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Multiple primary lung cancers
Multiple primary lung cancers Data on 50 patients with multiple separate primary carcinomas of the lung are presented. Eighteen had synchronous tumors and 32 had metachronous tumors, the intervals between diagnoses varying from 4 months to 16 years. Histologic patterns in the two different carcinomas were the same in 31 patients, most commonly epidermoid, and they were different in 19 patients. The problems involved in establishing the diagnosis of multiple primary lung cancers, the choice of treatment, and the expectation for survival are discussed.
Nael Martini, M.D.,* and Myron R. Melamed, M.D.** (by invitation), New York, N. Y.
The diagnosis of multiple primary carcinomas of the lung was made at Memorial Hospital for the first time in 1955. In the 20 years since then there has been a total of 50 such patients, representing slightly under 1 per cent (0.97 per cent) of the 5,163 patients treated for primary lung cancer during the same period (1955 to 1974). These 50 cases were selected from 108 that were initially recorded as possible multiple primary cancers of the lung on clinical, radiologic, or pathologic findings. This report is a summary of our clinical experience with these patients, and includes an effort to establish reasonable criteria for distinguishing multiple primary lung cancers from intrapulmonary metastases. Clinical material
The patients accepted for study included 38 men and 12 women, a ratio of 3 to 1. Two separate cancers were identified in 49 patients and three cancers in 1 patient. Eighteen patients had synchronous tumors: From the Departments of Surgery and Pathology, Memorial Sloan-Kettering Cancer Center 1275 York Ave., New York, N. Y. 10021. Read at the Fifty-fifth Annual Meeting of The American Association for Thoracic Surgery, New York, N. Y., April 14, 15, and 16, 1975. Address for reprints: Nael Martini, M.D., Memorial SloanKettering Cancer Center, 1275 York Ave., New York, N. Y. 10021. • Attending Surgeon, Chief, Thoracic Service. •• Attending Pathologist, Chief, Cytology Service.
606
In 4 patients, two lesions were evident preoperatively on chest x-ray films; in 11 cases, the two separate carcinomas were first diagnosed at thoracotomy; and in the 3 remaining patients, the tumors were found at autopsy. In 32 patients the tumors were metachronous, separated in time from 4 months to 16 years with a median interval of 42 months and an average of 57 months. In only 2 patients accepted in this study was the interval between carcinomas less than 1 year. In 23 it was 2 or more years. Of interest, in 7 of these patients, one of the carcinomas was radiologically occult and was detected by cytologic examination. In both the synchronous and metachronous groups of patients, the average age at time of diagnosis of the first lung cancer was 62 years and the median age was 63 years. Sixty-six per cent of multiple lung cancers encountered had identical histology, and 79 per cent of these were epidermoid or squamous cancers. Histology was dissimilar in 34 per cent of the patients, and 70 per cent of the lesions were epidermoid cancers combined with other types (Table I). The tumors were located in different lungs in 33 patients, in separate lobes of the same lung in 7 patients, and in separate segments of the same lobe in 10 patients (Fig. 1). There was no particular segmental or lobar predominance. Three patients had two sep-
Volume 70
Multiple primary lung cancers
Number 4 October, 1975
Histology
Same
Total
Synchronous
~
Different
C'J
Cd
3
7
1 (adeno.)
3
607
3 (all epid.)
5 13 18
M8tachronous
Same
~ (2 &j 22
3
0
25
7
0
0
7
Different
32
Fig. 1. Anatomic distribution.
Table I. Histology (50 patients) Tumor type First tumor Epidermoid Adenocarcinoma Bronchiolar Epidermoid Epidermoid Epidermoid Adenocarcinoma Adenocarcinoma Adenocarcinoma Bronchiolar Bronchiolar
I
Second tumor
Metachronous
Total
7 I
19 I 5
26 2
2
5
7
Synchronous
Epidermoid Adenocarcinoma Bronchiolar Adenocarcinoma Bronchiolar Oat cell Epidermoid Oat cell Bronchiolar Large cell Carcinoid
Totals
arate synchronous cancers of similar histology within one lobe; all three were epidermoid carcinomas in which separate origins from carcinoma in situ could be demonstrated. Only 1 patient had two synchronous cancers of similar histology in separate lobes of one lung; these were adenocarcinomas. Treatment. Fifteen of the 18 patients with synchronous carcinomas underwent thoracotomy and resection of the tumors. The three remaining patients received no treatment, and the diagnosis of cancer was established at autopsy (Table II). Five of
4 I I I I I
4
I I
18
5
I 32
50
15 patients had pneumonectomy, 6 had lobectomy, and 1 had two wedge resections at a single thoracotomy; in each case the carcinomas were unilateral. There were 4 patients with bilateral carcinomas, 3 of whom underwent staged bilateral surgical resections during one hospitalization; the fourth case was diagnosed at autopsy. Regional lymph node involvement (hilar and mediastinal) was present in only 3 patients, and all 3 had two cancers of different histology; one of these 3 patients had received no treatment, the diagnosis having been made at autopsy.
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Thoracic and Cardiovascular Surgery
% Synchronous 115 pta.) •••••• Metachronous (32 pta.) _
60 (54%)
40
20
Years
Fig. 2. Cumulative survival.
Table IIA. Treatment versus survival: Synchronous group (18 patients) Treatment No treatment Pneumonectomy Lobectomy Wedge Bilateral thoracotomy Lobe and lobe Lobe and wedge Wedge and wedge
I
No. ofcases
3 5 6 I 3
I
Survival (mo.)
