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The Effect of Histological Cell Type on the Prognosis of Patients with Bronchogenic Carcinoma
T H E ANNALS OF THORACIC SURGERY Journal of T h e Society of Thoracic Surgeons and the Southern Thoracic Surgical Association VOLUME 1 3 NUMBER 4 APRIL 1972
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The Effect of Histological Cell Type on the Prognosis of Patients with Bronchogenic Carcinoma Marvin M. Kirsh, M.D., Michael Prior, M.D., Otto Gago, M.D., William Y . Moores, M.D., Donald R. Kahn, M.D., Ronald V. Pellegrini, M.D., and Herbert Sloan, M.D. ABSTRACT Mediastinal lymph node dissection in conjunction with pulmonary resection was performed in 232 patients with bronchogenic carcinoma at the University of Michigan Medical Center from 1959 to 1965. The mediastinum was irradiated postoperatively in those patients with mediastinal metastases. The absolute five-year survival rate of the patients undergoing resection was 29.2%. Of 110 patients with squamous cell carcinoma, 37.2% lived five years free of disease. The overall five-year survival of those patients undergoing resection who had no hilar lymph node metastases was 45.7%, and it was 45% in those with hilar metastases only. The absolute five-year survival rate of the patients with mediastinal metastases who received radiation therapy was 29.5%. Of 76 patients with adenocarcinoma, 19.7% lived five years free of disease. The overall five-year survival of those patients undergoing resection who had no lymph node metastases was 33%, whereas none of the patients with hilar metastases survived and only 1 of 17 patients with mediastinal metastases survived five years free of disease. The findings suggest that the histological cell type is an important factor in determining the prognosis in bronchogenic carcinoma, especially if there is evidence of lymph node involvement. I n addition, this study also suggests that it is the presence, and not necessarily the extent, of lymph node metastases in patients with squamous cell carcinoma that determines the survival rate following pulmonary resection, provided those patients with mediastinal metastases undergo postoperative mediastinal irradiation. From the Department of Surgery, University of Michigan Medical Center, Ann Arbor, Mich. Presented at the Eighteenth Annual Meeting of the Southern Thoracic Surgical Association, Tampa, Fla.. Nov. 4-6, 1971. Address reprint requests to Dr. Kirsh, (2-7184, University Hospital, Ann Arbor, Mich. 48104.
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espite refinements in diagnostic measures that have led to earlier diagnosis and improvements in surgical technique that have permitted more radical excisional therapy, the overall five-year surbronchogenic carcinoma has varied little over the years. While pulmonary resection is the preferred method of treatment for bronchogenic carcinoma, the factors that influence long-term survival following pulmonary resection are still a subject of debate. The present study was undertaken to determine what factors influenced the survival rate in our patients following resection for bronchogenic carcinoma.
Clinical Experience During the six-year period 1959-1965, 259 patients were operated upon for bronchogenic carcinoma at the University of Michigan Medical Center. Whether pneumonectomy or lobectomy was performed depended on the location of the lesion and the extent of the carcinoma. Lobectomy was carried out whenever feasible. Pneumonectomy was employed for tumors that could not be removed with a lesser procedure. Segmentectomy was performed for peripheral lesions in those patients in whom it was believed that a lobectomy could not be tolerated because of inadequate pulmonary reserve. The perihilar and hilar lymph nodes were removed en bloc with the primary lesion whenever possible. Following the resection the superior mediastinal, subaortic, subcarinal, and paraesophageal lymph nodes were completely removed. We considered the resection to be curative if all the gross tumor was excised. When necessary, the operations included resection of adjacent chest wall, diaphragm, and pericardium. Postoperative mediastinal irradiation was given to those patients who had undergone curative resection and in addition had evidence of spread to mediastinal lymph nodes. Procedures in which exploratory thoracotomy without resection was carried out or in which gross tumor was left behind were not included in the final analysis. Current follow-up was obtained in 98.6% of the patients either until death or for a minimum of five years. A consideration of the patient’s symptoms and especially the duration of such symptoms was difficult to evaluate in this retrospective study and therefore has not been included.
R esu 1ts Two hundred sixty operations were performed on 259 patients (Table 1). One patient had a second primary tumor removed from the contralateral lung two years following her initial operation. She subsequently survived for five years and has been considered in our analysis as 2 separate cases. Twenty-eight patients had unresectable lesions. The reasons for unresectability included pulmonary reserve insufficient for the patient to tolerate the resection necessary to remove the tumor completely; extensive left atrial 304
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Cell T y p e and Prognosis in Lung Cancer TABLE 1. BRONCHOGENIC CARCINOMA, 1959-1965: OPERATIONS PERFORMED AND MORTALITY RATES IN 259 PATIENTS WITH BRONCHOGENIC CARCINOMAa
Operative Mortality
No. of
Patients 150 74 8 28
Operation Lobectomy Pneumonectomy Segmentectomy Thoracotomy only
(%)
5.3 10.8 12.5 3.6
"One patient had two operations.
or aortic wall involvement; and proximal extension of the tumor onto the main pulmonary artery. Two hundred thirty-two resections were performed. In 212 the resection was believed to be curative. There was no difference in mortality between patients undergoing a curative or a noncurative resection. Pulmonary embolism (4 patients), arrhythmias or myocardial infarction (4 patients), and empyema (4 patients) accounted for the majority of deaths. Respiratory insufficiency was responsible for only 2 postoperative deaths.
