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FILE NAME Talc TALC DATE 1996 DOC TALC174 DOCUMENT DESCRIPTION Journal Article - Atypical Mycobacteriosis as a Complication of Talc Pneumoconiosis 34 Deloster Deloster C. et al 1996. European Respiration J. Vol 9 0.1757-1759 Eur Respir J 1996 9 1757-1759 DOI 10 1183/09031936 96 09081757 Printed in UK - all rights reserved Copyright ERS Journals Ltd 1996 European Respiratory Journal ISSN 0303 - 1936 CASE REPORT Atypical mycobacteriosis as a complication of talc pneumoconiosis C. De Coster J.M. Verstraeten P. Dumortier P. De Vuyst Atypical mycobacteriosis mycobacteriosis as a complication of tale pneumoconiosis Verstraeten P Dumortier P De Vuyst @ERS Journals Ltd 1996 C De Coster JM ABSTRACT A 57 year old man receiving compensation for talc pneumoconiosis since 1977 was admitted to hospital for the first time in 1987 with symptoms of weight loss fever dyspnoea and productive cough A chest roentgenogram showed bilateral cavitation Two years later Mycobacterium xenopi was found in sputum cultures Despite specific oral antibiotherapy the patient's health deteriorated and he died in 1990 To the best of our knowledge this is the first reported case of an association of talcosis with a M. xenopi pneumonia The relative timing of the two diseases suggests that tale pneumoconiosis predisposed to the infection by M. xenopi Eur Respu J 1996 9 1757-1759 Chest Dept Erasme University Hospital Universit^' Libre de Bruxelles Brussels Akademisch Zieken nuts Sint Vincentius Ghent Belgium Correspondence P De Vuyst Chest Service Erasme University Hospital 808 route de Lennik 1070 Brussels Belgium Keywords Atypical mycobacteria talu pneumoconioSIS Received September 19 1995 Accepted after revision February 20 1996 Case report The patient born in 1932 worked as a talc miller from 1969 until 1980 in a Belgian factory The raw material was imported mainly from Montana US Yellowstone Talc was crushed without addition of other materials and served as a high grade talc for pharmaceutical purposes The patient had never previously been exposed to other minerals te g silica asbestos and had a smoking history of 35 years In 1977 the diagnosis of talc pneumoconiosis was made essentially on the basis of a chest radiograph In 1983 chest radiographs showed a progiession of the small opacities graded q 2/2 according to the International Labour Office ILO classification and the appearance of a large opacity in the right upper lobe graded A fig 1a The results of pulmonary function tests at that time were as follows forced vital capacity FVC 2.7 L 65 of predicted forcec expiratory volume FEV1 2.3 L 73 pied total lung capacity TLC 5.2 L 91 pied and transfer factor of the lung for carbon monoxide TL 61 pred A pronchoalveolar pronchoalveolar lavage BAL performed in 1983 showedshowed abundant tale particles talc bodies and traces of tremolite tremolite 1 Quartz was not detected in the BAL fluid but due to the con- siderable amount of talc particles traces of quartz could have remained undetected by this method b Fig 1 - a Chest radiograph in 1983 showing bilateral rounded opacities and a large opacity in the right uppet foht 1987 showing progression of the lesions with cavitations of both upper lobes b Chest radiograph in 1758 C. DE COSTER ET AL In 1987 at the age of 55 yrs the patient was admitted to the hospital with symptoms of fever dyspnoea and purulent sputum There was also a significant weight loss 38 kg body weight for 1.65 m Chest radiographs showed a progression of the large opacity in the right upper lobe and cavitations of both upper lobes predominating in the left upper lobe fig 1b Pulmonary function tests showed a deterioration of the spirometric values FVC 1.4 L 35 pred FEV 6 L 21 pred residual volume RV 4.0 L 190 pred and CO 11 pred The sedimentation rate reached 107 mm and the white blood cell count 10 cells Arterial blood gas examination disclo- sed severe hypoxaemia arterial oxygen tension Pa 49 kPa 37 mmHg Sputum smears for bacteria and acid bacilli were negative Clavulanic acid + amoxy- cillin had no effect on the fever but the patient recovered after antibiotic treatment of 10 days duration with trimoxazole In 1988 the patient was once more admitted because of fever and chest pain A chest radiograph showed a hy- droaenic level in the right upper lobe Blood cultures were negative and there were no pathogens detected in the sputum Oral antibiotherapy with trimoxazole was administrated for 3 days followed by cefuroxime One year later he was again admitted to the hospital with the same symptoms chest radiographs showing a progres- sion of the cavitary lesions At that time the sputum culture yielded 20 colonies of Mycobacterium xenopi but was negative for Mycobacte- Hum tuberculosis Oral rifampicin 600 day and,, Isoniazid INH 300 day were mitiated However because M. xenopi was resistant to INH it was replaced by ofloxacin 400 mg day ,, Four months later the patient was admitted for the last time because his condition had deteriorated He develo- ped severe renal failure anaemia leucocytosis and shock Despite intensive care the patient died a few days later Discussion The fust period 1977 198o7f this patient's disease is dominated by the diagnosis and the compensation for tale pneumoconiosis occupational period The second is dominated by mycobacterial infection leading to death 1987-1990 infectious period Knowing the diagno- SIS of M xenopi infection it is difficult to define its exact onset On the radiograph from 1983 it is possible that the right upper lobe opacity already corresponds to an infectious process Nevertheless the discussion will con- sider two phases in the patient's evolution the talc pneumoconiosis and the M xenopi infection and the possible relationship between them Talc pneumoconiosis in an uncommon pneumoconio- sis which classically requires a long duration of exposure to a high concentration of dust 2 3 Cigarette smoke appeals to increase the risk of developing this disease In the present case the prolonged exposure to high levels of respirable talc particles together with the presence of diffuse bilateral small rounded opacities on chest radiographs is compatible with the diagnosis of talcosis 2 3 BAL confirmed the retention of a very high concentration of talc particles The clinical and radiological data were compatible with