant mesothelioma. This tumor, exceedingly rare and relatively unknown until about 15 yean ago, has re cently received an enormous amount of publicity, not only in the medical literature but also in the lay press and on television. An informative discussion of meso thelioma and especially the problem of distinguishing it from adenocarcinoma was given at a recent dinicopachological exercise at this institution by Dr. Raymond L. H. Murphy.1' Briefly, the relation of this tumor to exposure to asbestos was first established by Wagner et al.20 only 20 years ago. Extensive publica tions since that time indicate that an exposure to as bestos can be established in about 80 per cent of the cases of pleural mesothelioma. It is now estimated that 1 to 3 per cent of asbestos workers will eventually succumb to this invariably fatal tumor. There are nu merous reports of the development of a mesothelioma in presumably indirectly or peripherally exposed per sons, such as remote workers in the plant or relatives of asbestos workers. Except lor anthophyllite. all types of asbestos can cause a mesothelioma, but there is prob ably a gradient of the risk, with crocidolite the most dangerous, chrysotile the least dangerous, and amosite somewhere in between. There is much to support the diagnosis ofa mesothe lioma in this case. The patient had a history of ade quate exposure. The latent period of 35 to 40 years is much more suggestive of a mesothelioma than a be nign pleural elusion. Furthermore, approximately 95 per cent of all patients wta a mesothelioma present with a pleural effusion. The tact that the patient was a nonsmoker does not mitigate against the diagnosis be cause no relation has been described between the prev alence of a mesothelioma and a history of smoking. The CT scan showed a pleural plaque on the contra lateral side, a finding that confirms that the patient had had exposure to asbestos, however slight. I am not suggesting that asbestos-related plaques undergo malignant degeneration. The present- of plaques themsehc* is unimportant except in the epidemiolog ic sense mat they are markers of exposure or what have been cail-d "leading fossils."21 Indeed, plaques have been referred to in the German literature as "Schonheitslehler," which literally translated means a beauty defect of the x-rav.n Plaques are demon strable radiographically 30 to 40 years after the ini tial exposure in 50 to 60 per cent .! the cases23 and are found at post-mortem examination in almost all the cases.24 Plaques do not cause symptoms t-r loss of pulimnarv function, and there is unanimous agreement that they never undergo malignant degeneration.23 The frequency of pulmonary and pleural tumors in persons with plaques is another matter. Obviously, inasmuch as plaques are markers of exposure :o asbestos and in tsmuch as pulmonarv and pleural tumors are more common in exposed persons the prevalence of such tumors must be higher in persons with plaques, for example, plaques were found in 27 of 47 cases of meso thelioma studied at autopsy, a prevalence far greater than that in the general population.23 The prognostic value of plaques in a uniformly exposed population is much more difficult to determine. It has been suggest ed that there is no evidence that their presence has any- meaning with respect to the development ofa mesothe lioma.2'In Great Britain a 10-year follow-up study of 408 dock workers with plaques and 444 without them showed that mesotheliomas' occurred slightly more often in those with plaques, but the difference was not statistically significant.2* A mesothelioma, then, w ould be the obvious diagno sis if it were not for the absence of certain clinical findings. I cannot recall a patient with this type of tumor who did not complain of chest pain and weight loss. VV'e have stored on tape the histories, clinical findings, physiologic data, coded roentgenograms, and pathological findings concerning all 8000 patients seen at our laboratory since 1950. Yesterday I scanned this tape to refresh my memory. We had no mesotheliomas from 1950 to 1960 but since then have seen 41, two abdominal and 39 pleural. At the initial