Analysis of Overall Results Only those patients undergoing curative resection were analyzed with regard to histological cell type and lymph node involvement. The absolute five-year survival rate for the entire group of 212 patients was 29.2%. Peribronchial or hilar lymph node metastases only were found in 37 patients. The five-year survival of these patients was 25.8% (Table 2). One hundred eight patients did not have either hilar or mediastinal metastases. Fortyfour, or 40% of these patients, were alive and free of disease at the end of five years. Mediastinal node metastases were found in 48 patients who survived operation. The absolute five-year survival rate among 36 patients who received radiation therapy in the immediate postoperative period was 19.4%. None of 12 patients who did not receive postoperative mediastinal irradiaTABLE 2. BRONCHOGENIC CARCINOMA, 1959-1965: OVERALL FIVE-YEAR SURVIVAL IN 212 PATIENTS ACCORDING T O METASTASES
Metastases
None Hilar only Mediastinal (radiation therapy)
Overall 40
25.8 19.4
Five-Year Survival (%) Squamous Cell AdenoCarcinoma carcinoma 45.7 33 45 0 29.5 5.9
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KTRSH ET AL. TABLE 3. BRONCHOGENIC CARCINOMA, 1959-1965: CLASSIFICATIOP: AND OVERALL FIVE-YEAR SURVIVAL ACCORDING T O HISTOLOGICAL CELL TYPE
Cell Type Squamous cell Adenocarcinoma Large cell undifferentiated Acanthoadenocarcinoma Oat cell
No. of Patients 110 76 14 9
Five-Year Survival (%I
4
37.2
19.2 7.3
22 25
tion survived five years. No patient undergoing exploration alone or palliative resection survived five years. The average survival of those undergoing thoracotomy only was 7.4 months and of those undergoing palliative resection, 7.7 months. SQUAMOUS CELL CARCINOMA
Squamous cell carcinoma was present in 110 patients (Table 3). One hundred five of these patients were men, and 5 were women. Most of the tumors were centrally located, and there was involvement of major bronchi in 71 patients. The five-year survival according to type of resection is shown in Table 4. Only 39 patients had tumors arising in the more peripheral regions of the lung. In 61 patients lymph node metastases were not present. The overall five-year survival in this group was 45.7%. Eighteen of these patients underwent lobectomy, and 9 underwent pneumonectomy. Twenty patients had perihilar or hilar metastases only. The five-year survival rate of these patients was 45%. Four of those who underwent lobectomy and 5 who underwent pneumonectomy were long-term survivors. Seventeen patients had superior mediastinal or subcarinal involvement, and in 14 there was also involvement of hilar nodes. Postoperative mediastinal irradiation (5,000 to 5,500 R)was carried out in these patients, and 5 survived five years free of disease. Three underwent lobectomy, and 2 underwent pneumonectomy. ADEN OCARCINOMA
Seventy-six patients had adenocarcinoma (see Table 3). Fifty-seven were men, and 19 were women. The tumors were located in the more peripheral TABLE 4. BRONCHOGENIC CARCINOMA, 1959-1965: FIVE-YEAR SURVIVAL ACCORDING T O RESECTION
Operation Lobectomy
Pneumonectomy Segmentectomy 306
Overall 33 20.3
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Five-YearSurvival (%) Squamous Cell Carcinoma 40.6 30 100
Adeno-
carcinoma 26.9 0 25
Cell T y p e and Prognosis in Lung Cancer
regions of the lung in 75% and were centrally located in 25% of the patients. In 42 patients lymph node metastases were not present. The overall five-year survival of these patients was 33%. Thirteen underwent lobectomy and 1 underwent segmentectomy. Nine patients had peribronchial or hilar metastases only. None of these patients survived five years. Postoperative mediastinal irradiation was carried out in 17 patients who had superior mediastinal or subcarinal involvement. In 14 there was also involvement of hilar nodes. Only 1 of these 17 patients is still alive; this patient has survived 66 months following left upper lobectomy for a 3 x 3 cm. mass located in the left midlung field. ACANTHOADENOCARCINOMA
Acanthoadenocarcinoma was present in 9 patients. One patient with hilar metastases and 1 patient without metastases are still living free of disease 72 and 84 months, respectively, following their operations. UNDIFFERENTIATED CARCINOMA
Only 1 of 4 patients with undifferentiated carcinoma lived for five years. This patient had a 6 cm. mass in the midportion of the right upper lobe and a 1.5 cm. node in the superior mediastinum and was treated by right upper lobectomy, mediastinal lymph node dissection, and postoperative mediastinal irradiation. LARGE CELL UNDIFFERENTIATED CARCINOMA
Large cell undifferentiated carcinoma was present in 14 patients. One patient who did not have lymph node involvement survived five years following left lower lobectomy.
