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BILATERAL SIMULTANEOUS BRONCHOGENIC CARCINOMA
BILATERAL SIMULTANEOUS BRONCHOGENIC CARCINOMA Report of a Case of Surgical Excision Hiram T. Langston, M.D., and Joseph C. Sherrick, M.D., Chicago, 111. of an acknowledged increase in the incidence of bronchogenic car cinoma, the occurrence of bilateral tumors is uncommon. Particularly un common is the simultaneous occurrence of such lesions. It seems worth while, therefore, to report the case of a patient simultaneously harboring bilateral squamous cell carcinomas that were treated by surgical excision.
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CASE REPORT* C. S., a 56-year-old man, was seen because of a " c o i n ' ' lesion in the anterior portion of the right upper lobe which had been present since June, 1956 (Figs. 1 and 2 ) . There were no pulmonary symptoms. On Nov. 30, 1956, bronchoscopy showed no abnormality on the right side. I n the left main-stem bronchus, immediately opposite the left upper lobe orifice, however, there was a lesion involving the bronchial wall, which was biopsied. The pathologic diagnosis follows: "Poorly differentiated squamous cell carcinoma in mucous membrane." (Surg. Spec. No. 2476.) As it was now established t h a t a tumor which might reasonably require a pneumonectomy was present on the left side, exploration of the rightsided lesion was proposed after due deliberation, since its nature was still unknown. On Dec. 14, 1956, through a right thoracotomy, the localized lesion was approached with the hope of local excision; but on the recognition t h a t it was almost certainly a primary carcinoma, a segmental resection was substituted. This lesion arose from a second a r y branch of the anterior segmental bronchus on the right side. The pathologic diagnosis follows: "Moderately well differentiated bronchogenic squamous cell carcinoma of lung." (Surg. Spec. No. 2582.) There was a clearly established point of origin within the lumen of the anterior segmental bronchus (Fig. 3). The tumor on the right side was, therefore, classed as a primary carcinoma.
bronchogenic
On F e b . 27, 1957, the patient was re-bronchoscoped, at which time the lesion in the left main-stem bronchus was now seen to extend one half way around the circumference of the bronchial lumen. There still was no fixation. I t was decided to explore this side, considering the possible necessity of a left pneumonectomy. On March 1, 1957, through a left thoracotomy, the lung was examined and the bronchus carefully palpated. There was no mass t h a t could be recognized a t the site of the known tumor, so a bronchotomy for purpose of examination was carried out. This showed the wall of the bronchus to be involved over approximately one half of its circumference with the tumor extending into the upper lobe orifice. I t was believed t h a t a left upper lobe lobectomy and excision of the endobronehial lesion could be accomplished, providing Prom Grant Hospital of Chicago, Department of Surgery, University of Illinois College of Medicine, and Department of Pathology, Northwestern University Medical School. Received for publication July 10, 1961. ♦Permission to report this case was kindly granted by Dr. B. H. Orndoff. 742
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Fig. 1.
Fig. 2. Figs. 1 and 2.—Chest roentgenogram in December, 1956, showing circumscribed area of in creased density in right mid-lung field.
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as good a margin on the left side as had been provided on the right, while at the same time avoiding a t o t a l pneumonectomy. This was carried out and the lower lobe bronchus was re-anastomosed t o the upper reaches of the left main-stem bronchus. The pathologic diagnosis of the specimen follows: "Well differentiated squamous cell carcinoma with extension through bronchial wall." (Surg. Spec. No. 3240.) The bulk of
Pig. 3.—Photomicrograph of tumor removed from right lung, showing point of origin from mucosa of branch of right anterior segmental bronchus. (Surg. Spec. No 2582 ■ X150 reduced %.)
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v., i. P i ? - 4w' s—tPuhm° to°r s r a p h of resected left main-stem bronchus, including left upper lobe stem, ?ofn^ arising from bronchial mucosa and protruding into lumen. (Surg. Spec.
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the tumor was endobronchial, and the microscopic sections showed a definite transition from normal epithelium to tumor (Figs. 4 and 5). Lymph nodes t h a t were removed with the specimen were not involved. On J a n . 30, 1958, because of evident recurrence at the site of the (first) right-sided resection, bronchoscopy was again carried out which showed an acceptable airway in the left main-stem bronchus, albeit distorted b y the re-expansion of the left lower lobe. There were no cytologic elements indicative of malignancy in the material obtained from this site.
Fig. 5.—Photomicrograph of point of origin of tumor of left main bronchus. (Surg. Spec. No. 3240; X125, reduced %.) I t was, therefore, decided to excise this recurrent right-sided lesion. On Feb. 1, 1958, through a right thoracotomy, the right upper lobectomy was completed, excising by narrow margin the recurrent lesion in this right lung. The pathologic examination this time showed it to be a poorly differentiated squamous cell carcinoma. A regional lymph node was involved. I t was believed t h a t this undoubtedly was a recurrence due to seeding because of the closely margined excision of the original lesion. The postoperative course was uneventful. The patient was discharged and returned home freely ambulatory. Subsequent checkups failed to show any evidence of recurrence; one film was made over one year later. By this time the over-all emphysema had en croached upon the respiratory reserve so t h a t oxygen was required on occasions. He died suddenly without explanation on Feb. 26, 1960; unfortunately, there was no autopsy. Death was believed to be due to respiratory insufficiency and cardiac failure, there having been no evidence up to t h a t time of recurrence. PREVIOUSLY REPORTED CASES
The occurrence of bilateral primary carcinomas of the lung is not men tioned in most reported surgical or autopsy studies of the disease. In reports from five clinics, comprising 2,493 cases of pulmonary carcinoma, bilateral tumors apparently did not occur.7' l s > 2 0 - 3 1 ' 4 1 ' 4 2 In Breckwoldt V group of 47 cases, 2 patients had bilateral carcinomas, and in 63 of 3,735 cases reported by Fischer there were bilateral carcinomas. In a statistical study of 4,192 car-
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cinomas of various organs, Junghanns 15 mentions one patient with bilateral bronchogenic carcinoma. Thirty-eight of Simons' 35 series of 2,177 lung cancers were bilateral. However, the abovementioned authors do not give details about the bilateral tumors. In studies of groups of patients with multiple primary carcinoma, in only a few cases were the multiple primary tumors both of the lung. "Warren and Gates40 were able to find only 2 cases of bilateral bronchogenic carcinoma and Slaughter 36 reported only 3 cases among 1,868 patients with multiple primary carcinomas. Other reports of large groups of patients with multiple primary carcinomas, totaling 7,093 cases, do not mention primary bilateral pulmonary carcinoma.22- 2i<25'29'43 Cahan and associates6 have made an interesting study of 25 patients with lung cancer who, in addition, had other primary malignant tumors. None of these patients had a second primary cancer of the lung. A third group of patients with multiple primary carcinomas of the lung include those in which the disease was noted at autopsy or was an incidental finding in pneumonectomy specimen. The 34 cases in this group are summarized in Table I. The diagnosis of multiple primary tumors was generally made on the basis of different histologic structure in each tumor. Some of the cases deserve special mention. In 1952, Williams 45 reported the case of a patient with left pneumonectomy for carcinoma of the lower lobe of the left lung. The patient died 3 years later and at autopsy was found to have extensive intraepithelial carcinoma in the bronchial mucosa, associated with a small carcinoma in the bronchus to the upper lobe of the right lung at its junction with the trachea. TABLE I.