visit 97 per cent of the patients complained of chest pain, which was usually pleuritic in nature, and 97 per cent had a weight loss of more than 5 kg. A pleural efTusion was present in 97 per cent, and 36 of 38 patients from whom we obtained an adequate occupational history, gave a history of exposure to asbestos. ^ In this case there is no record ofweight loss, and the patient recalled only one day of nonpleuritic right subscapular pain. A mesothelioma grows readily along tissue planes, and for that reason most patients have advanced lesions and extensive spread when first seen. The absence of chest pain and weight loss is therefore unusual-, although not unprecedented. As I stated in the beginning, no single diagnosis fits this case perfect ly. but if pushed to commit myself 1 would favor the diagnosis of a malignant mesothelioma. Da. Eugene J. Mark: This patient was seen on the Pulmonary Service. Dr. Kradin, do you have any com ments? Dr. Richard L. Kradin*: We favored the diagnosis of malignant tumor, either metastatic carcinoma or a mesothelioma, on the basis of both the radiographic appearance and the absence of identifiable pleural Auid. Dr. Mark: Dr. Calderwood. may we have the medical students' diagnosis? Dr. Stephen B. Calulrwood: Thev discussed in fectious orocessr* it.voiving the pleura, collagen vas cular diseases, ai.d nr. plasms, either arising in or metastatic to the pleura. They carefully consid ered rheumatoid involvement of the pleural surface but noted tnc absence of demonstrable pleural fluid or of subcutaneous nodules. Th<*\ iavored the diagnosis of a pleural mesothelioma w,:ti asbestosis, based on tht history of remote exposure to asbestos, the pres ence of bilateral pleural plaques, and the appearance o iu u im u u DOU 06680 Voi. 307 No. 2 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL 109 of (he right pleural abnormality on x-ray films of the chest and computed tomographic examination. Clinical Diagnosis ? Malignant mesothelioma or metastatic carcinoma. Rheumatoid arthritis, ? with rheumatoid lung disease. Da. Edward A. Gaxnsler's Diagnoses ? Mesothelioma. ? Benign asbestos effusion. ? Rheumatoid effusion. Asbestos-related pleural plaques. Pathological Discussion Dr. Marr: Dr. Goodson took care of this patient initially. Will you comment? Dr. John D. Gooosok: He was asymptomatic ex cept for mild prostatism and came to the hospital for cystoscopic examination. He had moderately active rheumatoid disease, which had been refractory to all previous types of therapy, including gold and various nonsteroidal antiinflammatory drugs. I started peni cillamine treatment approximately two months before admission. Since this drug is nephrotoxic a urinalysis was done and showed hematuria. The cystoscopic examination revealed that the prostate gland was somewhat enlarged and was the source of the hematu ria. The urine subsequently cleared. The pulmonary symptoms were limited to a very mild cough, and the right subscapular pain was fleeting. On the initial x-ray film of the chest it was not clear how much of the abnormal'*)' was an efTusion and how much was an infiltrate. I suspected at first that it might be a postinfectious process of oral origin or possibly due to a mycoplasma or a legionella infection. When it became clear that the patient had primarily a pleural abnor mality my concern shifted to whether it was rheuma toid lung disease or a mesothelioma related to the ex posure to asbestos. He had been deferred from military service became of the duodenal ulcer and as part ofhis obligation iJ been assigned to refit ships. He had substantial exposure to asbestos as a result. Dr. Mark: A PFD skin test was planned, but I cannot find the result. Dr. Goodson: It was negative, but the result was not entered in the hospital record. Subsequent cultures of the sputum showed no growth of fungi or tubercle bacilli. Dr. Marx: Dr. Hilgenberg, will you describe the operative findings? Dr. Alan D. Hilcenberc: I thought that a needle biopsy would not proride enough tissue to make a definitive diagnosis and therefore performed a very snu:! right thoracotomy. The parietai pleura was