Comment Numerous attempts have been made to determine what factors influence long-term survival following pulmonary resection for bronchogenic carcinoma. It has been found that there is no difference between survivors and nonsurvivors in the size or location of the primary lesion, degree of differentiation of tumor, and extent of resection performed. Johnson [ 151, Collier [9], and Reinhoff [21]and their associates emphasized the presence of blood vessel invasion by malignant cells as an important determinant in long-term survival. However, others have found that microscopical detection of vascular invasion seemed to be of little prognostic value, especially in patients with adenocarcinoma of the lung. Bennett and co-workers [2] found evidence of blood vessel invasion in all 6 of their patients surviving five years following pulmonary resection, while none of the 9 patients without blood vessel invasion survived five years. Similar results were reported by Hukill and Stern [13]. It is generally accepted that the presence and especially the extent of metastases to lymph nodes constitute an important prognostic VOL. 13, NO.
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factor. When there is no lymphatic involvement at all, the five-year survival rate following resection of bronchogenic carcinoma is between 25 and 40% [l, 3, 4, 7, 8, 11, 18, 191. Lymphatic involvement of the intersegmental or hilar nodes has a better prognosis than mediastinal node involvement. Fiveyear survival following resection of bronchogenic carcinoma with hilar involvement is between 15 and 20% but is less than 10% when mediastinal nodes are involved in most reported series. Jensen [14] reported a 1% threeyear survival and Bergh and Schersten [3] a 7% five-year survival following resection in patients with mediastinal node involvement. Cahan and his associates 1.51 have been performing extensive en bloc excision of hilar and mediastinal nodes in conjunction with pulmonary resection for bronchogenic carcinoma. The five-year survival was 21.6% in the group of patients in whom positive lymph nodes were found in the mediastinal lymphatics of the resected specimen. Similar results have recently been reported from this institution [171. Postoperative mediastinal irradiation was given to 36 patients in whom mediastinal lymph node metastases were found following pulmonary resection and mediastinal node dissection. The overall five-year survival rate of the patients receiving radiation therapy was 19.4%. There are conflicting reports in the literature concerning the effects of cell type, especially squamous cell carcinoma and adenocarcinoma, on survival rates. Bergh [3], Collins [lo], and Bennett [2] and their associates believe that adenocarcinoma has a lower survival rate than squamous cell carcinoma. On the other hand, Belcher and Anderson [l], Siddons [221, and Higgins and Beebe [12] think that the prognosis is similar for both squamous cell carcinoma and adenocarcinoma. There is uniform agreement concerning the overall poor results with small cell (oat cell) undifferentiated carcinoma [ 16, 201. The present study suggests that histological cell type is an important factor in determining the prognosis in patients with bronchogenic carcinoma, especially if there is evidence of lymph node involvement. In our series, patients with squamous cell carcinoma of the lung as a group had a greater five-year survival rate than those patients with adenocarcinoma of the lung (37.2% versus 19.7%).Even in the absence of lymph node metastases, patients with squamous cell carcinoma tended to survive longer than those with adenocarcinoma (cf. Table 2). The difference in survival between the two groups is more striking when there are hilar or mediastinal metastases. The five-year survival rate in patients with squamous cell carcinoma and hilar metastases treated by pulmonary resection alone was 45%, and it was 29.5% in patients with mediastinal metastases who were treated by pulmonary resection, mediastinal lymph node dissection, and postoperative mediastinal irradiation. In contrast are the poor results in patients with adenocarcinoma and lymph node metastases. None of the patients who had adenocarcinoma with hilar metas-
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Cell Type and Prognosis in Lung Cancer
tases survived five years following pulmonary resection, mediastinal node dissection, and postoperative mediastinal irradiation. T h e patients with adenocarcinoma, as a group, had a higher percentage of resectability and a lower operative mortality than those with squamous cell carcinoma. I t was impossible to determine in this retrospective study if there were differences in the size or number of lymph nodes involved between the two groups. T h e reasons for the low cure rates in patients with adenocarcinoma of the lung and lymph node metastases are unclear from this study and others. Although the number of patients involved is too small to be of statistical significance, this study also suggests that it is the presence, and not necessarily the extent, of lymph node metastases in patients with squamous cell carcinoma that determines the survival rate following pulmonary resection, provided those patients with mediastinal metastases undergo postoperative mediastinal irradiation. T h e five-year survival rate of 29.5% in patients with squamous cell carcinoma and mediastinal metastases treated with postoperative mediastinal irradiation compared favorably with the 45% five-year survival rate of patients with hilar metastases treated by pulmonary resection alone.
