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Distant visceral metastases in pleural mesothelioma
Br. J. Dis. Chest (2976) 70, 246
DISTANT VISCERAL METASTASES PLEURAL MESOTHELIOMA
IN
G. HEFIN ROBERTS Pathology
Department,
Southern
General Hospital,
Glasgow
Summary Distant visceral metastases were found in 15 of 32 cases of pleural mesothelioma (47%). Contrary to earlier reports pleural mesothelioma should be regarded as a tumour in which visceral metastases are not uncommon. No association was found between the histological type of mesothelioma and visceral metastases; the peritoneal involvement found in five cases is probably due to local infiltration and seeding.
mesothelioma is still generally regarded as a tumour in which distant metastases are unusual (Heard 1966; Wright & Heard 1966; Spencer 1968). The supposedly infrequent metastases have been emphasized so much that when found, the diagnosis tends to be regarded as doubtful or even to be rejected (Evans 1966). This paper will show that visceral metastases are not uncommon and that their presence is fully consistent with mesothelioma, provided that the other diagnostic criteria are fulfilled. These include diffuse serosal involvement, the absence of a primary tumour elsewhere in the body (including the possibility that the primary tumour may have been previously resected) and the variable histological pattern (McCaughey 1958, 1965; Hinson 1965). Pleural
Materials and Methods The series consists of 32 cases of pleural mesothelioma (Table I), histologically proven after a complete necropsy, except in a few of the earlier cases where the brain was not examined. A clinicopathological study of the first 20 cases has been previously reported (Roberts 1970). Local infiltration and lymph node metastases of pleural mesothelioma is a well recognized characteristic and will not be discussed except to deal with involvement of the peritoneal cavity. Tumours were classified histologically into three groups (McCaughey 1958): mixed tumours showing both a mesenchymal and epithelial pattern (10 cases) and tumours of either epithelial or mesenchymal structure (14 and eight cases respectively); within each of the main three groups there was usually considerable structural variation. For comparison, the necropsy reports of 100 consecutive cases of histologically proven bronchial carcinoma were examined and the incidence of distant visceral metastases noted. RESULTS
Distant visceral metastases were found in 15 of the 32 cases (47%), tumour was found in hilar and mediastinal glands in 17 (53%). Th e commonest site was the opposite lung (seven cases), followed by kidneys (five cases, bilateral in four); adrenals (three cases,
247
Distant Visceral Metastases in Pleural Mesothelioma
bilateral in one). The heart and brain were each involved in two cases. In one (Case 19), the anterior surface of both ventricles showed about a dozen small subepicardial deposits; there was no pericardial effusion and the parietal pericardium was free of tumour. In the other (Case 27), there was a solitary 1 cm deposit of tumour beneath the endoTubZe
I. Details
Case No.
Pleural cavity
Histology
1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
L R L R+L R R R L R L R L L L R+L R L L R+L R+L L R R R R R R
Mesenchymal Epithelial Epithelial Epithelial Mesenchymal Mesenchymal Epithelial Mesenchymal Epithelial Epithelial Epithelial Mixed Epithelial Epithelial Epithelial Mixed Mixed Mesenchymal Epithelial Mesenchymal Mixed Mixed Mixed Mesenchymal Mixed Epithelial Mixed
28 29 30 31
R+L R L R
Mixed Epithelial Mixed Epithelial
32
L
Mesenchymal
of 32 cases of pleural Visceral
mesothelioma
metastases
Left lung
-
Left lung Kidneys, left adrenal Lumbar vertebrae Heart Kidneys, adrenals Left kidney Left lung Left lung Brain, heart, kidneys, pancreas Left kidney, brain Left lung Right lung Kidneys, liver, thyroid, right adrenal Right lung
Peritoneal involvement
+ + + + -
Lymph node metastases
+ + + + + + + + + + + i-I+
+ -
+ + +
-
-
cardium of the right ventricle, the parietal pericardium was infiltrated in continuity with the right pleural tumour and there was a haemorrhagic effusion. Cerebral secondaries were found in two cases. In Case 27 there was a nodule 4 cm in diameter in the right parietal lobe; the patient developed right hemiparesis weeks before death. In the other (Case 28) two 1 cm tumour nodules were found in each of the parietal lobes: the patient was comatose for several days. In only one (Case 31) was a secondary tumour found deep in the parenchyma of the liver and with no evidence of infiltration of the liver surface from the right pleural
248
G. HeJin
Roberts
mesothelioma. In this patient solitary deposits were also found in the head of the pancreas, the right adrenal and the right lobe of the thyroid. Secondary tumour was found in the lumbar vertebrae in one case (Case 15), there was no continuity between this and the pleural tumour of epithelial pattern. The patient terminally developed urinary retention and bilateral spasticity of the lower limbs. Distant metastases were found with all three histological types of mesothelioma (Table II). In five (16%) (C ases 4, 20, 23, 24, ZS), tumour was found in the peritoneal cavity, either as large confluent plaques or as smaller multiple discrete nodules. In three of these both pleural cavities contained tumour, although of unequal extent; in two (Cases Table II. Histology of pleural metastases Histology Epithelial Mixed Mesenchymal Total Table III. Visceral bronchial Histology Oat cell Undifferentiated Squamous Adenocarcinoma Total
