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Multiple minute cancers of major bronchi
Multiple minute cancers of major bronchi A case report A case with early lung cancers of the major bronchi was reported. Thr ee separate m inute foci of carcinoma were found in the ma jor bronch i of the resected specim en which appeared unrelated to foci of atypical metaplasia or dysplasia. About 2 years after bilobectomy the patient died of carcinoma of the esophagus which was conside red to be an independent primary carcinoma.
Keiichi Suemasu, Yukio Shimosato , and Shichiro Ishikawa, Tokyo, Japan
Recently, the number of reported cases of early lung cancer of the major bronchi has been gradually increasing. A case of multiple minute lung cancers of the major bronchi is reported. This condition was preoperatively diagnosed and surgically resected but later a second primary carcinoma of the esophagus developed . Case report A 64-year-old Japanese man , a professor of ma thematic s who had lived mo st of his life in Tok yo and Nagoya, Japan, had been living between 1960 and 1970 in College Park, Md., U.S .A. In February, 1970, he was referred to a ho spital in the United States by his physician because of an episode of hemoptysis which had occurred 6 months previously. He had been a heav y cigarette smoker for many years. It was reported that a chest x-ray film taken at that time showed no abnormalit y. Bronchoscopy , carried out on Feb . 2, 1970, revealed an area sus picious of mal ignan cy in the bronchus intermedius close to the right upper lobe bronchus. A biopsy specimen taken from the lesion showed "severely dysplastic epithelium." The diF rom the Department of Surge ry and the Pathology Division , th e Na tional Cancer Center, Tokyo, Japan. Received for publication Ma y 3, 1974. Address for reprints : Dr. Keiichi Suem asu, D epartment of Surgery, Nati on al Cancer Center , Tsukiji S-chome, Chuo-Ku, T ok yo, J ap an.
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Fig. 1. Chest x-ray film taken on July 10, 1970, reveal ing no abnormalities. rect smear revealed tumor cells ( Papa nicolaou's Clas s V ). On March 11, 1970 , a second bronchoscopy was done. The biop sy from the suspicious area pre viously descr ibed showed again "severely dyspla stic epithelium ." A bronchoscopic smear from the r ight side showed Class III abnormal cells. On Jun e 1 I, 1970, the chest x-ray was again reported to be normal. A third bronchoscopy
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Fig. 2. Biopsy specimen obtained from the medial wall of the intermediate bronchus reveals neoplastic tissue with marked cellular atypia. The presence of bizarre tumor cells and arrangement of tumor cells in streams suggest invasive rather than in situ carcinoma, although stroma is not included in the section. (Left, x50; right, x200.) was done and multiple biopsy specimens were obtained from both lungs. The specimen obtained from the previously suspected area was covered by a normal bronchial epithelium. The bronchial mucosa of both lungs showed no abnormality except for the distal portion of the trachea with marked epithelial dysplasia and a focus of in situ carcinoma. Direct smears obtained from both lungs were reported to be Class II. The patient returned to Japan and visited our hospital. The x-ray films of the chest were essentially normal (Fig. 1). The biopsies obtained in February and March, 1970, were reviewed and interpreted as squamous-cell carcinoma. The first bronchoscopy was carried out in Japan on July 10, 1970. No tumor was seen but the mucosa of the distal portion of the trachea, lower brim of the orifice of the right upper lobe bronchus, and almost the entire right intermediate bronchus was congested. Bronchoscopic smears prepared from both lungs, including the "suspicious area," revealed no malignant cells. The biopsy of the medial wall of the right intermediate bronchus just below the upper lobe bronchus disclosed squamous-cell carcinoma (Fig. 2). Biopsies from other parts of the bronchus were negative for malignancy. An x-ray survey of the esophagus and stomach was done, revealing no abnormalities. The second bronchoscopy in Japan was done a week later with a flexible bronchofiberscope. Capillary dilatation of the mucosa from the distal trachea to the right bronchus intermedius was again noticed. A small ulcerlike lesion was seen at the orifice of the superior segmental bronchus of the right lower lobe. The bronchial smears showed suspicious cells and a sputum smear taken 3 days after the bronchofiberscopic examination revealed malignant cells of the squamous-cell type (Fig. 3).
