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The limitation of metastases in lung cancer
248
Tubercle, Lond., (1961), 42, 248
THE LIMITATION OF METASTASES IN LUNG CANCER SUMMARY
6,000 necropsy reports of lung cancer were collected from medical schools in Britain. Note was made of the number of organs with macroscopic metastases, eight organs being catalogued for this purpose. In almost it of the cases none of the listed organs revealed any deposits. One organ alone was reported to be invaded in 1,823 cases; two organs in 1,165, three in 617; four in 276; fivein 113; six in 25; seven in 6 cases; and all eight organs in only one patient. So infrequent indeed was metastasis to several organs in anyone patient that only 2·6 % of the patients had more than four organs attacked. The average rate of organ involvement was only 1'3. The low incidence of demonstrable deposits is such that the metastatic pattern must be considered anomalous, if the current theory of predominantly blood-borne metastasis is true. The pattern of met astasis in lung cancer is more compatible with lymph-borne than with blood-borne spread.
It is customary to describe and picture lung cancer as a tumour whose very location conduces to rapid and distant metastasis by way of the left side of the heart and the systemic arteries. In support of this view it is pointed out that (i) the pulmonary vascular bed is enormous, (ii) the pulmonary veins are easily accessible to the lung tumour, (iii) tumour cells are frequently demo nstra ble within these veins, (iv) movement of the lungs facilitates dislodgement of intravascular tumour cells, and (v) the entry of the emboli so formed into the systemic circulation is unimpeded by any capillary barrier. Clearly, therefore, lung cancers have unsurpassable opportunities for scattering their emboli. According to Willis (1960), lung cancer 'metastasizes with great frequency, often widely, and often alan early stage while the primary growth is still small and symptomless.' Since the 1920s many have been of the view that metastases in lung cancer are 'widespread'. For instance , Carlson and BaIlon (1933) wrote, 'It is generally assumed that a primary carcinoma of the lung gives rise to widespread metastases early .' More recently, LaDue (1955) stated that 'widespread metastases are the rule in bronchiogenic carcinoma.' Indeed, Businco (1950) affirmed, 'The strong tendency of carcinoma of the lung to form metastases has been emphasized and proved by almost all investigators.' On the other hand, Sellars (1954) came to the conclusion that 'on the whole, distant metastasis is less common than might be expected when the vascularity of the organ is considered.' Or, as Ballantyne, Clagett and McDonald (1957) put it , 'the lack of widespread distribution in all patients and the vagaries of sites of predilection for metastasis are puzzling.' Ochsner, DeBakey & Dunlap (1948) stated that distant metastases were 'relatively infrequent,' Flick & Bauer (1939) thought that they were 'seldom numerous', and Hill (1931) noted that metastatic limitation was a 'remarkable' feature oflung cancer. The present study examines two questions . How many organs exhibit metastases in patients dying with lung cancer? Is the metastatic pattern compatible with haematogenous or lymphogenous metastasis? A leading article in Tubercle (1958) drew attention to work on the possible role of the lymphatics in lung cancer spread (Onuigbo (1957) and suggested further study of the factors in metastasis, 'for we know remarkably little about them'.