previous descriptions of pneumoconiosis in exposed workers so that ro lung biopsies were taken The Belgian Occupational Disease Fund agreed to recognize and compensate this disease Large opacities are also described in talcosis and the abnormalities in the right upper lobe on the chest radiograph from 1983 were also considered as a part of the pneumoconiosis However the fact that this lesion was unilateral should have been considered as atypical This underscores the problem of differential diagrosis of lung opacities appearing in pneumoconiolic subjects subjects usually considered as coniotic masses without any complementary investigations Furthermore there was a clear progression of the bilateral small opacities No prior exposure to other mineral dust had been detected and even if a few tremolite asbestos fibres were found in BAL there were no evident signs of asbestosis no pleural plaques on thickening no evidence of interstitial fibrosis The fact that the asbestos type was tremolite suggests suggests a possible geological contamination of talc 1 It is actually admitted that M xenopi can bc pathogenic for humans and lead to severe disease but lung diseases due to this mycobacterial species are rare Underlying existing pulmonary diseases such as pulmonary tuberculosis chronic bronchitis emphysema bronchiectasis interstitial pulmonary fibrosis lung carcinorna and sarcoidosis are predisposing factors forM xenoni infection 4 6 Diagnostic criteria exist for identifying pulmonary disease where M xenopi is considered to be a pathogen including repeated positive cultures an abnormal chest roentgenogram consistent with mycobacterial infection and absence of other pathogens in the sputum 4 6 Various radiographic manifestations of M xchopi infection are described from multiple nodular shadows to Cavitary lesions 7 The clinical and radiological evolution of our patient since 1987 is consistent with a chronic lung infection by mycobacteria M xenopi was found twice in sputum cultures whereas M tuberculosis was never detected and could be excluded Therefore accord- ing to mycobacteriological and roentgenographic criteria it is obvious that the patient died from destructive lung infection by M xenopi There are only a few cases described in the literature in which lung disease caused by M xenopi led to death 4 5 7 As far as we know this is the first case report of the association of talc pneumoconiosis and lung infection by M xenopi Even if the succession of these two uncom- mon diseases in an individual case could be purely coincidental this seems unlikely and several clues suggest that the presence of talcosts predisposed to the secondary infection by M xenopi A parallel situation occurs in sili- cosis another pneumoconiosis which is a known predisposing condition for tuberculosis or even nontuberculous mycobacterial disease 8,9 8,9 The increased susceptibility to these other diseases could be explained by impaired function of macrophages due to sihca 10 11 Alveolar macrophages are important in the defence against mycobacteria not only through their phagocytic and bactericidal activities but also through the amplitication of the host defence by the release of cytokines interleukin IL and tumour necrosis factor TNF 12 In the case of talc pneumoconiosis in which macrophages are overloaded by tale particles is conceivable that these activities can be impaned ATYPICAL MYCOBACTEeriosis in TALC PNEUMOCONIOSIS 1759 In conclusion this case study suggests that lung infection by mycobacteria at least M xenopi can complicate talc pneumoconiosis In such a situation it should be considered as a part of the occupational disease and com- pensated as well References 1 De Vuyst P Dumortier P L^'ophonteP Vande Weyer R Yenault JC Mineralogical analysis of bronchoalve- olar lavage in talc pneumoconiosis Eur J Respir Dis 1987 70. 150-156 2 L^'ophonteP Fabie J Fortune JP Pincemin J Delaude A. Les silicatoses pulmonaires Poumon Coeur 1978 3. 193-201 3 In Parkes WE ed Occupational Lung Disorders 2nd edn London Butterworths 1982 Chapter 9 pp 296--310 4 Smith MJ Citron KM Clinical review of pulmonary disease caused by Mycobacterium Mycobacterium xenopi Thorax 1983 38 373 377 Banks J Hunter AM Campbell IA Jenkins PA Smith AP Pulmonary infection with Mycobacterium Mycobacterium xenopi review of treatment and response Thorax 1984 39 376-382 Wolinsky E Nontuberculous mycobacteria and associated diseases Am Rev Respu Dis 197 119 107 139 Simon AE Salt IE Vellend H The role of Mycobacterium xenopi in human disease Am Rev Respa Dis 1987 129 435-438 Morgan EJ 202-203 Silicosis and tuberculosis Chest 1979 75 Snider DE The relationship between tuberculosis and silicosis Am Rev Respu Dis 1978 113 455-460 Lowrie DB What goes wrong with the macrophage in silicosis Eur J Respir Dis 1982 63 80-182 Wallace RJ O'Brien R Glassroth J Raleigh J Dutt A Diagnosis and treatment of disease caused by nontuberculous mycobacteria ATS official statement Am Rev Respir Dis 1990 142 940-953 Rom NW Zhang Y The rising tide of tuberculosis and the human host response to Mycobacter Mycobacter tuberculosis J Lab Clin Med 1993 121 737-741 9002 peasasa s}UBU [ly Ajal00g jeapey syasnyoessey 6661 '1yBuAdoD Z1[ud The England Journal Journal of Medicine Medicine Wow pepeojUMoq 6661 STAINE est Massachusetts Massachusetts WW g 0} Z sajnpoayjdyjnyy Buimoys (g |euedg) seuo0z Bun] 4a -MO7] ay] YBno1Yy] UeDS 19 & pue ajnpoyJyejnGau4| ue Burmoys (y joueg) eqo7 saddy iyBiy ayy yBnosuy ueog [9 y 2%eanfily q Massachusetts General General Hospital Hospital Hospital ay} ul ajnpoy 4ejnBassy ue Bulmoys yseyD ay} yo YdesBolpey sojrazueosaysog |aanBly F -pe pue oqo] soddn qyZ11 oy) ul wd ATq Z o]Npou JepNSoin ue pamoys ([ B1q)vorssiumpry o10joq sdvp IT eudsoy sayzour 3 pourergo ydesZorpes o1ovs0y2 VY podojaasvpoudsAp pur aaa yZnosUdy 131 -IPD SYIIM [RIIAIS [HUN [Jaa U99q pey woned J, sajupoAuzeuowynd jo Surpuy s1sojorpes ay Jo asneo ajqendsoy 943 OJ poqtupr sem Uru pyo-reat-69 V ASVO AO A 66G6L-Le 9seD sueryaqqni e ut gol ev wo pamar sem juaned ayy, Teurdsoy SI] 0} DUILD JET porstsiodeoudsAp [euowsoXd IysrIs ing paaoiduynBnoo sguared ay, euoursse.Ouspe MOYSs O1 paliodai sem aqoy soddn 34S ay} ur ssew ay) jo Asdorq uonesdse-s]posu ev wo uawinads ev jo uoljeurtuenrd pestdossorspy sauoSzuny samo] IYI Ul GalateIp UI UW g 03 7 saTNpoJUaTeEWs opdaynuw pue osqoy szoddn