•
Fig. 3. Sputum smear 3 days after the second bronchoscopy in Japan with a clump of neoplastic squamous cells arranged in a whorl. (x400.) The third bronchoscopy, on Sept. I, 1970, revealed a small tumorous lesion at the orifice of the superior segmental bronchus of the right lower lobe (Fig. 4). Biopsy of the lesion revealed a bronchial epithelium with slightly increased numbers of goblet cells. A biopsy specimen taken from the medial wall of the right intermediate bronchus disclosed squamous-cell carcinoma. By repeated bronchoscopic examinations, biopsies positive for carcinoma were obtained from the walls of the right intermediate bronchus just below the lower brim of the orifice of the right upper lobe bronchus, the medial wall of the intermediate bronchus near the opening of the upper lobe, and the distal portion of the trachea. Grossly, a tumorous lesion was seen at the opening of the superior segmental bronchus of the right lower lobe, although the biopsy failed to confirm its nature (Table I). It was decided that the lesion must have been
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Suemasu, Shimosato, Ishikawa
Table I. Bronchoscopic examinations Date (1970)
Mar. 11
Just below lower lip of upper lobe bronchus Same as above
June 11
Same as above
Feb. 2
G ross findings
Location
Indefinite or suspicious area Slight thickening, redness, and small plaque Roughness
Distal trachea
July 10 July 17
Medial wall of truncus Capillary dilatation intermedius Orifice of superior segSmall ulcerlike lesion mental bronchus of right lower lobe
Sept. 1
Same as above
Small tumor
Medial wall of truncus intermedius
in the intermediate bronchus and/or in the orifice of superior segmental bronchus of the lower lobe because the biopsy specimen taken from the distal portion of the trachea in the United States was not available to us and that in Japan revealed no tumor. Right lower and middle lobectomy was carried out On Sept. 17, 1970. On opening the right side of the chest no lesion could be palpated. The intermediate bronchus was transected (transection line shown as line A in Fig. 5). On frozen section, the resected end of the bronchus was free of carcinoma. The lining of the bronchus was inspected through the stump and a small polypoid lesion was found at the anterior wall of the main bronchus. The additional resection of the distal part of the main bronchus was done. However, the polypoid lesion was proved to be non-neoplastic on frozen section and no tumor was present at the second resection line. The final resection line of the bronchus is shown in Fig. 5 as line B. Lower and middle lobe resection and hilar and mediastinal lymph node dissection were carried out. Bronchi of the resected lobes were opened and two separate lesions were found. One was at the orifice of the superior segmental
Suspicious cells (sputum following bronchoscopy, Class V) Slight increase in number of goblet cells; no malignancy Squamous-cell carcinoma
bronchus of the lower lobe, where the mucosa was slightly rough or granular for 5 mm. along its long axis (Fig. 6), and another was just distal to the orifice of the middle lobe bronchus, where a 4 by 4 rnrn. slightly congested, slightly depressed, area was noted (Fig. 7). Histologically the lesion of the superior segmental bronchus was composed of layers of polygonal cells with oval or irregular and hyperchromatic nuclei, small nucleoli, a moderate amount of eosinophilic cytoplasm, and occasional mitotic figures, ending abruptly at the pseudostratified ciliated columnar epithelium of the bronchus, infiltrating superficially into the underlying layer with scalloped borders. Intercellular bridges and occasional dyskeratotic cells were present (Figs. 8A and 8B). A small nest of neoplastic cells was seen which appeared to be a duct of a bronchial gland. The lesion of the middle lobe bronchus was a carcinoma in situ, which was 7 mm. long along the longitudinal axis of the bronchus, and composed of short spindle to cuboidal cells with pleomorphic and hyperchromatic nuclei, intercellular bridges, and occasional mitotic figures (Fig. 9). The neoplastic focus was covered by the ciliated cells at the periphery of the lesion, indicating lateral infiltra-
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Fig. 4. A small polypoid lesion at the orifice of the superior segmental bronchus of the right lower lobe, photographed through the flexible bronchofiberscope.
Fig. 6. Surgical specimen with a minute granular lesion in the orifice of superior segmental bronchu s of the lower lobe (arrow) .