0 5,7,18,* 24, 66* 4,* 4,* 6, 36, 108* 32+
o
13* 18*
• Alive and well.
There was one postoperative death from a massive pulmonary embolus. The absolute survival after treatment in this group of patients ranged from zero to 9 years, with a median survival of 16 months and an average survival of 25 months. Twenty per cent are still alive and well after 5 years. In all 32 patients with metachronous cancers, the first tumor was managed surgically. There were eight pneumonectomies, 23 lobectomies, and one wedge resection of a bronchus without sacrifice of lung tissue. The tumor was confined to lung parenchyma in 26 patients. It extended outside the lung in 6 patients: to the chest wall, the diaphragm, and the mediastinum in 2 cases each. Three patients had hilar or peribronchial node involvement, whereas the
remaining 29 patients had no nodal disease. There were no mediastinal node metastases in any of these patients. Absolute survival after treatment in this group of patients ranged from 9 months to 16 years, with a median survival of 54 months and an average survival of 76 months. Fifty per cent are alive and well after 5 years. Survival figures in this situation obviously are influenced by selection, since these patients had to survive long enough to develop a second carcinoma in order to be included. In metachronous tumors, treatment of the second lung cancer was by surgical resection in nearly 60 per cent of the patients. This consisted of lobectomy in 9 patients and wedge resection or segmentectomy in 10 patients. Twelve patients were treated by radiation: In 5 of them, radioactive sources were implanted interstitially at thoracotomy without sacrifice of lung tissue (internal radiation); the other 7 received external radiation therapy without surgery. One patient with an unresectable tumor died postoperatively from pulmonary insufficiency. In this group of patients, there were five postoperative deaths (20 per cent) caused primarily by pulmonary complications. In addition, 2 patients had severely compromised pulmonary reserve after surgery and died from pulmonary insufficiency in 3 and 4 months, respectively. Survival after treatment of the second lung cancer ranged from zero to 8 years with a median survival of 12 months and an average survival of 19 months. Only 9 per cent are alive and well after 5 years. Since some patients in this study are alive after less than 5 years' follow-up, cumulative survival curves are shown and compared in Fig. 2. One patient in this study had three separate primary lung cancers. A small peripheral adenocarcinoma of the right lung was resected by lobectomy in 1951 from a then 51-year-old man. He remained well until 1959, when a new bronchiolar carcinoma was removed by wedge resection from the right lung. Then, in 1967, he presented with a mass in the left upper lobe. This too was managed by wedge resection and proved
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Multiple primary lung cancers
609
Table lIB. Treatment versus survival: Metachronous group (32 patients) Treatment: First cancer Resection of bronchus Pneumonectomy
Lobectomy
Survival from second cancer (mo.)
Treatment: Second cancer I 8
23
Lobectomy Lobectomy Wedge Implant Radiation therapy Lobectomy Wedge or segment Explored only Implant Radiation therapy
I I
2 2 3
7 8 I 3
4
24
o
0,61 10,10 8,10,12 0,3,4, 13,36,49,96 0,4,* 6,* 7,11,* 12, 13,20
o
17,18,84 5,9,23,38
'Alive and well.
to be an epidermoid carcinoma. He died postoperatively from pulmonary complications. Pathology
Because of the manner in which these cases were selected, the tumors were available for study in their entirety, either as surgically resected specimens or at autopsy. Histologic criteria for classification, in use at Memorial Hospital for many years, have been described in detail elsewhere.i" In general they are the same as those of the World Health Organization." Tumors that had varying histologic patterns were classified according to their most dominant feature; in most cases the secondary patterns were minor. The categories of bronchiolar carcinoma and adenocarcinoma in our classification are distinguished by differences in growth pattern rather than cell type: Bronchiolar carcinomas grow along alveolar septa, with minimal tissue destruction and desmoplasia, and adenocarcinomas grow by infiltration and destruction of lung parenchyma. There were no diffusely infiltrating bronchioloalveolar carcinomas of the kind that histologically resemble jagziekte disease of sheep, perhaps because we were unable to distinguish a new primary carcinoma in those cases amid the extensive intrapulmonary metastases characteristically present. Our criteria for accepting two or three separate carcinomas as primary in the lung
are summarized in Table III. The simplest and most convincing cases were those involving tumors of different histology, particularly when they were widely spaced in time and in location." :J, 11, 15 The most difficult cases were those with tumors of similar histology appearing at the same time and in the same lobe. We felt that we could identify primary epidermoid carcinomas by tracing their origin from carcinoma in situ, 1, 4 but this method was not useful for other tumor types. The latter were accepted as primary only if it could be shown that there was no reasonable expectation of metastasis from one site to the other. Specifically, we required that the two tumors be physically distinct and separate C'coIIisian" tumors would be excluded) and that they arise in parts of the lung which do not share common lymphatics. We excluded cases in which regional lymph node metastases could have spawned retrograde lung metastasis or in which there was evidence of dissemination by blood-borne metastases. In only 7 cases that were accepted for this report were there hilar or peribronchial lymph node metastases from one of the tumors; in 3 of these cases the tumors had different histology, in 3 others they were separated by 3, 4, and 13 years in time of appearance, and in 1 case both carcinomas were epidermoid and separate origins from carcinoma in situ could be established. Bronchioloalveolar carcinoma with diffuse (pneumonic) or multinodular (three or