MULTIPLE PRIMARY BRONCHOGENIC CARCINOMA: A T SURGICAL SPECIMENS
AUTHOR
Beyreuthcr 1 Rostoski et a l . " Muller2f> Pirchan and Siklso Lindbergh McGrath et al.21 Williams^ Chauvet and Feuardent® Kainberger 1 " Howard and Williams 1 3 Stewartss Gurkan" Newman and Adkins 2 7 Robinson and Jackson^ 2 Mandel and Thomas 2 3 Le Gal and Bauer 1 ?
AUTOPSY
AND INCIDENTAL IN
YEAR
CASES
REMARKS
1924 1926 1930 1932 1935 1952 1952 1954 1955 1957 1957 1958 1958 1958 1959 1961
1 6 1 1 1 5 1 1 1 1 1 1 1 8 1 3
Autopsy; Schneeberg miner Autopsies; Schneeberg miner Autopsy; Jachymov miner Autopsy Autopsy Autopsies Surgical specimen and autopsy Autopsy Autopsy Surgical specimen and autopsy Surgical specimen and autopsy Autopsy Pneumonectomy specimen; 3 carcinomas Autopsies and surgical specimens Autopsy Surgical specimens and autopsies
In 1957 Howard and Williams 13 reported the case of a patient who had a right pneumonectomy for carcinoma in the posterior branch of the lower lobe bronchus, which microscopically proved to be a squamous cell carcinoma. The patient died 24 days after thoracotomy, and in the left lung there was much atypical squamous metaplasia with a microscopic squamous cell carcinoma in the junction of the main-stem bronchus and the bronchus to the lower lobe of the left lung.
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The study made by Robinson and Jackson 32 included 500 bronchogenic car cinomas of which 9 were dual primary carcinomas. The diagnosis was made by the presence of separate tumors of different histologic characteristics. In each case, one carcinoma was squamous cell in type and the other was oat cell in type. Four cases were discovered at autopsy and 5 occurred in living patients. In 4 cases of these last 5, the second carcinoma was more or less an incidental finding in a pneumonectomy specimen. In the other case, their Case 2, a squa mous cell carcinoma was found in the lower lobe of the left lung, and an oat cell carcinoma in the upper lobe of the right lung, both by endoscopic biopsy procedures. No treatment was given. The report of Le Gal and Bauer 17 in 1961 included a group of 182 patients with resectable carcinomas of the lung of whom 63 survived 30 months. A group in which they were particularly interested were 4 of the 63 patients (6.4 per cent) who developed a second primary carcinoma, separated from the first by an asymptomatic interval. Two patients were found at autopsy to have car cinoma in the remaining lung 5 and 4 years after pneumonectomy. In these 2 cases, the carcinomas were squamous cell in type. The third patient had a pneu monectomy for squamous cell carcinoma on the left side and died 5 years later, having been proved to have an undifferentiated carcinoma in the right lung by bronchoscopic biopsy. No autopsy was performed. The fourth patient under went a right lower lobectomy in 1954 for squamous cell carcinoma, and, in 1957, was found to have recurrent tumor on the left side. A left lower lobectomy was performed and the resected lobe contained a separate primary squamous cell carcinoma. Three years later, this patient was living and well. Of particular interest in the present study are cases of bilateral broncho genic carcinoma in which the diagnosis was made in the living patient, and which presented a distinct problem of clinical judgment. These cases are sum marized in Table II. The cases reported by Wiklund, 44 Robinson and Jackson 32 (Case 2), Drash and de Niord, 0 and Britt and associates5 were all detected by bronchoscopic biopsies and were deemed inoperable so that no surgical treatment was given. In Case 4 reported by Le Gal and Bauer, as was previously men tioned, the second carcinoma appeared 3 years after the first carcinoma had been removed, and hence, although the tumors were bilateral and did occur in the living patient, they did not present a problem of clinical treatment since they did not occur simultaneously. The same condition applies to the cases of Hughes and Blades.14 In their Case 1, tumor recurred on the right side after a left pneumonectomy 9 years previously for epidermoid carcinoma. A superior segmental resection was done and the pathologic diagnosis was grade 3 epider moid carcinoma. The patient died of metastasis 6 months later. In Case 2, tumor recurred on the right side 10 years after a left pneumonectomy for grade 2 epidermoid carcinoma. A biopsy of the right upper lobe bronchus revealed epidermoid carcinoma. No surgical treatment was instituted. In a discussion of bilateral bronchogenic carcinoma, one last group should be mentioned. These are cases like those reported by Ryan and McDonald34 in 1956 in which 5 patients with bronchogenic carcinoma were observed with in situ carcinoma in the opposite lung. In view of the findings by various auth-
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MULTIPLE PRIMARY BRONCHOGENIC CARCINOMA: DIAGNOSIS DURING L I F E
YEAR
CASES
REMARKS
Wiklund44
1951
1
Bronchoscopic biopsies; no surgical treat ment
Robinson and Jackson32
1958
Drash and de Niordo
1958
1
Bronchoscopic biopsies; no surgical treat ment
Britt et al.=
1960
1
Bronchoscopic biopsies; no surgical treat ment; x-ray
Le Gal and Baueri?