References 1. Belcher, J. R., and Anderson, R. Surgical treatment of carcinoma of the bronchus. Br. Med. J . 1:948, 1965. 2. Bennett, D. E., Sasser, W. F., and Ferguson, T. B. Adenocarcinoma of the lung in men-a clinicopathologic study of 100 cases. Cancer 23:431, 1969. 3. Bergh, N. P., and Schersten, T. Bronchogenic carcinoma: A follow-up study of a surgically treated series with special reference to the grognostic significance of lymph node metastases. Acta Chir. Scand. (Suppl. 3 7): 1, 1965. 4. Boucot, K. R., Cooper, D. A., and Weiss, W. The role of surgery in the cure of lung cancer. Arch. Intern. Med. 120:168, 1967. 5. Cahan, W. G., Watson, W. L., and Pool, J. L. Radical pneumonectomy. J . Thorac. Surg. 22:449, 1951. 6 . Carlens, E. Mediastinoscopy. Ann. Otol. Rhinol. Laryngol. 74: 1102, 1965. 7. Churchill, E. D., Sweet, R. H., Scannell, J. G., and Wilkins, E. W., Jr. Further studies in the surgical management of carcinoma of the lung: A further study of the cases treated at the Massachusetts General Hospital from 1950 to 1957. J. Thorac. Surg. 36:301, 1958. 8. Clagett, 0.T., Allen, T . H., Payne, W. S., and Woolner, L. B. The surgical treatment of pulmonary neoplasms: A 10-year experience. J. Thorac. Cardiovasc. Surg. 48:391, 1964. 9. Collier, F. C., Enterline, H. T., Kyle, R. H., Tristan, T. T., and Greening, R. The prognostic implications of vascular invasion in primary carcinomas of the lung: A clinicopathologic correlation of two hundred twenty-five cases with one hundred percent follow-up. A.M.A. Arch. Pathol. 66:594, 1958. 10. Collins, N. P. Bronchogenic carcinoma-importance of the cell type. A.M.A. Arch. Surg. 77:925, 1958. 11. Gibbon, J. H., Jr., Templeton, J. Y.,111, and Nealon, T. F., Jr. Factors which influence the long term survival of patients with cancer of the lung. Ann. Surg. 145:637, 1957. 12. Higgins, G. A., and Beebe, G. W. Bronchogenic carcinoma: Factors in survival. Arch. Surg. 94:539, 1967. 13. Hukill, P. B., and Stern, H. Adenocarcinoma of the lung: Histological facVOL. 19, NO.
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14. 15. 16. 17. 18. 19. 20. 21. 22.
tors affecting prognosis. A study of 38 patients with resection and five-year follow-up. Cancer 15:504, 1962. Jensen. Quoted by Bergh and Schersten 131. Johnson, J., Kirby, C. K., and Blakemore, W. S. Should we insist on “radical pneumonectomy” as a routine procedure in the treatment of carcinoma of the lung? J. Thorac. Surg. 36:309, 1958. Kato, Y., Ferguson, T. B., Bennett, D. E., and Burford, T. H. Oat cell carcinoma of the lung: A review of 138 cases. Cancer 23:517, 1969. Kirsh, M. M., Kahn, D. R., Gago, O., Lampe, I., Fayos, J. V., Prior, M., Moores, W. Y.,Haight, C., and Sloan, H. Treatment of bronchogenic carcinoma with mediastinal metastases. Ann. Thorac. Surg. 12:11, 1971. Nickell, W. B., Bartley, T. D., and Wheat, M. W. Bronchogenic carcinoma: Management at University of Florida Teaching Hospital. J . Flu. Med. Assoc. 56:846, 1969. Nohl, H. C. An investigation into the lymphatic and vascular spread of carcinoma of the bronchus. Thorax 11:172, 1956. Paulson, D. L. Carcinoma of the lung. Curr. Probl. Surg. (Nov.) 1967. P. 1. Rienhoff, W. F., 111, Talbert, J. L., and Wood, S., Jr. Bronchogenic carcinoma: A study of cases treated at Johns Hopkins Hospital from 1933 to 1958. Ann. Surg. 161:674, 1965. Siddons, A. H. M. Cell type in the choice of cases of carcinoma of the bronchus for surgery. Thorax 17:308, 1962.