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Table III. Criteria for diagnosis Metachronous tumors A. Histology different B. Histology the same, if: I. Free interval between cancers at least 2 years or 2. Origin from carcinoma in situ or 3. Second cancer in different lobe or lung, but: a. No carcinoma in lymphatics common to both b. No extrapulmonary metastases at time of diagnosis Synchronous tumors A. Tumors physically distinct and separate B. Histology: I. Different 2. Same, but in different segment, lobe, or lung, if: a. Origin from carcinoma in situ b. No carcinoma in lymphatics common to both c. No extrapulmonary metastases at time of diagnosis
more nodules) growth patterns were arbitrarily excluded because of difficulty in ruling out airborne or intrapulmonary lymphatic dissemination. Discussion
The incidence of multiple carcinomas of the lung in our series is just under 1 per cent of all lung cancers seen. It is higher in patients who are cured of the initial cancer, as was pointed out by Watson"? in a study of 10 year survivors. Moreover, of 28 patients with a radiologically occult cancer diagnosed at our Center," 7 or 25 per cent had a second and separate primary lung cancer. If the free interval after treatment of an initial lung cancer is long, 3 or more years, there is an expectation of cure. Any tumor detected on chest x-ray films after that period may well represent a second primary lung cancer rather than a metastasis." 6 On the other hand, the time interval between diagnosis of two separate tumors need not be prolonged for them to be identified as independent primary carcinomas. Although clinical and radiologic findings are often helpful in differentiating new cancers from
Thoracic and Cardiovascular Surgery
metastases, histologic confirmation generally is necessary and, in the case of synchronous tumors, it is essential. Multiple primary lung cancers detected at thoracotomy or in a specimen after resection are only of academic interest. Simultaneous detection of two separate lung tumors before treatment may deter adequate treatment because of a mistaken impression of metastasis from the lung or other sites. In that case, treatment may not be attempted or may be limited to external radiation or palliative resection. We feel that the presence of two or more cancers presenting simultaneously should not deter treatment by resection if feasible. Survival after adequate resection in this group of patients is essentially the same as in a single primary lung cancer managed in a similar manner. In treatment of the patient with a metachronous second lung cancer, the distinction between a new primary tumor and a solitary metastasis is of little importance if the new tumor is resectable. 7, 12 Management of metastases by resection, whether solitary or multiple but few, results in 5 year survival rates comparable to those obtained by surgical treatment of a single primary lung cancer. In metachronous lesions, if a lobectomy or segmentectomy was carried out initially, treatment by lobectomy may again be possible. For cancers developing after a pneumonectomy, wedge resection or segmentectomy has been shown to yield prolonged survival in at least 15 to 20 per cent of the patients." Moreover, limited resection for peripheral bronchogenic carcinoma is favored by some in recent years as the procedure of choice.v 14 An experience with the patients presented in this study emphasizes the importance of conserving lung tissue at the original operation. The patient who develops a second lung cancer may then be treated by resection if indicated without undue jeopardy to his already limited pulmonary reserve. REFERENCES Auerbach, 0., Stout, A. P., Hammond, E. C., and Garfinkel, L.: Multiple Primary Bronchiolar Carcinomas, Cancer 20: 699, 1967.
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October, 1975
2 Beyreuther, H.: Multiplicitat von Carcinomen bei einem Fall von Sog. "Schneeberger" Lungenkrebs mit Tuberkulose, Virchows Arch [Pathol. Anat.] 250: 230, 1924. 3 Biliroth, T.: Die Allgemeine Chirurgische Pathologic und Therapie in 51 Vorlesungen, in Handbuch fur Studirende und Aerzte, 14: G, Berlin, 1914, Reimer, p. 908. 4 Black, H., and Ackerman, L. V.: Importance of Epidermoid Carcinoma in Situ in Histogenesis of Carcinoma of Lung, Ann. Surg. 136: 44, 1952. 5 Cahan, W. G., Butler, F. S., Watson, W. L., and Pool, I. L.: Multiple Cancers: Primary in the Lung and Other Sites, I. THoRAc. SURG. 20: 335, 1950. 6 Cahan, W. G.: Multiple Primary Cancers, One of Which Is Lung, Surg. Clin. North Am. 49: 323, 1969. 7 Cliffton, E. E., DasGupta, T., and Pool, I. L.: Bilateral Resection for Primary or Metastatic Lung Cancer, Cancer 8: 86, 1964. 8 Iensik, R. I., Faber, L. P., Milloy, F. I., and Monson, D. 0.: Segmental Resection for Lung Cancer: A Fifteen-Year Experience, I. THoRAc. CARDIOVASC. SURG. 66: 563, 1973. 9 Martini, N., Beattie, E. I., Ir., Cliffton, E. E., and Melamed, M. R.: Radiologically Occult Lung Cancer, Surg. Clin. North Am. 54: 811, 1974. 10 Melamed, M. R.: Pathology, in Watson, W. L., editor: Lung Cancer: A Study of Five Thousand Memorial Hospital Cases, Chap. 3, St. Louis, 1968, The C. V. Mosby Company, p. 35. 11 Mobley, D. F., and Martinez, A. J.: Two Histologically Different Primary Carcinomas of the Lung: A Review of the Literature and Presentation of a Case, Cancer 22: 287, 1968. 12 Moersch, R. N., and Clagett, O. T.: Pulmonary Resection for Metastatic Tumors of Lung, Surgery 50: 579, 1961. 13 Ramsey, H. E., Cahan, W. G., Beattie, E. J., Jr., and Humphrey, c.: The Importance of Radical Lobectomy in Lung Cancer, J. THORAC. CARDIOVASC. SURG. 58: 225, 1969. 14 Shields, T. W., and Higgins, G. A., Jr.: Minimal Pulmonary Resection in Treatment of Carcinoma of the Lung, Arch. Surg. 108: 420, 1974. 15 Struve-Christensen, E.: Diagnosis and Treatment of Bilateral Primary Bronchogenic Carcinoma, I. THORAC. CARDIOVASC. SURG. 61: 501, 1971. 16 Watson, W. L.: Ten-Year Survival: A Study of Fifty-six Cases, in Watson, W. L., editor: Lung Cancer: A Study of Five Thousand Memorial Hospital Cases, Chap. 21, St. Louis, 1968, The C. V. Mosby Company, p. 514. 17 Histological Typing of Lung Tumours, Geneva, 1967, World Health Organization.