1961
Hughes and Blades 1 4
1961
AUTHOR
1 Bronchoscopic biopsies; no surgical treat ment (Case 2)
1 Surgical treatment; 3 year interval (Case 4) 2
Surgical treatment; 9 and 10 year interVf la
o r s 3 ' 2 1 ' 3 7 of multiple areas of squamous metaplasia and atypical squamous hyperplasia in the bronchi of patients with bronchogenic carcinoma, it is surprising that this observation has not been made more frequently and, indeed, it is sur prising that bilateral squamous cell carcinomas of the lung have not been more frequently encountered. DIAGNOSIS OP MULTIPLE PRIMARY TUMORS
The problem of establishing the diagnosis of multiple primary tumors has been studied by pathologists for many years. The postulates attributed to Billroth 11 ' 39 have been extensively quoted and were as follows: (1) separate loca tions of the tumors, (2) different histologic structure of each tumor, and (3) from each tumor, its own metastasis. However, Billroth evidently did not abide strictly by his own rules, since, in one of his own case reports, 2 he made the diagnosis of two separate primary tumors in a case in which there were no metastases. In this report, he stated that distinct difference in the microscopic structure of the two tumors may be ac cepted as proof of the double origin. The criteria followed by Frankel and his associates11 are clear and are more practical for general use: (1) each tumor must have the gross and microscopic features of the usual primary tumor at this location; (2) neither tumor should appear subordinate to the other, or resemble a metastasis; and (3) separate metastases substantiate the diagnosis of separate primary tumors. These criteria are in agreement with those established by other observers, such as Warren and Gates, who state that "each of the tumors must present a definite picture of malignancy, each must be distinct, and the probability of one being a metastasis of the other must be excluded." Microscopic and macro scopic independence have generally been accepted as establishing the diagnosis of dual or multiple primary tumors, and there is little problem if the tumors have widely differing histologic features; although in the lung, as Willis points out, it should be kept in mind that a single bronchogenic carcinoma may present widely different histologic features in different tissue blocks.
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Even if two widely separate tumors have similar histologic appearances, there is no reason why each may not be a separate primary tumor if each pre sents the typical gross and microscopic features of a primary tumor. In regard to bronchogenic carcinoma, the presence of such factors as typical mucosal intraluminal location, the presence of transitional mucosal changes at the margin of the tumor favor the diagnosis of dual primary tumors, or the diagnosis of multicentric cancers of the same stage of evolution. In the case herein recorded, the first tumor was located in a secondary branch of the anterior segmental bronchus to the upper lobe of the right lung, while the second tumor was located in the left main-stem bronchus. Thus, the tumors were located at two different and widely separated sites. Grossly, each tumor primarily involved the bronchial mucosa (see Pig. 3). Microscopically, in each tumor, there was a zone of transition from normal bronchial mucosa to abnormal mucosa to tumor (see Figs. 2 and 4). Although the tumors were of similar histologic type, both being moderately well-differentiated squamous cell carcinomas, had either tumor been present alone, a diagnosis of primary bronchogenic carcinoma would have been considered to be clearly established. Because of the separation in origin of the tumors, and because of the char acteristic gross and microscopic features of primary bronchogenic carcinoma in each of these tumors, the diagnosis of bilateral simultaneously occurring squa mous cell carcinomas of the bronchus is considered justified. CLINICAL
ASPECTS
In addition to the fact that this case represents one of the uncommon simul taneously occurring bilateral bronchogenic carcinomas, the patient presents an interesting finding from the clinical point of view, since he was treated by successful removal of both carcinomas. Whereas a wider excision of both of these lesions would be recommended under ideal conditions, a narrow excision was all that the circumstances would permit. The initial hope that the solitary lesion in the right upper lobe could be removed by enucleation expressed a de featist attitude and immediately resulted in the later operation for recurrence on the right side, which was undoubtedly due to local seeding, probably caused by the close margin of excision at the first operation. Once embarked on a pro gram of surgical excision, the successive steps were accepted under stimulation of the patient himself. That such a program could have succeeded is suggested by the available period of follow-up. Furthermore, if the viability of blood-borne metastasis is more influential in prognosis than local recurrence or extension by other routes, there is no question but that local excision can and, at times does, suffice in the treatment of bronchogenic carcinoma.28 In spite of the present trend toward more and more radical surgical procedures, one should keep in mind that, theo retically, there is no tumor that may not be cured at some point in its course by complete, if localized, excision. SUMMARY
Although the incidence of bronchogenic carcinoma has increased in the past
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50 years, the occurrence of bilateral simultaneously occurring squamous cell bronchogenic carcinomas is uncommon. A case of this type, which was treated by surgical procedures consisting of bilateral local excisions, is presented. After one recurrence, which was treated by further local excision, the patient survived 3 years without evidence of recurrence or metastasis. All other factors being equal, it should be kept in mind that it is occasionally possible to treat broncho genic carcinoma by local excision. REFERENCES 1. Beyreuther, H . : Multiplicitat von Carcinomen bei einem Fall von sog. "Schneeberger" Lungenkrebs mit Tuberkulose, Virchows Arch. path. Anat. 250: 230-243, 1924. 2. Billroth, T., and von Winiwarter, A.: General Surgical Pathology and Therapeutics, N e w York, 1883, D. Appleton Co. Translated from t h e fourth German edition and revised from the tenth edition by Chas. E. Hackley, p. 765. 3. Black, H., and Ackerman, L. V.: Importance of Epidermoid Carcinoma I n Situ in Histogenesis of Carcinoma of Lung, Ann. Surg. 136: 44-55, 1952. 4. Breckwoldt, E . : Zur F r a g e der Zunahme der Lungenkrebse, Ztschr. Krebsforsch. 2 3 : 128-152, 1926. 5. Britt, C. I., Christoforidis, A. J., and Andrews, N. C : Bilateral Simultaneous Squamous Cell Carcinoma of the Lung, J. THORACIC SURG. 40: 102-106, 1960. 6. Cahan, W. G., Butler, F . S., Watson, W. L., and Pool, J . L.: Multiple Cancers: Primary in the Lung and Other Sites, J. THOKACIC SURG. 20: 335-348, 1950. 7. Carlisle, J. C , McDonald, J. E., and Harrington, S. W.: Bronchogenic Squamous Cell Carcinoma, J. THORACIC SURG. 22: 74-82, 1951.
8. Chauvet, M., and Feuardent, E.: Cancer Bronchique Bilateral, J. franc. miid. et chir. thorac. 8: 377-380, 1954. 9. Drash, E. C , and de Niord, E. N., J r . : Bilateral P r i m a r y Simultaneous Bronchogenic Carcinoma, Dis. Chest. 34: 226-228, 1958. 10. Fischer, W.: Die Gevvachse der Lunge und des Brustfells, in Handbuch der speziellen pathologischen Anatomie und Histologie, edited by F . Henke and O. Lubarsch, Berlin, 1931, Julius Springer, p. 509-606. 11. Goetze, O.: Bemerkungen iiber multiplizitat primarer Carcinome in Anlehnung an einen Fall von dreifachem Carcinom. Ztschr. Krebsforsch. 13: 281-302, 1913. 12. Gurkan, K. I.: Bilateral Bronchogenic Carcinoma: Report of a Case, J. I n t e r n a t . Coll. Surgeons 29: 763-765, 1958. 13. Howard, S. A., and Williams, M. J.: Bilateral Simultaneous Occurrence of Primary Squamous-cell Carcinoma of the Lung, Cancer 10: 1182-1186, 1957. 14. Hughes, R. F . , and Blades, B . : Multiple Primary Bronchogenic Carcinoma J . THORACIC SURG. 4 1 : 421-429, 1961.