mesothelioma
and visceral
No. of cases
Visceral metastases
14 10 8 32
7 5 3 15
metastases carcinoma
in
No. of cases 33 27 23 17 100
100
patients
with
Visceral metastases 28 22 11 9 70
23, 24) only the right pleura was involved. In none of the 12 patients with left pleural mesothelioma was tumour found in the peritoneal cavity. In all five cases the diaphragm and the surface of the liver was infiltrated. Of these five tumours infiltrating the peritoneum, two were mesotheliomas of mixed pattern (Cases 23, 28) and two were of mesenchymal type (Cases 20, 24); there was one of the epithelial variety (Case 4). Distant visceral metastases were present in 70% of 100 consecutive cases of bronchial carcinoma (Table III). In the 60 with oat cell and undifferentiated carcinoma metastases were found in 50 (83%). In the 40 with squamous and adenocarcinoma metastases were found in 20 (50%). DISCUSSION
Distant visceral metastases were found in 15 of 32 cases of pleural mesothelioma (47%) and regional lymph node metastases were present in 53% (17 cases). These findings are similar to those reported by Whitwell and Rawcliffe (1971) in a series of 32 necropsied pleural mesotheliomas on Merseyside; distant visceral metastases were found in 15 cases, with tumour infiltration of the hilar and mediastinal lymph nodes in 14. The literature on mesothelioma has tended to emphasize the infrequent metastases,
Distant Visceral Metastases in Pleural Mesothelioma
249
although visceral metastases have been mentioned in several papers. Saccone & Coblenz (1943) said that while mesothelioma should shown only a ‘small tendency to metastasize’, visceral deposits had been found in all organs. Goodwin (1957) accepted distant metastases without comment but added that they did not occur as frequently as one would have expected with such extensive tumours. More recently Hourihane (1964) reviewed 17 cases of pleural mesothelioma and concluded that metastases in the viscera were rare, but nevertheless accepted four where solitary deposits were found in the adrenal, pancreas and liver. Bony metastases were restricted to the lumbar vertebrae and ribs and none were found in the right femur, which had been examined in all 17 cases. In none was secondary tumour in bone found which was not in continuity with the serosal tumour. However, Laurini (1974) reported a pleural mesothelioma of ‘mixed histological pattern, showing a metastasis in the head of the right humerus and with no continuity between the pleural tumour and humerus. Similarly in Case 15 of the present series a mesothelioma of epithelial type was found in the lumbar vertebrae with no continuity with the pleural tumour. McCaughey (1965) was cautious on the subject of metastases, but thought that their presence ‘should not by itself constitute a reason for rejecting the diagnosis, providing the other characteristics of the growth is typical.’ Evans (1966), h owever, was of the opinion that the diagnosis of mesothelioma with metastases was open to question. It is possible that with the emphasis on the absence of metastases that only tumours with no or only limited spread have been accepted as mesothelioma (Whitwell & Rawcliffe 1961). Churg and Se&off (1968) now accept that many mesotheliomas do metastasize; previously Churg et al. (1965) laid down as one of the diagnostic criteria for mesothelioma that metastases were by and large limited to the regional lymph nodes. Comparison of distant visceral metastases in pleural mesothelioma and bronchial carcinoma shows that while the incidence of metastases is higher in bronchial carcinoma (70% of 100 cases), this is weighted by the frequency of metastases in oat cell and undifferentiated carcinoma (83% of 60 cases). In 40 cases of squamous cell and adenocarcinoma metastases were present in SO%, which is close to the figure for pleural mesothelioma (47% of 32 cases). It is difficult to be certain whether the tumour infiltration of the peritoneal cavity seen in five cases should be regarded as distant metastases, local infiltration or evidence of multicentric origin. In all five tumour was present in both pleural cavities and there was infiltration through the right half of the diaphragm to involve the surface of the liver, which possibly suggests local infiltration with subsequent peritoneal seeding. The absence of peritoneal infiltration in 12 cases of left-sided pleural mesothelioma and not in such close proximity to the liver is some support for this. Ratzer et al. (1967) suggested an association between peritoneal infiltration, bilateral pleural involvement and the histological type of mesothelioma. Involvement of both pleural and peritoneal cavities was found only amongst their 16 cases of epithelial mesothelioma; in none of the 15 cases of fibrosarcomatous tumours was bilateral pleural or peritoneal involvement seen. No such association is seen in the present series; in the five cases showing peritoneal involvement, one only showed the epithelial type of mesothelioma, two were of the ‘mixed type’ and two showed a mesenchymal pattern. Similarly Campbell (1950) found that in 14 cases of pleural mesothelioma, the peritoneal cavity was involved in four; in three the tumours showed a mixed epithelial and sarcomatous pattern.