slightly thickened. In the pleural cavity we encoun tered a yellow, fibrinous exudate and about 200 ml of clear, yellow, loculated fluid. After the fluid and exu date were removed no tumor was risible. A pleural plaque was seen posteriori)'just above the diaphragm. The Tow er lobe of the lung was restricted by thickened visceral pleura. We biopsied the lung, the pleural plaque, and the parietal pleura. Dr. Mark: The open-lung-biopsy specimen was 2 cm in greatest dimension. The pleural surface was diffusely thickened by organizing fibrin and fibrous tissue. An elastic-tissue stain demonstrated that the thickening was superficial to the external and internal clastic lamina of the pleura, although the subjacent lung was fibrotic and atelectatic as well (Fig. 4). The pleural fibrous tissue contained many eventv distribut ed fibroblastic nuclei. The histologic pattern was not that of a hyaline plaque, in which the pleura is re placed by sparsely cellular, avascular hyalinized fi brous tissue. Portions of the surface of the visceral pleura and of a piece of separately biopsied parietal pleura exhibited a rigorous mesothelial-cell hyperpla sia with organization of fibrin (Fig. 5). In some areas histiocytes were palisaded perpendicular to the pleural surface. The mesothelial cells had abundant cyto plasm and large nuclei, without clumped chromatin or other features of a malignant tumor. Cytologic exami- Rgure 4. Lung-Biopsy Specimen (Vemosft-van Gieson Slain, *100). Intamal and xtamal clastic lemma* of the pleura (arrows) ssoarats compressed, tibrotic lung (bottom) trom thickened, fibrouc visceral pteuri (top). : STOU05403 DOW 06681 110 THE NEW ENGLAND JOURNAL OF MEDICINE Julv a. 1903 Figm 5. Pleural Surface (x2S6). The hyperplastic meeotheOei eats (arrows) ara cytoiogicaOy baragn. A dung of fibrin (right) it unoergcmg orgarszaaon. nation of the pleural fluid also showed only benign ceils. Culture of the fluid was negative for tuberde bacilli and fungi. The probable explanation for the pleural change is rheumatoid plruritis. No rheumatoid nodule was found in the pleura, and thus a definitive diagnosis is not possible. However, the pathological findings in the plcuritis of rheumatoid lung disease may consist of only mesothelial hyperplasia, with or without palisading of histiocytes and a lymphocytic infiltrate.30 The mesothelial cells in this case contained metachromatic, PAS-positive granules within their cytoplasm, which have betn d scribed in rheumatoid pleural effusion.31 The lung had a moderate increase of interstitial fi brous tissue around bronchovascular bundles (Fig. (5) and beneath the pleura but not in the interalveolar septa. These arv'U of fibrosis contained abundant amhracoitc pigment, which is a marker of possible deposnisrf - ' injurious materials.39 In these regions we found numerous asbestos bodies, which were long, thin, symmetric, beaded, and brown on hematoxylin and eosin staining (Fig. 71. The brown beads con tained iron, as demonstrated by the Prussian blue re action. Each asbestos body had a central, clear, translucent crystalline fiber, which distinguishes a true asbestos body from a pseudoasbestos body.33 The con centration of the asbestos bodies and the subplcural and peribronchiolar location of the fibrosis are consis tent with a diagnosis of parenchymal asbestosis. Di rect immunofluorescence of the lung-biopsy specimen would have been useful in excluding rheumatoid lung disease as the cause ofthe interstitial fibrosis. Marked deposition of Ig.M has been demonstrated in arterioles, interalveolar septa, and nodules in cases ofrheumatoid lung disease.34 In the presence ofthe interstitial fibrosis and numer ous asbestos bodies one must consider whether the pleural reaction was that seen in recurrent pleural effu sions related to exposure to asbestos.33 I cannot ex clude that possibility. In my experience the mesothe lial cells in patients with asbestosis associated with plcuritis and recurrent effusions but without a meso thelioma have tended to have dvsplastic nuclei, a fea ture not present in this case. Dr. McLoud, you have written about the normal findings on x-ray films of