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Multiple primary carcinomas of respiratory tract: Primary carcinoma of larynx followed by primary carcinomas involving two lungs consecutively
Brit. 3. Dis. C’hest (1974) 68,
I 28
MULTIPLE PRIMARY CARCINOMAS OF RESPIRATORY TRACT: PRIMARY CARCINOMA OF LARYNX FOLLOWED BY PRIMARY CARCINOMAS INVOLVING TWO LUNGS CONSECUTIVELY ALEX Redhill
General
SAKULA Hospital,
Surrey
CASESof multiple carcinomas occurring in different organs either concurrently or consecutively are well recognized. In the respiratory tract, however, such multiple carcinomas are infrequent. Cases of primary carcinoma in one lung accompanied or followed by the development of another primary carcinoma in the same or other lung are well documented. There have also been occasional reports of cases of primary carcinoma of the larynx accompanied or followed by the development of primary carcinoma in one lung, as well as very rare examples of primary carcinoma of one lung followed by the development of primary carcinoma of the larynx. There is only one case on record in which a primary carcinoma of one lung was followed by the development of primary carcinoma of the larynx and later another primary carcinoma in the other lung. The case described below is unique in that a primary carcinoma of the larynx was successfully treated, and later a primary carcinoma in one lung was also successfully treated, followed many years later by the development of a primary carcinoma in the other lung. It was the only example of its kind to occur in a personal series of 1500 cases of bronchial carcinoma observed in the past 20 years. Case Report A male of white Caucasian stock was first seen in May 1959 when he was aged 53. His mother had died aged 80 of ‘abdominal cancer’. He was one of 12 children; one brother died of lung cancer and one sister died of ‘cancer’ (nonpulmonary). Of his 5 children, one of his sons developed lung cancer and died of this. As far as could be ascertained he had not been exposed to an industrial carcinogenic hazard, e.g. asbestos. He had smoked cigarettes for many years, originally 30 daily, latterly 20 daily, and drank 6 pints of beer each day. There was no previous serious illness. A routine chest radiograph in 1941 was normal. When first seen in May 1959, he gave a 5 months’ history of cough, hoarseness and slight upper dysphagia. Clinically, there was no obvious abnormality. (ReceivedJar
publication
October
1973)
MULTIPLE
PRIMARY
CARCINOMAS
OF
RESPIRATORY
TRACT
129
The chest radiograph was normal. Radiographs of the sinuses showed opaque antra. Laryngoscopy revealed the left vocal cord to be swollen. Sputum and laryngeal swab cultures were negative for Mycobacterium tuberculosis. The blood Wasserman reaction was negative, and the blood count was normal. One month later a neck gland was enlarged in the right anterior triangle. Laryngoscopy now showed granulation-like tissue in the anterior commisure, and biopsy of this showed a well differentiated squamous-cell carcinoma (Fig. I). In September 1959, a total laryngectomy and block dissection of the glands of the
FIG. I. Photomicrograph nests
of the larynx. Well differentiated and dense fibroblastic stroma.
H.
squamous-cell & E. x
carcinoma
with
cell
IOO
right side of the neck were performed, and the right lobe of the thyroid was also removed. The carcinoma, an ulcerated mass, involved both false vocal cords, the true cords were not involved and there was no subglottic extension. The removed neck glands showed metastases of well differentiated squamouscell carcinoma. He did not receive radiotherapy. He remained with a permanent tracheostomy opening. There was no subsequent clinical suggestion of recurrence of this primary carcinoma of the larynx. He remained well until November rg6r when he developed a pyrexial illness with left pleuritic chest pain and cough; sputum and blood were expectorated through the tracheostomy opening. Chest radiographs revealed a dense opacity in the left lung, due to collapse-consolidation of the left lower lobe. Bronchoscopy through the tracheostomy revealed a bleeding neoplasm in the middle basal segment of the left lower lobe, and bronchial biopsy showed a necrotic
SAKULA
‘30
anaplastic carcinoma. In January 1962 a left lower lobectomy was performed. There was a large mass in the left lower lobe, with dense adhesions at the lower part especially to the diaphragm, and there was the possibility of malignant involvement of the chest wall. Histology showed an oat-cell carcinoma with The left hilar lymph nodes were areas of squamoid appearance (Fig. 2). not involved. He received radiotherapy to the left chest wall daily for three weeks. From 1962 onwards he remained well, and was able to work for the next I o years. Serial chest radiographs showed the left upper lobe to become fibrotic, considered to be a sequel of radiotherapy. In September 1969 he expectorated bloodstained sputum via the tracheostomy opening. The sputum did not contain malignant cells, and bronchoscopy showed no evidence of recurrence of the carcinoma.
FIG.
2. Photomicrograph
of the
left
lung. ance.