(
Fig. 5. Resection lines of the bronchus and loca tions of carcinomas or dysplastic epithelia found by bron choscopic biopsies and in the resected specimen. A , First transection line; B , second resection line; a, "severely dysplastic epithelium" obtained in February and Mar ch, 1970; b, positive biopsy obtained in July, 1970; c, positive biopsy obtained in June , 1970; d, squa mous-cell carcinoma in situ found in the surgical specimen; e, early invasive squamous-cell carcinoma found in the surgical specimen; t, squamou s-cell carcinoma in situ of a prob able bronchial gla nd duct found in the surgical specimen.
tion. A few minute nests of similar neoplastic cells were found in the subepithelial layer of the membranou s portion of the intermediate bronchus , probably repre senting bronchial gland duct with carcinoma in situ (Fig. 10). Altogether there were three neoplastic foci in the resected specimen, which were proved to be independent on step sections. No focus with atypical metaplasia or dyspla sia was found . Dissected lymph node s contained no meta stasis. The postoperative course was une ventful. One yea r after the operation the patient returned to the United State s. In the beginning of January , 1972, he experienced some dysphagia. Esoph agoscopy and bronchoscopy were done at a hospital in the United States . It was reported that esophagoscopy revealed an obstructing lesion, 33 em. from the upper incisor teeth, which appe ared to be a carcinoma; bronchoscopy revealed a soft, suspicious lesion just distal to the carina; biopsies from the bronchus and esophagus were both reported to be epidermoid carcinomas. Detailed information was not obt ained from the hospital, but it was stated that the patient
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Thorocic ond Cordiovoscular Surgery
Fig. 7. Surgical specimen with a slightly depressed and blood-stained lesion in the middle lobe bronchus (arrow).
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r .. -
..
. .. "' ; ~
... "
J
~
-1. _~
Fig. 8D. View of Fig. SA at higher magnification. (x200.)
Fig. SA. Histology of the lesion shown in Fig. 6, interpreted as early invasive squamous-cell carcinoma rather than in situ carcinoma. Note absence of metaplasia or dysplasia of the bronchial epithelium. (x50.)
received 5,600 rads of irradi ation to the whole mediastinum, including the lower esophagus, since both esophageal and bronchial lesions were considered to be secondary from the lung carcinomas removed in our hospital. Following radiotherapy the bronchial lesion disappeared but that of the lower esophagus showed no improvement. He returned to Japan and was readmitted to our hospital on June 20, 1972. Additional irradiation of 4,200 rads was given to the lesion of the lower esophagus and jejuno stomy was performed. The stenosi s of the esophagus was improved but its margin was still irregular. A perforation into the mediastinum was noted . The patient died on No v. 3, 1972. The cause of death was acute peritonitis due to the perfora-
tion of the esophageal carcinoma into the peritoneal cavity. Autop sy revealed no carcinomatous lesion in the lung or in the bronchial tree including the stump of the right main bronchus. No metastases were found in intrathoracic lymph nodes. Thorough histologic examinations of the epithelium from trachea to subsegmental bronchi did not reveal foci of dysplasia or carc inoma in situ but atypical basal cells scattered in the main and in several segmental bronchi. The esophageal carcinoma was considered to be an independent primary carcinoma, which invaded the stomach and liver , metastasized to perigastric and peripancreatic lymph nodes, and perforated into the peritoneal cavity .