NOTICE FROM THE SOUTHERN THORACIC SURGICAL ASSOCIATION The Nineteenth Annual Meeting of the Southern Thoracic Surgical Association will be held at the Trinidad Hilton Hotel, Port of Spain, Trinidad, November 2 4 , 1972. Reservations may be made by writing to the Reservations Manager, Trinidad Hilton Hotel, Port of Spain, Trinidad. Members wishing to participate in the scientific program should submit abstracts-typed double-spaced and in triplicate-to Paul C. Adkins, M.D. (Chairman of the Program Committee), George Washington University Hospital, Washington, D.C. 20037. The deadline for submission of abstracts is June 1, 1972. If additional information is required, inquiries should be directed to Dr. Adkins. Application for membership in the Southern Thoracic Surgical Association, on forms provided by the Association, should be sent directly to John L. Sawyers, M.D. (Chairman of the Membership Committee), Nashville General Hospital, Nashville, Tenn. 37210. The deadline for application to membership is September 1, 1972. Papers that are accepted for the program and are to be considered for publication in T h e Annals should be submitted to the Editor by October 15, 1972. W. BROOKS,M.D. Secretary-Treasurer
JAMES
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The Effect of Histological Cell Type on the Prognosis of Patients with Bronchogenic Carcinoma Marvin M. Kirsh, M.D., Michael Prior, M.D., Otto Gago, M.D., William Y . Moores, M.D., Donald R. Kahn, M.D., Ronald V. Pellegrini, M.D., and Herbert Sloan, M.D. ABSTRACT Mediastinal lymph node dissection in conjunction with pulmonary resection was performed in 232 patients with bronchogenic carcinoma at the University of Michigan Medical Center from 1959 to 1965. The mediastinum was irradiated postoperatively in those patients with mediastinal metastases. The absolute five-year survival rate of the patients undergoing resection was 29.2%. Of 110 patients with squamous cell carcinoma, 37.2% lived five years free of disease. The overall five-year survival of those patients undergoing resection who had no hilar lymph node metastases was 45.7%, and it was 45% in those with hilar metastases only. The absolute five-year survival rate of the patients with mediastinal metastases who received radiation therapy was 29.5%. Of 76 patients with adenocarcinoma, 19.7% lived five years free of disease. The overall five-year survival of those patients undergoing resection who had no lymph node metastases was 33%, whereas none of the patients with hilar metastases survived and only 1 of 17 patients with mediastinal metastases survived five years free of disease. The findings suggest that the histological cell type is an important factor in determining the prognosis in bronchogenic carcinoma, especially if there is evidence of lymph node involvement. I n addition, this study also suggests that it is the presence, and not necessarily the extent, of lymph node metastases in patients with squamous cell carcinoma that determines the survival rate following pulmonary resection, provided those patients with mediastinal metastases undergo postoperative mediastinal irradiation. From the Department of Surgery, University of Michigan Medical Center, Ann Arbor, Mich. Presented at the Eighteenth Annual Meeting of the Southern Thoracic Surgical Association, Tampa, Fla.. Nov. 4-6, 1971. Address reprint requests to Dr. Kirsh, (2-7184, University Hospital, Ann Arbor, Mich. 48104.
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espite refinements in diagnostic measures that have led to earlier diagnosis and improvements in surgical technique that have permitted more radical excisional therapy, the overall five-year surbronchogenic carcinoma has varied little over the years. While pulmonary resection is the preferred method of treatment for bronchogenic carcinoma, the factors that influence long-term survival following pulmonary resection are still a subject of debate. The present study was undertaken to determine what factors influenced the survival rate in our patients following resection for bronchogenic carcinoma.
Clinical Experience During the six-year period 1959-1965, 259 patients were operated upon for bronchogenic carcinoma at the University of Michigan Medical Center. Whether pneumonectomy or lobectomy was performed depended on the location of the lesion and the extent of the carcinoma. Lobectomy was carried out whenever feasible. Pneumonectomy was employed for tumors that could not be removed with a lesser procedure. Segmentectomy was performed for peripheral lesions in those patients in whom it was believed that a lobectomy could not be tolerated because of inadequate pulmonary reserve. The perihilar and hilar lymph nodes were removed en bloc with the primary lesion whenever possible. Following the resection the superior mediastinal, subaortic, subcarinal, and paraesophageal lymph nodes were completely removed. We considered the resection to be curative if all the gross tumor was excised. When necessary, the operations included resection of adjacent chest wall, diaphragm, and pericardium. Postoperative mediastinal irradiation was given to those patients who had undergone curative resection and in addition had evidence of spread to mediastinal lymph nodes. Procedures in which exploratory thoracotomy without resection was carried out or in which gross tumor was left behind were not included in the final analysis. Current follow-up was obtained in 98.6% of the patients either until death or for a minimum of five years. A consideration of the patient’s symptoms and especially the duration of such symptoms was difficult to evaluate in this retrospective study and therefore has not been included.
R esu 1ts Two hundred sixty operations were performed on 259 patients (Table 1). One patient had a second primary tumor removed from the contralateral lung two years following her initial operation. She subsequently survived for five years and has been considered in our analysis as 2 separate cases. Twenty-eight patients had unresectable lesions. The reasons for unresectability included pulmonary reserve insufficient for the patient to tolerate the resection necessary to remove the tumor completely; extensive left atrial 304
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Cell T y p e and Prognosis in Lung Cancer TABLE 1. BRONCHOGENIC CARCINOMA, 1959-1965: OPERATIONS PERFORMED AND MORTALITY RATES IN 259 PATIENTS WITH BRONCHOGENIC CARCINOMAa
Operative Mortality
No. of
Patients 150 74 8 28
Operation Lobectomy Pneumonectomy Segmentectomy Thoracotomy only
(%)
5.3 10.8 12.5 3.6
"One patient had two operations.
or aortic wall involvement; and proximal extension of the tumor onto the main pulmonary artery. Two hundred thirty-two resections were performed. In 212 the resection was believed to be curative. There was no difference in mortality between patients undergoing a curative or a noncurative resection. Pulmonary embolism (4 patients), arrhythmias or myocardial infarction (4 patients), and empyema (4 patients) accounted for the majority of deaths. Respiratory insufficiency was responsible for only 2 postoperative deaths.