250
G. Hejin Roberts
The present series has also shown that no one type of histological type of pleural mesothelioma is associated with visceral metastases; half of each histological variety showed secondary tumour in distant organs. Whitwell and Rawcliffe (1971) also found that all histological types of mesothelioma gave rise to visceral metastases, although there was a predominance of the sarcomatous variety. Hourihane (1964) suggested that whatever the histology of the pleural mesothelioma, contiguous invasion into bone always showed a mesenchymal pattern. Laurini (1974), h owever, found epithelial-like components in both direct infiltration and blood borne metastases; similarly in Case 15 of the present series, the metastases in the lumbar vertebrae showed an epithelial pattern. REFERENCES W. N. (1950) Pleural mesothelioma. Am. J. Puth. 26, 473. ROSEN, S. H. & MOOLTEN, S. (1965) Histological characteristics of mesothelioma associated with asbestos. Ann. N. Y. Acad. Sci. 132, 614. CHURG, J. & SELIKOFF, I. J. (1968) Geographic pathology of pleural mesothelioma. In The Lung: International Academy of Pathology Monograph, ed. A. A. Liebow and D. E. Smith, p. 284. Baltimore : Williams and Wilkins. EVANS, R. WINSTON (1966) Histological Appearances of Turnours, 2nd ed., p. 118. Edinburgh and London : Livingstone. GOODWIN, M. C. (1957) Diffuse mesotheliomas. With comment on their relation to localised fibrous mesotheliomas. Cancer, Philad. 10, 298. HEARD, B. E. (1966) Asbestosis. In Recent Advances in Pathology, ed. C. V. Harrison, 8th ed., p. 366. London: Churchill. HINSON, K. F. W. (1965) Cancer of the lungs and other diseases of the lungs after exposure to asbestos dust. Br. J. Dis. Chest 59, 121. HOURIHANE, D. O’B. (1964) The pathology of mesotheliomata and an analysis of their association with asbestos exposure. Thorax 19, 268. LAURINI, R. N. (1974) Diffuse pleural mesothelioma with distant bone metastasis. Acta path. microbial. stand. A 82, 298. MCCAUGHEY, W. T. E. (1958) Primary tumours of the pleura. J. Path. Bact. 76, 517. MCCAUGHEY, W. T. E. (1965) Criteria for diagnosis of diffuse mesothelial tumours. Ann. N. Y. Acad. Sci. 132, 603. RATZER, E. R., POOL, J. L. & MELAMED, M. R. (1967) Pleural mesotheliomas. Clinical experience with thirty-seven patients. Am. J: Roentgen. 99, 863. ROBERTS, G. HEFIN (1970) Diffuse pleural mesothelioma. A clinical and pathological study. Br. J. Dis. Chest 64, 201. SACCONE, A. & COBLENZ, A. (1943) Endothelioma of the pleura with report of two cases. Am. 3. clin. Path. 13, 186. SPENCER, H. (1968) Pathology of the Lung, 2nd ed., p. 926. Oxford: Pergamon. WHITVITELL, F. & RAWCLIFFE, R. M. (1971) Diffuse malignant mesothelioma and asbestos exposure. Thorax 26, 6. WRIGHT, G. PAYLING & HEARD, B. E. (1966) In Systemic Pathology, ed. G. Payling Wright and W. St C. Symmers, vol. I, p. 426. London: Longmans. CAMPBELL, CHURG, J.,
DISTANT VISCERAL METASTASES PLEURAL MESOTHELIOMA
IN
G. HEFIN ROBERTS Pathology
Department,
Southern
General Hospital,
Glasgow
Summary Distant visceral metastases were found in 15 of 32 cases of pleural mesothelioma (47%). Contrary to earlier reports pleural mesothelioma should be regarded as a tumour in which visceral metastases are not uncommon. No association was found between the histological type of mesothelioma and visceral metastases; the peritoneal involvement found in five cases is probably due to local infiltration and seeding.