Discussion DR. DONALD L. PAULSON Dallas, Texas
Our experience with dual carcinomas, or multiple primary lesions, is similar to that of the Memorial Hospital reviewed by Dr. Martini. Among 2,600 patients, there were 34 dual primary carcinomas, five of which were synchronous and 29 metachronous. This is an incidence in the total series of a little over 1 per cent. However, this is misleading, because the metachronous lesion can develop only in long-term survivors: Patients with inoperable lesions do not survive long enough to have a second lesion diagnosed. However, in this regard, the report of Auerbach, Stout, Hammond, and Garfinkel is significant. In a necropsy study of patients dying from bronchogenic carcinoma, they found a second lesion in about 3.5 per cent of the cases. The true frame of reference in our series for the incidence of metachronous, dual bronchogenic carcinomas is the group of 904 patients treated previously by resection of their initial lesion. Twenty-eight later developed second lesions, an incidence of 3.1 per cent. The peak incidence was after 5 years. Five were ipsilateral and 24 were contralateral lesions. Calculation of the incidence of second lesions by the actuarial method in our surviving patients reveals a peak incidence after 5 years, although there is another peak at about 2 years. This probably represents cases in which a second lesion was present at the time of the original operation but was not diagnosable. It is not surprising that patients do develop a second carcinoma inasmuch as the lungs are paired organs. Multiple carcinomas of paired organs, such as breasts and ovaries, are not infrequent, and they may be synchronous and metachronous, just as in the lung. Carcinogenesis is not an isolated biological accident, and the fact that the pathogenic processes may continue in the same or opposite lung after resection of one bronchial carcinoma should not be considered surprising or rare. These processes may occur more commonly than we generally appreciate. The highest incidence of metachronous dual carcinoma in our series is found in patients surviving 5 or more years, a fact which emphasizes the importance of continued follow-up beyond that time. DR. WILLIAM G. CAHAN New York, N. Y.
Twenty-five years ago, before this Association, we presented a paper reporting on 60 patients with multiple primary cancers one of which was lung cancer. Now we have encountered over 626 patients in this category. The extrathoracic cancers have occurred in virtually all organs of the body
6 12
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Martini and Melamed
and include melanomas, lymphomas, and leukemias. In 1972, we had 47 multiple primary lung cancers, but the largest association was with those originating in the head and neck and most particularly in the larynx. This suggests the possibility that a common etiologic agent, most likely tobacco, was affecting the upper and lower respiratory tract. Although not mentioned, I am sure that Dr. Martini's group must have had a history of a habit of this type. It is still a mystery why only 50 out of 3,000 lung cancer patients at Memorial Hospital developed multiple primary cancers of that organ. We must assume that oncogenesis has many facets, some of which are dependent upon local tissue or systemic immunity. This idea is given support if one recalls the multiple in situ carcinomas of the respiratory mucosae, very few of which progressed to invasive carcinoma, which Auerbach found upon serial sectioning of the tracheobronchial tree. We have always subscribed to Dr. Martini's conclusion that it is most unreliable to make a tissue diagnosis from a shadow on a lung x-ray film. All too often radiologists, knowing that a patient has a cancer elsewhere, report such a shadow as being a "metastasis." This can be an inaccurate guess and can lead to an incorrect treatment program as well as to an untrustworthy prognosis. Solitary shadows are unique and may be a primary lung cancer, a metastasis, or a berugn tumor. The diagnosis should be confirmed microscopically in all instances. Finally, we agree with Dr. Paulson that the concept of a 5 year cure can lead to a false sense of security for both the patient and physician. This is, after all, an arbitrary length of time; cancers do not confine themselves to such manmade limitations. As a consequence, not only new primary cancers but even metastases can surface as long as 25 years after treatment of the original tumor. Perhaps "5 year survival" reflects a truer state of affairs.
In all this, the implication is clear: Cancer patients require constant vigilance at stated intervals for their lifetime. DR. ROWAN NICKS Sydney. Australia
I enjoyed very much Dr. Martini's and Dr. Melamed's excellent and interesting paper on lung cancer. Our experience agrees with their general active outlook toward multiple cancers. In Sydney, our surgeons have managed each primary cancer on its own merits, as the authors report doing. I agree that the long-term survival depends on the pathological characteristics of individual cancers. [Slide] A 57-year-old town gardener from Young, a town in northern New South Wales (a very hot place) had been treated for years for multiple squamous epitheliomas of the face before being referred with carcinomas in both lungs. He had one carcinoma in the right lower lobe and two carcinomas in the left lower lobe. The lesion on the right side was a large cell carcinoma and abutted on the pleura. The two carcinomas in the left lower lobe were histologically identical to the lesion in the right lung. The man was treated by bilateral resection of the lower lobes 7 years ago. He is quite well, still works as a gardener, and still is sorely troubled by the skin lesions. [Slide] This slide shows our experience with multiple lung cancers in Sydney. Seven patients with unilateral multiple cancers survived an average of 7 years. Four lived for 10 years or more. The patients with synchronous bilateral lung cancers lived an average of 4 years. In 7 patients, metachronous cancers have arisen in the opposite lung, usually years after the initial resection. [Slide] The 5 patients operated upon at an average age of 63 years, usually by a bilateral lobectomy, have done well. They have survived an average of 8Vz years with a range of 21;2 to 16 years.