Analysis of Overall Results Only those patients undergoing curative resection were analyzed with regard to histological cell type and lymph node involvement. The absolute five-year survival rate for the entire group of 212 patients was 29.2%. Peribronchial or hilar lymph node metastases only were found in 37 patients. The five-year survival of these patients was 25.8% (Table 2). One hundred eight patients did not have either hilar or mediastinal metastases. Fortyfour, or 40% of these patients, were alive and free of disease at the end of five years. Mediastinal node metastases were found in 48 patients who survived operation. The absolute five-year survival rate among 36 patients who received radiation therapy in the immediate postoperative period was 19.4%. None of 12 patients who did not receive postoperative mediastinal irradiaTABLE 2. BRONCHOGENIC CARCINOMA, 1959-1965: OVERALL FIVE-YEAR SURVIVAL IN 212 PATIENTS ACCORDING T O METASTASES
Metastases
None Hilar only Mediastinal (radiation therapy)
Overall 40
25.8 19.4
Five-Year Survival (%) Squamous Cell AdenoCarcinoma carcinoma 45.7 33 45 0 29.5 5.9
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KTRSH ET AL. TABLE 3. BRONCHOGENIC CARCINOMA, 1959-1965: CLASSIFICATIOP: AND OVERALL FIVE-YEAR SURVIVAL ACCORDING T O HISTOLOGICAL CELL TYPE
Cell Type Squamous cell Adenocarcinoma Large cell undifferentiated Acanthoadenocarcinoma Oat cell
No. of Patients 110 76 14 9
Five-Year Survival (%I
4
37.2
19.2 7.3
22 25
tion survived five years. No patient undergoing exploration alone or palliative resection survived five years. The average survival of those undergoing thoracotomy only was 7.4 months and of those undergoing palliative resection, 7.7 months. SQUAMOUS CELL CARCINOMA
Squamous cell carcinoma was present in 110 patients (Table 3). One hundred five of these patients were men, and 5 were women. Most of the tumors were centrally located, and there was involvement of major bronchi in 71 patients. The five-year survival according to type of resection is shown in Table 4. Only 39 patients had tumors arising in the more peripheral regions of the lung. In 61 patients lymph node metastases were not present. The overall five-year survival in this group was 45.7%. Eighteen of these patients underwent lobectomy, and 9 underwent pneumonectomy. Twenty patients had perihilar or hilar metastases only. The five-year survival rate of these patients was 45%. Four of those who underwent lobectomy and 5 who underwent pneumonectomy were long-term survivors. Seventeen patients had superior mediastinal or subcarinal involvement, and in 14 there was also involvement of hilar nodes. Postoperative mediastinal irradiation (5,000 to 5,500 R)was carried out in these patients, and 5 survived five years free of disease. Three underwent lobectomy, and 2 underwent pneumonectomy. ADEN OCARCINOMA
Seventy-six patients had adenocarcinoma (see Table 3). Fifty-seven were men, and 19 were women. The tumors were located in the more peripheral TABLE 4. BRONCHOGENIC CARCINOMA, 1959-1965: FIVE-YEAR SURVIVAL ACCORDING T O RESECTION
Operation Lobectomy
Pneumonectomy Segmentectomy 306
Overall 33 20.3
25
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Five-YearSurvival (%) Squamous Cell Carcinoma 40.6 30 100
Adeno-
carcinoma 26.9 0 25
Cell T y p e and Prognosis in Lung Cancer
regions of the lung in 75% and were centrally located in 25% of the patients. In 42 patients lymph node metastases were not present. The overall five-year survival of these patients was 33%. Thirteen underwent lobectomy and 1 underwent segmentectomy. Nine patients had peribronchial or hilar metastases only. None of these patients survived five years. Postoperative mediastinal irradiation was carried out in 17 patients who had superior mediastinal or subcarinal involvement. In 14 there was also involvement of hilar nodes. Only 1 of these 17 patients is still alive; this patient has survived 66 months following left upper lobectomy for a 3 x 3 cm. mass located in the left midlung field. ACANTHOADENOCARCINOMA
Acanthoadenocarcinoma was present in 9 patients. One patient with hilar metastases and 1 patient without metastases are still living free of disease 72 and 84 months, respectively, following their operations. UNDIFFERENTIATED CARCINOMA
Only 1 of 4 patients with undifferentiated carcinoma lived for five years. This patient had a 6 cm. mass in the midportion of the right upper lobe and a 1.5 cm. node in the superior mediastinum and was treated by right upper lobectomy, mediastinal lymph node dissection, and postoperative mediastinal irradiation. LARGE CELL UNDIFFERENTIATED CARCINOMA
Large cell undifferentiated carcinoma was present in 14 patients. One patient who did not have lymph node involvement survived five years following left lower lobectomy.