aysiz aya jo Aroydiisd aya ur sseur poyynaids ev payeaaar (7 BLZ) / (1.9) sydessouw -0] poindwios speioyl y Agiedousprydu{y jeurserp -OUI JO ARTIY OU SEM JIIUT, SaTMpoyueJoepq FeuonIp 01IPY MVIBSY CMTANTIIQ W LIDVIS any SalLIld Cl AONT SDNIMIY HH ULIVS 4071py aiuvosy qd WAFTINOW gf OWVILILA A0UIpY aqviosy qd WAAVA [ INTNOAg orp gq WATIADRS GF MATA Yy LOGVO 9 GAUVHOIU AGT AAANi04 sastaaangy qwsfozoyrwdosuny 7y3a\4 Periphery Right Upper Lobe Diameter Diameter ze SpPlLoosa yy vsU-y nejm.org at LIBRARIES CONSORTIUM CONSORTIUM on bbbGl ime CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL TABLE 1. HLMATOLOGIC AND BLOOD CHEMICAL VALUES VARIABLE Hematocrit % Mean corpuscular volume m White cell count per mm Platelet count per mm Sodium mmol Potassium mmol Chlonde mmol Carbon dioxide mmol Urea nitrogen Creatinine Glucose VALUE 379 92 6,900 245,000 142 53 102 301 Normal Normal Normal TABLE 2. RESULTS OF PULMONARY TESIS VARIABLE RESULT value % of predicted FEV Inters Vital capacity liters FEV vital capacity Flow rate at 50 of vital capacity liters sec Maximal breathing capacity liters min Total lung capacity liteis Residual volume liters Residual volume total lung capacity Airway resistance cm of water Specific conductance liters of water breath carbon monoxide diffusing capacity min Hg Carbon monoxide diffusing constant min mm Hg Oxygen saturation % 49 164 164 49 251 275 275 64 059 059 76 104 104 23 52 49 98 98 176 7 29 324 0 74 180 128 128 0.0971 0.0971 160 160 67 44 96 99 97 FEV denotes forced expiratory volume in one second This value was obtained after the patient had inhaled a bronchodilator medication The value was based on the first measurements of FEV and vital capacity The predicted range is 08 to 24 cm of water per liter per second The predicted value is more than 012 liter per second per centimeter of water This value was obtained while the patient was breathing ambient au at rest This value was obtained after the patient had walked for three mmures where he had been exposed to talc for 28 years There was no history of exposure to asbestos He had smoked two cigarettes daily for six years He res~-dedin Ar~-zonaand was physically act ve His medications were metoprolol quinapril and terazosin There was no history of sputum production wheezing hemoptysis chest pain tuberculosis or exposure to it coccidioidomycosis weight loss or a malignant tumor The temperature was 36.8 the pulse was 67 and the respirations were 20 The blood pressure was 120/85 mm Hg On examination the patient was a slim man who appeared well The lungs were clear except for a few rhonchi on the right side Laboratory tests were performed Table ) An electrocardiogram revealed a sinus bradycardia at a rate of 50 with nonspecific segment and wave abnormalities The results of pulmonary studies performed at the other hospital are shown in Table 2 A diagnostic procedure was performed DIFFERENTIAL DIAGNOSIS DR SIMON D. SPIVACK This pauent had an defined respiratory illness characterized by fever cough and dyspnea Since his cough improved with- out any known treatment one can rule out the com- mon acute bilateral bacterial pneumonias such as those due to Legionella pneumophila Mycoplasma pneumoniae and Chlamydia pneumoniae particularly in the absence of known exposure to these organisms If the patient was immunocompromised how- ever a lung biopsy would be needed to rule out these infections Systemic immunocompromise such as that caused by the cell deficiency associated with lymphoma infection with the human immunodefi ciency virus HIV and use ofcorticosteroids or cyclosporine the cell deficiency associated with mul tiple myeloma neutrophil deficiency or the combined deficiencies that may follow an allogene'c bone marrow transplantation predisposes a host to infections with particular sets of organisms depending on the critical elements of the host's defense that are lack- ing Since this patient had no apparent risk factors for disseminated tuberculosis or pneumocystis pneu- monia these diagnoses are unlikely May we review the radiographic findings DR ANNE O. SHEPARD The chest film Fig 1 obtained before admission shows an irregular nod ulc 2 by 1.5 cm in the right upper lobe as well as smaller bilateral nodules The CT scan Fig 2 shows the irregular nodule in the posterior segment of the Attending physician Pulmonary and Critical Care Medicine Albany Medical Center associate professor Albany Medical College College research phy sician New York State Department of Health Division of Human Toxicol ogy and Molecular Epidemiology all in Albany Volume 341 3 Number 183 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12 2006 Copyright '1999 Massachusetts Medical Society All rights reserved The New England Journal of Medicine right upper lobe and numerous bilateral nodules 2 to 5 mm in diameter in the lower lung zones No lymphadenopathy or pleural plaques were visible DR SPIVACK Since the patient had radiographically stable disease without treatment over a period of at least 11 days we can rule out acute bacterial processes such as those attributable to Streptococcus pneumoniae Haemophilus influenzae Klebsiella pneu- moniae and oral anaerobes In the absence of a history of exposure and without a report ofpositive results of skin tests with purified protein derivative localized Mycobacterium tuberculosis infection is unlikely There is no clinical evidence that the patient had preexisting pulmonary abnormalities that might have made him susceptible to bacterial overgrowth such as cavitary disease which may lead to the formation of an aspergilloma Nor is there ciliary dyskinesia syndromes or cystic fibrosis in this case The radiologic finding of bilateral small nodular opacities suggests the presence of an underlying subacute or chronic lung process The differential diag- nosis of small nodules in this context includes exog- cnous as well as idiopathic and malignant disorders Subacute infections such as coccidioidomycosis blastomycosis histoplasmosis and miliary tuberculosis may account for the small nodules There was no apparent evidence of exposure to M. tuberculosis or a predisposition to miliary tuberculosis however and there is no information about skin testing Nodules and airflow abnormalities are typical of pneumoconioses such as talcosis and silicosis as well as hypersensitivity pneumonitis due to exposure