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Diffuse pleural mesothelioma
Brit. o7. Dis. Chest (197o) 64, 2ox.
Diffuse Pleural Mesothelioma A Clinical and Pathological Study G. HEFIN ROBERTS Pathology Department, Southern General Hospital, Glasgow, SWI
THE possible relationship of mesothelioma to asbestos exposure has been investigated in three shipbuilding centres of the United Kingdom: Belfast (McCaughey ct al. 1962; Elmes et al. 1965) ; Merseyside (Owen 1964) and Tyneside (Ashcroft 1968). U p to 1965 only two cases had been reported from Scotland (Wagner 1965). A retrospective epidemiological study of mesothelioma in Scotland and its relationship to asbestos exposure is now in progress (Gibson et al. 1968). In a study of the incidence of asbestos bodies in 400 consecutive routine hospital necropsies in Glasgow (Roberts I969) , they were found in 47~o of 222 men (lO 5 cases) and in io~o of 178 women (18 cases) ; amongst the lO5 men in whom asbestos bodies were found were two with pleural mesothelioma. The lack of information from one of the main centres of the shipbuilding industry in this country and the high incidence of asbestos bodies in hospital necropsies, prompted a retrospective clinico-pathological review of diffuse mesothelioma seen in the pathology department of one lOOO bed general hospital. This hospital serves a densely populated urban community occupied mainly in the shipyards.
Subjects and Methods The necropsy records of the Southern General Hospital, Glasgow, were reviewed for the 18 years 195o to 1967 . The necropsy findings and histology of all cases of bronchial carcinoma and of those reported as pleural mesothelioma were examined. A tumour was provisionally accepted as a mesothelioma if in the necropsy report there was mention of widespread or diffuse neoplastic thickening of the pleura with no tumour in the dissectable bronchi and with no other possible source of a primary lesion in other organs. A complete necropsy had been carried out, except in some where the brain had not been examined. Other possible sites of a primary tumour such as breast, thyroid, gastrointestinal tract and genitourinary system had been excluded, but histology was not available from these sites in the absence of any gross abnormality found in them at necropsy. Sections of the pleural tumours were stained with haematoxylin and eosin, supplemented by the periodic-acid-Schiff and mucicarmine methods for the detection of mucin and by Gordon Sweet's reticulin methods. Asbestos bodies (Receivedfor publication, August x969) VOL, LXIV
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were looked for in 5/~ and 25/z sections. If these were negative one blocked piece of tissue was sacrificed and the extraction technique for asbestos bodies was carried out (Gold & Kerr I967). Clinical details of all but one of the subjects with pleural mesothelioma were available for review; a note was made of the occupation, if mentioned, but detailed industrial histories were not available.
Results During the I8 years of the review 6406 necropsies in adults were done; there were 486 cases of bronchial carcinoma (7"6%) and 20 of diffuse pleural mesothelioma (o'370). Table I shows that in the 9 years I95o-58 there were 5 cases ofmesothelioma as compared to 15 in the next 9 years, i959-67; the proportion of bronchial carcinoma was relatively constant. TABLE I. INCIDENCEOF BRONCHIALCARCINOMAAND PLEURAL MESOTHELIOMA(I95o-58 ; I959-67) 2#ears
195o-58 I959-67 TOTAL
Adult necropsies
Bronchial Pleural carcinoma mesothelioma
2588 3818
I88 (7"3%) 298 (7"8%)
5 (0"2%) I5 (0"4%)
6406
486 (7"6%)
20 (0"3%)
Sex and age distribution There were 16 men and 4 women (M :F = 4 : i) with pleural mesothelioma. The ages ranged from 28 to 78 years (mean 61.2 years). Nineteen of the 2o cases were in the,middle aged and elderly, with 6 in the sixth decade, 8 in the seventh and 5 in the eighth decade. The youngest case was in a man of 28 years, described in the clinical notes as a labourer; scanty asbestos bodies were found in the lung, there was also histological evidence of asbestosis. Occupation The occupation was mentioned in the hospital notes in 12 of the 16 male cases. There was a definite history of work in the shipyards in 2 (electrician, joiner) ; in a further 4 the brief description in the clinical notes also suggested an association with the shipbuilding industry (boiler coverer, caulker, plater and riveter). Three cases were simply described as 'labourers', 2 as 'engineers' and one as a 'lodging-house keeper'. O f the 4 women 3 were housewives, one was a ' canteen worker'.
Clinical Findings In the 19 cases of patients for whom clinical details were available, dyspnoea and chest pain were the two commonest presenting symptoms, and were mentioned by 18. In 3 cases chest pain alone was complained of, in 5 dyspnoea
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occurred alone and in IO both chest pain and dyspnoea were the presenting symptoms. The back, axillary region, precordium and retrosternal areas were all mentioned as the site of pain, which was described in various terms from 'tightness' to 'sharp'. Aggravating factors mentioned included respiration, cough and movement of the arm. Only in one case was neither chest pain nor dyspnoea complained of at the time of initial examination. Other symptoms were cough (7 cases), only in I was blood stained sputum mentioned; weight loss and lassitude were each mentioned in 2. In 15 of the 19 cases there were signs of a pleural effusion at the time of initial examination. Bilateral finger clubbing was found in 4; in one, a woman of 74 years, finger clubbing was accompanied by hypertrophic pulmonary osteoarthropathy involving the wrists, knees and ankles. In addition to dyspnoea and chest pain this patient presented with 'tingling of the fingers' and pain in both knees. Tenderness over the chest wall was elicited in one case.
Prognosis Only 3 patients lived for 12 months or more, 6 died within two months of the onset of symptoms and I I lived for 3 to 12 months.
Special Investigations Details of the radiological findings at the first examination were available in 17 cases. Pleural effusion was present in i5, in 8 effusion was the only abnormality detected. In 7, effusion was accompanied by other changes; 'pleural calcification' (I), 'pleural or basal thickening' (3); 'opacity posterior to the oesophagus' (i), ' patchy basal opacity' (I), osteolytic lesions on the same side as the effusion (i). In only 2 cases was pleural effusion not evident on first examination, effusion developed later in one. Bronchoscopy was performed in 2 cases, neither showed evidence of neoplasm and malignant cells were not seen in the bronchial smears. The sputum was examined for asbestos bodies in one case, and they were found in all three specimens examined.
Necropsyfindings The outstanding macroscopic feature of all 2o cases was the extent of pleural involvement by tumour, with either complete or partial obliteration of the pleural cavity. In not one of the 486 cases of pulmonary carcinoma reviewed, was diffuse infiltration of the pleura mentioned in the necropsy report. Where secondary carcinoma of the pleura was noted, discrete nodules were seen. In 16 cases (8O~o) the mesothelioma was unilateral (right 7, left 9), in 4 both pleural cavities were involved. The lung parenchyma was infiltrated with tumour in 16 cases: in 8 the tumour was found only at the periphery of the lung in relation to the thickened pleura and in the other 8 pulmonary infiltration was more widespread and showed either solid columns of tumour extending deeply into the lung from the thickened pleura or smaller discrete nodules of tumour.
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The mediastinal lymph nodes were infiltrated with tumour in 9 cases (45 ~o) ; it was impossible to be certain whether this was due to direct infiltration or lymphatic dissemination, but in 2 the lymph nodes along the trachea and not in close proximity to the pleural tumour showed secondary deposits. The intercostal muscles were infiltrated in 5 cases; in 6 the tumour infiltrated the pericardium, in 5 of these only the parietal pericardium was involved, in I tumour nodules were also present over the epicardium of the ventricles. Spread outside the thorax was found in 4 cases (2O~o). In 2 the peritoneal cavity contained tumour, in these both pleural cavities contained tumour. Small metastatic nodules were found in the adrenals in 2, in both, small multiple deposits of tumour were found in both kidneys. In one case metastatic tumour was found in the lumbar vertebrae.