Oat-cell carcinoma H. & E. x IOO
with
areas
of squamoid
appear-
In March 1972, he had a further chest infection, and again bloodstained sputum was expectorated through the tracheostomy opening. He lost 3 kg in weight. Chest radiographs now showed a new opacity at the right hilum which later excavated and presented the appearance of an abscess cavity with a fluid level. Bacteriological examination of the sputum revealed only coliform organisms. Despite antibiotic therapy his condition deteriorated and he died in November 1972 at the age of 67. This was 14 years after the laryngectomy for primary carcinoma of the larynx, and I I years after resection of the prmzary carcinoma of the left lower lobe.
MULTIPLE
PRIMARY
CARCINOMAS
OF
RESPIRATORY
TRACT
13’
Au topsyjindings The larynx was absent; there was no evidence of local recurrence of the laryngeal carcinoma or metastic involvement of lymph nodes in the neck. The tracheostomy opening was sound. fibrotic left The left lung contained many adhesions over the remaining upper lobe. There was no local recurrence of the left lower lobe carcinoma, nor was there any involvement of the left hilar lymph nodes. Right lung. The right upper lobe was firmly adherent to the chest wall. Near the hilum was a firm centrally necrotic greyish-white mass, which on dissection was seen to be an extension of a tubular mass arising in and encircling the right main bronchus. It commenced 2 cm from the main carina and extended distally into the right upper lobe bronchus and its posterior segmental branch, where it broadened out into a rounded mass (4 cm diameter) in the posterior segment of the right upper lobe. The mediastinal and right hilar lymph nodes were not involved. There was no evidence of malignant disease-primary or metastatic-in any other organ.
FIG.
3. Photomicrograph
of the
right
lung.
Oat-cell
carcinoma.
H.
& E.
x
IOO
Histology showed an oat-cell carcinoma arising in the bronchial wall and infiltrating the outer wall of the right pulmonary vein (Fig. 3). At the periphery of the advancing edge of the carcinoma the lung was partially collapsed and studded with small abscesses, and the alveoli were filled with macrophages. Discussion
Attention was first drawn to multiple primary visceral malignant disease by Billroth and von Winiwarter (1883) who proposed three criteria for diagnosis:
132
SAKULA
(a) separate location of the tumours; (6) different histological structure of each tumour; and (c) from each tumour, its own metastasis. The later studies by Warren and Gates (1932) of 1078 cancer autopsies showed 3.7% to have more than one primary malignancy. Their criteria for diagnosis were slightly different : (u) each tumour must be malignant; (6) each tumour must be distinct; and (c) the possibility of one tumour being a metastasis of another must be excluded. Wallace (1957) studied 3006 cases of malignant disease and found I 12 with 2 primaries, 16 with 3 primaries, 3 with 4 primaries and 3 with 5 primaries. He calculated that I of 20 patients with malignant disease would develop another primary. These findings referred, of course, to every variety of malignant disease in any organ, but multiple malignancy in the respiratory tract appeared to be exceedingly rare. In fact, Warren and Gates (1932)) in their series, were not able to find one case of multiple malignancy in the respiratory tract. Multiple carcinomas involving lungs on& With the increased prevalence of lung cancer in recent years, occasional reports of multiple malignancies of the lungs began to appear, and were of two varieties: (a) synchronous or concomitant, where the two primary malignancies were observed simultaneously, and (6) metachronous or consecutive, where one primary malignancy was seen subsequent to another. Beyreuther (1924) described the first case of double lung cancer, a well differentiated squamouscell carcinoma in the right lung and an adenocarcinoma in the left lung. Robinson and Jackson (I 958) were able to collect g examples out of their series of 500 cases of bronchial carcinoma, in which 2 primary carcinomas each involved different lungs. Le Gal and Bauer (I g6 I) found 4 cases out of a series of 182 bronchial carcinomas in which a second primary appeared in the opposite lung after resection of the first primary and described this as ‘a complication of successful lung cancer surgery’. Further cases have now been reported by Hartsock and Fisher (1961)) Langston and Sherrick ( 1962)) Glennie et al. (1964)) Shields et al. (I 964)) Knudsen et al. (I g65), Holleran and Okinaka ( 1969) and Chaudhuri (197 I). In some of these reports, the second primary involved the same lung, in others the opposite lung. Onuigbo (1962) described a remarkable case in which three separate primary bronchial carcinomas involved different lobes in the right lung. Incidence of carcinoma of larynx compared with carcinoma of lung Despite the marked rise in the incidence of lung cancer in recent years, there has been a surprisingly less pronounced changed in the incidence of laryngeal cancer. Maxwell (1955) drew attention to the fact that the mortality of carcinoma of the larynx did not show the same rise in incidence as carcinoma of the bronchus for the years 1911-52. More recent statistics (Registrar General 1970) showed a slight fall between 1960 and 1967 but more recently a slight increase in the incidence of carcinoma of the larynx. The explanation for this disparity in the incidence of these two carcinomas of the respiratory tract is not clear. It has been suggested that the ciliated columnar-cell bronchial epithelium
MULTIPLE
PRIMARY
CARCINOMAS
OF
is more susceptible than the squamous-cell such as contained in tobacco.