Discussion This case of multiple minute lung cancers of the major bronchi showed no abnormalities on the chest x-ray films and was diagnosed by endoscopic examination preoperatively. Twelve cases of in situ or equivocally invasive carcinoma similar to the case reported herein were collected from the
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Multiple minute cancers of major bronchi
English literature>" (Table II). Eight were symptomatic and four asymptomatic. Among the symptomatic group, three patients complained of hemoptysis and the remainder of productive or nonproductive cough. Seven cases presented some abnormal findings on chest x-ray films such as infiltration or pneumonitis. These findings were considered as secondary parenchymal changes due to stenosis of the bronchus. There were five cases with negative chest x-ray. It should be noted that many of the cases with in situ or equivocally invasive carcinoma presented unexpected symptoms and abnormal chest x-ray findings . Valaitis and associates- investigated sputum cytology of smokers and nonsmokers and stated that, among 3,123 smokers, three were positive for tumor cells, two of which were proved to be carcinoma in situ. There were only four patients whose findings could be related to smoking among the 12, all of whom were moderate to heavy smokers. The patient reported herein had been a heavy cigarette smoker for many years. All of the 12 patients were male; 11 were in the fifth or sixth decade, as was our patient, and one was in the forties. Male patients of cancer age, with heavy smoking habits and respiratory symptoms, especially hemoptysis or bloody sputum, and with minimal or no x-ray findings, are very likely to have cancer of the major bronchus in the early stage and should be examined in detail. Lung cancer of the major bronchi in the early stage can be very difficult to locate. Bronchoscopy is most useful for localization. Among the 12 cases collected with in situ or equivocally invasive carcinoma , six showed some mucosal abnormalities which were described as granular surface, roughness, or redness corresponding to the lesion. In the remaining six, with no visible abnormality at the time of bronchoscopic examination, the tumors were localized by the examinations of separate bronchoscopic smears or by aspiration cytology, and then the lesions were successfully removed. On the other hand, Neuhof and Aufses? reported two cases in which bronchoscopic
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Fig. 9. Histology of the lesion shown in Fig. 7, showing features of in situ squamous-cell carcinoma. (xlOO.)
Fig. 10. branous vealing placing (x50 .)
Histology of the lesion found in the memportion of the truncus intermedius, reneoplastic squamous cells probably rethe lining of the bronchial gland duct.
biopsy was positive preoperatively and no carcinoma was found in the surgically resected specimens. Meyer, Bechtold, and Jones ' reported a case in which a pneumonitis-like shadow was seen in the upper lobe on chest x-ray films and positive sputum cytology was obtained but the resected right upper lobe contained no carcinomatous lesion. One patient reported by Aufses and Neuhof" became a long-term survivor and another developed a hilar mass, 4 by 3 cm., 5 years after operation. In the case of Meyer, Bechtold, and Jones ' a tumor was found at the entrance to the right lower lobe bronchus 6 years after operation. In the present case locations of the abnormal mucosa and histologically veri-
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Table II. Cases of early in situ or equivocally invasive cancers of major bronchus collected
ISmoking I
X-ray findings
Authors Ref. No.
Age
Sex
1
58
M
+
2 4
43 50
M M
+
4
64
M
Cough
5 5 5
55 63 62
M M M
Cough Cold, hemoptysis Pneumonia, hemoptysis
5 5
67 58
M M
5
52
M
3
57
M
+
3
51
M
+
habit
Symptoms
No findings Weakness, cough, sputum No findings Cough, hemoptysis Fever, cough, sputum Infiltration Obstructive pneumonitis Local emphysema Infiltration No findings
Pneumonitis Widening of mediastinum Cold, yellow sputum Enlarged hilum; infiltration No findings