Histolog~ Eleven tumours showed an epithelial pattern, 6 were of mesenchymal sarcomatous type and in 3, both epithelial and mesenchymal elements were present (mixed). Even in the 11 ' epithelial' tumours the pattern varied within each tumour; in all, differentiated adenopapillary or tubular elements were associated with more solid, cellular compact areas in which narrow clefts or spaces were present (Figs. I and 2). These two patterns frequently mingled and merged with each other so that differentiated glandular elements were separated by the more solid epithelial elements. The more solid, compact pattern tended to occur deep in the turnout, the better differentiated glandular areas were more prominent in the superficial portions of the pleura. The individual cells in both patterns of the 'epithelial tumours' were large, round or polygonal with either an eosinophilic or amphophilic cytoplasm. The nuclei were prominent and vesicular, large eosinophilic nucleoli were common, the nuclear membranes were sharp and distinct. In a few cases, cells in the differentiated glandular structures were smaller with hyperchromatic, finely stippled nuclear chromatin. In two cases large vacuolated cells with eccentric vesicular nuclei were seen. The nature of the connective tissue in the epithelial tumours varied from case to case and also from site to site in the same tumour. Dense acellular collagen in which differentiated glandular elements were widely separated was seen in most (Fig. 3), merging with more cellular fibroblastic stroma. In two cases, mucoid, faintly haematoxyphil material was present; in this material either small compact clumps of cells or larger better differentiated adenopapillary elements were present. Mitotic figures in all I I tumours were scanty; none of the tumours showed evidence of mucin secretion. The 6 tumours of mesenchymal type also showed a variation of pattern in different parts of such tumour. The better differentiated areas showed a spindle cell fibroblastic appearance (Fig. 4) arranged in broad or narrow bands of interweaving or whorled pattern; denser and less cellular collagenous bands were also seen. With such differentiated areas there were areas of more cellular pleomorphic undifferentiated turnout (Fig. 5), in which cells had an intimate
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relation to reticulum fibres, mitotic figures were more easily found and multinucleate tumour giant cells were present in 4 cases. In all 6 cases, areas of necrosis with inflammatory cell exudate was present. In the 3 mesotheliomata of 'mixed pattern' both epithelial and mesenchymal elements were present. There was in places a gradual transition between one type and the other, at other sites the change in pattern was sharp. The epithelial components did not differ from those seen in the pure epithelial tumours and they were best seen in the more superficial portions of the tumour. Similarly, the mesenchymal portions showed both differentiated and more cellular pleomorphic areas.
Asbestos bodies and asbestosis Asbestos bodies were present in the lungs in 18 of the 2o eases. These were identified in both 5/~ and 25/~ thick sections in 16 cases. In two none were found in the sections but scanty typical asbestos bodies were identified with the 'extraction technique'. In two asbestos bodies were looked for in smears from both lower lobes at the time of necropsy, and asbestos bodies were found in both. Histological evidence ofasbestosis was found in 13 of the 2o cases (657o). In a further 5 only a fringe of lung tissue around the tumour was available for examination; asbestos bodies were found in all, but asbestosis was not present. Discussion Incidence The rarity of pleural mesotheliomas, the diversity of their histological pattern and the prolonged controversy as to even their existence as a separate pathological entity all contribute to the difficulty in trying to estimate their incidence. I n the 18 years of the present survey 20 examples of diffuse pleural mesothelioma were found in 6406 adult necropsies (o.3~o) ; Hourihane (I 965) gave the incidence of diffuse mesothelioma at necropsy in the London Hospital from J a n u a r y 1954 to J u l y 1964 as approximately o-3 ~o. Thomson (1965) on the basis of his studies on the prevalence of asbestos bodies in necropsies, suggested that the combination of exposure to asbestos from urban air contamination together with small amounts of asbestos inhaled in an increasing number of occupations, would possibly make pleural and peritoneal mesotheliomata commoner conditions than they were in the past. The present study of 20 cases is not large enough for definite conclusions to be reached on this point, but 15 of the 20 tumours (75~o) were seen in the 9 years 1 959-67 as compared to 5 seen in the previous 9 years. There is some evidence from a larger series that the incidence of mesot h e l i o m a is increasing. Newhouse and Thomson (1965) found that of 83 deaths from mesothelioma in the London Hospital for the years 1917-63, IO died before 195o and 33 between 195o and 1959; the remaining 4o died in the four-and-a-half years between J a n u a r y 196o and J u n e I963 .
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Age and sex distribution Pleural mesothelioma appears tO be predominantly a disease of middle aged and elderly men, 14 cases were in the sixth and seventh decades. Other published reports confirm this (Wagner et ah I96O; Sleggs et al. 1961 ; Newhouse & Thomson 1965). Of 85 cases of pleural and peritoneal mesothelioma found in the Scottish survey (Gibson et ah 1968 ) 77 were male, the mean age at death was 6o'4 years, which is close to the findings in the present series (61.2 years) from one Glasgow hospital. Clinical features In 19 cases diffuse pleural mesothelioma was a disease of fairly uniform presentation and course. The history in most was of weeks or months and the symptoms were mainly chest pain and dyspnoea. Similarly Owen (i 964) in a study of 16 pleural mesotheliomata found that all had dyspnoea and all but one complained of chest pain. Manguikian and Prior (1963) in a clinicopathological study of 5 cases found chest pain and dyspnoea in all; Ratzer et ah (1967) studied 31 patients of whom 22 presented with chest pain, 3 with dyspnoea only and 6 with both dyspnoea and chest pain. Birnbaum (Saccone & Coblenz 1943) stated that the pleural pain of mesothelioma differed from that of bronchogenic carcinoma in that pain was a late manifestation in lung cancer, but a presenting symptom in mesothelioma. It was a presenting symptom in 19 cases in the present series. A further difference in the presenting symptoms of pleural mesothelioma and bronchial carcinoma appears to be the frequency of cough and haemoptysis; in only 7 cases in the present series was cough mentioned and only in one was cough with blood-stained sputum a symptom. Saccone and Coblenz (1943) and Smart and Hinson (1957) similarly stress the absence of haemoptysis as a presenting symptom, and in a study of 31 cases Ratzer and his colleagues (i 967) found that cough was a presenting symptom only in 4, of whom two had bloodstained sputum. The initial physical examination revealed signs of a pleural effusion in 15 of the 19 cases, in all but two the fluid was haemorrhagic and re-accumulated quickly. The early development of effusion has been commented on by several workers. Sleggs et al. (I96i) described three clinical stages for pleural mesothelioma. The first is an acute pleuritic illness with bronchitis. The second is pleural effusion, and the third and last stage is obvious intrathoracic malignancy. Manguikian and Prior (I963), in their 5 cases, found that when the patient was first seen the tumour had already extensively involved the pleural space and was associated with an effusion. Owen (i 964) found pleural effusion in 11 of 16 cases at the time of first examination, a further 4 developed later in the course of the illness. Finger clubbing and the more widespread changes of hypertrophic pulmonary osteoarthropathy are well recognized clinical manifestations of intrathoracic malignant disease (Wierman et al. 1954; Coury 196o). In the present series of 2o cases finger clubbing was mentioned in 4, and in one of these
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clubbing was accompanied by clinical and radiological evidence of hypertrophic pulmonary osteoarthropathy involving the wrists, knees and ankles. The association between pulmonary osteoarthropathy and localized pleural fibromas is well recognized (Thomas & Drew 1953; Manguikian & Prior 1963) ; it appears to be an unusual complication of diffuse mesothelioma. In 14 cases with a pleural tumour, Wierman and his colleagues found hypertrophic pulmonary osteoarthropathy in 8, all but one a localized pleural fibroma.