249
THE LIMITATION OF METASTASES IN LUNG CANCER
TABLE 1.-THE DISTRIBUTION OF 6,000 CASES OF LUNG CANCER ACCORDING TOTHENUMBER OFORGANS METASTASIZED) THE ORGANS CATALOGUED BEING BRAIN, THYROID, LIVER, ADRENAL, KIDNEY, SPLEEN, PANCREAS, OVARY OR TESTIS .---
,
Number of organs me tastasized
Total cases
Medical School
I Glasgow-Western Infirmary Royal Infirmary Edinburgh Aberdeen Dundee London-Hammersmith St. Mary's London Hospital St. George's Guy's Middlesex University College St. Thomas's Westminster King's College Charing Cross S1. Bart's Royal Free Hospital Leeds Oxford Manchester Newcastle Cambridge Birmingham Bristol Cardiff Sheffield Liverpool Totals
352 359 355 200 100 419 400 400 266 246 200 200 133 130 119 117 100 100 548 300 200 172 100 100 100 100 100 84 6000
0
J
2
3
4
5
6
99
112 121 126 57 26 127 117 99 92 84 55 54 31
81 87 75 43 15 86
40 33 22 26 12 52 38 51 19 29 23 26 20 13 7
12 18 19 16 5 18 27 16 15 9 7 8 14 4 3
6 5
2
9
3
I 95 1 10 1
57 40 130 123 143
85
I
70 72 66 26 38 48 43 27 29 210 12] 69 60 36 53 21 47 30 35
44
38 28 30 33 160 101 64 45 34 24 29 31 37 24
11974 1823
76 77 46 49 42 43 31 29 21 24 22 18 98 31 39 33 14
16
29 10 15 15 1165
11
8
11 17 52 36 13 24 10 2 10 5
5 1 21
8
6
6 7 2 3 8 5 7 4
617
276
9
7
8
1
2 5
1
13
6 3 1
10
8 5 1
3 8 1 2 2 4 2 5 2 7 2 4 1 2 2 1
3
113
25
1
2
6
Method 6,000 cases of lung cancer have been surveyed by reference to the necropsy records of medical schools throughout Britain. In reviewing the records note was made of macroscopic evidence of tumour deposits in eight organs: brain, thyroid, liver, adrenal, kidney, spleen, pancreas, and ovary or testis. In each case the number of organs metastasized was determined, the count being irrespective of whether there was one deposit or several described in each single or paired organ. Data obtained in this way were next related to figures collected from the literature. Results Table I shows that, in 6,000 cases of lung cancer abstracted, none of the eight organs listed was involved in 1,974 (32'9 %) instances. This was the commonest single finding. In relating this finding to the published necropsy figures, it is to be remembered that the latter include metastatic sites other than the eight catalogued in the present study. In 866 cases Bryson (1949) found no metastases in 240 (27'7 %); in 741 cases Galluzi & Payne (1955) found no 'blood-borne' metastases in 30·2 %. Storey, Knudston & Lawrence (1953), who studied bronchiolar ('alveolar cell') carcinoma of the lung, stated that 46 % of 205 patients had no metastases at autopsy. From the reports of Bayliss (1947), Bonser (1938), Horn (1946), Young (1958), and Oswald (1956) lung cancer necropsies did not reveal extrathoracic metastases in 22'3,22'9,24-4,25, and 28·3 %of the cases. Further analysis of my series shows that in 63·3 %only one or no organ was found to be invaded, and in as many as 82·7 % less than three organs were found to have been involved. So infrequent indeed was metastasis to several organs in the same patient that only 2·6 % had metastases in K
250
TUBERCLE
more than 4 organs. Maxwell's (1930) analysis of 184 cases revealed that in 59·2 %metastases were either not found or limited to the 'mediastinal glands with perhaps a few small deposits in one other organ.' The experience of Schuster (1929) may also be quoted: 'It often happens that there is no multiple dissemination of growth but that only one organ, or pair of organs, is selected; thus, two suprarenals may be the only site of secondary deposits, or the liver or pancreas alone may be affected. General carcinomatosis or metastasis in several dissociated organs is uncommon.' In my series it was in a lone patient, a woman of 46, that all eight organs under consideration were discernibly attacked. Atkin (1931) in his survey of93 cases from the Brompton Hospital cited as his worst case of 'extensive' metastases a 39-year-old man, but even this man had deposits in only six of the eight organs we are now considering. We may conclude, therefore, that generalized metastases are decidedly rare. The 6,000 cases in this survey exhibited metastases in 7,873 organs (only 8 organs being recorded). The metastatic frequency was thus 1·3 per patient. Howell and Piggot (1957) counted 651 secondary sites in their 300 lung cancers, a metastatic frequency of 2·2. But they included lymph nodes, which commonly contain metastases at necropsies; and if these are