the chest in patients with clinical or physiologic ev idence of chronic diffuse in filtrative lung disease. Will you comment on the nor mal appearance of the lungs in this case in view of (he mild interstitial fibrosis found on pathological exami nation? Du McLoud: The lung parenchyma appeared normal for the patient's age. Some increase in linear densities throughout the interstitium is seen radio graphically in normal persons with aging, and the den sities may be more marked if the person has had pre vious infections or is a heavy smoker. We have found that approximately 9 per cent of patients with biopsyproved interstitial lung disease have normal x-ray films of the chest.30 In the patients with normal x-ray films, however, the most common diagnoses were sar coidosis. desquamative interstitial pneumonia, and al lergic alveolitis. Dr. Mark: Dr. Gaensler, in view of the additional information about this man's rheumatoid arthritis that Dr. Goodson has presented and the pathological find- Figure 6. Sroncnovascuto' Bundle with Increased AdveneM Fibrous Tissue Contemns Anthracooc Pigment (*6*). The fibrosis extends for only a snort distance into interalveolar sepia. >STOUUSl 10 ! DOW 06682 Vol. JOT So. 7 CASE RECORDS Of THE MASSACHUSETTS GENERAL HOSPITAL 111 which may result in pulmonary fibrosis. Were there any measurements of pulmonary gas exchange? Da. Goodson: Full pulmonary-function testing was not done. Da. Maak: Pent* illamine has been reported to cause diffuse interstitial inflammation and fibrosis with dysplasia of alveolar lining cells,1* features com mon to many types of drug pneumonitis but absent in the biopsy specimen in this case. Peribronchiolar and subpieural fibrosis with normal interalveolar septa, which was seen in this case, is not characteristic of drug reactions in the lung. Bronchiolitis obliterans19 and peripheral-blood eosinophilia40 have also been de scribed with penicillamine therapy. These findings were also absent in this case. Da. Gaenslea: We have seen patients with a pul ings. what do you think caused the pleural and pulmo monary reaction to penicillamine, but it has been prin nary abnormalities? cipally bronchiolitis or bronchiolitis obliterans rather Da. Gaenslza: An asbestos-induced effusion would than diffuse fibrosis.19 The bronchiolar changes have be very unusual so late after exposure. Ifl had known also been described in Great Britain.41 that the patient had problems related to the rheuma Da. Robcat Fienbeac: Is this patient still at risk for toid arthritis I would have suggested rheumatoid dis the development of a mesothelioma? ease of the pleura as more probable than an asbestos Da. Maak: Occasional patients with recurrent effusion. hemorrhagic pleural effusions due to asbestosis11 or The presence of asbestos bodies in the lung is not of indeterminate cause41 later have a diffuse malig diagnostic of asbcstosis. Indeed, all dry-dwellers have nant mesothelioma. In this case we haw not proved some asbestos bodies in their lungs. The pulmonary that the pleural disease was due to the exposure to fibrosis in this case is difficult to evaluate because the asbestos. piece of tissue was immediately subpieural, and the Da. Gaenslea: We tend to think ofthe biopsy as the patient had had pleural disease in that area. It is diffi definitive solution to many diagnostic problems. The i cult to make a diagnosis of asbestosis from a biopsy lungs can react to injury or disease in a relatively limit specimen because of sampling problems and particu ed number of ways, and yet an open biopsy of the lung larly in the presence of other pulmonary or pleural for diffuse disease is diagnostic in 91 per cent of the disease. If a patient has normal results of pulmonary- cases.41 The spectrum of pleural reactions is much function studies, normal lung fields on roentgeno more limited. A pleural effusion reflects an imbala- re grams of the chest, and no rales, clubbing or dyspnea between fluid production and resorption. It may not the diagnosis is not asbcstosis from a clinical viewpoint be due to disease in the pleura itself. It is not surpris despite the presence of a minimal fibrotic