Duration of illness Only 3 patients in the present series lived for 12 months or more and all died within 15 months. Similarly Saccone and Coblenz (1943) in a review of 19 reported cases found that I6 were dead in 12 months; Hochberg (1951) reviewed 43 cases of whom 37 (86%) were dead within the first year. Sleggs et al. (1961) reported 34 cases of which 28 had died, 18 (6I %) within I2 months of the onset of symptoms, 7 lived for 1-2 years and 2 for 2-3 years; all 5 cases of diffuse mesothelioma reported by Manguikian and Prior (1963) died within 12 months. However in Owen's 15 cases ofpleural mesothelioma from Merseyside (Owen I964) , 2 cases (histologically proven at necropsy), lived for six years. Ratzer et al. (1967) found that 15 of I6 patients with pleural mesothelioma of epithelial pattern died I I to 58 months after the onset of symptoms (mean 21 months); all 15 patients with mesothelioma of mesenchymal type died 3 to 82 months after the onset of symptoms (mean 19 months). It appears therefore that few patients will live longer than 12 months. A few patients with histologically confirmed lesions have lived for as long as 6 years, and this makes prognosis difficult in the individual patient.
Morbid anatomy and histology Most pathologists believe that diffuse mesothelioma of the pleura is a distinct but rare pathological entity, which is in m a n y cases difficult to diagnose (Spencer 1963; Evans 1966 ). None of the cases in the present series was accepted as a mesothelioma unless the necropsy reports stressed the widespread neoplastic pleural infiltration in the absence of any other possible site of a primary turnout (Stout & Murray i942; McCaughey I958 ). There is no evidence in the present series that any one or other pleural cavity is more frequently affected by mesothelioma, in 7 cases the right pleura was the site of the tumour, the left pleura was involved in 9. In 4 both pleural cavities were infiltrated with tumour, and in two of these tumour was also found in the peritoneal cavity. Owen (I 964) found bilateral pleural involvement in 3 of 12 cases, in 2 of these, the peritoneum was also infiltrated with tumour. Ratzer et al. (1967) describes 4 cases showing bilateral pleural infiltration, in 2 of these the peritoneum was also involved. It is possible that such cases represent either multicentric involvement of the serosal surface or metastatic spread. The diffuse pleural infiltration so characteristic of these tumours is usually associated with macroscopic evidence of invasion of surrounding structures
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(Campbell 195 °; Godwin 1957; McCaughey 1958). Other reports while mentioning invasion of adjacent structures also stress the limited extent of this infiltration (Stout & Murray 1942 ; Hourihane 1964; Churg et al. 1965) ; this was not always so in the present series. Infiltration of surrounding structures was noted at necropsy in 18 of our 20 cases (9o~o), the lungs were infiltrated in 16. In 8 only limited invasion at the periphery was noted, in the other 8 pulmonary infiltration was more widespread and deep into the lung. In contrast to local infiltration, distant visceral metastases are seen relatively infrequently in pleural mesothelioma (Stout & M u r r a y 1942; Campbell I95 o; Owen i964), but McCaughey (i958) considered that even widespread metastases were not necessarily incompatible with mesothelioma provided that the other criteria for diagnosis were satisfied. In the present series of 20 cases, visceral metastases were found in only 3 (excluding tumour infiltration of the peritoneum) ; in only 2 of the 20 cases did the adrenals show secondary deposits. Such metastatic deposits were found in 18o (37~o) of 486 cases of bronchial carcinoma. The histology of the 20 cases in the present series displays most of the features dcscribed by other workers (Campbell 195o; McCaughey 1958 , 1965; Hourihane 1964; Ghurg et al. 1965). Eleven of the 20 mesotheliomata showed an epithelial pattern, 6 showed mesenchymal sarcomatous features and in 3 a mixed epithelial and mesenchymal structure was found. The epithelial pattern either alone or with mesenchymal elements is the most constant feature of these tumours (Campbell 1950 ) ; it was present in 14 of the 20 in the present series. Within each histological type of mesothelioma there is a wide range of structural variation. McCaughey (1965) has pointed out that recognition of some of these more specific histological patterns within the three broad groups allows a diagnosis of mesothelioma to be made with some degree of confidence. In this series of 20 cases structural variations distinguished each. In all 1 I turnouts of epithelial pattern, differentiated tubular or adenopapillary elements were present. In addition to glandular elements a more solid epithelial pattern was found (Churg et al. I965; Hourihane I965). Structural variation was also a feature of the stroma of the tumours. In places this was composed of fibrocellular connective tissue as seen in carcinoma. Elsewhere a more specific pattern for mesothelioma was present, composed of dense hyaline collagen showing irregularly scattered spindle shaped clefts; in both types of stroma the epithelial elements tended to be more widely spaced than in adenocarcinoma. The individual cells of the epithelial type tumours showed a striking degree of uniformity, as opposed to the more pleomorphic appearances in adenocarcinoma (McCaughey 1965). This cytological uniformity contrasts with the structural variation in t h e histology. Ghurg et al (1965) have commented on this as a useful diagnostic aid. No evidence of mucin secretion was found in any of these epithelial tumours. The 6 tumours of pure mesenchymal pattern also showed structural variation. In addition to differentiated fibroblastic areas of spindle cell tumours, all 6 showed large or small areas of more cellular pleomorphic tumour, in which mitotic figures were easily found; multinucleated tumour giant cells were
PLATE
II
Fro. r. Mesothelioma of epithelial type showing adenopapillary p a t t e r n . H.E. x 2oo
FIG. 2. Mesothelioma of epithelial type showing cellular p a t t e r n with n a r r o w clefts a n d fibrocellular stroma. H.E. x 2oo
To face page 208. 2"
PLATE
III
FIo. 3- Mesothelioma of epithelial type. Papillary elements with dense hyaline stroma. H.E. x 2 oo
FIG. 4" Mesothelioma of m e s e n c h y m a l type. Cellular spindle cell p a t t e r n with necrotic area. H.E. x ~oo
PLATE IV
FIG. 5. Mesothelioma ofmesenchymal type, showing cellular, pleomorphic pattern. H.E. x 2oo
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common in such areas. Areas of tumour necrosis infiltrated with inflammatory cells were found in all.
Mesothelioma and Asbestos Exposure Evidence of exposure to asbestos was based on finding asbestos bodies in the lungs at necropsy. Asbestos bodies were found in 18 of the 20 cases (9o~o), and were present in 15 of the i6 men (93.87o) and in 3 of the 4 women (75~o). In the study of asbestos bodies in routine hospital necropsies in the same hospital (Roberts i969) asbestos bodies were found in lO3 of 220 men without mesothelioma (46~o) and in 18 of I78 women (IO~o). There appears to be little doubt that asbestos bodies are to be found in a significantly higher proportion of lungs of those dying with mesothelioma, than in lungs of those dying without mesothelioma. The incidence reported of asbestos bodies in reported series of mesothelioma has varied from 27~o of 45 (Selikoff et al. 1965) to IOO~o of 3° cases (Gibson et al. 1968 ) ; Selikoff and his colleagues suggest that the relatively low incidence in their cases was due to the small amount of lung tissue available for examination, especially in biopsy specimens obtained at thoracotomy. In all other reports 6O~o or more of cases in each series have shown asbestos bodies in the lungs. Wagner et al. (196o) found asbestos bodies in 8 of IO subjects in South Africa. In Belfast McCaughey et al. (1962) found asbestos bodies in 12 of 15 subjects with pleural mesothelioma; a further series of 24 from the same city (Elmes et al. 1965) showed asbestos bodies in 88~o of cases. From Merseyside, Owen (1964) found asbestos bodies in 7O~o of IO cases. In London, Hourihane (I 964) identified bodies in 6 of 7 subjects with pleural mesothelioma (867o) and Newhouse and Thomson (1965) found asbestos bodies in lung or sputum in 63% of 37. Ashcroft (I968) reported asbestos bodies in 9I~o of 23 cases of mesothelioma on Tyneside. In none of the 2o cases in the present series was there a detailed occupational history, but there is either conclusive or strong presumptive evidence of work in the shipyards in 6 of the 12 men where the occupation was mentioned in the hospital notes. The shipyards are the largest users of asbestos in Southwest Glasgow, and in this community there is a strong tradition of work in the 'yards'; fuller occupational details would undoubtedly have revealed more men with an association with the shipbuilding industry. In the necropsy study on the incidence of asbestos bodies in hospital necropsies (Roberts 1969) there were 27 men with a definite history of work in the shipyards; asbestos bodies were found in the basal smears in 22 (8I'6~o). It is only recently that shipyard workers have become covered by the extended new Asbestos Regulations (Lancet 1968), previously such occupations as 'lagging' were not recognized officially as a hazard.