excluded the frequency is reduced to about 1·2. Similarly, Enticknap (1952) in 196 cases found an average of 3·6 metastatic sites, but in his reckoning of sites he did not merely include lymph nodes but lymph node 'groups' so that deposits in hilar, cervical, and abdominal groups of nodes would in all probability be recorded as three sites. This is probably equally applicable to the figures of 2·1,3'1,3'6, and 3'9 obtained by Smetana, Iverson & Swan (1952), who classified the different cell types separately. Discussion The objection may be raised that necropsy statistics cannot do full justice to the true frequency of metastases. This is undoubtedly true and it was for this reason that bones were not included in this study. However, necropsy statistics are the best evidence available. On what better evidence are based the views that lung cancer metastases are widespread, bizarre, perverse, and protean-to mention only a few of the ephithets employed? Are we to rely on the unusual or freak manifestations, or are we to base Our view on the general picture? To my mind, such a picture definitely emerges: lung cancer does not scatter deposits widely throughout the body. This is an important fact, for lung cancer is certainly endowed with rich opportunities for dispersal. The concept of widespread metastases in lung cancer is really recent. Almost a century ago, Walshe (1871) remarked that 'the lung, so ready to afford a resting-place to cancer-elements travelling from other sites, exhibits but feeble inclination to inoculate distant parts with its own disease.' This view of the limitation of metastasis in lung cancer was still in vogue up to the first decade of the present century. The prevailing view that lung cancer spreads widely is erroneous. The true position which ought to be taken is that maintained by Graham (1936), namely, that this growth metastasizes 'in particular organs to a marked extent'. My own view accords with this statement or its variant made by Maher & Staderman (1940), viz. that this tumour in its spread is most often restricted to particular sites such as the mediastinum, liver and adrenal. If true, is this not inconsistent with the hypothesis of predominant blood-stream spread? If the hypothesis of spread to the viscera by the blood is accepted, it is necessary to postulate that, in the majority of cases, some factors within the tissues themselves inhibit the development of metastases in all organs or in all but one of them. An alternative hypothesis is that spread does not, in general, occur by blood vessels, but by the lymphatics, the tumour cells being carried directly through lymphatic vessels and nodes from the primary tumour to one or more of the viscera. This hypothesis seems the more simple one to explain the limitation of visceral metastases to a few sites. It also accounts for the observation (Onuigbo (1959» that visceral metastases more commonly occur on the same side as the primary tumour. There is, however, one further difficulty. There is no doubt that tumour cells and fragments enter
THE LIMITATION OF METASTASES IN LUNG CANCER
251
the blood-stream. If metastasis in lung cancer is largely through the lymphatic system it is necessary to explain why these cells and fragments in the blood do not cause metastases in viscera. The seeming ineffectiveness of the blood in spreading lung cancer should be an important subject for research. For the opportunity to carry out this survey I am gratefully indebted to Professor D. F. Cappell, my chief, and to Professors J. W. S. Blacklock, Sir Roy Cameron, A. C. P . Campbell, D. H. Collins, T. Crawford, R. C. Curran, J. B. Duguid, J. Gough, C. V. Harrison, T. F. Hewer, K. R. Hill, A. C. Lendrum, C. E. Liimsden, H. A. Magnus, J. W. Orr, G. L. Montgomery, D . M. Pryce, R. J . V. Pulvertaft, D . S. Russell, R. W. Scarff, H. L. Sheehan, T . Symington, W . S1. C. Symers, G . P. Wright, and J . S. Young, and to Drs. A. M. Barrett, and A. H. T . Robb-Srnith. During the collection of the data I received helpful assistance from Drs . Georgiana M. Bonser, D. B. Brewer, W. A. J. Crane, A. G. Hepplestone, W. A. Gillespie, W. R. L. James, G. Sclare, H. Spencer, A. G . Stansfield, T. W. Sutherland and A. C. Thackray. A grant from Glasgow University defrayed part of the expenses, as did scholarship funds from the Government of Eastern Nigeria.
Department of Pathology, Western Infirmary, Glasgow.