to an organic antigen or beryllium but the history in this case does not suggest either type of exposure Moreover the patient's pulmonary dysfunction is not characteristic ofasbestosis mixed discase or exposure to heavy metals Idiopathic disorders including sarcoidosis eosinophilic granuloma and bronchocentric granulomatosis may be accompanied by fever early in the course of the disease and may be associated with obstruc- tive or mixed obstructive and restrictive pulmonary dysfunction Lymphocytic interstitial pneumonitis is an unlikely diagnosis in the absence of progressive dyspnea cough and underlying disease Similarly Strauss vasculitis is unlikely in the absence of preexisting atopy or reactive airway disease This pa- tient may have had a bronchiole disorder such as bronchiolitis obliterans or bronchiolitis obliterans with organizing pneumonia particularly in view of the profound air trapping with the preservation of large airway conductance and resistance Patients with malignant tumors present infrequently with bilateral small nodules Hodgkin's lymphoma is an unlikely diagnosis in the absence of peripheral or hilar lymphadenopathy Patients with bronchi- oloalveolar carcinoma may present with nodular or alveolus lesions Lymphangitic spread ofcar- cinoma or leukemia may also be characterized by the presence of such lesions I shall return to the possi- bility of a malignant tumor Coccidioidomycosis deserves serious consideration in this case because the patient lived in Arizona Coccidioides immitis is present in soil and is endemic in the southwestern United States Clusters of cases in other areas have been attributed to dust storms that carried the pathogen to distant sites The fun gus is dimorphic existing as a saprobe or a parasite Mycelial forms grow in soil and disarticulate releasing arthroconidia into the air which are inhaled by the host person transmission and indirect transmission through secretion contact are very rare 13 Respiratory isolation is therefore not required Inhalation of arthroconidia froin soil is VIItually the only route of entry into the human host placing those who have frequent contact with contaminated soil such as archaeologists and excavators at highest risk The immune response is partly celldependent and the infection has increased among infected persons who live in the Southwest The parasitic portion of the life cycle entails the re lease of a substance with elastase activity that pro- motes the degradation of molecules in the connec tissue matrix of the host resulting in the spread of infection and the formation of the microcysts or 13 macrocysts seen on microscopical examination Clinical evidence of disease is barely apparent in approximately 60 percent ofpatients with acute pri- mary infections In these patients symptoms are ab- sent or if present consist of a mild cough and lowgrade fever making them difficult to distinguish from the symptoms of an upper respiratory tract in- fection The remaining 40 percent of patients have an illness one to three weeks after exposure that of- ten mimics a lower respiratory tract infection with fever diaphoresis dyspnea chest pain sputum production anorexia arthralgias and weakness Radiologic examination may show an infiltrate an effusion hilar lymphadenopathy or a combination of these findings Skin manifestations include erythroderma erythroderma erythema nodosum and erythema multiforme Without specific therapy the primary infection resolves spontaneously within several weeks in most cases Radiographic residua in the form ofnodules or thin- walled cavities are present in 5 percent of such cases Spontaneous clinical resolution and radiographic residua were features of this patient's illness at the time of admission Extrapulmonary disease which develops in less than 1 percent of patients with C. immitis infections in- cludes meningitis osteomyelitis septic arthritis gentourinary infection and skin involvement The meningitis may be subtle in terms of both clinical findings and cerebrospinal fluid characteristics ranting diagnostic vigilance In regions where the infection is endemic rapid and widespread dissemination in im- 184 - July 15 1999 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12 2006 Copyright '1999 Massachusetts Medical Society All rights reserved CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL munocompromised patients has closely paralleled the epidemic of the acquired immunodeficiency syndrome Patients receiving corticosteroids or other cell suppressants infants and nonwhites particularly Filipinos for unclear reasons are also susceptible to coccidioidomycosis 13 The diagnosis can be confirmed by examination of smears of aspirated fluid from pulmonary or other sites False positive results may be caused by the presence of contaminating pollens from mulberry cottonwood and elm trees.4 False negative results may be due to sampling error or a failure to alert the cy- topathologist to the possibility of C. immitis infection As in this case reactive atypia of pneumocytes is often seen in cytologic aspirates and if spherules are undetected the reactive atypia may be mistaken for carcinoma.57 biopsy specimens are superior to cytologic aspirates for direct visualization of the organism the large endosporulating spherules are readily visible with routine staining Culture of the organism is possible but poses a major biohazard Growth is generally visible within three to four days although the yield is reduced in patients with HIV infection Skin testing shows a delayed type of hypersensitivity to intradermally injected antigen in 93 percent of patients 14 days after the onset of symptoms and in 99 percent at 21 days An area of induration at least 5 mm in diameter that develops 24 to 72 hours after injection is considered a positive result and determining the result within this period reduces the false positive rate Waning of the reaction is slow and a positive skin test therefore does not indicate the date ofonset of the infection Con- versely anergy which may result from overwhelm- ing infection impairs the sensitivity of the test Serologic testing is very useful for diagnosing C. immitis infection Primary infection elicits IgM antibodies in 90 percent of symptomatic patients within one to three weeks after the onset of symp- toms as detected by precipitin immunodiffu- sion or