Comment Numerous attempts have been made to determine what factors influence long-term survival following pulmonary resection for bronchogenic carcinoma. It has been found that there is no difference between survivors and nonsurvivors in the size or location of the primary lesion, degree of differentiation of tumor, and extent of resection performed. Johnson [ 151, Collier [9], and Reinhoff [21]and their associates emphasized the presence of blood vessel invasion by malignant cells as an important determinant in long-term survival. However, others have found that microscopical detection of vascular invasion seemed to be of little prognostic value, especially in patients with adenocarcinoma of the lung. Bennett and co-workers [2] found evidence of blood vessel invasion in all 6 of their patients surviving five years following pulmonary resection, while none of the 9 patients without blood vessel invasion survived five years. Similar results were reported by Hukill and Stern [13]. It is generally accepted that the presence and especially the extent of metastases to lymph nodes constitute an important prognostic VOL. 13, NO.
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factor. When there is no lymphatic involvement at all, the five-year survival rate following resection of bronchogenic carcinoma is between 25 and 40% [l, 3, 4, 7, 8, 11, 18, 191. Lymphatic involvement of the intersegmental or hilar nodes has a better prognosis than mediastinal node involvement. Fiveyear survival following resection of bronchogenic carcinoma with hilar involvement is between 15 and 20% but is less than 10% when mediastinal nodes are involved in most reported series. Jensen [14] reported a 1% threeyear survival and Bergh and Schersten [3] a 7% five-year survival following resection in patients with mediastinal node involvement. Cahan and his associates 1.51 have been performing extensive en bloc excision of hilar and mediastinal nodes in conjunction with pulmonary resection for bronchogenic carcinoma. The five-year survival was 21.6% in the group of patients in whom positive lymph nodes were found in the mediastinal lymphatics of the resected specimen. Similar results have recently been reported from this institution [171. Postoperative mediastinal irradiation was given to 36 patients in whom mediastinal lymph node metastases were found following pulmonary resection and mediastinal node dissection. The overall five-year survival rate of the patients receiving radiation therapy was 19.4%. There are conflicting reports in the literature concerning the effects of cell type, especially squamous cell carcinoma and adenocarcinoma, on survival rates. Bergh [3], Collins [lo], and Bennett [2] and their associates believe that adenocarcinoma has a lower survival rate than squamous cell carcinoma. On the other hand, Belcher and Anderson [l], Siddons [221, and Higgins and Beebe [12] think that the prognosis is similar for both squamous cell carcinoma and adenocarcinoma. There is uniform agreement concerning the overall poor results with small cell (oat cell) undifferentiated carcinoma [ 16, 201. The present study suggests that histological cell type is an important factor in determining the prognosis in patients with bronchogenic carcinoma, especially if there is evidence of lymph node involvement. In our series, patients with squamous cell carcinoma of the lung as a group had a greater five-year survival rate than those patients with adenocarcinoma of the lung (37.2% versus 19.7%).Even in the absence of lymph node metastases, patients with squamous cell carcinoma tended to survive longer than those with adenocarcinoma (cf. Table 2). The difference in survival between the two groups is more striking when there are hilar or mediastinal metastases. The five-year survival rate in patients with squamous cell carcinoma and hilar metastases treated by pulmonary resection alone was 45%, and it was 29.5% in patients with mediastinal metastases who were treated by pulmonary resection, mediastinal lymph node dissection, and postoperative mediastinal irradiation. In contrast are the poor results in patients with adenocarcinoma and lymph node metastases. None of the patients who had adenocarcinoma with hilar metas-
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Cell Type and Prognosis in Lung Cancer
tases survived five years following pulmonary resection, mediastinal node dissection, and postoperative mediastinal irradiation. T h e patients with adenocarcinoma, as a group, had a higher percentage of resectability and a lower operative mortality than those with squamous cell carcinoma. I t was impossible to determine in this retrospective study if there were differences in the size or number of lymph nodes involved between the two groups. T h e reasons for the low cure rates in patients with adenocarcinoma of the lung and lymph node metastases are unclear from this study and others. Although the number of patients involved is too small to be of statistical significance, this study also suggests that it is the presence, and not necessarily the extent, of lymph node metastases in patients with squamous cell carcinoma that determines the survival rate following pulmonary resection, provided those patients with mediastinal metastases undergo postoperative mediastinal irradiation. T h e five-year survival rate of 29.5% in patients with squamous cell carcinoma and mediastinal metastases treated with postoperative mediastinal irradiation compared favorably with the 45% five-year survival rate of patients with hilar metastases treated by pulmonary resection alone.