15. Junghanns, H . : Eine Krebsstatistik iiber 35 J a h r e . (4,192 Carcinome bei 36,408 Leichenoffnungen.), Ztschr. Krebsforsch. 29: 623-664, 1929. 16. Kainberger, F . : tiber einen F a l l von doppeltem primarem Bronehuskarzinom, Klin. med. 10: 354-360, 1955. 17. Le Gal, Y., and Bauer, W. C.: Second P r i m a r y Bronchogenic Carcinoma: A Compli cation of Successful Lung Cancer Surgery, J. THORACIC SURG. 4 1 : 114-124, 1961. 18. Liavaag, K.: Bronchogenic Carcinoma, Acta chir. scandinav. 98: 182-204, 1949. 19. Lindberg, K.: ttber die Histologie des primaren Lungenkrebs, Arb. path. Inst. Univ. Heisingfors 8: 225-473, 1935. 20. McBurney, E. P., McDonald, J. E., and Clagett, O. T.: Bronchogenic Small-cell Car cinoma, J . THORACIC SURG. 22: 63-73, 1951.
21. McGrath, E. J., Gall, E. A., and Kessler, 1). P . : Bronchogenic Carcinoma: Product of Multiple Sites of Origin, J. THORACIC SURG. 24: 271-283, 1952. 22. Malmio, K.: Multiple P r i m a r y Cancer: A Clinical-Statistical Investigation Based on 650 Cases, Ann. chir. gynaec Fenniae 48: Suppl. 92, 1959. 23. Mandel, W., and Thomas, J. H.: Simultaneous Occurrence of Squamous and Adenocarcinoma of the Lung, California Med. 9 1 : 358-360, 1959. 24. Mider, G. B., Schilling, J. A., Donovan, J. C , and Rendall, E. S.: Multiple Cancer: A Study of Other Cancers Arising in P a t i e n t s W i t h P r i m a r y Malignant Neo plasms of the Stomach, Uterus, Breast, Large Intestine, or Hematopoietic System, Cancer 5: 1104-1109, 1952. 25. Moertel, C. G., Dockerty, M. B., and Baggenstoss, A. H . : Multiple P r i m a r y Malignant Neoplasms. I. Introduction and Presentation of Data. I I . Tumors of Different Tissues or Organs. I I I . Tumors of Multicentric Origin, Cancer 14: 221-231, 231238, and 238-249, 1961.
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26. Muller, R. F.: tJber multiple, nichtsj^stematisierte Primarcarcinome und ihre Haufigkeit, Ztschr. Krebsforsch. 3 1 : 339-360, 1930. 27. Newman, W., and Adkins, P. C.: Three P r i m a r y Carcinomas of the Lung Arising in a Left Lower Lobe W i t h Metastasis of Two of the Tumors, J. THORACIC SURG. 35: 474-482, 1958. 28. Paulson, D. L., and Shaw, R. R.: Results of Bronchoplastic Procedures for Broncho genic Carcinoma, Ann. Surg. 151: 729-739, 1960. 29. Phillips, C , and Shirey, R. W.: Multiple Primary Cancer: I t s Prognostic Significance, Acta I n t e r n a t . Union Against Cancer 6: 957-963, 1950. 30. Pirehan, A., and Sikl, H.: Cancer of the Lung in the Miners of Jachymov ( Joachim s t a l ) : Report of Cases Observed in 1929-1930, Am. J. Cancer 16: 681-722, 1932. 31. Rienhoff, W. F., King, J. D. B., and Dana, G. W. J r . : Surgical Treatment of Carcinoma of the L u n g : E v a l u a t i o n of 699 Cases From 1933 Through 1956, J. A. M. A. 166: 228-232, 1958. 32. Robinson, C. L. N., and Jackson, C. A.: Multiple P r i m a r y Cancer of t h e Lung, J . THORACIC SURG. 36: 166-173,
1958.
33. Rostoski, Saupe, and Schmorl: Die Bergkrankheit der Erzbergleute in Schneeberg in Sachsen. ("Schneeberger Lungenkrebs."), Ztschr. Krebsforsch. 23: 360-384, 1926. 34. Ryan, R. F., and McDonald, J. R.: Bronchogenic Carcinoma With In Situ Carcinoma in the Opposite Lung, Proc. Staff Meet. Mayo Clin. 3 1 : 478-485, 1956. 35. Simons, E. J.: P r i m a r y Carcinoma of the Lung, Chicago, 1937,-Year Book Publishers, Inc. 36. Slaughter, D. P . : The Multiplicity of Origin of Malignant Tumors, I n t e r n a t . Abstr. Surg. 79: 89-98, 1944. 37. Spain, D. M., and Parsonnet, V.: Multiple Origin of Minute Bronchiolargenic Car cinomas: Report of a Case, Cancer 4: 277-285, 1951. 38. Stewart, F . W.: Factors Influencing the Curability of Cancer. Third National Cancer Conference Proceedings, Philadelphia, 1957, J. B. Lippincott Co., p. 65. 39. Theilhaber, A., and Edelburg, H.: Zur Lehre von der multiplizitat der Tumoren, Insbesondere der Carcinome, Deutsche Ztschr. Chir. 117: 457-489, 1912. 40. Warren, S., and Gates, O.: Multiple P r i m a r y Malignant Tumors: A Survey of the L i t e r a t u r e and a Statistical Study, Am. J . Cancer 16: 1358-1414, 1932. 41. Walter, J. B., and Pryce, D. M.: The Histology of Lung Cancer, Thorax 10: 107-116, 1955. 42. Walter, J. B., and Pryce, D. M.: The Site of Origin of Lung Cancer and I t s Relation to Histological Type, Thorax 10: 117-126, 1955. 43. Watson, T. A.: Incidence of Multiple Cancers, Cancer 6: 365-371, 1953. < 44. Wiklund, T.: Bronchiogenic Carcinoma: A Clinical Study of 259 Cases, 100 of Which Were Resected. Follow-up Study of the Resected Cases, Acta chir. scandinav. Suppl. 162, 1951. 45. Williams, M. J.: Extensive Carcinoma In Situ in the Bronchial Mucosa Associated W i t h Two Invasive Bronchogenic Carcinomas: Report of Case, Cancer 5 : 740747, 1952. 46. Willis, R. A.: Pathology of Tumors, St. Louis, 1948, The C. V. Mosby Company, p. 367.