RESPIRATORY
laryngeal
TRACT
epithelium
‘33 to carcinogens
Carcinoma of larynx followed by carcinoma of one lung
The development of primary carcinoma of the lung following primary carcinoma of the larynx tends to be extremely uncommon, but there have now been reports by Warren and Ehrenreich (rg44), Cahan et al. (rg5o), Cahan (rg55), Thomson et al. (rg56), Lewis and Schaff (rg56), Wallace (rg57), Rubenstein et al. (I g58), Frazell and Gerold ( rg6o), Brownell (rg6r), Hughes and Klopp (rg6r), Cahan and Montemayor (I 962) and Knudsen et al. (1965). Most of these associations have been metachronous, the longest reported interval between the two carcinomas being 23 years (Perez et al. 1961). Carcinoma of one lung followed by carcinoma of larynx
If primary carcinoma of the lung following a primary carcinoma of the larynx is uncommon, even more rare is the development of primary carcinoma of the larynx after a primary carcinoma of the lung. The probable reason for this is that the prognosis of treated primary carcinoma of larynx is better than than that of primary carcinoma of lung, and so the patient with primary carcinoma of larynx is more likely to survive long enough to develop a primary carcinoma of lung than vice versa. One such case was described by Cahan (1955) and later Cahan and Montemayor (1962) reviewed 4200 cases of lung cancer and 2500 cases of laryngeal cancer, and found 60 examples of the combined diseases, of which in only 3 did the primary carcinoma of larynx follow the primary carcinoma of lung. Further examples have now been reported by Goorwitch ( 1963) and Knudsen et al. (1965). Carcinoma of larynx associated with carcinomas in two lungs
There has been only one case report of primary carcinoma of bronchus being followed by primary carcinoma of larynx and later a further primary carcinoma of lung. Lavelle (1969) described a man aged 40 who had had a left pneumonectomy for bronchial carcinoma, and IO years later developed a primary carcinoma of larynx treated by radiotherapy; after 2 years he developed a further primary carcinoma in the right lung and died following radiotherapy. The case described in this paper is therefore unique in that there is no previous reported example of a primary carcinoma of larynx followed by independent development of primary carcinomas first in one lung and then in the other. The time intervals between the three primary carcinomas and their different histological patterns and the autopsy findings did not suggest any connection between them. Pathogenesis
Four possible explanations (Thomson et al. 1956) :
for this phenomenon
need to be considered
‘34
SAKULA
I. The carcinoma of bronchus develops as a result of the attachment and growth of tumour cells separated from the laryngeal carcinoma higher up. This, however, is unlikely as the physiological upward movement of the cilia and mucus blanket would tend to prevent this. 2. The carcinoma of bronchus is a true metastasis from the primary laryngeal carcinoma. This again is unlikely, as the lymphatic spread downwards to involve the bronchi would not occur until the cervical lymph nodes had been previously saturated by malignant disease. This did not obtain in the case described here. 3. The carcinoma of the larynx may be metastatic from the bronchial carcinoma, or be involved by retrograde surface implantation. No case of metastasis of primary bronchial carcinoma to the larynx has ever been reported. 4. The primary carcinomas in the larynx and the bronchus are separate and distinct diseases, quite unconnected, except as a result of (u) a generalized cancer proneness, (b) a general precancerous change of the respiratory tract or (c) exposure to a common carcinogenic agent, e.g. in tobacco. There was a suggestion of cancer proneness in the case described here, in so far as the family history revealed several cases of primary lung cancer. But the more likely explanation is the exposure of the larynx and bronchi to a common carcinogenic agent. The reported cases of multiple cancer of the respiratory tract have all tended to occur in males aged 50-70 who were heavy cigarette smokers. The respiratory tract is exposed to potential carcinogens throughout its ramifications, and development of primary carcinoma of the larger bronchi is preceded by widespread precancerous changes, with carcinoma-in-situ (Auerbach et al. 1957). It had previously been thought that only in the case of alveolar-cell carcinoma was there a potential for multicentric development of primary malignant disease of the lung. The origin of carcinoma in multiple sites has been discussed by Slaughter (1944) by McGrath et al. (1952) and by Willis (1960). Bronchial carcinomas often present a complex histological pattern (Ashley & Davies 1967). If multiple carcinomas are of the same histological type they are liable to be labelled as ‘primary’ and ‘secondary’, while if they are of two or more distinct types they are more likely to be labelled ‘multiple primaries’. In theory, anyway, multiple primary carcinomas of the respiratory tract may well occur more frequently than has been previously appreciated.