mesothelioma is still generally regarded as a tumour in which distant metastases are unusual (Heard 1966; Wright & Heard 1966; Spencer 1968). The supposedly infrequent metastases have been emphasized so much that when found, the diagnosis tends to be regarded as doubtful or even to be rejected (Evans 1966). This paper will show that visceral metastases are not uncommon and that their presence is fully consistent with mesothelioma, provided that the other diagnostic criteria are fulfilled. These include diffuse serosal involvement, the absence of a primary tumour elsewhere in the body (including the possibility that the primary tumour may have been previously resected) and the variable histological pattern (McCaughey 1958, 1965; Hinson 1965). Pleural
Materials and Methods The series consists of 32 cases of pleural mesothelioma (Table I), histologically proven after a complete necropsy, except in a few of the earlier cases where the brain was not examined. A clinicopathological study of the first 20 cases has been previously reported (Roberts 1970). Local infiltration and lymph node metastases of pleural mesothelioma is a well recognized characteristic and will not be discussed except to deal with involvement of the peritoneal cavity. Tumours were classified histologically into three groups (McCaughey 1958): mixed tumours showing both a mesenchymal and epithelial pattern (10 cases) and tumours of either epithelial or mesenchymal structure (14 and eight cases respectively); within each of the main three groups there was usually considerable structural variation. For comparison, the necropsy reports of 100 consecutive cases of histologically proven bronchial carcinoma were examined and the incidence of distant visceral metastases noted. RESULTS
Distant visceral metastases were found in 15 of the 32 cases (47%), tumour was found in hilar and mediastinal glands in 17 (53%). Th e commonest site was the opposite lung (seven cases), followed by kidneys (five cases, bilateral in four); adrenals (three cases,
247
Distant Visceral Metastases in Pleural Mesothelioma
bilateral in one). The heart and brain were each involved in two cases. In one (Case 19), the anterior surface of both ventricles showed about a dozen small subepicardial deposits; there was no pericardial effusion and the parietal pericardium was free of tumour. In the other (Case 27), there was a solitary 1 cm deposit of tumour beneath the endoTubZe
I. Details
Case No.
Pleural cavity
Histology
1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
L R L R+L R R R L R L R L L L R+L R L L R+L R+L L R R R R R R
Mesenchymal Epithelial Epithelial Epithelial Mesenchymal Mesenchymal Epithelial Mesenchymal Epithelial Epithelial Epithelial Mixed Epithelial Epithelial Epithelial Mixed Mixed Mesenchymal Epithelial Mesenchymal Mixed Mixed Mixed Mesenchymal Mixed Epithelial Mixed
28 29 30 31
R+L R L R
Mixed Epithelial Mixed Epithelial
32
L
Mesenchymal
of 32 cases of pleural Visceral
mesothelioma
metastases
Left lung
-
Left lung Kidneys, left adrenal Lumbar vertebrae Heart Kidneys, adrenals Left kidney Left lung Left lung Brain, heart, kidneys, pancreas Left kidney, brain Left lung Right lung Kidneys, liver, thyroid, right adrenal Right lung
Peritoneal involvement
+ + + + -
Lymph node metastases
+ + + + + + + + + + + i-I+
+ -
+ + +
-
-
cardium of the right ventricle, the parietal pericardium was infiltrated in continuity with the right pleural tumour and there was a haemorrhagic effusion. Cerebral secondaries were found in two cases. In Case 27 there was a nodule 4 cm in diameter in the right parietal lobe; the patient developed right hemiparesis weeks before death. In the other (Case 28) two 1 cm tumour nodules were found in each of the parietal lobes: the patient was comatose for several days. In only one (Case 31) was a secondary tumour found deep in the parenchyma of the liver and with no evidence of infiltration of the liver surface from the right pleural
248
G. HeJin
Roberts
mesothelioma. In this patient solitary deposits were also found in the head of the pancreas, the right adrenal and the right lobe of the thyroid. Secondary tumour was found in the lumbar vertebrae in one case (Case 15), there was no continuity between this and the pleural tumour of epithelial pattern. The patient terminally developed urinary retention and bilateral spasticity of the lower limbs. Distant metastases were found with all three histological types of mesothelioma (Table II). In five (16%) (C ases 4, 20, 23, 24, ZS), tumour was found in the peritoneal cavity, either as large confluent plaques or as smaller multiple discrete nodules. In three of these both pleural cavities contained tumour, although of unequal extent; in two (Cases Table II. Histology of pleural metastases Histology Epithelial Mixed Mesenchymal Total Table III. Visceral bronchial Histology Oat cell Undifferentiated Squamous Adenocarcinoma Total
mesothelioma
and visceral
No. of cases
Visceral metastases
14 10 8 32
7 5 3 15
metastases carcinoma
in
No. of cases 33 27 23 17 100
100
patients
with
Visceral metastases 28 22 11 9 70