W. 1. B. ONUIGBO
REFERENCES ATKIN, E . E. (1931). J. Path. Bact., 34, 343 . BALLANTYNE, A. J ., CLAGETT, O. T., & McDONALD, J. R. (1957). Thorax, 12,294. BAYLISS, R.I. S. (1947). M.D . Thesis, University of Cambridge, p . 72. BONSER, G. M . (1938). Acta Un. int o Cancr., 3, 119. BRYSON, C. C. (1949) . M.D . Thesis, University of Cambridge, p, 80. BUSINCO, A. (1950). Scient. med. Ital. , 1, 656. CARLSON, H. A., & BALLON, H. C . (1933). J. Thoracic Surg., 4, 323. ENTICKNAP, J. B. (1952). Guy's Hasp. Rep., 101, 273. FLICK, J. B., & BAUER, J. T. (1939). Penn. med. J., 42, 874. GALLUZI, S., & PAYNE, P. M. (1955). Brit. J. Cancer, 9, 511. GRAHAM, E. A. (1936). Ann. Surg., 103, I. HILL, R . M . (1931). M .D. Thesis, University of Edinburgh, p. 71. HORN, H . A. (1946). BIII/. ScM. med. Unlv, Maryland, 30, 169. HOWELL, T., & PIGGOT, A. P. (1957). Geriatrics, 12, 190. LA DUE, J. S. (1955). III Pulmonary Diseases, edited by R. L. Pullen, p , 209. Kimpton, London. LEADING ARTICLE (1958) . Tubercle, Lond., 39, 58. MAXWELL, J. (1930). J. Path. Bact. , 33, 233. OCHSNER, A ., DEBAKEY, M. , & DUNLAP, C . E . (1948). Rocky Min. 11Ied. J., 45, 1010 . ONUIGBO, W . 1. B. (1959). J. thorac . Surg. 37 , 771. ONUIGBO, W. I. B. (1957). Brit. J. Cancer, 11, 175. OSWALD, N . C. (1956). Brit. med. J ., 1, 761. SCHUSTER, N. H. (1929). J. Path. Bact., 32, 802. SELLaRS, T. H. (1954). In The British Encyclopaedia 0/ Medical Practice, editor in chief the Lord Horder, Medical Progress, 1954, p. 43, Butterworth, London. SMETANA, H. P., IVERSON, L., & SWAN, L. L. (1952). Milit. Surr., 111, 335. STOREY, C. P., KNUDSTON, K. P ., & LAWRENCE, B. J. (1953). J. thorac. Surg., 26, 331. WALSHE, W . H. (1871). A Practical Treatise 011 the Diseases 0/ the Lungs, 4th edition, p. 515, Smith, Elder & Co., London. WILLIS, R. A. (1960). Pathology ofTumours , 3rd ed., p. 375. Butterworths, London. YOUNG, R. D. (1958). M.D. Thesis, University of Edinburgh, p. 54.
Tubercle, Lond., (1961), 42, 248
THE LIMITATION OF METASTASES IN LUNG CANCER SUMMARY
6,000 necropsy reports of lung cancer were collected from medical schools in Britain. Note was made of the number of organs with macroscopic metastases, eight organs being catalogued for this purpose. In almost it of the cases none of the listed organs revealed any deposits. One organ alone was reported to be invaded in 1,823 cases; two organs in 1,165, three in 617; four in 276; fivein 113; six in 25; seven in 6 cases; and all eight organs in only one patient. So infrequent indeed was metastasis to several organs in anyone patient that only 2·6 % of the patients had more than four organs attacked. The average rate of organ involvement was only 1'3. The low incidence of demonstrable deposits is such that the metastatic pattern must be considered anomalous, if the current theory of predominantly blood-borne metastasis is true. The pattern of met astasis in lung cancer is more compatible with lymph-borne than with blood-borne spread.
It is customary to describe and picture lung cancer as a tumour whose very location conduces to rapid and distant metastasis by way of the left side of the heart and the systemic arteries. In support of this view it is pointed out that (i) the pulmonary vascular bed is enormous, (ii) the pulmonary veins are easily accessible to the lung tumour, (iii) tumour cells are frequently demo nstra ble within these veins, (iv) movement of the lungs facilitates dislodgement of intravascular tumour cells, and (v) the entry of the emboli so formed into the systemic circulation is unimpeded by any capillary barrier. Clearly, therefore, lung cancers have unsurpassable opportunities for scattering their emboli. According to Willis (1960), lung cancer 'metastasizes with great frequency, often widely, and often alan early stage while the primary growth is still small and symptomless.' Since the 1920s many have been of the view that metastases in lung cancer are 'widespread'. For instance , Carlson and BaIlon (1933) wrote, 'It is generally assumed that a primary carcinoma of the lung gives rise to widespread metastases early .' More recently, LaDue (1955) stated that 'widespread metastases are the rule in bronchiogenic carcinoma.' Indeed, Businco (1950) affirmed, 'The strong tendency of carcinoma of the lung to form metastases has been emphasized and proved by almost all investigators.' On the other hand, Sellars (1954) came to the conclusion that 'on the whole, distant metastasis is less common than might be expected when the vascularity of the organ is considered.' Or, as Ballantyne, Clagett and McDonald (1957) put it , 'the lack of widespread distribution in all patients and the vagaries of sites of predilection for metastasis are puzzling.' Ochsner, DeBakey & Dunlap (1948) stated that distant metastases were 'relatively infrequent,' Flick & Bauer (1939) thought that they were 'seldom numerous', and Hill (1931) noted that metastatic limitation was a 'remarkable' feature oflung cancer. The present study examines two questions . How many organs exhibit metastases in patients dying with lung cancer? Is the metastatic pattern compatible with haematogenous or lymphogenous metastasis? A leading article in Tubercle (1958) drew attention to work on the possible role of the lymphatics in lung cancer spread (Onuigbo (1957) and suggested further study of the factors in metastasis, 'for we know remarkably little about them'.