Summary This clinico-pathological study of diffuse pleura'l mesothelioma was carried out in one Glasgow hospital serving a densely populated urban community in which work in the shipyards has been the main occupation.
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In the i8 years I95O-67 20 cases of diffuse pleural mesothelioma were found in 6406 adult necropsies (0.3°7o) ; 15 of these were seen in the second nine-year period (I 959-67) as compared to 5 in the previous 9 years. Nineteen of the 20 cases were in the middle aged and elderly, 16 were men. The outstanding presenting symptoms were chest pain and dyspnoea, and the commonest physical and radiological finding at the initial examination was pleural effusion. Only 3 cases lived longer than 12 months after diagnosis. The findings indicate that diffuse pleural mesothelioma is a disease of relatively uniform clinical presentation, course and outcome. The morbid anatomy is described; infiltration of surrounding structures is common, distant metastases are unusual. Eleven of the tumours showed an epithelial pattern, 6 were of mesenchymal type and in 3 both epithelial and mesenchymal features were found. Evidence of exposure to asbestos, based on the presence of asbestos bodies in the lungs was present in 18 cases (9007o); there was histological evidence of asbestosis in 13 cases (65°7o). The results confirm previous reports of the association between asbestos exposure and mesothelioma. R(erences ASHCROFT, T. (1968) Asbestos bodies in routine necropsies in Tyneside; a pathological and social study. Brit. Med. J., i, 614. CAMPBELL, W. N. (195o) Pleural mesothelioma. Amer. 07. Path., 26, 473. Cmmo, J., ROSEN, S. H. & MOOLTEN, S. (I965) Histological characteristics of mesothelioma associated with asbestos. Ann. N.Y. Acad. Sci., x32, 614. CouRY, C. (I 96o) Hippocratic fingers and hypertrophic osteoarthropathy. A study of 35 ° cases. Brit. J. Dis. Chest, 54, 202. CULLINO, C. F. A. (I963) Handbook of Histopathological Technique, 2nd Edition, Butterworths, London, p. 342. ELMES, P. C., McCAuGHEY,W. T. E. & WADE, O. L. (1965) Diffuse mesothelioma of the pleura and asbestos. Brit. Med. J., I, 350. EVANS, R. W. (1966) Histological appearances ofTumours 2nd Edition. E. and S. Livingstone, Ltd., Edinburgh, p. 115. GIBSON, A; A. M., McEwEN, J., FINLAYSON,Angela and MAIR, A. (1968) Contribution to II International Conference on the Biological Effects of Asbestos, Dresden. GODWIN,M. C. (1957) Diffuse mesothelioma. With comments on their relations to localised fibrous mesothelioma. Cancer, IO, 298. GOLD, C. & KERR, A. W. (I967) Spring Meeting Association of Clinical Pathologists. HOGHBERO, L. A. (I95I) Endothelioma (mesothelioma)of pleura; review with report of 7 cases, 4 of which were extirpated surgically. Ann. Rev. Tubere. 63, 15o. HOURIHANE, D. O'B. (1964) The pathology of mesotheliomata and an analysis of their association with asbestos exposure. Thorax, 19, 268. HOURIHANE,D. O'B. (1965) A biopsy series of mesotheliomata, and attempts to identify asbestos within some of the tumours. Ann. N.T. Aead. Sci., x32, 647. LANCET. Leading Article (I968) Asbestos regulations. Lancet, 2, 551. MANOUIKIAN& PRIOR,J. T. (1963) Mesotheliomas of the pleura. A clinico-pathologic study of eight cases. Arch. Path. 75, 236. McCAuGHEY, W. T. E. (I958) Primary turnouts of the pleura. 07. Path. Baet., 76, 517 • McCAuGHEY, W. T. E. (1965) Criteria for diagnosis of diffuse mesothelial turnouts. Ann. N. Y. Acad. Sci., 132, 603. McCAuGI-IEY, W. T. E., WADE, O. L. & ELMES, P. C. (1962) Exposure to asbestos dust and diffuse pleural mesothelioma. Brit. Med. 07., 2, 1397.
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NEWHOUSE, M. L. & THOMPSON, H. (1965) Mesothelioma of pleura and peritoneum following exposure to asbestos in the London area. Brit. 07. Indust. Med., 22, 26I. OWEN, W. G. (1964) Diffuse mesothelioma and exposure to asbestos dust in the Merseyside area. Brit. Med. 07., 2, 214. RATZER, E. R., PooL, J. L. & MELAM~D, M. R. (I967) Pleural mesotheliomas. Clinical experience with thirty-seven patients. Amer. 07. Roentgenol., 99, 863. ROBERTS, G. Herin (1969) M.D. Thesis, University of Wales. SACCONE, A. & COBLENZ, A. (1943) Endothelioma of the pleura with report of two cases. Amer. 07. Clin. Path., 13, 186. SELIKOFF, I . J . , CHURG, J. & HAMMOND, E. C. (1965) Relation between exposure to asbestos and mesothelioma. New Engl. 07. Med., 272, 560. SLEGG8,C. A., MARCHAND,P. ~: WAGNER,J. C. (1961) Diffuse pleural mesothelioma in South Africa. S. Aft. Med. 07, 35, 28. SMART,J. & HmSON, K. F. W. (1957) Pleural neoplasma. Brit. 07. Tuberc. Dis. Chest, 5 I, 319 . SPENCER, H. (1963) Pathology of the lung. Pergamon Press Ltd., Oxford, p. 724. STOUT, A. P. & MURRAY, M. R. (1942) Localised pleural mesothelioma. Investigation of its characteristics and histogenesis by the method of tissue culture. Arch. Path., 34, 95 I. THOMAS, C. P. & DREW, C. E. (1953) Fibroma of the visceral pleura. Thorax, 8, i8o. THOMSON,J. G. (1965) Asbestos and the urban dweller. Ann. W.~'. Acad. Sci., x32 , 196. WAGNER,J. C. (I965) Epidermiology of diffuse mesothelial tumours; Evidence of an association from studies in South Africa and the United Kingdom. Ann. dV. T. Acad. Sci., I32 , 575. WAGNER, J. C., SLEOGS, C. A. & MARCHAI~D, P. (I96O) Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Brit. 07. Indust. Med., XT, 260. WIERMAN, W. H., CLAGOET, O. T. & McDoNALD, J. R. (1954) Articular manifestations in pulmonary disease. 07. Arner. Ailed. Ass. x55, 1459.