23, 24) only the right pleura was involved. In none of the 12 patients with left pleural mesothelioma was tumour found in the peritoneal cavity. In all five cases the diaphragm and the surface of the liver was infiltrated. Of these five tumours infiltrating the peritoneum, two were mesotheliomas of mixed pattern (Cases 23, 28) and two were of mesenchymal type (Cases 20, 24); there was one of the epithelial variety (Case 4). Distant visceral metastases were present in 70% of 100 consecutive cases of bronchial carcinoma (Table III). In the 60 with oat cell and undifferentiated carcinoma metastases were found in 50 (83%). In the 40 with squamous and adenocarcinoma metastases were found in 20 (50%). DISCUSSION
Distant visceral metastases were found in 15 of 32 cases of pleural mesothelioma (47%) and regional lymph node metastases were present in 53% (17 cases). These findings are similar to those reported by Whitwell and Rawcliffe (1971) in a series of 32 necropsied pleural mesotheliomas on Merseyside; distant visceral metastases were found in 15 cases, with tumour infiltration of the hilar and mediastinal lymph nodes in 14. The literature on mesothelioma has tended to emphasize the infrequent metastases,
Distant Visceral Metastases in Pleural Mesothelioma
249
although visceral metastases have been mentioned in several papers. Saccone & Coblenz (1943) said that while mesothelioma should shown only a ‘small tendency to metastasize’, visceral deposits had been found in all organs. Goodwin (1957) accepted distant metastases without comment but added that they did not occur as frequently as one would have expected with such extensive tumours. More recently Hourihane (1964) reviewed 17 cases of pleural mesothelioma and concluded that metastases in the viscera were rare, but nevertheless accepted four where solitary deposits were found in the adrenal, pancreas and liver. Bony metastases were restricted to the lumbar vertebrae and ribs and none were found in the right femur, which had been examined in all 17 cases. In none was secondary tumour in bone found which was not in continuity with the serosal tumour. However, Laurini (1974) reported a pleural mesothelioma of ‘mixed histological pattern, showing a metastasis in the head of the right humerus and with no continuity between the pleural tumour and humerus. Similarly in Case 15 of the present series a mesothelioma of epithelial type was found in the lumbar vertebrae with no continuity with the pleural tumour. McCaughey (1965) was cautious on the subject of metastases, but thought that their presence ‘should not by itself constitute a reason for rejecting the diagnosis, providing the other characteristics of the growth is typical.’ Evans (1966), h owever, was of the opinion that the diagnosis of mesothelioma with metastases was open to question. It is possible that with the emphasis on the absence of metastases that only tumours with no or only limited spread have been accepted as mesothelioma (Whitwell & Rawcliffe 1961). Churg and Se&off (1968) now accept that many mesotheliomas do metastasize; previously Churg et al. (1965) laid down as one of the diagnostic criteria for mesothelioma that metastases were by and large limited to the regional lymph nodes. Comparison of distant visceral metastases in pleural mesothelioma and bronchial carcinoma shows that while the incidence of metastases is higher in bronchial carcinoma (70% of 100 cases), this is weighted by the frequency of metastases in oat cell and undifferentiated carcinoma (83% of 60 cases). In 40 cases of squamous cell and adenocarcinoma metastases were present in SO%, which is close to the figure for pleural mesothelioma (47% of 32 cases). It is difficult to be certain whether the tumour infiltration of the peritoneal cavity seen in five cases should be regarded as distant metastases, local infiltration or evidence of multicentric origin. In all five tumour was present in both pleural cavities and there was infiltration through the right half of the diaphragm to involve the surface of the liver, which possibly suggests local infiltration with subsequent peritoneal seeding. The absence of peritoneal infiltration in 12 cases of left-sided pleural mesothelioma and not in such close proximity to the liver is some support for this. Ratzer et al. (1967) suggested an association between peritoneal infiltration, bilateral pleural involvement and the histological type of mesothelioma. Involvement of both pleural and peritoneal cavities was found only amongst their 16 cases of epithelial mesothelioma; in none of the 15 cases of fibrosarcomatous tumours was bilateral pleural or peritoneal involvement seen. No such association is seen in the present series; in the five cases showing peritoneal involvement, one only showed the epithelial type of mesothelioma, two were of the ‘mixed type’ and two showed a mesenchymal pattern. Similarly Campbell (1950) found that in 14 cases of pleural mesothelioma, the peritoneal cavity was involved in four; in three the tumours showed a mixed epithelial and sarcomatous pattern.