agglutination tests Tests for comple- fixing IgG antibody become positive weeks after the onset of symptoms after the IgM response and the titer may parallel the disease activity and dis- semination False positive results can be caused by reactivity of the organism with Histoplasma capsulatum and Blastomyces dermatitidis Serologic results may be negative if infection is confined to the meninges Methods that circumvent these problems are being developed such as direct detection of cir- culating antigen and detection of circulating genom- ic material by the polymerase assay.1-3 Inhalation of talc may explain the bilateral micro- nodular disease in this patient Industrial talc is commonly used to dust rubber products it is lu- bricating flaky fibrous and chemically inert Talc is a hydrous magnesium silicate that also contains iron and trace amounts of aluminum Industrial talc of- ten contains mixtures of silicate tremolite amphibole and serpentine asbestos anthophyllite and other talcose rocks The content depends on the mining source and contamination by silica and asbestos has caused considerable confusion about the fibrogenicity and carcinogenicity of tale Obtaining a precise history of exposure to talc includ ng the respi ratory protection used and data on confounding exposure such as exposure to other dusts or to to bacco smoke is often a problem Inhalation is the most frequent form of exposure to talc Although most related illnesses are caused by exposure during the milling and processing oftalc industrial use of the end product and even the use of talc in high doses for personal care have caused respiratory illness Among the respiratory diseas- es associated with the inhalation of talc hat does not contain silica or asbestos is talcosis a bilateral diffuse micronodular granulomatous discase affecting the pulmonary interstitium with acute or chronic bronchitis Emphysema with the formation of bullae may be present The microscopical fincings include diffuse interstitial fibrosis occasionally with bron chial or bronchiolar distortion defined nodules with birefringent talc particles but with little of the whorled collagen that is characteristic of silicosis and foreign granulomas with or without interstitial and pleural fibrosis Pleural plaques may be present especially after exposure to asbestos taining talc Reactions to pure talc usually result in less fibrosis than those to talc that contains silica asbestos or both Although there is a general response relation in talcosis progressive disease can occur in the absence of continued exposure leading to progressive dyspnea weight loss from labored breathing and hypoxia and cor pulmonale with eventual right heart failure This patient had mild dyspnea and was slim but no signs of profound hypoxia or cor pulmonale were apparent on physical examination or on the electrocardiogram In patients with talcosis chest radiographs typically show interstitial infiltration or granulomas in the midzones and bases of the lungs with sparing of the apexes in contrast to the distribution of lesions in patients with silicosis Since tale is frequently mixed with silica and asbestos the clinical and radiographic findings associated with these three dusts may merge Both restrictive and obstructive disease can occur and even coexist in talcosis as in other granulomatous diseases such as silicosis and sarcoidosis Both airflow obstruction and small way disease have been observed in talc workers in the rubber industry Symptoms are often mild despite abnormalities on radiographs and pulmofunction testing again as with silicosis and sar- coidosis Rubber workers who have never been exposed to talc may have industrial bronchitis that persists in- Volume 341 3 Number + 185 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12 2006 Copyright '1999 Massachusetts Medical Society All rights reserved The New England Journal of Medicine definitely after their exposure to rubber has ceased and they have retired Multivariate analyses stratified for the confounding influences of cigarette smoking and preexisting lung disease suggest that in addition to talc fumes from curing and other particulates involved in rubber manufacturing are important air- way irritants 12,16-18 The biopsy report of adenocarcinoma of the lung in this case bears close scrutiny Cellular atypia particularly in the presence of an acute inflammatory condition can be difficult to distinguish from carcinoma cytologically A positive test for p53 protein may prove helpful in confirming the diagnosis ofcar- cinoma in the future The possibility of a false positive cytologic report must be considered in this man who had symptoms of an acute illness compatible with tracheobronchitis Atypia as a result of coccidioidomycosis has been reported.57 In this case the radiographic stability of the lesion over the course of the illness although nonspecific is more compatible with the diagnosis of a subacute or chronic inflammation than with the diagnosis ofcarcinoma If the patient had adenocarcinoma of the lung it may have been metastatic The cancer may have originated in the gastrointestinal tract kidney or prostate gland Gastric carcinoma has been linked to substances used in the chemical and rubber industries including benzidine a- and naphthylamine crystalline silica and asbestos and also to drinking water containing nitrates 22 However there is no evidence that this man who appeared well had an ex- trapulmonary primary tumor The carcinogenicity of inhaled talc is controver- Sial 10,23 25 Stille and Tabershaw25 did not find an in- creased number of cases oflung cancer in employees of a processing plant in New York State over a period of 31 years Similar findings have been reported by other investigators Exposure to a combination of silica and talc however results in a higher rate of death from lung cancer than exposure to silica alone The carcinogenicity of silica has been proposed but has not been definitively demonstrated in humans the carcinogenicity of asbestos is well documented.29 Industrial exposure to a mixture of talc and silica or talc and asbestos may explain the development of lung cancer in this patient who did not have a history of heavy smoking but it is an unlikely explanation A considerable number of nontale substances used in the rubber industry are also known or suspected lung carcinogens