Diffuse Pleural Mesothelioma A Clinical and Pathological Study G. HEFIN ROBERTS Pathology Department, Southern General Hospital, Glasgow, SWI
THE possible relationship of mesothelioma to asbestos exposure has been investigated in three shipbuilding centres of the United Kingdom: Belfast (McCaughey ct al. 1962; Elmes et al. 1965) ; Merseyside (Owen 1964) and Tyneside (Ashcroft 1968). U p to 1965 only two cases had been reported from Scotland (Wagner 1965). A retrospective epidemiological study of mesothelioma in Scotland and its relationship to asbestos exposure is now in progress (Gibson et al. 1968). In a study of the incidence of asbestos bodies in 400 consecutive routine hospital necropsies in Glasgow (Roberts I969) , they were found in 47~o of 222 men (lO 5 cases) and in io~o of 178 women (18 cases) ; amongst the lO5 men in whom asbestos bodies were found were two with pleural mesothelioma. The lack of information from one of the main centres of the shipbuilding industry in this country and the high incidence of asbestos bodies in hospital necropsies, prompted a retrospective clinico-pathological review of diffuse mesothelioma seen in the pathology department of one lOOO bed general hospital. This hospital serves a densely populated urban community occupied mainly in the shipyards.
Subjects and Methods The necropsy records of the Southern General Hospital, Glasgow, were reviewed for the 18 years 195o to 1967 . The necropsy findings and histology of all cases of bronchial carcinoma and of those reported as pleural mesothelioma were examined. A tumour was provisionally accepted as a mesothelioma if in the necropsy report there was mention of widespread or diffuse neoplastic thickening of the pleura with no tumour in the dissectable bronchi and with no other possible source of a primary lesion in other organs. A complete necropsy had been carried out, except in some where the brain had not been examined. Other possible sites of a primary tumour such as breast, thyroid, gastrointestinal tract and genitourinary system had been excluded, but histology was not available from these sites in the absence of any gross abnormality found in them at necropsy. Sections of the pleural tumours were stained with haematoxylin and eosin, supplemented by the periodic-acid-Schiff and mucicarmine methods for the detection of mucin and by Gordon Sweet's reticulin methods. Asbestos bodies (Receivedfor publication, August x969) VOL, LXIV
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were looked for in 5/~ and 25/z sections. If these were negative one blocked piece of tissue was sacrificed and the extraction technique for asbestos bodies was carried out (Gold & Kerr I967). Clinical details of all but one of the subjects with pleural mesothelioma were available for review; a note was made of the occupation, if mentioned, but detailed industrial histories were not available.
Results During the I8 years of the review 6406 necropsies in adults were done; there were 486 cases of bronchial carcinoma (7"6%) and 20 of diffuse pleural mesothelioma (o'370). Table I shows that in the 9 years I95o-58 there were 5 cases ofmesothelioma as compared to 15 in the next 9 years, i959-67; the proportion of bronchial carcinoma was relatively constant. TABLE I. INCIDENCEOF BRONCHIALCARCINOMAAND PLEURAL MESOTHELIOMA(I95o-58 ; I959-67) 2#ears
195o-58 I959-67 TOTAL
Adult necropsies
Bronchial Pleural carcinoma mesothelioma
2588 3818
I88 (7"3%) 298 (7"8%)
5 (0"2%) I5 (0"4%)
6406
486 (7"6%)
20 (0"3%)
Sex and age distribution There were 16 men and 4 women (M :F = 4 : i) with pleural mesothelioma. The ages ranged from 28 to 78 years (mean 61.2 years). Nineteen of the 2o cases were in the,middle aged and elderly, with 6 in the sixth decade, 8 in the seventh and 5 in the eighth decade. The youngest case was in a man of 28 years, described in the clinical notes as a labourer; scanty asbestos bodies were found in the lung, there was also histological evidence of asbestosis. Occupation The occupation was mentioned in the hospital notes in 12 of the 16 male cases. There was a definite history of work in the shipyards in 2 (electrician, joiner) ; in a further 4 the brief description in the clinical notes also suggested an association with the shipbuilding industry (boiler coverer, caulker, plater and riveter). Three cases were simply described as 'labourers', 2 as 'engineers' and one as a 'lodging-house keeper'. O f the 4 women 3 were housewives, one was a ' canteen worker'.
Clinical Findings In the 19 cases of patients for whom clinical details were available, dyspnoea and chest pain were the two commonest presenting symptoms, and were mentioned by 18. In 3 cases chest pain alone was complained of, in 5 dyspnoea
DIFFUSE PLEURAL
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occurred alone and in IO both chest pain and dyspnoea were the presenting symptoms. The back, axillary region, precordium and retrosternal areas were all mentioned as the site of pain, which was described in various terms from 'tightness' to 'sharp'. Aggravating factors mentioned included respiration, cough and movement of the arm. Only in one case was neither chest pain nor dyspnoea complained of at the time of initial examination. Other symptoms were cough (7 cases), only in I was blood stained sputum mentioned; weight loss and lassitude were each mentioned in 2. In 15 of the 19 cases there were signs of a pleural effusion at the time of initial examination. Bilateral finger clubbing was found in 4; in one, a woman of 74 years, finger clubbing was accompanied by hypertrophic pulmonary osteoarthropathy involving the wrists, knees and ankles. In addition to dyspnoea and chest pain this patient presented with 'tingling of the fingers' and pain in both knees. Tenderness over the chest wall was elicited in one case.
Prognosis Only 3 patients lived for 12 months or more, 6 died within two months of the onset of symptoms and I I lived for 3 to 12 months.
Special Investigations Details of the radiological findings at the first examination were available in 17 cases. Pleural effusion was present in i5, in 8 effusion was the only abnormality detected. In 7, effusion was accompanied by other changes; 'pleural calcification' (I), 'pleural or basal thickening' (3); 'opacity posterior to the oesophagus' (i), ' patchy basal opacity' (I), osteolytic lesions on the same side as the effusion (i). In only 2 cases was pleural effusion not evident on first examination, effusion developed later in one. Bronchoscopy was performed in 2 cases, neither showed evidence of neoplasm and malignant cells were not seen in the bronchial smears. The sputum was examined for asbestos bodies in one case, and they were found in all three specimens examined.
Necropsyfindings The outstanding macroscopic feature of all 2o cases was the extent of pleural involvement by tumour, with either complete or partial obliteration of the pleural cavity. In not one of the 486 cases of pulmonary carcinoma reviewed, was diffuse infiltration of the pleura mentioned in the necropsy report. Where secondary carcinoma of the pleura was noted, discrete nodules were seen. In 16 cases (8O~o) the mesothelioma was unilateral (right 7, left 9), in 4 both pleural cavities were involved. The lung parenchyma was infiltrated with tumour in 16 cases: in 8 the tumour was found only at the periphery of the lung in relation to the thickened pleura and in the other 8 pulmonary infiltration was more widespread and showed either solid columns of tumour extending deeply into the lung from the thickened pleura or smaller discrete nodules of tumour.
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The mediastinal lymph nodes were infiltrated with tumour in 9 cases (45 ~o) ; it was impossible to be certain whether this was due to direct infiltration or lymphatic dissemination, but in 2 the lymph nodes along the trachea and not in close proximity to the pleural tumour showed secondary deposits. The intercostal muscles were infiltrated in 5 cases; in 6 the tumour infiltrated the pericardium, in 5 of these only the parietal pericardium was involved, in I tumour nodules were also present over the epicardium of the ventricles. Spread outside the thorax was found in 4 cases (2O~o). In 2 the peritoneal cavity contained tumour, in these both pleural cavities contained tumour. Small metastatic nodules were found in the adrenals in 2, in both, small multiple deposits of tumour were found in both kidneys. In one case metastatic tumour was found in the lumbar vertebrae.