tied lesions did not coincide very well in the course of several endoscopic examinations performed at different times, so that we felt uneasy until the surgical specimen was thoroughly inspected, whether or not the carcinomatous foci were in the suspected site. Among the 12 cases collected from the literature, seven patients underwent pneumonectomy, four lobectomy, and one no operation. In the follow-up study of two cases previously cited, in which the carcinoma could not be found in the resected specimens, Aufses and Neuhof" stated that if the pathologist made an unequivocal diagnosis of malignancy upon examination of a specimen obtained from a major bronchus, the surgeon should have performed a pneumonectomy even though no gross evidence of malignancy was found at operation. In our case, inspection through the bronchial stump, quick cytology, and frozen sections were carried out during the operation and the bilobectomy was done. If the focus of carcinoma found in the bronchial stump at a hospital in the United States one year and four months postoperatively had been a recurrence from the submucosal focus
No findings
Sputum cytology
I
Bronchoscopic findings
+
No findings
+
Granular area Roughness
+
No findings
+ + +
No findings No findings Roughness Nodular Blood Mucosal abnormality
+
No findings
+
No findings
found in the intermediate bronchus in the resected specimen pneumonectomy might have been preferable, but it could well have been another focus of carcinoma. The histologic type of the present case was squamous-cell carcinoma, as was that of most of the cases collected. In our case there were three separate foci of minute carcinomas in the resected specimen, one in the superior segmental bronchus of the lower lobe, one in the middle lobe bronchus, and the other in the intermediate bronchus. Fig. 5 is a schematic representation of the location of neoplastic or severely dysplastic epithelia found by several endoscopic biopsies and in the resected specimen. Foci a, b, and f were situated close to the entrance of the intermediate bronchus. It is possible that the superficial part of a minute carcinoma was completely removed by repeated biopsies and only a ductal lesion was found in the resected specimen. In no case collected were multiple primary lesions found. It has been reported that only 2.7 per cent of 37 cases of carcinoma in situ of the uterine cervix regressed spontaneously," and that the "spontaneous" regression observed
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from English literature Bronchoscopic IBrOllcllOSCOPiCI
cytology
biopsy
+
+
±
+ +
Histology
Operation
Location
±
Pneumonectomy
Epidermoid cell carciLower trunk noma Neoplastic epithelium Segmental branches of lower trunk Squamous-cell carcinoma Main bronchus, upper, intermediate, and lower trunk Squamous-cell carcinoma Segmental bronchus of upper trunk
+
Lobectomy Pneumonectomy Pneumonectomy
Squamous-cell carcinoma Segmental bronchus of upper lobe Carcinoma Upper trunk, its segmental branches Squamous-cell carcinoma Main bronchus, upper trunk
+
Pneumonectomy Pneumonectomy
Carcinoma Carcinoma
Upper trunk, its segmental branches Segmental bronchus of upper lobe
+
Pneumonectomy
Carcinoma
Main bronchus
Lobectomy
Squamous-cell carcinoma Segmental and subsegmental bronchi of upper lobe Squamous-cell carcinoma Segmental bronchus of upper lobe
+ +
+
+
+ +
+
+
Lobectomy Pneumonectomy
Lobectomy
might not be spontaneous in nature but the result of multiple and repeated biopsy samplings. Auerbach and associates'? stated that in some lung cancer cases there were separate carcinomas in situ in the bronchus. Ryan and McDonald" reported five cases of bronchogenic carcinoma with carcinoma in situ in the opposite lung. We also experienced a case in which carcinoma in situ was present apart from the small carcinoma confined to the bronchial wall." This patient developed later carcinomas of the larynx and of the opposite lung but was sucessfully treated and survived for 7 years after initial surgery.» These observations support the assumption that squamous-cell carcinomas of the major bronchi are probably induced by chemical carcinogens. All the minute in situ or early invasive squamous-cell carcinomas we experienced so far ended abruptly at the pesudostratified ciliated columnar epithelium. And no focus of squamous-cell metaplasia or dysplasia was observed in or adjacent to the lesions. This finding may indicate that bronchial squamous-cell carcinomas developed in some instances from the normal-appearing epithelium, not through the stage of atypical