Nael Martini, M.D.,* and Myron R. Melamed, M.D.** (by invitation), New York, N. Y.
The diagnosis of multiple primary carcinomas of the lung was made at Memorial Hospital for the first time in 1955. In the 20 years since then there has been a total of 50 such patients, representing slightly under 1 per cent (0.97 per cent) of the 5,163 patients treated for primary lung cancer during the same period (1955 to 1974). These 50 cases were selected from 108 that were initially recorded as possible multiple primary cancers of the lung on clinical, radiologic, or pathologic findings. This report is a summary of our clinical experience with these patients, and includes an effort to establish reasonable criteria for distinguishing multiple primary lung cancers from intrapulmonary metastases. Clinical material
The patients accepted for study included 38 men and 12 women, a ratio of 3 to 1. Two separate cancers were identified in 49 patients and three cancers in 1 patient. Eighteen patients had synchronous tumors: From the Departments of Surgery and Pathology, Memorial Sloan-Kettering Cancer Center 1275 York Ave., New York, N. Y. 10021. Read at the Fifty-fifth Annual Meeting of The American Association for Thoracic Surgery, New York, N. Y., April 14, 15, and 16, 1975. Address for reprints: Nael Martini, M.D., Memorial SloanKettering Cancer Center, 1275 York Ave., New York, N. Y. 10021. • Attending Surgeon, Chief, Thoracic Service. •• Attending Pathologist, Chief, Cytology Service.
606
In 4 patients, two lesions were evident preoperatively on chest x-ray films; in 11 cases, the two separate carcinomas were first diagnosed at thoracotomy; and in the 3 remaining patients, the tumors were found at autopsy. In 32 patients the tumors were metachronous, separated in time from 4 months to 16 years with a median interval of 42 months and an average of 57 months. In only 2 patients accepted in this study was the interval between carcinomas less than 1 year. In 23 it was 2 or more years. Of interest, in 7 of these patients, one of the carcinomas was radiologically occult and was detected by cytologic examination. In both the synchronous and metachronous groups of patients, the average age at time of diagnosis of the first lung cancer was 62 years and the median age was 63 years. Sixty-six per cent of multiple lung cancers encountered had identical histology, and 79 per cent of these were epidermoid or squamous cancers. Histology was dissimilar in 34 per cent of the patients, and 70 per cent of the lesions were epidermoid cancers combined with other types (Table I). The tumors were located in different lungs in 33 patients, in separate lobes of the same lung in 7 patients, and in separate segments of the same lobe in 10 patients (Fig. 1). There was no particular segmental or lobar predominance. Three patients had two sep-
Volume 70
Multiple primary lung cancers
Number 4 October, 1975
Histology
Same
Total
Synchronous
~
Different
C'J
Cd
3
7
1 (adeno.)
3
607
3 (all epid.)
5 13 18
M8tachronous
Same
~ (2 &j 22
3
0
25
7
0
0
7
Different
32
Fig. 1. Anatomic distribution.
Table I. Histology (50 patients) Tumor type First tumor Epidermoid Adenocarcinoma Bronchiolar Epidermoid Epidermoid Epidermoid Adenocarcinoma Adenocarcinoma Adenocarcinoma Bronchiolar Bronchiolar
I
Second tumor
Metachronous
Total
7 I
19 I 5
26 2
2
5
7
Synchronous
Epidermoid Adenocarcinoma Bronchiolar Adenocarcinoma Bronchiolar Oat cell Epidermoid Oat cell Bronchiolar Large cell Carcinoid
Totals
arate synchronous cancers of similar histology within one lobe; all three were epidermoid carcinomas in which separate origins from carcinoma in situ could be demonstrated. Only 1 patient had two synchronous cancers of similar histology in separate lobes of one lung; these were adenocarcinomas. Treatment. Fifteen of the 18 patients with synchronous carcinomas underwent thoracotomy and resection of the tumors. The three remaining patients received no treatment, and the diagnosis of cancer was established at autopsy (Table II). Five of
4 I I I I I
4
I I
18
5
I 32
50
15 patients had pneumonectomy, 6 had lobectomy, and 1 had two wedge resections at a single thoracotomy; in each case the carcinomas were unilateral. There were 4 patients with bilateral carcinomas, 3 of whom underwent staged bilateral surgical resections during one hospitalization; the fourth case was diagnosed at autopsy. Regional lymph node involvement (hilar and mediastinal) was present in only 3 patients, and all 3 had two cancers of different histology; one of these 3 patients had received no treatment, the diagnosis having been made at autopsy.
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% Synchronous 115 pta.) •••••• Metachronous (32 pta.) _
60 (54%)
40
20
Years
Fig. 2. Cumulative survival.
Table IIA. Treatment versus survival: Synchronous group (18 patients) Treatment No treatment Pneumonectomy Lobectomy Wedge Bilateral thoracotomy Lobe and lobe Lobe and wedge Wedge and wedge
I
No. ofcases
3 5 6 I 3
I
Survival (mo.)
0 5,7,18,* 24, 66* 4,* 4,* 6, 36, 108* 32+
o
13* 18*
• Alive and well.