Conclusion
Any carcinogen such as tobacco smoke acts throughout the respiratory tract. A new lesion appearing after apparent cure of a primary carcinoma is not necessarily a metastasis, but may represent a further separate primary carcinomatous process. This would explain the occasional case of carcinoma multiplex such as that described in this paper, and possibly also partly account for the disappointingly low cure rate of lung cancer.
MULTIPLE
PRIMARY
CARCINOMAS
OF
RESPIRATORY
TRACT
I35
Summary
A 53-year-old man, a heavy cigarette smoker, developed a primary well differentiated squamous-cell carcinoma of the larynx which was successfully treated by total laryngectomy and block dissection of involved cervical lymph nodes. Two and a half years later, a primary carcinoma of mixed oat-cell and squamous-cell type developed in the left lower lobe bronchus and was successfully treated by lobectomy and radiotherapy. He remained well for a further ten years, and then developed and died from another primary carcinoma of oat-cell type in the right main bronchus and right upper lobe. Autopsy did not show any connection between these three successive primary carcinomas. The significance of this unique case of respiratory tract carcinoma multiplex is discussed. ACKNOWLEDGEMENTS I wish to thank Mr J. F. Simpson who performed the laryngectomy; Mr R. Rowlandson who resected the left lower lobe; Mr J. Jackson-Richmond for the radiotherapy to the left chest wall ; Dr W. K. Taylor for the histological report of the left lung tumour; and Dr T. A. J. Wickham for the autopsy report and his help with the photomicrographs. REFERENCES ASHLEY, D. J. B. & DAVIES, H. D. (1967) Mixed glandular and squamous-cell carcinoma of the bronchus. Thorax, 22, 43 I. AUERBACH, O., GERE, J. B., PAWLOWSKI, J. M., MUESHAM, G. E., SMOLIN, H. J. & STOUT, A. P. (1957) Carcinoma-in-situ and early invasive carcinoma occurring in tracheobronchial trees in cases of bronchial carcinoma. 3. thorac. Surg., 34, 298. BEYREUTHER, H. ( I 924) Multiplicitlt von Carcinomen bei einem Fall von Sog. ‘Schneeberger’ Lungenkreks mit Tuberkulose. Virchow’s Arch. Path. Anat. Physiol., 250, 230. BILLROTH, T. & VON WINIWARTER, A. (1883) A G eneral Surgical Pathology and Therapeutics. New York: Appleton. BROWNELL, R. B. (1961) Concurrent or subsequent carcinoma of larynx and bronchus. J. Okla. med. Ass., 54, 3 I 7. CAHAN, W. G. (1955) Lung cancer associated with cancer primary in other sites. Amer. 3.
Sw., 4, 494. CAHAN, W. G., BUTLER, F. S., WATSON, W. L. & PAUL, J. L. (I 950) Multiple cancers primary in the lung and other sites. 3. thorac. Surg., 20, 335. CAHAN, W. G. & MONTEMAYOR, P. B. (1962) Cancer of the larynx and lung in the same patient: A report of 60 cases. 3. thorac. cardiovasc. Surg., 44, 309. CHAUDHURI, M. R. (1971) Independent bilateral primary bronchial carcinomas. Thorax, 26, 476. FRAZELL, E. L. & GEROLD, F. R. (1960) Early cancer of larynx. Postgrad. Med., 27, 394. GLENNIE, J. S., HARVEY, P. W. & SALAMA, V. (1964) Multiple primary carcinoma of bronchus. A report of three cases. 3. thorac. cardiouasc. Surg., 48, 40. GOORWITCH, J. (1963) Consecutive primary carcinomas of bronchus and larynx. Report case. 3. Amer. med. Ass., 183, 375. HARTSOCK, R. J. & FISHER, E. R. (1961) Bilateral primary invasive carcinoma of lungs. Chest, 39, 421. HOLLERAN, B. J. & OKINAKA, A. J. (1969) Bilateral apical carcinomas of the lung. A report. 3. thorac. cardiovasc. Surg., 57, 853. HUGHES, R. K. & KLOPP, C. T. (1961) Associated carcinomas of larynx and lung. Amer. surg., IOI, 51 I. KNUDSEN, R. J., HATCH, H. B., OCHSNER, A. & LEJEUNE, F. E. (1965) Multiple carcinomas the lung and upper respiratory tract. Dir. Chest, 48, 140.