Histolog~ Eleven tumours showed an epithelial pattern, 6 were of mesenchymal sarcomatous type and in 3, both epithelial and mesenchymal elements were present (mixed). Even in the 11 ' epithelial' tumours the pattern varied within each tumour; in all, differentiated adenopapillary or tubular elements were associated with more solid, cellular compact areas in which narrow clefts or spaces were present (Figs. I and 2). These two patterns frequently mingled and merged with each other so that differentiated glandular elements were separated by the more solid epithelial elements. The more solid, compact pattern tended to occur deep in the turnout, the better differentiated glandular areas were more prominent in the superficial portions of the pleura. The individual cells in both patterns of the 'epithelial tumours' were large, round or polygonal with either an eosinophilic or amphophilic cytoplasm. The nuclei were prominent and vesicular, large eosinophilic nucleoli were common, the nuclear membranes were sharp and distinct. In a few cases, cells in the differentiated glandular structures were smaller with hyperchromatic, finely stippled nuclear chromatin. In two cases large vacuolated cells with eccentric vesicular nuclei were seen. The nature of the connective tissue in the epithelial tumours varied from case to case and also from site to site in the same tumour. Dense acellular collagen in which differentiated glandular elements were widely separated was seen in most (Fig. 3), merging with more cellular fibroblastic stroma. In two cases, mucoid, faintly haematoxyphil material was present; in this material either small compact clumps of cells or larger better differentiated adenopapillary elements were present. Mitotic figures in all I I tumours were scanty; none of the tumours showed evidence of mucin secretion. The 6 tumours of mesenchymal type also showed a variation of pattern in different parts of such tumour. The better differentiated areas showed a spindle cell fibroblastic appearance (Fig. 4) arranged in broad or narrow bands of interweaving or whorled pattern; denser and less cellular collagenous bands were also seen. With such differentiated areas there were areas of more cellular pleomorphic undifferentiated turnout (Fig. 5), in which cells had an intimate
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relation to reticulum fibres, mitotic figures were more easily found and multinucleate tumour giant cells were present in 4 cases. In all 6 cases, areas of necrosis with inflammatory cell exudate was present. In the 3 mesotheliomata of 'mixed pattern' both epithelial and mesenchymal elements were present. There was in places a gradual transition between one type and the other, at other sites the change in pattern was sharp. The epithelial components did not differ from those seen in the pure epithelial tumours and they were best seen in the more superficial portions of the tumour. Similarly, the mesenchymal portions showed both differentiated and more cellular pleomorphic areas.
Asbestos bodies and asbestosis Asbestos bodies were present in the lungs in 18 of the 2o eases. These were identified in both 5/~ and 25/~ thick sections in 16 cases. In two none were found in the sections but scanty typical asbestos bodies were identified with the 'extraction technique'. In two asbestos bodies were looked for in smears from both lower lobes at the time of necropsy, and asbestos bodies were found in both. Histological evidence ofasbestosis was found in 13 of the 2o cases (657o). In a further 5 only a fringe of lung tissue around the tumour was available for examination; asbestos bodies were found in all, but asbestosis was not present. Discussion Incidence The rarity of pleural mesotheliomas, the diversity of their histological pattern and the prolonged controversy as to even their existence as a separate pathological entity all contribute to the difficulty in trying to estimate their incidence. I n the 18 years of the present survey 20 examples of diffuse pleural mesothelioma were found in 6406 adult necropsies (o.3~o) ; Hourihane (I 965) gave the incidence of diffuse mesothelioma at necropsy in the London Hospital from J a n u a r y 1954 to J u l y 1964 as approximately o-3 ~o. Thomson (1965) on the basis of his studies on the prevalence of asbestos bodies in necropsies, suggested that the combination of exposure to asbestos from urban air contamination together with small amounts of asbestos inhaled in an increasing number of occupations, would possibly make pleural and peritoneal mesotheliomata commoner conditions than they were in the past. The present study of 20 cases is not large enough for definite conclusions to be reached on this point, but 15 of the 20 tumours (75~o) were seen in the 9 years 1 959-67 as compared to 5 seen in the previous 9 years. There is some evidence from a larger series that the incidence of mesot h e l i o m a is increasing. Newhouse and Thomson (1965) found that of 83 deaths from mesothelioma in the London Hospital for the years 1917-63, IO died before 195o and 33 between 195o and 1959; the remaining 4o died in the four-and-a-half years between J a n u a r y 196o and J u n e I963 .
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Age and sex distribution Pleural mesothelioma appears tO be predominantly a disease of middle aged and elderly men, 14 cases were in the sixth and seventh decades. Other published reports confirm this (Wagner et ah I96O; Sleggs et al. 1961 ; Newhouse & Thomson 1965). Of 85 cases of pleural and peritoneal mesothelioma found in the Scottish survey (Gibson et ah 1968 ) 77 were male, the mean age at death was 6o'4 years, which is close to the findings in the present series (61.2 years) from one Glasgow hospital. Clinical features In 19 cases diffuse pleural mesothelioma was a disease of fairly uniform presentation and course. The history in most was of weeks or months and the symptoms were mainly chest pain and dyspnoea. Similarly Owen (i 964) in a study of 16 pleural mesotheliomata found that all had dyspnoea and all but one complained of chest pain. Manguikian and Prior (1963) in a clinicopathological study of 5 cases found chest pain and dyspnoea in all; Ratzer et ah (1967) studied 31 patients of whom 22 presented with chest pain, 3 with dyspnoea only and 6 with both dyspnoea and chest pain. Birnbaum (Saccone & Coblenz 1943) stated that the pleural pain of mesothelioma differed from that of bronchogenic carcinoma in that pain was a late manifestation in lung cancer, but a presenting symptom in mesothelioma. It was a presenting symptom in 19 cases in the present series. A further difference in the presenting symptoms of pleural mesothelioma and bronchial carcinoma appears to be the frequency of cough and haemoptysis; in only 7 cases in the present series was cough mentioned and only in one was cough with blood-stained sputum a symptom. Saccone and Coblenz (1943) and Smart and Hinson (1957) similarly stress the absence of haemoptysis as a presenting symptom, and in a study of 31 cases Ratzer and his colleagues (i 967) found that cough was a presenting symptom only in 4, of whom two had bloodstained sputum. The initial physical examination revealed signs of a pleural effusion in 15 of the 19 cases, in all but two the fluid was haemorrhagic and re-accumulated quickly. The early development of effusion has been commented on by several workers. Sleggs et al. (I96i) described three clinical stages for pleural mesothelioma. The first is an acute pleuritic illness with bronchitis. The second is pleural effusion, and the third and last stage is obvious intrathoracic malignancy. Manguikian and Prior (I963), in their 5 cases, found that when the patient was first seen the tumour had already extensively involved the pleural space and was associated with an effusion. Owen (i 964) found pleural effusion in 11 of 16 cases at the time of first examination, a further 4 developed later in the course of the illness. Finger clubbing and the more widespread changes of hypertrophic pulmonary osteoarthropathy are well recognized clinical manifestations of intrathoracic malignant disease (Wierman et al. 1954; Coury 196o). In the present series of 2o cases finger clubbing was mentioned in 4, and in one of these
DIFFUSE PLEURAL
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clubbing was accompanied by clinical and radiological evidence of hypertrophic pulmonary osteoarthropathy involving the wrists, knees and ankles. The association between pulmonary osteoarthropathy and localized pleural fibromas is well recognized (Thomas & Drew 1953; Manguikian & Prior 1963) ; it appears to be an unusual complication of diffuse mesothelioma. In 14 cases with a pleural tumour, Wierman and his colleagues found hypertrophic pulmonary osteoarthropathy in 8, all but one a localized pleural fibroma.