I
N SPITE
CASE REPORT* C. S., a 56-year-old man, was seen because of a " c o i n ' ' lesion in the anterior portion of the right upper lobe which had been present since June, 1956 (Figs. 1 and 2 ) . There were no pulmonary symptoms. On Nov. 30, 1956, bronchoscopy showed no abnormality on the right side. I n the left main-stem bronchus, immediately opposite the left upper lobe orifice, however, there was a lesion involving the bronchial wall, which was biopsied. The pathologic diagnosis follows: "Poorly differentiated squamous cell carcinoma in mucous membrane." (Surg. Spec. No. 2476.) As it was now established t h a t a tumor which might reasonably require a pneumonectomy was present on the left side, exploration of the rightsided lesion was proposed after due deliberation, since its nature was still unknown. On Dec. 14, 1956, through a right thoracotomy, the localized lesion was approached with the hope of local excision; but on the recognition t h a t it was almost certainly a primary carcinoma, a segmental resection was substituted. This lesion arose from a second a r y branch of the anterior segmental bronchus on the right side. The pathologic diagnosis follows: "Moderately well differentiated bronchogenic squamous cell carcinoma of lung." (Surg. Spec. No. 2582.) There was a clearly established point of origin within the lumen of the anterior segmental bronchus (Fig. 3). The tumor on the right side was, therefore, classed as a primary carcinoma.
bronchogenic
On F e b . 27, 1957, the patient was re-bronchoscoped, at which time the lesion in the left main-stem bronchus was now seen to extend one half way around the circumference of the bronchial lumen. There still was no fixation. I t was decided to explore this side, considering the possible necessity of a left pneumonectomy. On March 1, 1957, through a left thoracotomy, the lung was examined and the bronchus carefully palpated. There was no mass t h a t could be recognized a t the site of the known tumor, so a bronchotomy for purpose of examination was carried out. This showed the wall of the bronchus to be involved over approximately one half of its circumference with the tumor extending into the upper lobe orifice. I t was believed t h a t a left upper lobe lobectomy and excision of the endobronehial lesion could be accomplished, providing Prom Grant Hospital of Chicago, Department of Surgery, University of Illinois College of Medicine, and Department of Pathology, Northwestern University Medical School. Received for publication July 10, 1961. ♦Permission to report this case was kindly granted by Dr. B. H. Orndoff. 742
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Fig. 1.
Fig. 2. Figs. 1 and 2.—Chest roentgenogram in December, 1956, showing circumscribed area of in creased density in right mid-lung field.
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as good a margin on the left side as had been provided on the right, while at the same time avoiding a t o t a l pneumonectomy. This was carried out and the lower lobe bronchus was re-anastomosed t o the upper reaches of the left main-stem bronchus. The pathologic diagnosis of the specimen follows: "Well differentiated squamous cell carcinoma with extension through bronchial wall." (Surg. Spec. No. 3240.) The bulk of
Pig. 3.—Photomicrograph of tumor removed from right lung, showing point of origin from mucosa of branch of right anterior segmental bronchus. (Surg. Spec. No 2582 ■ X150 reduced %.)
S
v., i. P i ? - 4w' s—tPuhm° to°r s r a p h of resected left main-stem bronchus, including left upper lobe stem, ?ofn^ arising from bronchial mucosa and protruding into lumen. (Surg. Spec.
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the tumor was endobronchial, and the microscopic sections showed a definite transition from normal epithelium to tumor (Figs. 4 and 5). Lymph nodes t h a t were removed with the specimen were not involved. On J a n . 30, 1958, because of evident recurrence at the site of the (first) right-sided resection, bronchoscopy was again carried out which showed an acceptable airway in the left main-stem bronchus, albeit distorted b y the re-expansion of the left lower lobe. There were no cytologic elements indicative of malignancy in the material obtained from this site.
Fig. 5.—Photomicrograph of point of origin of tumor of left main bronchus. (Surg. Spec. No. 3240; X125, reduced %.) I t was, therefore, decided to excise this recurrent right-sided lesion. On Feb. 1, 1958, through a right thoracotomy, the right upper lobectomy was completed, excising by narrow margin the recurrent lesion in this right lung. The pathologic examination this time showed it to be a poorly differentiated squamous cell carcinoma. A regional lymph node was involved. I t was believed t h a t this undoubtedly was a recurrence due to seeding because of the closely margined excision of the original lesion. The postoperative course was uneventful. The patient was discharged and returned home freely ambulatory. Subsequent checkups failed to show any evidence of recurrence; one film was made over one year later. By this time the over-all emphysema had en croached upon the respiratory reserve so t h a t oxygen was required on occasions. He died suddenly without explanation on Feb. 26, 1960; unfortunately, there was no autopsy. Death was believed to be due to respiratory insufficiency and cardiac failure, there having been no evidence up to t h a t time of recurrence. PREVIOUSLY REPORTED CASES
The occurrence of bilateral primary carcinomas of the lung is not men tioned in most reported surgical or autopsy studies of the disease. In reports from five clinics, comprising 2,493 cases of pulmonary carcinoma, bilateral tumors apparently did not occur.7' l s > 2 0 - 3 1 ' 4 1 ' 4 2 In Breckwoldt V group of 47 cases, 2 patients had bilateral carcinomas, and in 63 of 3,735 cases reported by Fischer there were bilateral carcinomas. In a statistical study of 4,192 car-
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cinomas of various organs, Junghanns 15 mentions one patient with bilateral bronchogenic carcinoma. Thirty-eight of Simons' 35 series of 2,177 lung cancers were bilateral. However, the abovementioned authors do not give details about the bilateral tumors. In studies of groups of patients with multiple primary carcinoma, in only a few cases were the multiple primary tumors both of the lung. "Warren and Gates40 were able to find only 2 cases of bilateral bronchogenic carcinoma and Slaughter 36 reported only 3 cases among 1,868 patients with multiple primary carcinomas. Other reports of large groups of patients with multiple primary carcinomas, totaling 7,093 cases, do not mention primary bilateral pulmonary carcinoma.22- 2i<25'29'43 Cahan and associates6 have made an interesting study of 25 patients with lung cancer who, in addition, had other primary malignant tumors. None of these patients had a second primary cancer of the lung. A third group of patients with multiple primary carcinomas of the lung include those in which the disease was noted at autopsy or was an incidental finding in pneumonectomy specimen. The 34 cases in this group are summarized in Table I. The diagnosis of multiple primary tumors was generally made on the basis of different histologic structure in each tumor. Some of the cases deserve special mention. In 1952, Williams 45 reported the case of a patient with left pneumonectomy for carcinoma of the lower lobe of the left lung. The patient died 3 years later and at autopsy was found to have extensive intraepithelial carcinoma in the bronchial mucosa, associated with a small carcinoma in the bronchus to the upper lobe of the right lung at its junction with the trachea. TABLE I.