250
G. Hejin Roberts
The present series has also shown that no one type of histological type of pleural mesothelioma is associated with visceral metastases; half of each histological variety showed secondary tumour in distant organs. Whitwell and Rawcliffe (1971) also found that all histological types of mesothelioma gave rise to visceral metastases, although there was a predominance of the sarcomatous variety. Hourihane (1964) suggested that whatever the histology of the pleural mesothelioma, contiguous invasion into bone always showed a mesenchymal pattern. Laurini (1974), h owever, found epithelial-like components in both direct infiltration and blood borne metastases; similarly in Case 15 of the present series, the metastases in the lumbar vertebrae showed an epithelial pattern. REFERENCES W. N. (1950) Pleural mesothelioma. Am. J. Puth. 26, 473. ROSEN, S. H. & MOOLTEN, S. (1965) Histological characteristics of mesothelioma associated with asbestos. Ann. N. Y. Acad. Sci. 132, 614. CHURG, J. & SELIKOFF, I. J. (1968) Geographic pathology of pleural mesothelioma. In The Lung: International Academy of Pathology Monograph, ed. A. A. Liebow and D. E. Smith, p. 284. Baltimore : Williams and Wilkins. EVANS, R. WINSTON (1966) Histological Appearances of Turnours, 2nd ed., p. 118. Edinburgh and London : Livingstone. GOODWIN, M. C. (1957) Diffuse mesotheliomas. With comment on their relation to localised fibrous mesotheliomas. Cancer, Philad. 10, 298. HEARD, B. E. (1966) Asbestosis. In Recent Advances in Pathology, ed. C. V. Harrison, 8th ed., p. 366. London: Churchill. HINSON, K. F. W. (1965) Cancer of the lungs and other diseases of the lungs after exposure to asbestos dust. Br. J. Dis. Chest 59, 121. HOURIHANE, D. O’B. (1964) The pathology of mesotheliomata and an analysis of their association with asbestos exposure. Thorax 19, 268. LAURINI, R. N. (1974) Diffuse pleural mesothelioma with distant bone metastasis. Acta path. microbial. stand. A 82, 298. MCCAUGHEY, W. T. E. (1958) Primary tumours of the pleura. J. Path. Bact. 76, 517. MCCAUGHEY, W. T. E. (1965) Criteria for diagnosis of diffuse mesothelial tumours. Ann. N. Y. Acad. Sci. 132, 603. RATZER, E. R., POOL, J. L. & MELAMED, M. R. (1967) Pleural mesotheliomas. Clinical experience with thirty-seven patients. Am. J: Roentgen. 99, 863. ROBERTS, G. HEFIN (1970) Diffuse pleural mesothelioma. A clinical and pathological study. Br. J. Dis. Chest 64, 201. SACCONE, A. & COBLENZ, A. (1943) Endothelioma of the pleura with report of two cases. Am. 3. clin. Path. 13, 186. SPENCER, H. (1968) Pathology of the Lung, 2nd ed., p. 926. Oxford: Pergamon. WHITVITELL, F. & RAWCLIFFE, R. M. (1971) Diffuse malignant mesothelioma and asbestos exposure. Thorax 26, 6. WRIGHT, G. PAYLING & HEARD, B. E. (1966) In Systemic Pathology, ed. G. Payling Wright and W. St C. Symmers, vol. I, p. 426. London: Longmans. CAMPBELL, CHURG, J.,