Duration of illness Only 3 patients in the present series lived for 12 months or more and all died within 15 months. Similarly Saccone and Coblenz (1943) in a review of 19 reported cases found that I6 were dead in 12 months; Hochberg (1951) reviewed 43 cases of whom 37 (86%) were dead within the first year. Sleggs et al. (1961) reported 34 cases of which 28 had died, 18 (6I %) within I2 months of the onset of symptoms, 7 lived for 1-2 years and 2 for 2-3 years; all 5 cases of diffuse mesothelioma reported by Manguikian and Prior (1963) died within 12 months. However in Owen's 15 cases ofpleural mesothelioma from Merseyside (Owen I964) , 2 cases (histologically proven at necropsy), lived for six years. Ratzer et al. (1967) found that 15 of I6 patients with pleural mesothelioma of epithelial pattern died I I to 58 months after the onset of symptoms (mean 21 months); all 15 patients with mesothelioma of mesenchymal type died 3 to 82 months after the onset of symptoms (mean 19 months). It appears therefore that few patients will live longer than 12 months. A few patients with histologically confirmed lesions have lived for as long as 6 years, and this makes prognosis difficult in the individual patient.
Morbid anatomy and histology Most pathologists believe that diffuse mesothelioma of the pleura is a distinct but rare pathological entity, which is in m a n y cases difficult to diagnose (Spencer 1963; Evans 1966 ). None of the cases in the present series was accepted as a mesothelioma unless the necropsy reports stressed the widespread neoplastic pleural infiltration in the absence of any other possible site of a primary turnout (Stout & Murray i942; McCaughey I958 ). There is no evidence in the present series that any one or other pleural cavity is more frequently affected by mesothelioma, in 7 cases the right pleura was the site of the tumour, the left pleura was involved in 9. In 4 both pleural cavities were infiltrated with tumour, and in two of these tumour was also found in the peritoneal cavity. Owen (I 964) found bilateral pleural involvement in 3 of 12 cases, in 2 of these, the peritoneum was also infiltrated with tumour. Ratzer et al. (1967) describes 4 cases showing bilateral pleural infiltration, in 2 of these the peritoneum was also involved. It is possible that such cases represent either multicentric involvement of the serosal surface or metastatic spread. The diffuse pleural infiltration so characteristic of these tumours is usually associated with macroscopic evidence of invasion of surrounding structures
208
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(Campbell 195 °; Godwin 1957; McCaughey 1958). Other reports while mentioning invasion of adjacent structures also stress the limited extent of this infiltration (Stout & Murray 1942 ; Hourihane 1964; Churg et al. 1965) ; this was not always so in the present series. Infiltration of surrounding structures was noted at necropsy in 18 of our 20 cases (9o~o), the lungs were infiltrated in 16. In 8 only limited invasion at the periphery was noted, in the other 8 pulmonary infiltration was more widespread and deep into the lung. In contrast to local infiltration, distant visceral metastases are seen relatively infrequently in pleural mesothelioma (Stout & M u r r a y 1942; Campbell I95 o; Owen i964), but McCaughey (i958) considered that even widespread metastases were not necessarily incompatible with mesothelioma provided that the other criteria for diagnosis were satisfied. In the present series of 20 cases, visceral metastases were found in only 3 (excluding tumour infiltration of the peritoneum) ; in only 2 of the 20 cases did the adrenals show secondary deposits. Such metastatic deposits were found in 18o (37~o) of 486 cases of bronchial carcinoma. The histology of the 20 cases in the present series displays most of the features dcscribed by other workers (Campbell 195o; McCaughey 1958 , 1965; Hourihane 1964; Ghurg et al. 1965). Eleven of the 20 mesotheliomata showed an epithelial pattern, 6 showed mesenchymal sarcomatous features and in 3 a mixed epithelial and mesenchymal structure was found. The epithelial pattern either alone or with mesenchymal elements is the most constant feature of these tumours (Campbell 1950 ) ; it was present in 14 of the 20 in the present series. Within each histological type of mesothelioma there is a wide range of structural variation. McCaughey (1965) has pointed out that recognition of some of these more specific histological patterns within the three broad groups allows a diagnosis of mesothelioma to be made with some degree of confidence. In this series of 20 cases structural variations distinguished each. In all 1 I turnouts of epithelial pattern, differentiated tubular or adenopapillary elements were present. In addition to glandular elements a more solid epithelial pattern was found (Churg et al. I965; Hourihane I965). Structural variation was also a feature of the stroma of the tumours. In places this was composed of fibrocellular connective tissue as seen in carcinoma. Elsewhere a more specific pattern for mesothelioma was present, composed of dense hyaline collagen showing irregularly scattered spindle shaped clefts; in both types of stroma the epithelial elements tended to be more widely spaced than in adenocarcinoma. The individual cells of the epithelial type tumours showed a striking degree of uniformity, as opposed to the more pleomorphic appearances in adenocarcinoma (McCaughey 1965). This cytological uniformity contrasts with the structural variation in t h e histology. Ghurg et al (1965) have commented on this as a useful diagnostic aid. No evidence of mucin secretion was found in any of these epithelial tumours. The 6 tumours of pure mesenchymal pattern also showed structural variation. In addition to differentiated fibroblastic areas of spindle cell tumours, all 6 showed large or small areas of more cellular pleomorphic tumour, in which mitotic figures were easily found; multinucleated tumour giant cells were
PLATE
II
Fro. r. Mesothelioma of epithelial type showing adenopapillary p a t t e r n . H.E. x 2oo
FIG. 2. Mesothelioma of epithelial type showing cellular p a t t e r n with n a r r o w clefts a n d fibrocellular stroma. H.E. x 2oo
To face page 208. 2"
PLATE
III
FIo. 3- Mesothelioma of epithelial type. Papillary elements with dense hyaline stroma. H.E. x 2 oo
FIG. 4" Mesothelioma of m e s e n c h y m a l type. Cellular spindle cell p a t t e r n with necrotic area. H.E. x ~oo
PLATE IV
FIG. 5. Mesothelioma ofmesenchymal type, showing cellular, pleomorphic pattern. H.E. x 2oo
DIFFUSE PLEURAL
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common in such areas. Areas of tumour necrosis infiltrated with inflammatory cells were found in all.
Mesothelioma and Asbestos Exposure Evidence of exposure to asbestos was based on finding asbestos bodies in the lungs at necropsy. Asbestos bodies were found in 18 of the 20 cases (9o~o), and were present in 15 of the i6 men (93.87o) and in 3 of the 4 women (75~o). In the study of asbestos bodies in routine hospital necropsies in the same hospital (Roberts i969) asbestos bodies were found in lO3 of 220 men without mesothelioma (46~o) and in 18 of I78 women (IO~o). There appears to be little doubt that asbestos bodies are to be found in a significantly higher proportion of lungs of those dying with mesothelioma, than in lungs of those dying without mesothelioma. The incidence reported of asbestos bodies in reported series of mesothelioma has varied from 27~o of 45 (Selikoff et al. 1965) to IOO~o of 3° cases (Gibson et al. 1968 ) ; Selikoff and his colleagues suggest that the relatively low incidence in their cases was due to the small amount of lung tissue available for examination, especially in biopsy specimens obtained at thoracotomy. In all other reports 6O~o or more of cases in each series have shown asbestos bodies in the lungs. Wagner et al. (196o) found asbestos bodies in 8 of IO subjects in South Africa. In Belfast McCaughey et al. (1962) found asbestos bodies in 12 of 15 subjects with pleural mesothelioma; a further series of 24 from the same city (Elmes et al. 1965) showed asbestos bodies in 88~o of cases. From Merseyside, Owen (1964) found asbestos bodies in 7O~o of IO cases. In London, Hourihane (I 964) identified bodies in 6 of 7 subjects with pleural mesothelioma (867o) and Newhouse and Thomson (1965) found asbestos bodies in lung or sputum in 63% of 37. Ashcroft (I968) reported asbestos bodies in 9I~o of 23 cases of mesothelioma on Tyneside. In none of the 2o cases in the present series was there a detailed occupational history, but there is either conclusive or strong presumptive evidence of work in the shipyards in 6 of the 12 men where the occupation was mentioned in the hospital notes. The shipyards are the largest users of asbestos in Southwest Glasgow, and in this community there is a strong tradition of work in the 'yards'; fuller occupational details would undoubtedly have revealed more men with an association with the shipbuilding industry. In the necropsy study on the incidence of asbestos bodies in hospital necropsies (Roberts 1969) there were 27 men with a definite history of work in the shipyards; asbestos bodies were found in the basal smears in 22 (8I'6~o). It is only recently that shipyard workers have become covered by the extended new Asbestos Regulations (Lancet 1968), previously such occupations as 'lagging' were not recognized officially as a hazard.