MULTIPLE PRIMARY BRONCHOGENIC CARCINOMA: A T SURGICAL SPECIMENS
AUTHOR
Beyreuthcr 1 Rostoski et a l . " Muller2f> Pirchan and Siklso Lindbergh McGrath et al.21 Williams^ Chauvet and Feuardent® Kainberger 1 " Howard and Williams 1 3 Stewartss Gurkan" Newman and Adkins 2 7 Robinson and Jackson^ 2 Mandel and Thomas 2 3 Le Gal and Bauer 1 ?
AUTOPSY
AND INCIDENTAL IN
YEAR
CASES
REMARKS
1924 1926 1930 1932 1935 1952 1952 1954 1955 1957 1957 1958 1958 1958 1959 1961
1 6 1 1 1 5 1 1 1 1 1 1 1 8 1 3
Autopsy; Schneeberg miner Autopsies; Schneeberg miner Autopsy; Jachymov miner Autopsy Autopsy Autopsies Surgical specimen and autopsy Autopsy Autopsy Surgical specimen and autopsy Surgical specimen and autopsy Autopsy Pneumonectomy specimen; 3 carcinomas Autopsies and surgical specimens Autopsy Surgical specimens and autopsies
In 1957 Howard and Williams 13 reported the case of a patient who had a right pneumonectomy for carcinoma in the posterior branch of the lower lobe bronchus, which microscopically proved to be a squamous cell carcinoma. The patient died 24 days after thoracotomy, and in the left lung there was much atypical squamous metaplasia with a microscopic squamous cell carcinoma in the junction of the main-stem bronchus and the bronchus to the lower lobe of the left lung.
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BEONCHOGENIC CAECINOMA
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The study made by Robinson and Jackson 32 included 500 bronchogenic car cinomas of which 9 were dual primary carcinomas. The diagnosis was made by the presence of separate tumors of different histologic characteristics. In each case, one carcinoma was squamous cell in type and the other was oat cell in type. Four cases were discovered at autopsy and 5 occurred in living patients. In 4 cases of these last 5, the second carcinoma was more or less an incidental finding in a pneumonectomy specimen. In the other case, their Case 2, a squa mous cell carcinoma was found in the lower lobe of the left lung, and an oat cell carcinoma in the upper lobe of the right lung, both by endoscopic biopsy procedures. No treatment was given. The report of Le Gal and Bauer 17 in 1961 included a group of 182 patients with resectable carcinomas of the lung of whom 63 survived 30 months. A group in which they were particularly interested were 4 of the 63 patients (6.4 per cent) who developed a second primary carcinoma, separated from the first by an asymptomatic interval. Two patients were found at autopsy to have car cinoma in the remaining lung 5 and 4 years after pneumonectomy. In these 2 cases, the carcinomas were squamous cell in type. The third patient had a pneu monectomy for squamous cell carcinoma on the left side and died 5 years later, having been proved to have an undifferentiated carcinoma in the right lung by bronchoscopic biopsy. No autopsy was performed. The fourth patient under went a right lower lobectomy in 1954 for squamous cell carcinoma, and, in 1957, was found to have recurrent tumor on the left side. A left lower lobectomy was performed and the resected lobe contained a separate primary squamous cell carcinoma. Three years later, this patient was living and well. Of particular interest in the present study are cases of bilateral broncho genic carcinoma in which the diagnosis was made in the living patient, and which presented a distinct problem of clinical judgment. These cases are sum marized in Table II. The cases reported by Wiklund, 44 Robinson and Jackson 32 (Case 2), Drash and de Niord, 0 and Britt and associates5 were all detected by bronchoscopic biopsies and were deemed inoperable so that no surgical treatment was given. In Case 4 reported by Le Gal and Bauer, as was previously men tioned, the second carcinoma appeared 3 years after the first carcinoma had been removed, and hence, although the tumors were bilateral and did occur in the living patient, they did not present a problem of clinical treatment since they did not occur simultaneously. The same condition applies to the cases of Hughes and Blades.14 In their Case 1, tumor recurred on the right side after a left pneumonectomy 9 years previously for epidermoid carcinoma. A superior segmental resection was done and the pathologic diagnosis was grade 3 epider moid carcinoma. The patient died of metastasis 6 months later. In Case 2, tumor recurred on the right side 10 years after a left pneumonectomy for grade 2 epidermoid carcinoma. A biopsy of the right upper lobe bronchus revealed epidermoid carcinoma. No surgical treatment was instituted. In a discussion of bilateral bronchogenic carcinoma, one last group should be mentioned. These are cases like those reported by Ryan and McDonald34 in 1956 in which 5 patients with bronchogenic carcinoma were observed with in situ carcinoma in the opposite lung. In view of the findings by various auth-
748
LANGSTON AND SHERRICK TABLE I I .
J. Thoracic and Cardiovas. Surg.
MULTIPLE PRIMARY BRONCHOGENIC CARCINOMA: DIAGNOSIS DURING L I F E
YEAR
CASES
REMARKS
Wiklund44
1951
1
Bronchoscopic biopsies; no surgical treat ment
Robinson and Jackson32
1958
Drash and de Niordo
1958
1
Bronchoscopic biopsies; no surgical treat ment
Britt et al.=
1960
1
Bronchoscopic biopsies; no surgical treat ment; x-ray
Le Gal and Baueri?