metaplasia or dysplasia. The biopsy specimens obtained prior to operation and diagnosed as severely dysplastic epithelium elsewhere were reviewed and interpreted by one of us as squamous-cell carcinoma, supporting this assumption. Association of metaplastic or dysplastic epithelium with squamous-cell carcinoma, which is considered to be a general rule by some, may be related to potency and types of carcinogen and to the period of time during which patients are exposed to it. If the esophageal lesion had been metastatic from the lung cancer, the route of the spread could have been either a direct extension from the lung, or from the lymph node metastasis of the lower mediastinum, or blood borne. No carcinomatous continuation, however, was seen between the esophageal lesion and the remaining lung, including the bronchial stump. No metastasis was found in any of the lymph nodes removed surgically or examined at autopsy. Furthermore, it has been widely recognized that the esophagus is a very rare site of hematogenous metastasis of lung cancer. We have never seen this type of metastasis. The bronchial lesions
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were reasonably considered to be primary from the growth pattern. From the clinicopathological features and the autopsy findings, therefore, the patient was considered to have developed small lung cancers of the major bronchi which were followed by an independent primary esophageal cancer. REFERENCES
2
3
4
5
6
Papanicolaou, G. N., and Korpowska, I.: Carcinoma In Situ of the Right Lower BronchusA Case Report, Cancer 4: 141, 1951. Umiker, W., and Storey, c.: Bronchogenic Carcinoma In Situ-Report of a Case With Positive Biopsy, Cytological Examination and Lobectomy, Cancer 5: 369, 1952. Valaitis, J., McGrew, E. A., Chomet, B., CorreI, N., and Head, J.: Bronchogenic Carcinoma In Situ in Asymptomatic High-Risk Population of Smokers. Wierman, W. H., McDonald, J. R., and Clagett, O. T.: Occult Carcinoma of the Major Bronchi, Surgery 35: 335, 1954. Woolner, L. B., Andersen, H. A., and Bernatz, P. E.: Occult Carcinoma of the Bronchus: A Study of 15 Cases of in Situ or Early Invasive Bronchogenic Carcinoma. Neuhof, H., and Aufses, A H.: Cancer of the Lung. Interval and Late Results of Operation
Thorocic ond Cardiovascular Surgery
7
8
9
10
II
12 13
in Relation to Topography and Gross Pathology, J. THORAC. SURG. 17: 297, 1948. Meyer, J. A., Bechtold, E., and Jones, D. B.: Positive Sputum Cytologic Tests for Five Years Before Specific Detection of Bronchial Carcinoma, J. THORAC. CARDIOVASC. SURG. 57: 318, 1969. Aufses, A H., and Neuhof, H.: Minute Carcinoma of the Major Bronchi-A Follow-up Report, J. THoRAc. SURG. 23: 219, 1952. Kurihara, S.: Precancerous Changes in Uterine Cervix (in Japanese), 1972, Published by Kurihara, p. 22. Auerbach, 0., Gere, J. B., Pawlowski, J. M., Muehsam, G. E., Smolin, H. J., and Stout, A. P.: Carcinoma In Situ and Early Invasive Carcinoma Occurring in the Tracheobronchial Trees in Cases of Bronchial Carcinoma, J. THORAC. SURG. 34: 298, 1957. Ryan, R., and McDonald, J. R.: Bronchogenic Carcinoma With Carcinoma in Situ in the Oppositte Lung: Report of Five Cases, Proc. Staff Meet., Mayo Clin. 31: 478, 1956. Ishikawa, S.: Atlas of Lung Cancer (in Japanese), 1968, Nakayama Shoten, pp. 47-52. Miyazawa, N., Shimosato, Y., Suemasu, K., Ogata, T., Yoneyama, T., Naruka, T., Ikeda, S., and Suzuki, A: Pathological and Clinical Study of 6 Cases of Early Lung Cancer, Hilar Type, J. Jap. Assoc. Thorac Surg. 21: 688, 1973 (in Japanese).
Keiichi Suemasu, Yukio Shimosato , and Shichiro Ishikawa, Tokyo, Japan
Recently, the number of reported cases of early lung cancer of the major bronchi has been gradually increasing. A case of multiple minute lung cancers of the major bronchi is reported. This condition was preoperatively diagnosed and surgically resected but later a second primary carcinoma of the esophagus developed . Case report A 64-year-old Japanese man , a professor of ma thematic s who had lived mo st of his life in Tok yo and Nagoya, Japan, had been living between 1960 and 1970 in College Park, Md., U.S .A. In February, 1970, he was referred to a ho spital in the United States by his physician because of an episode of hemoptysis which had occurred 6 months previously. He had been a heav y cigarette smoker for many years. It was reported that a chest x-ray film taken at that time showed no abnormalit y. Bronchoscopy , carried out on Feb . 2, 1970, revealed an area sus picious of mal ignan cy in the bronchus intermedius close to the right upper lobe bronchus. A biopsy specimen taken from the lesion showed "severely dysplastic epithelium." The diF rom the Department of Surge ry and the Pathology Division , th e Na tional Cancer Center, Tokyo, Japan. Received for publication Ma y 3, 1974. Address for reprints : Dr. Keiichi Suem asu, D epartment of Surgery, Nati on al Cancer Center , Tsukiji S-chome, Chuo-Ku, T ok yo, J ap an.