There was one postoperative death from a massive pulmonary embolus. The absolute survival after treatment in this group of patients ranged from zero to 9 years, with a median survival of 16 months and an average survival of 25 months. Twenty per cent are still alive and well after 5 years. In all 32 patients with metachronous cancers, the first tumor was managed surgically. There were eight pneumonectomies, 23 lobectomies, and one wedge resection of a bronchus without sacrifice of lung tissue. The tumor was confined to lung parenchyma in 26 patients. It extended outside the lung in 6 patients: to the chest wall, the diaphragm, and the mediastinum in 2 cases each. Three patients had hilar or peribronchial node involvement, whereas the
remaining 29 patients had no nodal disease. There were no mediastinal node metastases in any of these patients. Absolute survival after treatment in this group of patients ranged from 9 months to 16 years, with a median survival of 54 months and an average survival of 76 months. Fifty per cent are alive and well after 5 years. Survival figures in this situation obviously are influenced by selection, since these patients had to survive long enough to develop a second carcinoma in order to be included. In metachronous tumors, treatment of the second lung cancer was by surgical resection in nearly 60 per cent of the patients. This consisted of lobectomy in 9 patients and wedge resection or segmentectomy in 10 patients. Twelve patients were treated by radiation: In 5 of them, radioactive sources were implanted interstitially at thoracotomy without sacrifice of lung tissue (internal radiation); the other 7 received external radiation therapy without surgery. One patient with an unresectable tumor died postoperatively from pulmonary insufficiency. In this group of patients, there were five postoperative deaths (20 per cent) caused primarily by pulmonary complications. In addition, 2 patients had severely compromised pulmonary reserve after surgery and died from pulmonary insufficiency in 3 and 4 months, respectively. Survival after treatment of the second lung cancer ranged from zero to 8 years with a median survival of 12 months and an average survival of 19 months. Only 9 per cent are alive and well after 5 years. Since some patients in this study are alive after less than 5 years' follow-up, cumulative survival curves are shown and compared in Fig. 2. One patient in this study had three separate primary lung cancers. A small peripheral adenocarcinoma of the right lung was resected by lobectomy in 1951 from a then 51-year-old man. He remained well until 1959, when a new bronchiolar carcinoma was removed by wedge resection from the right lung. Then, in 1967, he presented with a mass in the left upper lobe. This too was managed by wedge resection and proved
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609
Table lIB. Treatment versus survival: Metachronous group (32 patients) Treatment: First cancer Resection of bronchus Pneumonectomy
Lobectomy
Survival from second cancer (mo.)
Treatment: Second cancer I 8
23
Lobectomy Lobectomy Wedge Implant Radiation therapy Lobectomy Wedge or segment Explored only Implant Radiation therapy
I I
2 2 3
7 8 I 3
4
24
o
0,61 10,10 8,10,12 0,3,4, 13,36,49,96 0,4,* 6,* 7,11,* 12, 13,20
o
17,18,84 5,9,23,38
'Alive and well.
to be an epidermoid carcinoma. He died postoperatively from pulmonary complications. Pathology
Because of the manner in which these cases were selected, the tumors were available for study in their entirety, either as surgically resected specimens or at autopsy. Histologic criteria for classification, in use at Memorial Hospital for many years, have been described in detail elsewhere.i" In general they are the same as those of the World Health Organization." Tumors that had varying histologic patterns were classified according to their most dominant feature; in most cases the secondary patterns were minor. The categories of bronchiolar carcinoma and adenocarcinoma in our classification are distinguished by differences in growth pattern rather than cell type: Bronchiolar carcinomas grow along alveolar septa, with minimal tissue destruction and desmoplasia, and adenocarcinomas grow by infiltration and destruction of lung parenchyma. There were no diffusely infiltrating bronchioloalveolar carcinomas of the kind that histologically resemble jagziekte disease of sheep, perhaps because we were unable to distinguish a new primary carcinoma in those cases amid the extensive intrapulmonary metastases characteristically present. Our criteria for accepting two or three separate carcinomas as primary in the lung
are summarized in Table III. The simplest and most convincing cases were those involving tumors of different histology, particularly when they were widely spaced in time and in location." :J, 11, 15 The most difficult cases were those with tumors of similar histology appearing at the same time and in the same lobe. We felt that we could identify primary epidermoid carcinomas by tracing their origin from carcinoma in situ, 1, 4 but this method was not useful for other tumor types. The latter were accepted as primary only if it could be shown that there was no reasonable expectation of metastasis from one site to the other. Specifically, we required that the two tumors be physically distinct and separate C'coIIisian" tumors would be excluded) and that they arise in parts of the lung which do not share common lymphatics. We excluded cases in which regional lymph node metastases could have spawned retrograde lung metastasis or in which there was evidence of dissemination by blood-borne metastases. In only 7 cases that were accepted for this report were there hilar or peribronchial lymph node metastases from one of the tumors; in 3 of these cases the tumors had different histology, in 3 others they were separated by 3, 4, and 13 years in time of appearance, and in 1 case both carcinomas were epidermoid and separate origins from carcinoma in situ could be established. Bronchioloalveolar carcinoma with diffuse (pneumonic) or multinodular (three or