1961
Hughes and Blades 1 4
1961
AUTHOR
1 Bronchoscopic biopsies; no surgical treat ment (Case 2)
1 Surgical treatment; 3 year interval (Case 4) 2
Surgical treatment; 9 and 10 year interVf la
o r s 3 ' 2 1 ' 3 7 of multiple areas of squamous metaplasia and atypical squamous hyperplasia in the bronchi of patients with bronchogenic carcinoma, it is surprising that this observation has not been made more frequently and, indeed, it is sur prising that bilateral squamous cell carcinomas of the lung have not been more frequently encountered. DIAGNOSIS OP MULTIPLE PRIMARY TUMORS
The problem of establishing the diagnosis of multiple primary tumors has been studied by pathologists for many years. The postulates attributed to Billroth 11 ' 39 have been extensively quoted and were as follows: (1) separate loca tions of the tumors, (2) different histologic structure of each tumor, and (3) from each tumor, its own metastasis. However, Billroth evidently did not abide strictly by his own rules, since, in one of his own case reports, 2 he made the diagnosis of two separate primary tumors in a case in which there were no metastases. In this report, he stated that distinct difference in the microscopic structure of the two tumors may be ac cepted as proof of the double origin. The criteria followed by Frankel and his associates11 are clear and are more practical for general use: (1) each tumor must have the gross and microscopic features of the usual primary tumor at this location; (2) neither tumor should appear subordinate to the other, or resemble a metastasis; and (3) separate metastases substantiate the diagnosis of separate primary tumors. These criteria are in agreement with those established by other observers, such as Warren and Gates, who state that "each of the tumors must present a definite picture of malignancy, each must be distinct, and the probability of one being a metastasis of the other must be excluded." Microscopic and macro scopic independence have generally been accepted as establishing the diagnosis of dual or multiple primary tumors, and there is little problem if the tumors have widely differing histologic features; although in the lung, as Willis points out, it should be kept in mind that a single bronchogenic carcinoma may present widely different histologic features in different tissue blocks.
BRONCHOGENIC CARCINOMA
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749
Even if two widely separate tumors have similar histologic appearances, there is no reason why each may not be a separate primary tumor if each pre sents the typical gross and microscopic features of a primary tumor. In regard to bronchogenic carcinoma, the presence of such factors as typical mucosal intraluminal location, the presence of transitional mucosal changes at the margin of the tumor favor the diagnosis of dual primary tumors, or the diagnosis of multicentric cancers of the same stage of evolution. In the case herein recorded, the first tumor was located in a secondary branch of the anterior segmental bronchus to the upper lobe of the right lung, while the second tumor was located in the left main-stem bronchus. Thus, the tumors were located at two different and widely separated sites. Grossly, each tumor primarily involved the bronchial mucosa (see Pig. 3). Microscopically, in each tumor, there was a zone of transition from normal bronchial mucosa to abnormal mucosa to tumor (see Figs. 2 and 4). Although the tumors were of similar histologic type, both being moderately well-differentiated squamous cell carcinomas, had either tumor been present alone, a diagnosis of primary bronchogenic carcinoma would have been considered to be clearly established. Because of the separation in origin of the tumors, and because of the char acteristic gross and microscopic features of primary bronchogenic carcinoma in each of these tumors, the diagnosis of bilateral simultaneously occurring squa mous cell carcinomas of the bronchus is considered justified. CLINICAL
ASPECTS
In addition to the fact that this case represents one of the uncommon simul taneously occurring bilateral bronchogenic carcinomas, the patient presents an interesting finding from the clinical point of view, since he was treated by successful removal of both carcinomas. Whereas a wider excision of both of these lesions would be recommended under ideal conditions, a narrow excision was all that the circumstances would permit. The initial hope that the solitary lesion in the right upper lobe could be removed by enucleation expressed a de featist attitude and immediately resulted in the later operation for recurrence on the right side, which was undoubtedly due to local seeding, probably caused by the close margin of excision at the first operation. Once embarked on a pro gram of surgical excision, the successive steps were accepted under stimulation of the patient himself. That such a program could have succeeded is suggested by the available period of follow-up. Furthermore, if the viability of blood-borne metastasis is more influential in prognosis than local recurrence or extension by other routes, there is no question but that local excision can and, at times does, suffice in the treatment of bronchogenic carcinoma.28 In spite of the present trend toward more and more radical surgical procedures, one should keep in mind that, theo retically, there is no tumor that may not be cured at some point in its course by complete, if localized, excision. SUMMARY
Although the incidence of bronchogenic carcinoma has increased in the past
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50 years, the occurrence of bilateral simultaneously occurring squamous cell bronchogenic carcinomas is uncommon. A case of this type, which was treated by surgical procedures consisting of bilateral local excisions, is presented. After one recurrence, which was treated by further local excision, the patient survived 3 years without evidence of recurrence or metastasis. All other factors being equal, it should be kept in mind that it is occasionally possible to treat broncho genic carcinoma by local excision. REFERENCES 1. Beyreuther, H . : Multiplicitat von Carcinomen bei einem Fall von sog. "Schneeberger" Lungenkrebs mit Tuberkulose, Virchows Arch. path. Anat. 250: 230-243, 1924. 2. Billroth, T., and von Winiwarter, A.: General Surgical Pathology and Therapeutics, N e w York, 1883, D. Appleton Co. Translated from t h e fourth German edition and revised from the tenth edition by Chas. E. Hackley, p. 765. 3. Black, H., and Ackerman, L. V.: Importance of Epidermoid Carcinoma I n Situ in Histogenesis of Carcinoma of Lung, Ann. Surg. 136: 44-55, 1952. 4. Breckwoldt, E . : Zur F r a g e der Zunahme der Lungenkrebse, Ztschr. Krebsforsch. 2 3 : 128-152, 1926. 5. Britt, C. I., Christoforidis, A. J., and Andrews, N. C : Bilateral Simultaneous Squamous Cell Carcinoma of the Lung, J. THORACIC SURG. 40: 102-106, 1960. 6. Cahan, W. G., Butler, F . S., Watson, W. L., and Pool, J . L.: Multiple Cancers: Primary in the Lung and Other Sites, J. THOKACIC SURG. 20: 335-348, 1950. 7. Carlisle, J. C , McDonald, J. E., and Harrington, S. W.: Bronchogenic Squamous Cell Carcinoma, J. THORACIC SURG. 22: 74-82, 1951.
8. Chauvet, M., and Feuardent, E.: Cancer Bronchique Bilateral, J. franc. miid. et chir. thorac. 8: 377-380, 1954. 9. Drash, E. C , and de Niord, E. N., J r . : Bilateral P r i m a r y Simultaneous Bronchogenic Carcinoma, Dis. Chest. 34: 226-228, 1958. 10. Fischer, W.: Die Gevvachse der Lunge und des Brustfells, in Handbuch der speziellen pathologischen Anatomie und Histologie, edited by F . Henke and O. Lubarsch, Berlin, 1931, Julius Springer, p. 509-606. 11. Goetze, O.: Bemerkungen iiber multiplizitat primarer Carcinome in Anlehnung an einen Fall von dreifachem Carcinom. Ztschr. Krebsforsch. 13: 281-302, 1913. 12. Gurkan, K. I.: Bilateral Bronchogenic Carcinoma: Report of a Case, J. I n t e r n a t . Coll. Surgeons 29: 763-765, 1958. 13. Howard, S. A., and Williams, M. J.: Bilateral Simultaneous Occurrence of Primary Squamous-cell Carcinoma of the Lung, Cancer 10: 1182-1186, 1957. 14. Hughes, R. F . , and Blades, B . : Multiple Primary Bronchogenic Carcinoma J . THORACIC SURG. 4 1 : 421-429, 1961.