the of a Dis. case
3. of
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LANGSTON, H. T. & SHERRICK, J. C. (1962) Bilateral simultaneous bronchogenic carcinoma. 3. thorac. cardiovasc. Surg., 43, 742. LAVELLE, R. J. (1969) Metachronous carcinoma of the larynx following successful treatment of carcinoma of the bronchus. &it. 3. Cancer, 23, Tog. LE GAL, Y. & BAUER, W. C. ( I g6 I) Second primary bronchogenic carcinoma-a complication of successful lung cancer surgery. 3. thorac. Surg., 4r, I 14. LEWIS, E. C. I. & SCHAFF, B. (1956) Carcinoma of Larynx associated with bronchogenic carcinoma. Amer. Rev. Tuberc., 74, 438. MCGRATH, E. J., GALL, E. A. & KESSLER, D. P. (1952) Bronchogenic carcinoma, a product of multiple sites of origin. 3. thorac. Surg., 24. 27 I. MAXWELL, J. (I 955) Incidence of cancer of larynx in relation to incidence of cancer of bronchi. Lance& i, 193. ONUIGBO, W. I. (1962) Multiple carcinomata of the lung (a case with three primary tumours). Brit. 3. Dis. Chest, 56, 144. PEREZ, P. E., BERNATZ, P. E., DEVINE, K. D. & WOOLNER, L. B. (1961) Associated primary endolaryngeal carcinoma and bronchogenic carcinoma. 3. Amer. med. Ass., 177, 596. REGISTRAR GENERAL (1970) Statistical Rev&w of England and Wales, part I, p. 18. London: HMSO. ROBINSON, C. L. N. & JACKSON, C. A. (1958) Multiple primary cancer of the lung. 3. thorac. Surg., 36, 166. RUBENSTEIN, A. S., GRAHAM, J. & BARNES, N. (1958) Associated carcinoma of larynx and lung. Archs Otolar., 68, 710. SHIELDS, T. W., DRAKE, C. T. & SHERRICK, J. C. (1964) Bilateral primary bronchogenic carcinoma. 3. thorac. cardiovax. Surg., 48, 401. SLAUGHTER, D. P. (1944) Multiplicity of origin of malignant turnours: collective review. Znt Abstr. Surg., 79, 89. THOMSON, R. V., SCHAFF, B. & GABLES, C. (1956) Carcinoma of larynx with concurrent or subsequent development of bronchial carcinoma. Report of five cases, with autopsy findings. Surgery, 39, 805. WALLACE, A. F. (1957) Multiple primary malignant neoplasms. Brit. 3. Surg., 45, 165. WARREN, S. & EHRENREICH, T. (1944) Multiple primary malignant tumours and susceptibility to cancer. Cancer Res., 4, 554. WARREN, S. & GATES, 0. (1932) Multiple primary malignant tumours: a survey of literature and a statistical study. Amer. 3. Cancer, 16, 1358. WILLIS, R. A. (1960) Pathology of Turnours, 3rd ed, p. 189. London: Butterworths.
I 28
MULTIPLE PRIMARY CARCINOMAS OF RESPIRATORY TRACT: PRIMARY CARCINOMA OF LARYNX FOLLOWED BY PRIMARY CARCINOMAS INVOLVING TWO LUNGS CONSECUTIVELY ALEX Redhill
General
SAKULA Hospital,
Surrey
CASESof multiple carcinomas occurring in different organs either concurrently or consecutively are well recognized. In the respiratory tract, however, such multiple carcinomas are infrequent. Cases of primary carcinoma in one lung accompanied or followed by the development of another primary carcinoma in the same or other lung are well documented. There have also been occasional reports of cases of primary carcinoma of the larynx accompanied or followed by the development of primary carcinoma in one lung, as well as very rare examples of primary carcinoma of one lung followed by the development of primary carcinoma of the larynx. There is only one case on record in which a primary carcinoma of one lung was followed by the development of primary carcinoma of the larynx and later another primary carcinoma in the other lung. The case described below is unique in that a primary carcinoma of the larynx was successfully treated, and later a primary carcinoma in one lung was also successfully treated, followed many years later by the development of a primary carcinoma in the other lung. It was the only example of its kind to occur in a personal series of 1500 cases of bronchial carcinoma observed in the past 20 years. Case Report A male of white Caucasian stock was first seen in May 1959 when he was aged 53. His mother had died aged 80 of ‘abdominal cancer’. He was one of 12 children; one brother died of lung cancer and one sister died of ‘cancer’ (nonpulmonary). Of his 5 children, one of his sons developed lung cancer and died of this. As far as could be ascertained he had not been exposed to an industrial carcinogenic hazard, e.g. asbestos. He had smoked cigarettes for many years, originally 30 daily, latterly 20 daily, and drank 6 pints of beer each day. There was no previous serious illness. A routine chest radiograph in 1941 was normal. When first seen in May 1959, he gave a 5 months’ history of cough, hoarseness and slight upper dysphagia. Clinically, there was no obvious abnormality. (ReceivedJar
publication
October
1973)
MULTIPLE
PRIMARY
CARCINOMAS
OF
RESPIRATORY
TRACT
129
The chest radiograph was normal. Radiographs of the sinuses showed opaque antra. Laryngoscopy revealed the left vocal cord to be swollen. Sputum and laryngeal swab cultures were negative for Mycobacterium tuberculosis. The blood Wasserman reaction was negative, and the blood count was normal. One month later a neck gland was enlarged in the right anterior triangle. Laryngoscopy now showed granulation-like tissue in the anterior commisure, and biopsy of this showed a well differentiated squamous-cell carcinoma (Fig. I). In September 1959, a total laryngectomy and block dissection of the glands of the
FIG. I. Photomicrograph nests
of the larynx. Well differentiated and dense fibroblastic stroma.