such as nitrosamines Although bronchogenic carcinoma especially adenocarcinoma can occur in the absence of known exposure to carcinogens such cases account for less than 5 percent of cases oflung cancers in the general population The risk of lung cancer depends partly on host factors including the presence or absence of preexisting lung discase dict family history and genetic factors Polymorphisms of genes associated with carcinogenesis have been reported to confer a risk of lung cancer The need to identify a carcinogen or a host risk factor would be obviated by ruling out carcinoma in the lesion in question Radiographic evidence of multiple lesions usually indicates the presence of either metastatic cancer or a noncancerous process Bronchioloalveolar carcinoma is a notab e exception with lesions that are often multifocal A careful re- view of the cytopathological smears would therefore be an important diagnostic approach It is not clear whether this patient could tolerate resection of an adenocarcinoma A curative lobecto- my might remove enough functioning lung tissue to impair his subsequent tolerance of physical exertion Until recently the criterion for resectability of the lung was an estimated postoperative forced expira- tory volume in one second FEV of0 80 liter a re- quirement this man might meet if he needed a right upper lobectomy but not if he requied a pneumonectomy The refined criteria for operability include a measure of integrated cardiopulmonary and muscular function a test readily available in most pulmonaryfunction laboratories 34 Some surgeons consider this test excessive and instead have patients walk upstairs to test their tolerance of exertion The ability to climb three flights of stairs may be correlated with maximal oxygen uptake rate 3 This patient's ratio of FEV to vital capacity is low clearly indicating an obstructive component of his pulmonary dysfunction that was unresponsive to the inhalation of a agonist The usual sites of airflow obstruction that are evident on spirometry are the small bronchi and bronchioles as in patients with asthma emphysema or chronic bronchi is This pa- tient's low forced expiratory volume may be due to air trapping behind obstructed airways or to an independent restrictive process such as interstitial fibrosis These two possibilities are best distinguished by body plethysmography The high values for residual volume and total lung capacity are compatible with severe air trapping as the predominant dysfunctional process Major or minor airway obstruction bullous lung disease or both can cause this pattern but bullae were absent on CT scanning The low carbon monoxide diffusing capacity which can be falsely decreased by anemia and heavy cigarette smoking neither of which applies to this patient must be attributed to parenchymal damage probably sim- ~-larto that causing the air trapping Possible explanations for this patient's lung dvs. function include one or more of the following smallairway disease due to coccidioidomycosis chronic obstructive airway disease caused by exposure to talc or rubber fumes previously undetected chronic airflow obstruction of unknown origin or a con- founding repair process such as bronchiolitis obliterans with or without organizing pneumonia A patho- 186 - July 15 1999 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12 2006 Copyright '1999 Massachusetts Medical Society All rights reserved CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL logic repair process often occurs after a variety of pulmonary insults such as viral infections in infants and young children M. pneumoniae or L. pneumophila infection in adults inhalation of nitrogen oxide connective disease drug reactions and bone marrow and lung transplantation.36,37 Tests of airway resistance and conductance measure airflow across the smallest total sectional area of the air- ways - paradoxically the large airways thus bronchiole lesions have relatively little effect on such measurements In cases of bronchiolitis measurements of lung volume may reveal hyperinflation reflected by high values for functional residual volume and total lung capacity One usually expects a greater abnormality in gas transfer than that demonstrated by ambulatory oximetry in this patient although the technique used even for this simple maneuver can be questioned Finally this patient's initial chest CT scan was not of high resolution and there- fore would not have revealed the bronchiolar thickening bronchiolar dilatation and mosaic perfusion that have been reported on resolution CT scanning in patients with this disorder Ex- piratory resolution CT scanning which might have been helpful in detecting air trapping was not performed In conclusion I believe that this patient had acute coccidioidomycosis possibly complicated by obliterative bronchiolitis with underlying talcosis and silicosis I doubt that he had bronchogenic carcinoma The most important diagnostic procedure would have been a reexamination of the cytologic smear to detect coccidioidomycosis spherules or to confirm the presence of a malignant tumor The decision to perform an excisional biopsy would have depended on the results of this reexamination CLINICAL DIAGNOSES Talcosis Carcinoma of the lung DR SIMON D. SPIVACK'S DIAGNOSES Talcosis and silicosis due to occupational inha- lation of talc Acute primary coccidioidomycosis possibly with obliterative bronchiolitis PATHOLOGICAL DISCUSSION DR EUGENE J. MARK The diagnostic procedure was an exploratory thoracotomy The surgeon felt a mass in the right upper lobe and performed a lobec- tomy He also removed two smaller nodules from the right lower lobe The right upper lobe contained numerous firm gray nodules 1 to 7 mm in diameter On microscopical examination they were circular or resembled a caput medusae Fig 3 They were composed of histiocytes including multinucleated forms of a for- wae 0S s Lk Po Figure 3. Cellular Nodule with a Caput Medusae Configuration Hematoxylin and Eosin X35 re Figure 4. Clusters of Birefringent Talc Crystals within Fibrotic Tissue Viewed under Partially Polarized Light 75 Volume 341 Number 3 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12 2006 Copyright '1999 Massachusetts Medical Society All rights reserved 187 The New England Journal of Medicine ~ or S ae, . ^' Ea * # aR * + z e ae : . om * em 2 =~" .