References 1. Belcher, J. R., and Anderson, R. Surgical treatment of carcinoma of the bronchus. Br. Med. J . 1:948, 1965. 2. Bennett, D. E., Sasser, W. F., and Ferguson, T. B. Adenocarcinoma of the lung in men-a clinicopathologic study of 100 cases. Cancer 23:431, 1969. 3. Bergh, N. P., and Schersten, T. Bronchogenic carcinoma: A follow-up study of a surgically treated series with special reference to the grognostic significance of lymph node metastases. Acta Chir. Scand. (Suppl. 3 7): 1, 1965. 4. Boucot, K. R., Cooper, D. A., and Weiss, W. The role of surgery in the cure of lung cancer. Arch. Intern. Med. 120:168, 1967. 5. Cahan, W. G., Watson, W. L., and Pool, J. L. Radical pneumonectomy. J . Thorac. Surg. 22:449, 1951. 6 . Carlens, E. Mediastinoscopy. Ann. Otol. Rhinol. Laryngol. 74: 1102, 1965. 7. Churchill, E. D., Sweet, R. H., Scannell, J. G., and Wilkins, E. W., Jr. Further studies in the surgical management of carcinoma of the lung: A further study of the cases treated at the Massachusetts General Hospital from 1950 to 1957. J. Thorac. Surg. 36:301, 1958. 8. Clagett, 0.T., Allen, T . H., Payne, W. S., and Woolner, L. B. The surgical treatment of pulmonary neoplasms: A 10-year experience. J. Thorac. Cardiovasc. Surg. 48:391, 1964. 9. Collier, F. C., Enterline, H. T., Kyle, R. H., Tristan, T. T., and Greening, R. The prognostic implications of vascular invasion in primary carcinomas of the lung: A clinicopathologic correlation of two hundred twenty-five cases with one hundred percent follow-up. A.M.A. Arch. Pathol. 66:594, 1958. 10. Collins, N. P. Bronchogenic carcinoma-importance of the cell type. A.M.A. Arch. Surg. 77:925, 1958. 11. Gibbon, J. H., Jr., Templeton, J. Y.,111, and Nealon, T. F., Jr. Factors which influence the long term survival of patients with cancer of the lung. Ann. Surg. 145:637, 1957. 12. Higgins, G. A., and Beebe, G. W. Bronchogenic carcinoma: Factors in survival. Arch. Surg. 94:539, 1967. 13. Hukill, P. B., and Stern, H. Adenocarcinoma of the lung: Histological facVOL. 19, NO.
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14. 15. 16. 17. 18. 19. 20. 21. 22.
tors affecting prognosis. A study of 38 patients with resection and five-year follow-up. Cancer 15:504, 1962. Jensen. Quoted by Bergh and Schersten 131. Johnson, J., Kirby, C. K., and Blakemore, W. S. Should we insist on “radical pneumonectomy” as a routine procedure in the treatment of carcinoma of the lung? J. Thorac. Surg. 36:309, 1958. Kato, Y., Ferguson, T. B., Bennett, D. E., and Burford, T. H. Oat cell carcinoma of the lung: A review of 138 cases. Cancer 23:517, 1969. Kirsh, M. M., Kahn, D. R., Gago, O., Lampe, I., Fayos, J. V., Prior, M., Moores, W. Y.,Haight, C., and Sloan, H. Treatment of bronchogenic carcinoma with mediastinal metastases. Ann. Thorac. Surg. 12:11, 1971. Nickell, W. B., Bartley, T. D., and Wheat, M. W. Bronchogenic carcinoma: Management at University of Florida Teaching Hospital. J . Flu. Med. Assoc. 56:846, 1969. Nohl, H. C. An investigation into the lymphatic and vascular spread of carcinoma of the bronchus. Thorax 11:172, 1956. Paulson, D. L. Carcinoma of the lung. Curr. Probl. Surg. (Nov.) 1967. P. 1. Rienhoff, W. F., 111, Talbert, J. L., and Wood, S., Jr. Bronchogenic carcinoma: A study of cases treated at Johns Hopkins Hospital from 1933 to 1958. Ann. Surg. 161:674, 1965. Siddons, A. H. M. Cell type in the choice of cases of carcinoma of the bronchus for surgery. Thorax 17:308, 1962.
NOTICE FROM THE SOUTHERN THORACIC SURGICAL ASSOCIATION The Nineteenth Annual Meeting of the Southern Thoracic Surgical Association will be held at the Trinidad Hilton Hotel, Port of Spain, Trinidad, November 2 4 , 1972. Reservations may be made by writing to the Reservations Manager, Trinidad Hilton Hotel, Port of Spain, Trinidad. Members wishing to participate in the scientific program should submit abstracts-typed double-spaced and in triplicate-to Paul C. Adkins, M.D. (Chairman of the Program Committee), George Washington University Hospital, Washington, D.C. 20037. The deadline for submission of abstracts is June 1, 1972. If additional information is required, inquiries should be directed to Dr. Adkins. Application for membership in the Southern Thoracic Surgical Association, on forms provided by the Association, should be sent directly to John L. Sawyers, M.D. (Chairman of the Membership Committee), Nashville General Hospital, Nashville, Tenn. 37210. The deadline for application to membership is September 1, 1972. Papers that are accepted for the program and are to be considered for publication in T h e Annals should be submitted to the Editor by October 15, 1972. W. BROOKS,M.D. Secretary-Treasurer
JAMES
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