H.
squamous-cell & E. x
carcinoma
with
cell
IOO
right side of the neck were performed, and the right lobe of the thyroid was also removed. The carcinoma, an ulcerated mass, involved both false vocal cords, the true cords were not involved and there was no subglottic extension. The removed neck glands showed metastases of well differentiated squamouscell carcinoma. He did not receive radiotherapy. He remained with a permanent tracheostomy opening. There was no subsequent clinical suggestion of recurrence of this primary carcinoma of the larynx. He remained well until November rg6r when he developed a pyrexial illness with left pleuritic chest pain and cough; sputum and blood were expectorated through the tracheostomy opening. Chest radiographs revealed a dense opacity in the left lung, due to collapse-consolidation of the left lower lobe. Bronchoscopy through the tracheostomy revealed a bleeding neoplasm in the middle basal segment of the left lower lobe, and bronchial biopsy showed a necrotic
SAKULA
‘30
anaplastic carcinoma. In January 1962 a left lower lobectomy was performed. There was a large mass in the left lower lobe, with dense adhesions at the lower part especially to the diaphragm, and there was the possibility of malignant involvement of the chest wall. Histology showed an oat-cell carcinoma with The left hilar lymph nodes were areas of squamoid appearance (Fig. 2). not involved. He received radiotherapy to the left chest wall daily for three weeks. From 1962 onwards he remained well, and was able to work for the next I o years. Serial chest radiographs showed the left upper lobe to become fibrotic, considered to be a sequel of radiotherapy. In September 1969 he expectorated bloodstained sputum via the tracheostomy opening. The sputum did not contain malignant cells, and bronchoscopy showed no evidence of recurrence of the carcinoma.
FIG.
2. Photomicrograph
of the
left
lung. ance.
Oat-cell carcinoma H. & E. x IOO
with
areas
of squamoid
appear-
In March 1972, he had a further chest infection, and again bloodstained sputum was expectorated through the tracheostomy opening. He lost 3 kg in weight. Chest radiographs now showed a new opacity at the right hilum which later excavated and presented the appearance of an abscess cavity with a fluid level. Bacteriological examination of the sputum revealed only coliform organisms. Despite antibiotic therapy his condition deteriorated and he died in November 1972 at the age of 67. This was 14 years after the laryngectomy for primary carcinoma of the larynx, and I I years after resection of the prmzary carcinoma of the left lower lobe.
MULTIPLE
PRIMARY
CARCINOMAS
OF
RESPIRATORY
TRACT
13’
Au topsyjindings The larynx was absent; there was no evidence of local recurrence of the laryngeal carcinoma or metastic involvement of lymph nodes in the neck. The tracheostomy opening was sound. fibrotic left The left lung contained many adhesions over the remaining upper lobe. There was no local recurrence of the left lower lobe carcinoma, nor was there any involvement of the left hilar lymph nodes. Right lung. The right upper lobe was firmly adherent to the chest wall. Near the hilum was a firm centrally necrotic greyish-white mass, which on dissection was seen to be an extension of a tubular mass arising in and encircling the right main bronchus. It commenced 2 cm from the main carina and extended distally into the right upper lobe bronchus and its posterior segmental branch, where it broadened out into a rounded mass (4 cm diameter) in the posterior segment of the right upper lobe. The mediastinal and right hilar lymph nodes were not involved. There was no evidence of malignant disease-primary or metastatic-in any other organ.
FIG.
3. Photomicrograph
of the
right
lung.
Oat-cell
carcinoma.
H.
& E.