249
THE LIMITATION OF METASTASES IN LUNG CANCER
TABLE 1.-THE DISTRIBUTION OF 6,000 CASES OF LUNG CANCER ACCORDING TOTHENUMBER OFORGANS METASTASIZED) THE ORGANS CATALOGUED BEING BRAIN, THYROID, LIVER, ADRENAL, KIDNEY, SPLEEN, PANCREAS, OVARY OR TESTIS .---
,
Number of organs me tastasized
Total cases
Medical School
I Glasgow-Western Infirmary Royal Infirmary Edinburgh Aberdeen Dundee London-Hammersmith St. Mary's London Hospital St. George's Guy's Middlesex University College St. Thomas's Westminster King's College Charing Cross S1. Bart's Royal Free Hospital Leeds Oxford Manchester Newcastle Cambridge Birmingham Bristol Cardiff Sheffield Liverpool Totals
352 359 355 200 100 419 400 400 266 246 200 200 133 130 119 117 100 100 548 300 200 172 100 100 100 100 100 84 6000
0
J
2
3
4
5
6
99
112 121 126 57 26 127 117 99 92 84 55 54 31
81 87 75 43 15 86
40 33 22 26 12 52 38 51 19 29 23 26 20 13 7
12 18 19 16 5 18 27 16 15 9 7 8 14 4 3
6 5
2
9
3
I 95 1 10 1
57 40 130 123 143
85
I
70 72 66 26 38 48 43 27 29 210 12] 69 60 36 53 21 47 30 35
44
38 28 30 33 160 101 64 45 34 24 29 31 37 24
11974 1823
76 77 46 49 42 43 31 29 21 24 22 18 98 31 39 33 14
16
29 10 15 15 1165
11
8
11 17 52 36 13 24 10 2 10 5
5 1 21
8
6
6 7 2 3 8 5 7 4
617
276
9
7
8
1
2 5
1
13
6 3 1
10
8 5 1
3 8 1 2 2 4 2 5 2 7 2 4 1 2 2 1
3
113
25
1
2
6
Method 6,000 cases of lung cancer have been surveyed by reference to the necropsy records of medical schools throughout Britain. In reviewing the records note was made of macroscopic evidence of tumour deposits in eight organs: brain, thyroid, liver, adrenal, kidney, spleen, pancreas, and ovary or testis. In each case the number of organs metastasized was determined, the count being irrespective of whether there was one deposit or several described in each single or paired organ. Data obtained in this way were next related to figures collected from the literature. Results Table I shows that, in 6,000 cases of lung cancer abstracted, none of the eight organs listed was involved in 1,974 (32'9 %) instances. This was the commonest single finding. In relating this finding to the published necropsy figures, it is to be remembered that the latter include metastatic sites other than the eight catalogued in the present study. In 866 cases Bryson (1949) found no metastases in 240 (27'7 %); in 741 cases Galluzi & Payne (1955) found no 'blood-borne' metastases in 30·2 %. Storey, Knudston & Lawrence (1953), who studied bronchiolar ('alveolar cell') carcinoma of the lung, stated that 46 % of 205 patients had no metastases at autopsy. From the reports of Bayliss (1947), Bonser (1938), Horn (1946), Young (1958), and Oswald (1956) lung cancer necropsies did not reveal extrathoracic metastases in 22'3,22'9,24-4,25, and 28·3 %of the cases. Further analysis of my series shows that in 63·3 %only one or no organ was found to be invaded, and in as many as 82·7 % less than three organs were found to have been involved. So infrequent indeed was metastasis to several organs in the same patient that only 2·6 % had metastases in K
250
TUBERCLE