15. Junghanns, H . : Eine Krebsstatistik iiber 35 J a h r e . (4,192 Carcinome bei 36,408 Leichenoffnungen.), Ztschr. Krebsforsch. 29: 623-664, 1929. 16. Kainberger, F . : tiber einen F a l l von doppeltem primarem Bronehuskarzinom, Klin. med. 10: 354-360, 1955. 17. Le Gal, Y., and Bauer, W. C.: Second P r i m a r y Bronchogenic Carcinoma: A Compli cation of Successful Lung Cancer Surgery, J. THORACIC SURG. 4 1 : 114-124, 1961. 18. Liavaag, K.: Bronchogenic Carcinoma, Acta chir. scandinav. 98: 182-204, 1949. 19. Lindberg, K.: ttber die Histologie des primaren Lungenkrebs, Arb. path. Inst. Univ. Heisingfors 8: 225-473, 1935. 20. McBurney, E. P., McDonald, J. E., and Clagett, O. T.: Bronchogenic Small-cell Car cinoma, J . THORACIC SURG. 22: 63-73, 1951.
21. McGrath, E. J., Gall, E. A., and Kessler, 1). P . : Bronchogenic Carcinoma: Product of Multiple Sites of Origin, J. THORACIC SURG. 24: 271-283, 1952. 22. Malmio, K.: Multiple P r i m a r y Cancer: A Clinical-Statistical Investigation Based on 650 Cases, Ann. chir. gynaec Fenniae 48: Suppl. 92, 1959. 23. Mandel, W., and Thomas, J. H.: Simultaneous Occurrence of Squamous and Adenocarcinoma of the Lung, California Med. 9 1 : 358-360, 1959. 24. Mider, G. B., Schilling, J. A., Donovan, J. C , and Rendall, E. S.: Multiple Cancer: A Study of Other Cancers Arising in P a t i e n t s W i t h P r i m a r y Malignant Neo plasms of the Stomach, Uterus, Breast, Large Intestine, or Hematopoietic System, Cancer 5: 1104-1109, 1952. 25. Moertel, C. G., Dockerty, M. B., and Baggenstoss, A. H . : Multiple P r i m a r y Malignant Neoplasms. I. Introduction and Presentation of Data. I I . Tumors of Different Tissues or Organs. I I I . Tumors of Multicentric Origin, Cancer 14: 221-231, 231238, and 238-249, 1961.
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26. Muller, R. F.: tJber multiple, nichtsj^stematisierte Primarcarcinome und ihre Haufigkeit, Ztschr. Krebsforsch. 3 1 : 339-360, 1930. 27. Newman, W., and Adkins, P. C.: Three P r i m a r y Carcinomas of the Lung Arising in a Left Lower Lobe W i t h Metastasis of Two of the Tumors, J. THORACIC SURG. 35: 474-482, 1958. 28. Paulson, D. L., and Shaw, R. R.: Results of Bronchoplastic Procedures for Broncho genic Carcinoma, Ann. Surg. 151: 729-739, 1960. 29. Phillips, C , and Shirey, R. W.: Multiple Primary Cancer: I t s Prognostic Significance, Acta I n t e r n a t . Union Against Cancer 6: 957-963, 1950. 30. Pirehan, A., and Sikl, H.: Cancer of the Lung in the Miners of Jachymov ( Joachim s t a l ) : Report of Cases Observed in 1929-1930, Am. J. Cancer 16: 681-722, 1932. 31. Rienhoff, W. F., King, J. D. B., and Dana, G. W. J r . : Surgical Treatment of Carcinoma of the L u n g : E v a l u a t i o n of 699 Cases From 1933 Through 1956, J. A. M. A. 166: 228-232, 1958. 32. Robinson, C. L. N., and Jackson, C. A.: Multiple P r i m a r y Cancer of t h e Lung, J . THORACIC SURG. 36: 166-173,
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33. Rostoski, Saupe, and Schmorl: Die Bergkrankheit der Erzbergleute in Schneeberg in Sachsen. ("Schneeberger Lungenkrebs."), Ztschr. Krebsforsch. 23: 360-384, 1926. 34. Ryan, R. F., and McDonald, J. R.: Bronchogenic Carcinoma With In Situ Carcinoma in the Opposite Lung, Proc. Staff Meet. Mayo Clin. 3 1 : 478-485, 1956. 35. Simons, E. J.: P r i m a r y Carcinoma of the Lung, Chicago, 1937,-Year Book Publishers, Inc. 36. Slaughter, D. P . : The Multiplicity of Origin of Malignant Tumors, I n t e r n a t . Abstr. Surg. 79: 89-98, 1944. 37. Spain, D. M., and Parsonnet, V.: Multiple Origin of Minute Bronchiolargenic Car cinomas: Report of a Case, Cancer 4: 277-285, 1951. 38. Stewart, F . W.: Factors Influencing the Curability of Cancer. Third National Cancer Conference Proceedings, Philadelphia, 1957, J. B. Lippincott Co., p. 65. 39. Theilhaber, A., and Edelburg, H.: Zur Lehre von der multiplizitat der Tumoren, Insbesondere der Carcinome, Deutsche Ztschr. Chir. 117: 457-489, 1912. 40. Warren, S., and Gates, O.: Multiple P r i m a r y Malignant Tumors: A Survey of the L i t e r a t u r e and a Statistical Study, Am. J . Cancer 16: 1358-1414, 1932. 41. Walter, J. B., and Pryce, D. M.: The Histology of Lung Cancer, Thorax 10: 107-116, 1955. 42. Walter, J. B., and Pryce, D. M.: The Site of Origin of Lung Cancer and I t s Relation to Histological Type, Thorax 10: 117-126, 1955. 43. Watson, T. A.: Incidence of Multiple Cancers, Cancer 6: 365-371, 1953. < 44. Wiklund, T.: Bronchiogenic Carcinoma: A Clinical Study of 259 Cases, 100 of Which Were Resected. Follow-up Study of the Resected Cases, Acta chir. scandinav. Suppl. 162, 1951. 45. Williams, M. J.: Extensive Carcinoma In Situ in the Bronchial Mucosa Associated W i t h Two Invasive Bronchogenic Carcinomas: Report of Case, Cancer 5 : 740747, 1952. 46. Willis, R. A.: Pathology of Tumors, St. Louis, 1948, The C. V. Mosby Company, p. 367.