reaction in ing. therefore, that a thoracotomy to determine the the lungs. The discrepancy in this case between the cause of an efTusion is nondiagnostic in nearly half the clinical and the pathological findings suggests that the cases.41 The biopsy in this case probably excluded the subpieural fil>-..sis may well have been the result of diagnosis ofa mesothelioma, although the problems of pleural disca % sampling and of differentiation of this tumor from ac Da. Mask: Jr. Goodson, will you describe what tive non-neoplastic mesothelial proliferation have has happened to the patient* been described.41 The possibilities ofan effusion relat Da. Goodson: Since the process proved to be benign ed to the exposure to asbestos or rheumatoid disease we continued the penicillamine therapy. In addition to were raised by the history' and were not resolved by the the information in the case record we did request acute biopsy. The findings of asbestos bodies and pleural and convalescent deers for influenza A and B, Legion- thickening reinforced the former possibility, but the tlta pneumophiic. Mycoplasma pneumoniae, and adeno subsequently revealed history ofmoderate rheumatoid virus. and the results, reported several weeks after the arthritis treated unsuccessfully with a number ofdrugs operation, were negative. The patient has continued to supported the latter diagnosis. respond to the penicillamine as far as the rheumatoid arthritis is concerned, and the x-ray films of the chest obtained three months after the operation show im Anatomical Diagnosis provement as well. Improvement of rheumatoid pleu Pleuritic, fibrinous, ood pineal fibrosis, probably rhn- ral reactions as a result of penicillamine therapy has matoid. been reported.17 Peribronchial and subpieuralfibrosis with numerous asbestos Da. Homayocx Kazemi: We cannot ignore the pos bodies, consistent with pulmonary asbestosis. sibility of a pulmonary reaction to penicillamine, (Rheumatoid arthritis). rSTF0T5TT7 ij | i I I DOW 06683 THE NEW ENGLAND JOURNAL OF MEDICINE Julv S. 1983 RcruxNcss 1 Sapymsaoxx aM. RiMaMarp EF Vacant iniaas aaaanaud Mt dm> Maw uMwrii aimm. AickFukof. IW; 33 303-16 2 Smm CL. Bautr WE. Ithriuimmrt anknux. Cxmbndf*. Mtu Harvard Uncanny has*. 19)7. 3 Hart** AR. TWiptaa M. TKt ptnni and puianaary rnmplirmaai of mamtmcid armnm Am liwra Mad. 1959: 31:1179-20] * Tattoo JA. Ca&iM E. Mawan awali rmaai ikcumaid 9wa. JAMA. 196a. 119*11-). ! JthnMMMd pkmuT Laacn 1961:1.1)5-4. a Walker we. Wnpki V Rheumatoid pkunut. Am Una Ok. 1967: 26:447-74 7 Jama. PuJmooan Itsaaot aad fTwummaid anknoa. Madiraaa llikraua). 1961. 47 301-20. Fcrpuxoa CC Chotwrot pktail rfflaaaoa at rOnanawad lm| fiimi Thorax 19*6: 21:377*2 9 Carr DT. Maine JC Hawuy Kh tJTuaiaa m rtwamaiaid anhnm. mb Hitrace me loo raicaamuoa of plume ta pfcwal land. Aa Rav lopr Ola 1962:13:343-30. 10 Campbell CD. Ftmnfioa E Rheumatoid plaunui oak effwioa. On Chau. 1*61. 33.521-7 11 Canatcr EA. Kaplaa Al. Aakcaoa pfcml affuuaa. Am lauraMad. 1971: 74 176-91 12. Fknekar W. Vika FJ Jr. Cade RL. Onakar P A ImMi survey ad papa coraruip openuan a ceaaarunui| naval vasaals. J lad Hyp Taxml. 1946: 219-16. I). Murp6y RLH Jr. fern K Jr. Buipan WA. WanaMr J. Cataalar EA. Eflacn of ln emetamnen of asbnaoa: cluacal. mvraurumal. ndwtapir aad apwnmukf* otiarvanooa ui itupyard pip* coitian aad caaoeta. N Eafl J Mad. 1971: 213:1271-1. 14 Einaatadi HB Flaaral atbewou- Aa. Fran. 1942: 13:373-1. 13. EpkrGR. McLoud 7C. Gaamirf Ea. FirvaJaac* aad ncidaac* af baaifii ubrunt pkiaal tJAaaim a vrtutj pnpulawa JAMA. 1912: 2*7417- 16. Lana* R.\. Denial* JM. Wapeaar JX. Epidnmokp; af utlanta rrland dnaaa*. Eamfoa Haahh hnpaci. 19(0: 3*1-11. 17. Ttwra* EC. Fnpm OS- Pkiaal aunen aad pulmoaary ikenaei ddfawatnl diagram. Saima Roantpaael 1977: ] 2.239-47 II. CliamooB.SaluiSA. Carnramaioua invotvatncai of th* pkun: aa malym of 96 panel**. Am J Med. 1977: 6) 693-702. 19. Caa* Rccoeda of ill* Maaaadaaaiu Caaarkl Hoapaal (Caaa 9-19771. N Eafl J Mad. 1977: 296-500-7 20. Wafacr JC. Skffa CA. Marchand P Diffiia* plaaral mavxhalioma aad askcaioa capOMtr* at the aordi neater* Capa Ptovmcx. Br J lad Mad. I960: 17260-71. 