more than 4 organs. Maxwell's (1930) analysis of 184 cases revealed that in 59·2 %metastases were either not found or limited to the 'mediastinal glands with perhaps a few small deposits in one other organ.' The experience of Schuster (1929) may also be quoted: 'It often happens that there is no multiple dissemination of growth but that only one organ, or pair of organs, is selected; thus, two suprarenals may be the only site of secondary deposits, or the liver or pancreas alone may be affected. General carcinomatosis or metastasis in several dissociated organs is uncommon.' In my series it was in a lone patient, a woman of 46, that all eight organs under consideration were discernibly attacked. Atkin (1931) in his survey of93 cases from the Brompton Hospital cited as his worst case of 'extensive' metastases a 39-year-old man, but even this man had deposits in only six of the eight organs we are now considering. We may conclude, therefore, that generalized metastases are decidedly rare. The 6,000 cases in this survey exhibited metastases in 7,873 organs (only 8 organs being recorded). The metastatic frequency was thus 1·3 per patient. Howell and Piggot (1957) counted 651 secondary sites in their 300 lung cancers, a metastatic frequency of 2·2. But they included lymph nodes, which commonly contain metastases at necropsies; and if these are excluded the frequency is reduced to about 1·2. Similarly, Enticknap (1952) in 196 cases found an average of 3·6 metastatic sites, but in his reckoning of sites he did not merely include lymph nodes but lymph node 'groups' so that deposits in hilar, cervical, and abdominal groups of nodes would in all probability be recorded as three sites. This is probably equally applicable to the figures of 2·1,3'1,3'6, and 3'9 obtained by Smetana, Iverson & Swan (1952), who classified the different cell types separately. Discussion The objection may be raised that necropsy statistics cannot do full justice to the true frequency of metastases. This is undoubtedly true and it was for this reason that bones were not included in this study. However, necropsy statistics are the best evidence available. On what better evidence are based the views that lung cancer metastases are widespread, bizarre, perverse, and protean-to mention only a few of the ephithets employed? Are we to rely on the unusual or freak manifestations, or are we to base Our view on the general picture? To my mind, such a picture definitely emerges: lung cancer does not scatter deposits widely throughout the body. This is an important fact, for lung cancer is certainly endowed with rich opportunities for dispersal. The concept of widespread metastases in lung cancer is really recent. Almost a century ago, Walshe (1871) remarked that 'the lung, so ready to afford a resting-place to cancer-elements travelling from other sites, exhibits but feeble inclination to inoculate distant parts with its own disease.' This view of the limitation of metastasis in lung cancer was still in vogue up to the first decade of the present century. The prevailing view that lung cancer spreads widely is erroneous. The true position which ought to be taken is that maintained by Graham (1936), namely, that this growth metastasizes 'in particular organs to a marked extent'. My own view accords with this statement or its variant made by Maher & Staderman (1940), viz. that this tumour in its spread is most often restricted to particular sites such as the mediastinum, liver and adrenal. If true, is this not inconsistent with the hypothesis of predominant blood-stream spread? If the hypothesis of spread to the viscera by the blood is accepted, it is necessary to postulate that, in the majority of cases, some factors within the tissues themselves inhibit the development of metastases in all organs or in all but one of them. An alternative hypothesis is that spread does not, in general, occur by blood vessels, but by the lymphatics, the tumour cells being carried directly through lymphatic vessels and nodes from the primary tumour to one or more of the viscera. This hypothesis seems the more simple one to explain the limitation of visceral metastases to a few sites. It also accounts for the observation (Onuigbo (1959» that visceral metastases more commonly occur on the same side as the primary tumour. There is, however, one further difficulty. There is no doubt that tumour cells and fragments enter