x
IOO
Histology showed an oat-cell carcinoma arising in the bronchial wall and infiltrating the outer wall of the right pulmonary vein (Fig. 3). At the periphery of the advancing edge of the carcinoma the lung was partially collapsed and studded with small abscesses, and the alveoli were filled with macrophages. Discussion
Attention was first drawn to multiple primary visceral malignant disease by Billroth and von Winiwarter (1883) who proposed three criteria for diagnosis:
132
SAKULA
(a) separate location of the tumours; (6) different histological structure of each tumour; and (c) from each tumour, its own metastasis. The later studies by Warren and Gates (1932) of 1078 cancer autopsies showed 3.7% to have more than one primary malignancy. Their criteria for diagnosis were slightly different : (u) each tumour must be malignant; (6) each tumour must be distinct; and (c) the possibility of one tumour being a metastasis of another must be excluded. Wallace (1957) studied 3006 cases of malignant disease and found I 12 with 2 primaries, 16 with 3 primaries, 3 with 4 primaries and 3 with 5 primaries. He calculated that I of 20 patients with malignant disease would develop another primary. These findings referred, of course, to every variety of malignant disease in any organ, but multiple malignancy in the respiratory tract appeared to be exceedingly rare. In fact, Warren and Gates (1932)) in their series, were not able to find one case of multiple malignancy in the respiratory tract. Multiple carcinomas involving lungs on& With the increased prevalence of lung cancer in recent years, occasional reports of multiple malignancies of the lungs began to appear, and were of two varieties: (a) synchronous or concomitant, where the two primary malignancies were observed simultaneously, and (6) metachronous or consecutive, where one primary malignancy was seen subsequent to another. Beyreuther (1924) described the first case of double lung cancer, a well differentiated squamouscell carcinoma in the right lung and an adenocarcinoma in the left lung. Robinson and Jackson (I 958) were able to collect g examples out of their series of 500 cases of bronchial carcinoma, in which 2 primary carcinomas each involved different lungs. Le Gal and Bauer (I g6 I) found 4 cases out of a series of 182 bronchial carcinomas in which a second primary appeared in the opposite lung after resection of the first primary and described this as ‘a complication of successful lung cancer surgery’. Further cases have now been reported by Hartsock and Fisher (1961)) Langston and Sherrick ( 1962)) Glennie et al. (1964)) Shields et al. (I 964)) Knudsen et al. (I g65), Holleran and Okinaka ( 1969) and Chaudhuri (197 I). In some of these reports, the second primary involved the same lung, in others the opposite lung. Onuigbo (1962) described a remarkable case in which three separate primary bronchial carcinomas involved different lobes in the right lung. Incidence of carcinoma of larynx compared with carcinoma of lung Despite the marked rise in the incidence of lung cancer in recent years, there has been a surprisingly less pronounced changed in the incidence of laryngeal cancer. Maxwell (1955) drew attention to the fact that the mortality of carcinoma of the larynx did not show the same rise in incidence as carcinoma of the bronchus for the years 1911-52. More recent statistics (Registrar General 1970) showed a slight fall between 1960 and 1967 but more recently a slight increase in the incidence of carcinoma of the larynx. The explanation for this disparity in the incidence of these two carcinomas of the respiratory tract is not clear. It has been suggested that the ciliated columnar-cell bronchial epithelium
MULTIPLE
PRIMARY
CARCINOMAS
OF
is more susceptible than the squamous-cell such as contained in tobacco.
RESPIRATORY
laryngeal
TRACT
epithelium
‘33 to carcinogens
Carcinoma of larynx followed by carcinoma of one lung
The development of primary carcinoma of the lung following primary carcinoma of the larynx tends to be extremely uncommon, but there have now been reports by Warren and Ehrenreich (rg44), Cahan et al. (rg5o), Cahan (rg55), Thomson et al. (rg56), Lewis and Schaff (rg56), Wallace (rg57), Rubenstein et al. (I g58), Frazell and Gerold ( rg6o), Brownell (rg6r), Hughes and Klopp (rg6r), Cahan and Montemayor (I 962) and Knudsen et al. (1965). Most of these associations have been metachronous, the longest reported interval between the two carcinomas being 23 years (Perez et al. 1961). Carcinoma of one lung followed by carcinoma of larynx
If primary carcinoma of the lung following a primary carcinoma of the larynx is uncommon, even more rare is the development of primary carcinoma of the larynx after a primary carcinoma of the lung. The probable reason for this is that the prognosis of treated primary carcinoma of larynx is better than than that of primary carcinoma of lung, and so the patient with primary carcinoma of larynx is more likely to survive long enough to develop a primary carcinoma of lung than vice versa. One such case was described by Cahan (1955) and later Cahan and Montemayor (1962) reviewed 4200 cases of lung cancer and 2500 cases of laryngeal cancer, and found 60 examples of the combined diseases, of which in only 3 did the primary carcinoma of larynx follow the primary carcinoma of lung. Further examples have now been reported by Goorwitch ( 1963) and Knudsen et al. (1965). Carcinoma of larynx associated with carcinomas in two lungs