% arr. ote a4, ree * % ak een > na 7 Figure 5. Large Nodule with Hyalinized Fibrous Tissue in the Center Hematoxylin and Eosin 20 Figure 6. Multiple Ferruginous Bodies and Histiocytes in an Alveolus Hematoxylin and Eosin x330 body type yellow birefringent crystals were packed into clumps and sheaves within the histiocytes or in fibrotic tissue Fig 4 The centers of the larger nodules were replaced by hyal~-n~-zedfibrous tissue Fig 5 Long crystals of talc encrusted with iron formed ferruginous bodies in some areas Fig 6 These crystals account for one type of pseudoasbestos body True asbestos bodies were present as well but the interstitial fibrosis characteristic of as- bestosis was absent The appearance of the lesions and the presence of the crystals are characteristic of talcosis The largest mass which was 3 cm in diameter had a central cavity that contained a watery mixture of tale Fig 7 The only case with similar pathological features described in the literature consisted of multiple loculated cavities filled with talc the talc in that case however had probably entered the lung through a bronchopleural fistula after the instillation of talc in the pleural cavity to treat recurrent pleural effusions Inhalation of finely dispersed tale probably caused the diffuse disease in this case and a plug of talc probably led to the formation of the cavity Also histiocytes and talc crystals had eroded nto pulmonary arteries in the vicinity of the cavity and caused an obliterative endarteritis Fig 8 which may have had a role in causing cavitation Take and other silicates tend to cause intense vascular inflammation and sclerosis which contributes to the pulmonary scarring 45 There were no compact granulomas the presence of which would have suggested infection nor were any organisms detected with special stains Pneumocytes in areas of scarring were reactive and atypical probably accounting for the cytologic diagnosis of adenocarcinoma Unfortunately the cytologic smears were not available for review at this hospital Talc usually produces small nodular scars or lincar interstitial fibrosis which can lead to bronchiectasis honeycomb fibrosis or both as well as progressive massive fibrosis Areas of massive fibrosis can ap- pear radiographically as central or peripheral masses and in some cases they have been resected surgically +1 Impacted talc was found to have plugged and destroyed bronchioles in a child who died after aspirating talcum powder.46 Tumor masses on chest radiographs of workers in two talc factories in Greece were thought to be due to concretions of tak that had obstructed bronchioles and then caused atelecta- sis and fibrosis.47 Historically workers in talc mines and mills were at greatest risk for talcosis Rubber workers are now probably the most commonly exposed persons 48 DR DAVID J. KANAREK This patient worked in eastern Massachusetts for 28 years making bands eight hours a day and every time he made a rubber band he sprayed it with talc Then he moved to Arizona His exercise tolerance was very good despite the results of the pulmonary tests 188 - July 15 1999 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12 2006 Copyright '1999 Massachusetts Medical Society All rights reserved CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL : % ca s . ~ > ~ Per . hoa * $ * > . eedrat H * a a sos 4 * ; % * pe * Bab es ' cad * Z 7 a * Fy, ew ts ob, * 4 Pr ; | %, tee . , 4 a a y at * ae 2 a eo. a2 J ter wot eek Pa ty we ay. 4 > etfs a an , af ge tw * Ps . a oe x7 a * a cS * z . at .f bo * er g * , 4 + H: 4 ~ a at on fea * xe > 2 ge, ee . 6 * * . * : > 4H ~ . * + 93 nn a > 1 s? - * Pe > 9t : : x, . & > . a 4 4 s .* at toe . wets Le 1 fekee ify 4 eee we * e * fe ave te * . * . . > > Le oe 5a + oe ne & Or ana wae , to * ^' foes eon . od * * * ME * cutee . 4 rE fegtes a ars eat 76 te ow Pa 2 Myo a4 a * hem et > * . robe Pn * - ae S& #& & re * . Figure 7. Edge of a Cavity C Containing Groups of Pale Talc Crystals between Arrows and Laden Histiocytes H Hematoxylin and Eosin x20 Calcified concretions dark staining are present top oe car & tre ue * on fdas ae ater RSS poe oy bh 5 ann Figure 8. Thrombosed Artery Adjacent to the Cavity VerhoeffIvan Gieson Stain 150 Histiocytes arrows with talc crystals have eroded the arterial wall causing reduplication of elastic fibers black and fibrosis and narrowing of the lumen L Dr. Spivack What was the acute illness and why did the pulmonary studies show such marked abnormalities DR KANAREK The patient probably had a respiratory tract infection which prompted his physician to obtain the radiograph of the chest the talcosis was an incidental finding The pulmonary studies showed much more hyperinflation than one would expect from viewing the radiologic images The hyperinflation was probably related to the obliteration of the airways seen on microscopical exam~-- nation DR MARK In addition to bronchiola scarring due to the inhalation of talc there was also marked centriac~-naremphysema probably related to smoking ANATOMICAL DIAGNOSIS Pulmonary talcosis with liquified mineral in cav itated tumor mass granulomatous granulomatous inflamma tion and sclerosis REFERENCES 1. Stevens DA Coccidioidomycosis N Engl J Med 1995,332 1077 82 2. Deresinski SC Coccidioidomycosis immitis In Gorbach SL Bundch JG Blacklow NR eds Infectious discases Philadelphia WB Saunders 1992 1912-22 3. Kirkland TN FiererJ Coccidioidomycosis a reemerging infectious dis ease Emerg Infect Dis 1996,2 192-9 4. Nunez D Stanley C Robertstad GW Drow DL Pseudoepidemic of coccidioidomycosis Am J Infect Control 1982,10 68-71 5. Chen KT Cytodiagnostic pitfalls in pulmonary coccidioidomycosis Di agn Cytopathol 1995,12 177-80 6 Raab SS Silverman JF Zimmerman KG Fine needle aspiration biopsy of pulmonary coccidioidomycosis spectrum ofcytologic findings in 73 pa tients Am J Clin Pathol 1993,99 582 7 7. NaryshkiSn Young NA Respiratory cytology review of non ncoplas tic munus of malignancy Diagn Cytopathol 1993,9 89-97 8. Smith CE Diagnosis of pulmonary coccidioidal infections infections Calif Mod 1951,75 385-91 9. Woodruff WW III Buckley CE III Gallis HA Colu JR Who RW Reactivity to spherule derived coccidioidin in the southeastern southeastern United States Infect Immun 1984,43 860-9 10. Kleinfeld M Messite , Gil CP Tale and related lung diseases In Rom WN ed Environmental and occupational medicine 