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Table III. Criteria for diagnosis Metachronous tumors A. Histology different B. Histology the same, if: I. Free interval between cancers at least 2 years or 2. Origin from carcinoma in situ or 3. Second cancer in different lobe or lung, but: a. No carcinoma in lymphatics common to both b. No extrapulmonary metastases at time of diagnosis Synchronous tumors A. Tumors physically distinct and separate B. Histology: I. Different 2. Same, but in different segment, lobe, or lung, if: a. Origin from carcinoma in situ b. No carcinoma in lymphatics common to both c. No extrapulmonary metastases at time of diagnosis
more nodules) growth patterns were arbitrarily excluded because of difficulty in ruling out airborne or intrapulmonary lymphatic dissemination. Discussion
The incidence of multiple carcinomas of the lung in our series is just under 1 per cent of all lung cancers seen. It is higher in patients who are cured of the initial cancer, as was pointed out by Watson"? in a study of 10 year survivors. Moreover, of 28 patients with a radiologically occult cancer diagnosed at our Center," 7 or 25 per cent had a second and separate primary lung cancer. If the free interval after treatment of an initial lung cancer is long, 3 or more years, there is an expectation of cure. Any tumor detected on chest x-ray films after that period may well represent a second primary lung cancer rather than a metastasis." 6 On the other hand, the time interval between diagnosis of two separate tumors need not be prolonged for them to be identified as independent primary carcinomas. Although clinical and radiologic findings are often helpful in differentiating new cancers from
Thoracic and Cardiovascular Surgery
metastases, histologic confirmation generally is necessary and, in the case of synchronous tumors, it is essential. Multiple primary lung cancers detected at thoracotomy or in a specimen after resection are only of academic interest. Simultaneous detection of two separate lung tumors before treatment may deter adequate treatment because of a mistaken impression of metastasis from the lung or other sites. In that case, treatment may not be attempted or may be limited to external radiation or palliative resection. We feel that the presence of two or more cancers presenting simultaneously should not deter treatment by resection if feasible. Survival after adequate resection in this group of patients is essentially the same as in a single primary lung cancer managed in a similar manner. In treatment of the patient with a metachronous second lung cancer, the distinction between a new primary tumor and a solitary metastasis is of little importance if the new tumor is resectable. 7, 12 Management of metastases by resection, whether solitary or multiple but few, results in 5 year survival rates comparable to those obtained by surgical treatment of a single primary lung cancer. In metachronous lesions, if a lobectomy or segmentectomy was carried out initially, treatment by lobectomy may again be possible. For cancers developing after a pneumonectomy, wedge resection or segmentectomy has been shown to yield prolonged survival in at least 15 to 20 per cent of the patients." Moreover, limited resection for peripheral bronchogenic carcinoma is favored by some in recent years as the procedure of choice.v 14 An experience with the patients presented in this study emphasizes the importance of conserving lung tissue at the original operation. The patient who develops a second lung cancer may then be treated by resection if indicated without undue jeopardy to his already limited pulmonary reserve. REFERENCES Auerbach, 0., Stout, A. P., Hammond, E. C., and Garfinkel, L.: Multiple Primary Bronchiolar Carcinomas, Cancer 20: 699, 1967.
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2 Beyreuther, H.: Multiplicitat von Carcinomen bei einem Fall von Sog. "Schneeberger" Lungenkrebs mit Tuberkulose, Virchows Arch [Pathol. Anat.] 250: 230, 1924. 3 Biliroth, T.: Die Allgemeine Chirurgische Pathologic und Therapie in 51 Vorlesungen, in Handbuch fur Studirende und Aerzte, 14: G, Berlin, 1914, Reimer, p. 908. 4 Black, H., and Ackerman, L. V.: Importance of Epidermoid Carcinoma in Situ in Histogenesis of Carcinoma of Lung, Ann. Surg. 136: 44, 1952. 5 Cahan, W. G., Butler, F. S., Watson, W. L., and Pool, I. L.: Multiple Cancers: Primary in the Lung and Other Sites, I. THoRAc. SURG. 20: 335, 1950. 6 Cahan, W. G.: Multiple Primary Cancers, One of Which Is Lung, Surg. Clin. North Am. 49: 323, 1969. 7 Cliffton, E. E., DasGupta, T., and Pool, I. L.: Bilateral Resection for Primary or Metastatic Lung Cancer, Cancer 8: 86, 1964. 8 Iensik, R. I., Faber, L. P., Milloy, F. I., and Monson, D. 0.: Segmental Resection for Lung Cancer: A Fifteen-Year Experience, I. THoRAc. CARDIOVASC. SURG. 66: 563, 1973. 9 Martini, N., Beattie, E. I., Ir., Cliffton, E. E., and Melamed, M. R.: Radiologically Occult Lung Cancer, Surg. Clin. North Am. 54: 811, 1974. 10 Melamed, M. R.: Pathology, in Watson, W. L., editor: Lung Cancer: A Study of Five Thousand Memorial Hospital Cases, Chap. 3, St. Louis, 1968, The C. V. Mosby Company, p. 35. 11 Mobley, D. F., and Martinez, A. J.: Two Histologically Different Primary Carcinomas of the Lung: A Review of the Literature and Presentation of a Case, Cancer 22: 287, 1968. 12 Moersch, R. N., and Clagett, O. T.: Pulmonary Resection for Metastatic Tumors of Lung, Surgery 50: 579, 1961. 13 Ramsey, H. E., Cahan, W. G., Beattie, E. J., Jr., and Humphrey, c.: The Importance of Radical Lobectomy in Lung Cancer, J. THORAC. CARDIOVASC. SURG. 58: 225, 1969. 14 Shields, T. W., and Higgins, G. A., Jr.: Minimal Pulmonary Resection in Treatment of Carcinoma of the Lung, Arch. Surg. 108: 420, 1974. 15 Struve-Christensen, E.: Diagnosis and Treatment of Bilateral Primary Bronchogenic Carcinoma, I. THORAC. CARDIOVASC. SURG. 61: 501, 1971. 16 Watson, W. L.: Ten-Year Survival: A Study of Fifty-six Cases, in Watson, W. L., editor: Lung Cancer: A Study of Five Thousand Memorial Hospital Cases, Chap. 21, St. Louis, 1968, The C. V. Mosby Company, p. 514. 17 Histological Typing of Lung Tumours, Geneva, 1967, World Health Organization.