THE LIMITATION OF METASTASES IN LUNG CANCER
251
the blood-stream. If metastasis in lung cancer is largely through the lymphatic system it is necessary to explain why these cells and fragments in the blood do not cause metastases in viscera. The seeming ineffectiveness of the blood in spreading lung cancer should be an important subject for research. For the opportunity to carry out this survey I am gratefully indebted to Professor D. F. Cappell, my chief, and to Professors J. W. S. Blacklock, Sir Roy Cameron, A. C. P . Campbell, D. H. Collins, T. Crawford, R. C. Curran, J. B. Duguid, J. Gough, C. V. Harrison, T. F. Hewer, K. R. Hill, A. C. Lendrum, C. E. Liimsden, H. A. Magnus, J. W. Orr, G. L. Montgomery, D . M. Pryce, R. J . V. Pulvertaft, D . S. Russell, R. W. Scarff, H. L. Sheehan, T . Symington, W . S1. C. Symers, G . P. Wright, and J . S. Young, and to Drs. A. M. Barrett, and A. H. T . Robb-Srnith. During the collection of the data I received helpful assistance from Drs . Georgiana M. Bonser, D. B. Brewer, W. A. J. Crane, A. G. Hepplestone, W. A. Gillespie, W. R. L. James, G. Sclare, H. Spencer, A. G . Stansfield, T. W. Sutherland and A. C. Thackray. A grant from Glasgow University defrayed part of the expenses, as did scholarship funds from the Government of Eastern Nigeria.
Department of Pathology, Western Infirmary, Glasgow.
W. 1. B. ONUIGBO
REFERENCES ATKIN, E . E. (1931). J. Path. Bact., 34, 343 . BALLANTYNE, A. J ., CLAGETT, O. T., & McDONALD, J. R. (1957). Thorax, 12,294. BAYLISS, R.I. S. (1947). M.D . Thesis, University of Cambridge, p . 72. BONSER, G. M . (1938). Acta Un. int o Cancr., 3, 119. BRYSON, C. C. (1949) . M.D . Thesis, University of Cambridge, p, 80. BUSINCO, A. (1950). Scient. med. Ital. , 1, 656. CARLSON, H. A., & BALLON, H. C . (1933). J. Thoracic Surg., 4, 323. ENTICKNAP, J. B. (1952). Guy's Hasp. Rep., 101, 273. FLICK, J. B., & BAUER, J. T. (1939). Penn. med. J., 42, 874. GALLUZI, S., & PAYNE, P. M. (1955). Brit. J. Cancer, 9, 511. GRAHAM, E. A. (1936). Ann. Surg., 103, I. HILL, R . M . (1931). M .D. Thesis, University of Edinburgh, p. 71. HORN, H . A. (1946). BIII/. ScM. med. Unlv, Maryland, 30, 169. HOWELL, T., & PIGGOT, A. P. (1957). Geriatrics, 12, 190. LA DUE, J. S. (1955). III Pulmonary Diseases, edited by R. L. Pullen, p , 209. Kimpton, London. LEADING ARTICLE (1958) . Tubercle, Lond., 39, 58. MAXWELL, J. (1930). J. Path. Bact. , 33, 233. OCHSNER, A ., DEBAKEY, M. , & DUNLAP, C . E . (1948). Rocky Min. 11Ied. J., 45, 1010 . ONUIGBO, W . 1. B. (1959). J. thorac . Surg. 37 , 771. ONUIGBO, W. I. B. (1957). Brit. J. Cancer, 11, 175. OSWALD, N . C. (1956). Brit. med. J ., 1, 761. SCHUSTER, N. H. (1929). J. Path. Bact., 32, 802. SELLaRS, T. H. (1954). In The British Encyclopaedia 0/ Medical Practice, editor in chief the Lord Horder, Medical Progress, 1954, p. 43, Butterworth, London. SMETANA, H. P., IVERSON, L., & SWAN, L. L. (1952). Milit. Surr., 111, 335. STOREY, C. P., KNUDSTON, K. P ., & LAWRENCE, B. J. (1953). J. thorac. Surg., 26, 331. WALSHE, W . H. (1871). A Practical Treatise 011 the Diseases 0/ the Lungs, 4th edition, p. 515, Smith, Elder & Co., London. WILLIS, R. A. (1960). Pathology ofTumours , 3rd ed., p. 375. Butterworths, London. YOUNG, R. D. (1958). M.D. Thesis, University of Edinburgh, p. 54.