2nd ed Boston Little Brown 1992 11. Wegman DH Peters JM Boundy MAG Smith IJ Evaluation of res piratory effects in miners and millers exposed to talc free of asbestos and silica Br J Ind Med 1982,39 233-8 12. Fine LJ Peters JM Burgess WA Di Berardinis LJ Studies of respira tory morbidity in rubber workers respiratory morbidity in tak workers Arch Environ Health 1976,31 195-200 13. Merchant JA Occupational respiratory diseases Washington DC Government Printing Office 1986 256-67 DHHS publication no NIOSH 86-102) 14. Schwartz MI King TE Jr eds Interstitial lung diseases Toronto BC Decker 1988 63 15 Kleinfeld M Giel CP Majeranowski JF Messite J Tale pneumocomi osis a report of six patients with postmortem findings Arch Environ Health 1963,7 101 15 16 Time LJ Peters JM Respiratory morbidny in rubber sorkers 1 Pres alence of respiratory symptoms and disease in curing workers Arch Livi 1on Health 1976,31 5-14 17 Idem Respiratory morbidity in rubber workers II Pilmonary tion in curing workers Arch Environ Health 1976,31 10 4 18. Idem Studies of respiratory morbidity among rubber workers Respiratory morbidity in processing workers Arch Environ Health 31 136-40 fune III 1976 Cagle 19. PT Fratre AE Greenberg SD Cox A Brown RW Potential utility of p53 immunopositivity in differentiation of adenocarcinomas from reactive epithelial atypias of the lung Hum Pathol 1996,27 1198 203 Volume 341 Numbe 3. 189 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12 2006 Copyright '1999 Massachusetts Medical Society All rights reserved The New England Journal of Medicine 20. Monson RR Fine LJ Cancer mortality and morbidity among rubber workers J Natl Cancer Inst 1978,61 1047-53 21. Parent ME Siemiatycki J Fritschi L Occupational exposures and gastric cancer Epidemiology 1998,9 48-55 22 Pang ZC Zhang Z Wang Y Zhang H Mortality from a Chinese asbestos plant overall cancer mortality Am J Ind Med 1997,32 442-4 23. Thomas TL Stewart PA Mortality from lung cancer and respiratory disease among pottery workers exposed to silica and talc Am J Epidemiol 1987,125 35-43 24. Wergeland E Andersen A Baerheim A Morbidity and mortality in tale exposed workers Am J Ind Med 1990,17 505 13 25 Stille WT Tabershaw IR The mortality experience of upstate New York tale workers J Occup Med 1982,24 480 4 26. Silica and some silicates In IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans Vol 42 Lyon France International Agency for Research on Cincer 1987 27 Spivack SD Silica and lung cancer Lancet 1990,335 854-5 28. Paron JC Brochaid P Jautand MC Bignon J Silica and lung cancer a controversial issue Eu Respu J 1991,4 730 29. Mossman BT Gee JBL Asbestos diseases N Engl J Med 1989 320 1721-30 30. Saraceno JL Spivack SD Strategies for early detection of lung cancer Chin Pulm Med 1999,19969,6 66-72 31 Spivack SD Fasco MF Walker VE Kaminsky LS The molecular epidemiology of lung cancer Crit Rev Toxicol 1997,27 319-65 32. Spivack SD Saraceno JL Preoperative evaluation and management of the respiratory disease patient In Davis GS Marcy T eds Medical management of pulmonary discases New York Marcel Dekker in press 33. Olsen GN The evolving role of exercise testing prior to lung resection Chest 1989,95 218-25 34 Epstem SK Faling LJ Daly BDT Celli BR Inability to perform bicy cle ergometry predicts increased morbidity and mortality after lung resection Chest 1995,107 311-6 35. Pollock M Roi J Benditt J Celli B Estimation of ventilatory reseive by stair climbing a study in patients with chronic auflow obstruction obstruction Chest 1993,104 1378-83 36. Epler GR Colby TV McLoud TC Carrington CB Gachsler EA Bronchiolitis obliterans organizing pneumonia N Engl J Med 1985 312 152-8 37. King TE Jr Bronchiolitis obliterans keys to diagnosis and manage ment Immunol Allergy Pract 1989,11 472-8 38. Bass~-r~-AG Girgis RE Doyle RI Theodore ] Detection of small air way dysfunction using specific airway conductance Chest 1997,111 1533 5 39. Muller NL Miller RR_ Diseases of the bronchioles CT and histo pathologic findings Radiology 1995,196 3 12 40. Wcbb WR Muller NL Naidich DP High resolution CT of the lung 2nd ed Philadelphia Lippincott 1996 258 65 41 Gibbs AE Pooley FD Griffiths DM Mitha R Craighead JE Ruituci JR Tak pneumoconiosis a pathologic and mineralogic st idy Hum Pathol 1992,23 1344 54 42. Factor SM Granulomatous pneumonitis a result of intrapleural instillation of quinacrine and talcum powder Arch Pathol 1975,99 499- 502 43. Hunt AC Massive pulmonary fibrosis from the inhal tion of talk Tho rax 1956,11 287-94 44 Uehlinger E Zollinger R. Die klinische Bedeutung der silikonischen Gefassschadigung Bull Schweiz Akad Med Wiss 1946,2 176 83 45. Geever EF Pulmonary vascular lesions in silicosis and related patho logic changes Am J Med Sci 1947,214 292-304 46. Molnar JJ Nathenson G Edberg S Fatal aspiration of talcum powder by child report of a case N Engl J Med 1962,266 36 7 47. Alivisatos GP Pontikakis AF Terzis B. Talcosis of unusually rapid du velopment Br J Ind Med 1955,12 43 9 48 Miller A Turstem AS Bader ME Bader RA Schko't IJ Tak pneu motomosis significance of sublight microscopic mineral particles Am ] Med 1971,50 395-402 49. Case Records of the Massachusetts General Hospital Case 35 1982 N Engl J Med 1982,307 605-14 1999 Massachusetts Medical Society MILLIMETER SLIDES FOR THE CASE RECORDS Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a medical teaching exercise or reference material is eligible to receive mm slides with identifying legends of the pertinent ray films electrocardiograms gross specimens and photomicrographs of each case The slides are in by 2 in for use with a standard mm projector These slides which illustrate the current cases in the Journal are mailed from the Department of Pathology to corespond to the week of publication and may be retained by the subscriber Each year approximately 250 slides from 40 cases are sent to each subscriber The cost of the subscription is 450 per year Application forms for the current subscription year which began in January may be obtained from Lantern Slides Service Department of Pathology Massachusetts General Hospital Boston MA 02114 telephone 617 726-4369 Slides from individual cases may be obtained at a cost of 35 per case 190 July 15 1999 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12 2006 Copyright '1999 Massachusetts Medical Society All rights reserved