Discussion DR. DONALD L. PAULSON Dallas, Texas
Our experience with dual carcinomas, or multiple primary lesions, is similar to that of the Memorial Hospital reviewed by Dr. Martini. Among 2,600 patients, there were 34 dual primary carcinomas, five of which were synchronous and 29 metachronous. This is an incidence in the total series of a little over 1 per cent. However, this is misleading, because the metachronous lesion can develop only in long-term survivors: Patients with inoperable lesions do not survive long enough to have a second lesion diagnosed. However, in this regard, the report of Auerbach, Stout, Hammond, and Garfinkel is significant. In a necropsy study of patients dying from bronchogenic carcinoma, they found a second lesion in about 3.5 per cent of the cases. The true frame of reference in our series for the incidence of metachronous, dual bronchogenic carcinomas is the group of 904 patients treated previously by resection of their initial lesion. Twenty-eight later developed second lesions, an incidence of 3.1 per cent. The peak incidence was after 5 years. Five were ipsilateral and 24 were contralateral lesions. Calculation of the incidence of second lesions by the actuarial method in our surviving patients reveals a peak incidence after 5 years, although there is another peak at about 2 years. This probably represents cases in which a second lesion was present at the time of the original operation but was not diagnosable. It is not surprising that patients do develop a second carcinoma inasmuch as the lungs are paired organs. Multiple carcinomas of paired organs, such as breasts and ovaries, are not infrequent, and they may be synchronous and metachronous, just as in the lung. Carcinogenesis is not an isolated biological accident, and the fact that the pathogenic processes may continue in the same or opposite lung after resection of one bronchial carcinoma should not be considered surprising or rare. These processes may occur more commonly than we generally appreciate. The highest incidence of metachronous dual carcinoma in our series is found in patients surviving 5 or more years, a fact which emphasizes the importance of continued follow-up beyond that time. DR. WILLIAM G. CAHAN New York, N. Y.
Twenty-five years ago, before this Association, we presented a paper reporting on 60 patients with multiple primary cancers one of which was lung cancer. Now we have encountered over 626 patients in this category. The extrathoracic cancers have occurred in virtually all organs of the body
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and include melanomas, lymphomas, and leukemias. In 1972, we had 47 multiple primary lung cancers, but the largest association was with those originating in the head and neck and most particularly in the larynx. This suggests the possibility that a common etiologic agent, most likely tobacco, was affecting the upper and lower respiratory tract. Although not mentioned, I am sure that Dr. Martini's group must have had a history of a habit of this type. It is still a mystery why only 50 out of 3,000 lung cancer patients at Memorial Hospital developed multiple primary cancers of that organ. We must assume that oncogenesis has many facets, some of which are dependent upon local tissue or systemic immunity. This idea is given support if one recalls the multiple in situ carcinomas of the respiratory mucosae, very few of which progressed to invasive carcinoma, which Auerbach found upon serial sectioning of the tracheobronchial tree. We have always subscribed to Dr. Martini's conclusion that it is most unreliable to make a tissue diagnosis from a shadow on a lung x-ray film. All too often radiologists, knowing that a patient has a cancer elsewhere, report such a shadow as being a "metastasis." This can be an inaccurate guess and can lead to an incorrect treatment program as well as to an untrustworthy prognosis. Solitary shadows are unique and may be a primary lung cancer, a metastasis, or a berugn tumor. The diagnosis should be confirmed microscopically in all instances. Finally, we agree with Dr. Paulson that the concept of a 5 year cure can lead to a false sense of security for both the patient and physician. This is, after all, an arbitrary length of time; cancers do not confine themselves to such manmade limitations. As a consequence, not only new primary cancers but even metastases can surface as long as 25 years after treatment of the original tumor. Perhaps "5 year survival" reflects a truer state of affairs.
In all this, the implication is clear: Cancer patients require constant vigilance at stated intervals for their lifetime. DR. ROWAN NICKS Sydney. Australia
I enjoyed very much Dr. Martini's and Dr. Melamed's excellent and interesting paper on lung cancer. Our experience agrees with their general active outlook toward multiple cancers. In Sydney, our surgeons have managed each primary cancer on its own merits, as the authors report doing. I agree that the long-term survival depends on the pathological characteristics of individual cancers. [Slide] A 57-year-old town gardener from Young, a town in northern New South Wales (a very hot place) had been treated for years for multiple squamous epitheliomas of the face before being referred with carcinomas in both lungs. He had one carcinoma in the right lower lobe and two carcinomas in the left lower lobe. The lesion on the right side was a large cell carcinoma and abutted on the pleura. The two carcinomas in the left lower lobe were histologically identical to the lesion in the right lung. The man was treated by bilateral resection of the lower lobes 7 years ago. He is quite well, still works as a gardener, and still is sorely troubled by the skin lesions. [Slide] This slide shows our experience with multiple lung cancers in Sydney. Seven patients with unilateral multiple cancers survived an average of 7 years. Four lived for 10 years or more. The patients with synchronous bilateral lung cancers lived an average of 4 years. In 7 patients, metachronous cancers have arisen in the opposite lung, usually years after the initial resection. [Slide] The 5 patients operated upon at an average age of 63 years, usually by a bilateral lobectomy, have done well. They have survived an average of 8Vz years with a range of 21;2 to 16 years.