21 Oafauaa P. Hiar I. Dabkan AF Pkmplaqgai. Aataaaoia nad AtfccaieipoMiion. tin* epidrmiolofiwtir Smdie aw dadi Hamburger Raw*. pnitflionoiofit 197*1- 143 73-42. 22. Suhlif H. Oaiouaa P. Ham E Epidcrmolofi* n*wntidin|ur GnuadhauaKhadca. Isamu iBerlin). 1972. 13:311-23. 23. SelikofT U. Tin occunaaca af Worn amoaf umilanoa warian m dn United Sum. Ann NY Acad So. 1963: 132.139-33. 24 Hounhaat DO B. Leaiof L. Richaidion PC. Hyalui* aM cakdkd pleural ptapuea a> an uidti of aipowet lo aabesiot: a mdy af nrtiolofical aM paiholofical laanuaa of 100 carat mek a tsiiiOtranaa of epadamtoeof) Br Med J. 19*6. I 1069-74 23. Graeabarp M. Lto*d Davits TA. Matadnlmu ftprar 1967-61 Ir J Im MM. 1974: 31.91-104. 26 Edpa JR. Chaudhan SL. Malifaaat mnsheliams af *a pkun m Barronm-Fumau. Thorax |97|. 33 26-30 27. Wnfki cw. Asbtaat aM kcaJdi in 1969 Aa Rev Ra^a On. 1969: 100:467.79. 21. Fkidnr DE. A iranalnv uudv af dupyaed vcrtin widi pleural plaautx. Br J IM Mad. 1972: 291*2-3 29. UaPR. SoaMC. Sana PS. Wood CA. Fkumywnh afTuxioa m rbaunuimd ardmm. Arak laun Mad 1939: 104 634-9 30 Ward! Ptauraltffimo*aMrtnunutoidankmn Lancet 1961.2:1)36-1 31 Feafkr JR. Ssetiuon CD. Rounfeld MC. QuanaM CXRhcumatei* pm- ill efftmoa Arc* Rural 1971: 91257-66. 32 Mari EJ. Tin vecond diagram: dn raft of dn padiolofni at idtaufy- aifpenaaioceaioiatuiliuifiaacirMfariiBiiar MuarPadiol. 1961:12.5157. )). Chart a. Wamack ML. Crean K Aaalyin af dn com af fampinow laikattotl bodut from dn ftnanl pepulatiew. R Tnn aabeaot kdai aM ptaudoubcuoi bodnx. Lak lava*. 1979: 40:31-1. H OcHerarnn RJ. Abnuso JL. William* RC Jr. Inrnmnoduorarcain aM immunolapK midniaf rtnumaioid hiaf. Arck lane* MM. 1972: 129 4414. 33. Rabinasn BWS. Mink AW ff rnifn iitirrri (rlrirtl iffimna lufantn mil count. Thorax 1911. 36:199900. 16 Epkr CR. McLoud TC. Gamier EA. Mikw JP. CamapM CB. Normal Chen ramfcaofnan in ckramc diffuac udUoitiva half duoaao. N Eopl J Med. 1971: 291.934-9 37. Coodmaa M. Turnar-Wanaick M. Filai aMy af pcmciUaawn dnrap; n conicoMcmtd failart parnau **k mdatpraad pukneaan Memo. CkoL 1971: 74:331 abisn. 31. Carnot F. Dtyat OR. Jnarrabo E. Jrineiui L. D-pcaiciUaaian-aakicM mara pwcumoaiut Onn. 1912:11:3764. 39 Epkr CR. Saidcr CL. Caemler EA. Cadican ES. FiuCcrald MY. Camap an CB Brencluolms aM bednekmt ai connective uliuc dnaaw: a potaibk iclanonthip 10 lln me of pemcillaffiun JAMA. 1979: 242:321-32. 40. Davnt 0. Janet JKL. Fulmenarv catmepkdia caiuad k\ pramUamun. Thorax 1910: 35*57-1. 41. Caddai 0M. Coenn B. Brewama DA. Dana RJ. Turner-Warwick M. Fropmtivt airway o6luciwioa in adulu aM in aateciaiien nn rtnumaioid dnaaw Q J Mad. 1977: 46 ar-44. 42. Ryan CJ. Rodfen RF. Unm KX. Happcr NCC. The outran! of parnau wur. pleural effusion of mdatcmiinait eaurc ar dioracoiomy Mayo Oia Pmc 1911: 56.143-9 a], Caemler EA. Camapren CB Open bwpty lor chrome difTuw tnhliraiiv* lun( dixaaat: clinical, idcniptaoprapmc. aM phyuolotical comiauaaa m 302 patrema. Ana Thane Surf I960: 30:411-26. Contimwd pTBoaratron ol tnesa Case Records Has been made possible by a generous grant to the Massachusetts General Hospital from Pfize* Pharmaceuticals m s o o o iS : 33-MILLIMETER L\XTER` SLIDES FOR THE CASE RECORDS An\ trader of the Journal who uses the Case Records ! the Massachusetts General Hospital as a medical teaching exercise or rrfermcr material is eligible to receive 33-mm lantern slides, with identifying legends, of the pertinent x-ray films, efrctrocardingrami. gross specimens, and pho(omini*;raphh ofeach case. The slides are 3 in. by 3 in., for use with a standard 33-mm projector. These slides, which illustrate the lurrrni cases in the Joonuil. are mailed weekly from the Department of Paiin-iogy and nu- be retained by the subscriber. Each year L..jroximaieJy 400 slides are sent to each subscriber. Because of the increased ti of preparation of the material and mailing. ii has been necessary to raise the cost to S330 per year. Appiicaiu-i: forms for the curr-.-ni subscription year, which began on March I. 1983. may be obtained from Mrs. Bettv L\ McXeelv, Department of Pathology, Massachusetts General Hospital, Boston. Massachusetts 03114 (telephone (6ITJ 720-8897). ' DOW 0C>684