Summary This clinico-pathological study of diffuse pleura'l mesothelioma was carried out in one Glasgow hospital serving a densely populated urban community in which work in the shipyards has been the main occupation.
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In the i8 years I95O-67 20 cases of diffuse pleural mesothelioma were found in 6406 adult necropsies (0.3°7o) ; 15 of these were seen in the second nine-year period (I 959-67) as compared to 5 in the previous 9 years. Nineteen of the 20 cases were in the middle aged and elderly, 16 were men. The outstanding presenting symptoms were chest pain and dyspnoea, and the commonest physical and radiological finding at the initial examination was pleural effusion. Only 3 cases lived longer than 12 months after diagnosis. The findings indicate that diffuse pleural mesothelioma is a disease of relatively uniform clinical presentation, course and outcome. The morbid anatomy is described; infiltration of surrounding structures is common, distant metastases are unusual. Eleven of the tumours showed an epithelial pattern, 6 were of mesenchymal type and in 3 both epithelial and mesenchymal features were found. Evidence of exposure to asbestos, based on the presence of asbestos bodies in the lungs was present in 18 cases (9007o); there was histological evidence of asbestosis in 13 cases (65°7o). The results confirm previous reports of the association between asbestos exposure and mesothelioma. R(erences ASHCROFT, T. (1968) Asbestos bodies in routine necropsies in Tyneside; a pathological and social study. Brit. Med. J., i, 614. CAMPBELL, W. N. (195o) Pleural mesothelioma. Amer. 07. Path., 26, 473. Cmmo, J., ROSEN, S. H. & MOOLTEN, S. (I965) Histological characteristics of mesothelioma associated with asbestos. Ann. N.Y. Acad. Sci., x32, 614. CouRY, C. (I 96o) Hippocratic fingers and hypertrophic osteoarthropathy. A study of 35 ° cases. Brit. J. Dis. Chest, 54, 202. CULLINO, C. F. A. (I963) Handbook of Histopathological Technique, 2nd Edition, Butterworths, London, p. 342. ELMES, P. C., McCAuGHEY,W. T. E. & WADE, O. L. (1965) Diffuse mesothelioma of the pleura and asbestos. Brit. Med. J., I, 350. EVANS, R. W. (1966) Histological appearances ofTumours 2nd Edition. E. and S. Livingstone, Ltd., Edinburgh, p. 115. GIBSON, A; A. M., McEwEN, J., FINLAYSON,Angela and MAIR, A. (1968) Contribution to II International Conference on the Biological Effects of Asbestos, Dresden. GODWIN,M. C. (1957) Diffuse mesothelioma. With comments on their relations to localised fibrous mesothelioma. Cancer, IO, 298. GOLD, C. & KERR, A. W. (I967) Spring Meeting Association of Clinical Pathologists. HOGHBERO, L. A. (I95I) Endothelioma (mesothelioma)of pleura; review with report of 7 cases, 4 of which were extirpated surgically. Ann. Rev. Tubere. 63, 15o. HOURIHANE, D. O'B. (1964) The pathology of mesotheliomata and an analysis of their association with asbestos exposure. Thorax, 19, 268. HOURIHANE,D. O'B. (1965) A biopsy series of mesotheliomata, and attempts to identify asbestos within some of the tumours. Ann. N.T. Aead. Sci., x32, 647. LANCET. Leading Article (I968) Asbestos regulations. Lancet, 2, 551. MANOUIKIAN& PRIOR,J. T. (1963) Mesotheliomas of the pleura. A clinico-pathologic study of eight cases. Arch. Path. 75, 236. McCAuGHEY, W. T. E. (I958) Primary turnouts of the pleura. 07. Path. Baet., 76, 517 • McCAuGHEY, W. T. E. (1965) Criteria for diagnosis of diffuse mesothelial turnouts. Ann. N. Y. Acad. Sci., 132, 603. McCAuGI-IEY, W. T. E., WADE, O. L. & ELMES, P. C. (1962) Exposure to asbestos dust and diffuse pleural mesothelioma. Brit. Med. 07., 2, 1397.
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MESOTHELIOMA
2II
NEWHOUSE, M. L. & THOMPSON, H. (1965) Mesothelioma of pleura and peritoneum following exposure to asbestos in the London area. Brit. 07. Indust. Med., 22, 26I. OWEN, W. G. (1964) Diffuse mesothelioma and exposure to asbestos dust in the Merseyside area. Brit. Med. 07., 2, 214. RATZER, E. R., PooL, J. L. & MELAM~D, M. R. (I967) Pleural mesotheliomas. Clinical experience with thirty-seven patients. Amer. 07. Roentgenol., 99, 863. ROBERTS, G. Herin (1969) M.D. Thesis, University of Wales. SACCONE, A. & COBLENZ, A. (1943) Endothelioma of the pleura with report of two cases. Amer. 07. Clin. Path., 13, 186. SELIKOFF, I . J . , CHURG, J. & HAMMOND, E. C. (1965) Relation between exposure to asbestos and mesothelioma. New Engl. 07. Med., 272, 560. SLEGG8,C. A., MARCHAND,P. ~: WAGNER,J. C. (1961) Diffuse pleural mesothelioma in South Africa. S. Aft. Med. 07, 35, 28. SMART,J. & HmSON, K. F. W. (1957) Pleural neoplasma. Brit. 07. Tuberc. Dis. Chest, 5 I, 319 . SPENCER, H. (1963) Pathology of the lung. Pergamon Press Ltd., Oxford, p. 724. STOUT, A. P. & MURRAY, M. R. (1942) Localised pleural mesothelioma. Investigation of its characteristics and histogenesis by the method of tissue culture. Arch. Path., 34, 95 I. THOMAS, C. P. & DREW, C. E. (1953) Fibroma of the visceral pleura. Thorax, 8, i8o. THOMSON,J. G. (1965) Asbestos and the urban dweller. Ann. W.~'. Acad. Sci., x32 , 196. WAGNER,J. C. (I965) Epidermiology of diffuse mesothelial tumours; Evidence of an association from studies in South Africa and the United Kingdom. Ann. dV. T. Acad. Sci., I32 , 575. WAGNER, J. C., SLEOGS, C. A. & MARCHAI~D, P. (I96O) Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Brit. 07. Indust. Med., XT, 260. WIERMAN, W. H., CLAGOET, O. T. & McDoNALD, J. R. (1954) Articular manifestations in pulmonary disease. 07. Arner. Ailed. Ass. x55, 1459.