There has been only one case report of primary carcinoma of bronchus being followed by primary carcinoma of larynx and later a further primary carcinoma of lung. Lavelle (1969) described a man aged 40 who had had a left pneumonectomy for bronchial carcinoma, and IO years later developed a primary carcinoma of larynx treated by radiotherapy; after 2 years he developed a further primary carcinoma in the right lung and died following radiotherapy. The case described in this paper is therefore unique in that there is no previous reported example of a primary carcinoma of larynx followed by independent development of primary carcinomas first in one lung and then in the other. The time intervals between the three primary carcinomas and their different histological patterns and the autopsy findings did not suggest any connection between them. Pathogenesis
Four possible explanations (Thomson et al. 1956) :
for this phenomenon
need to be considered
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SAKULA
I. The carcinoma of bronchus develops as a result of the attachment and growth of tumour cells separated from the laryngeal carcinoma higher up. This, however, is unlikely as the physiological upward movement of the cilia and mucus blanket would tend to prevent this. 2. The carcinoma of bronchus is a true metastasis from the primary laryngeal carcinoma. This again is unlikely, as the lymphatic spread downwards to involve the bronchi would not occur until the cervical lymph nodes had been previously saturated by malignant disease. This did not obtain in the case described here. 3. The carcinoma of the larynx may be metastatic from the bronchial carcinoma, or be involved by retrograde surface implantation. No case of metastasis of primary bronchial carcinoma to the larynx has ever been reported. 4. The primary carcinomas in the larynx and the bronchus are separate and distinct diseases, quite unconnected, except as a result of (u) a generalized cancer proneness, (b) a general precancerous change of the respiratory tract or (c) exposure to a common carcinogenic agent, e.g. in tobacco. There was a suggestion of cancer proneness in the case described here, in so far as the family history revealed several cases of primary lung cancer. But the more likely explanation is the exposure of the larynx and bronchi to a common carcinogenic agent. The reported cases of multiple cancer of the respiratory tract have all tended to occur in males aged 50-70 who were heavy cigarette smokers. The respiratory tract is exposed to potential carcinogens throughout its ramifications, and development of primary carcinoma of the larger bronchi is preceded by widespread precancerous changes, with carcinoma-in-situ (Auerbach et al. 1957). It had previously been thought that only in the case of alveolar-cell carcinoma was there a potential for multicentric development of primary malignant disease of the lung. The origin of carcinoma in multiple sites has been discussed by Slaughter (1944) by McGrath et al. (1952) and by Willis (1960). Bronchial carcinomas often present a complex histological pattern (Ashley & Davies 1967). If multiple carcinomas are of the same histological type they are liable to be labelled as ‘primary’ and ‘secondary’, while if they are of two or more distinct types they are more likely to be labelled ‘multiple primaries’. In theory, anyway, multiple primary carcinomas of the respiratory tract may well occur more frequently than has been previously appreciated.
Conclusion
Any carcinogen such as tobacco smoke acts throughout the respiratory tract. A new lesion appearing after apparent cure of a primary carcinoma is not necessarily a metastasis, but may represent a further separate primary carcinomatous process. This would explain the occasional case of carcinoma multiplex such as that described in this paper, and possibly also partly account for the disappointingly low cure rate of lung cancer.
MULTIPLE
PRIMARY
CARCINOMAS
OF
RESPIRATORY
TRACT
I35
Summary
A 53-year-old man, a heavy cigarette smoker, developed a primary well differentiated squamous-cell carcinoma of the larynx which was successfully treated by total laryngectomy and block dissection of involved cervical lymph nodes. Two and a half years later, a primary carcinoma of mixed oat-cell and squamous-cell type developed in the left lower lobe bronchus and was successfully treated by lobectomy and radiotherapy. He remained well for a further ten years, and then developed and died from another primary carcinoma of oat-cell type in the right main bronchus and right upper lobe. Autopsy did not show any connection between these three successive primary carcinomas. The significance of this unique case of respiratory tract carcinoma multiplex is discussed. ACKNOWLEDGEMENTS I wish to thank Mr J. F. Simpson who performed the laryngectomy; Mr R. Rowlandson who resected the left lower lobe; Mr J. Jackson-Richmond for the radiotherapy to the left chest wall ; Dr W. K. Taylor for the histological report of the left lung tumour; and Dr T. A. J. Wickham for the autopsy report and his help with the photomicrographs. REFERENCES ASHLEY, D. J. B. & DAVIES, H. D. (1967) Mixed glandular and squamous-cell carcinoma of the bronchus. Thorax, 22, 43 I. AUERBACH, O., GERE, J. B., PAWLOWSKI, J. M., MUESHAM, G. E., SMOLIN, H. J. & STOUT, A. P. (1957) Carcinoma-in-situ and early invasive carcinoma occurring in tracheobronchial trees in cases of bronchial carcinoma. 3. thorac. Surg., 34, 298. BEYREUTHER, H. ( I 924) Multiplicitlt von Carcinomen bei einem Fall von Sog. ‘Schneeberger’ Lungenkreks mit Tuberkulose. Virchow’s Arch. Path. Anat. Physiol., 250, 230. BILLROTH, T. & VON WINIWARTER, A. (1883) A G eneral Surgical Pathology and Therapeutics. New York: Appleton. BROWNELL, R. B. (1961) Concurrent or subsequent carcinoma of larynx and bronchus. J. Okla. med. Ass., 54, 3 I 7. CAHAN, W. G. (1955) Lung cancer associated with cancer primary in other sites. Amer. 3.
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the of a Dis. case
3. of
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