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Fig. 1. Chest x-ray film taken on July 10, 1970, reveal ing no abnormalities. rect smear revealed tumor cells ( Papa nicolaou's Clas s V ). On March 11, 1970 , a second bronchoscopy was done. The biop sy from the suspicious area pre viously descr ibed showed again "severely dyspla stic epithelium ." A bronchoscopic smear from the r ight side showed Class III abnormal cells. On Jun e 1 I, 1970, the chest x-ray was again reported to be normal. A third bronchoscopy
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Fig. 2. Biopsy specimen obtained from the medial wall of the intermediate bronchus reveals neoplastic tissue with marked cellular atypia. The presence of bizarre tumor cells and arrangement of tumor cells in streams suggest invasive rather than in situ carcinoma, although stroma is not included in the section. (Left, x50; right, x200.) was done and multiple biopsy specimens were obtained from both lungs. The specimen obtained from the previously suspected area was covered by a normal bronchial epithelium. The bronchial mucosa of both lungs showed no abnormality except for the distal portion of the trachea with marked epithelial dysplasia and a focus of in situ carcinoma. Direct smears obtained from both lungs were reported to be Class II. The patient returned to Japan and visited our hospital. The x-ray films of the chest were essentially normal (Fig. 1). The biopsies obtained in February and March, 1970, were reviewed and interpreted as squamous-cell carcinoma. The first bronchoscopy was carried out in Japan on July 10, 1970. No tumor was seen but the mucosa of the distal portion of the trachea, lower brim of the orifice of the right upper lobe bronchus, and almost the entire right intermediate bronchus was congested. Bronchoscopic smears prepared from both lungs, including the "suspicious area," revealed no malignant cells. The biopsy of the medial wall of the right intermediate bronchus just below the upper lobe bronchus disclosed squamous-cell carcinoma (Fig. 2). Biopsies from other parts of the bronchus were negative for malignancy. An x-ray survey of the esophagus and stomach was done, revealing no abnormalities. The second bronchoscopy in Japan was done a week later with a flexible bronchofiberscope. Capillary dilatation of the mucosa from the distal trachea to the right bronchus intermedius was again noticed. A small ulcerlike lesion was seen at the orifice of the superior segmental bronchus of the right lower lobe. The bronchial smears showed suspicious cells and a sputum smear taken 3 days after the bronchofiberscopic examination revealed malignant cells of the squamous-cell type (Fig. 3).
•
Fig. 3. Sputum smear 3 days after the second bronchoscopy in Japan with a clump of neoplastic squamous cells arranged in a whorl. (x400.) The third bronchoscopy, on Sept. I, 1970, revealed a small tumorous lesion at the orifice of the superior segmental bronchus of the right lower lobe (Fig. 4). Biopsy of the lesion revealed a bronchial epithelium with slightly increased numbers of goblet cells. A biopsy specimen taken from the medial wall of the right intermediate bronchus disclosed squamous-cell carcinoma. By repeated bronchoscopic examinations, biopsies positive for carcinoma were obtained from the walls of the right intermediate bronchus just below the lower brim of the orifice of the right upper lobe bronchus, the medial wall of the intermediate bronchus near the opening of the upper lobe, and the distal portion of the trachea. Grossly, a tumorous lesion was seen at the opening of the superior segmental bronchus of the right lower lobe, although the biopsy failed to confirm its nature (Table I). It was decided that the lesion must have been
666
The Journol 0/ Thoracic and Cardiovascular Surgery
Suemasu, Shimosato, Ishikawa
Table I. Bronchoscopic examinations Date (1970)
Mar. 11
Just below lower lip of upper lobe bronchus Same as above
June 11
Same as above
Feb. 2
G ross findings
Location
Indefinite or suspicious area Slight thickening, redness, and small plaque Roughness
Distal trachea
July 10 July 17
Medial wall of truncus Capillary dilatation intermedius Orifice of superior segSmall ulcerlike lesion mental bronchus of right lower lobe
Sept. 1
Same as above
Small tumor
Medial wall of truncus intermedius
in the intermediate bronchus and/or in the orifice of superior segmental bronchus of the lower lobe because the biopsy specimen taken from the distal portion of the trachea in the United States was not available to us and that in Japan revealed no tumor. Right lower and middle lobectomy was carried out On Sept. 17, 1970. On opening the right side of the chest no lesion could be palpated. The intermediate bronchus was transected (transection line shown as line A in Fig. 5). On frozen section, the resected end of the bronchus was free of carcinoma. The lining of the bronchus was inspected through the stump and a small polypoid lesion was found at the anterior wall of the main bronchus. The additional resection of the distal part of the main bronchus was done. However, the polypoid lesion was proved to be non-neoplastic on frozen section and no tumor was present at the second resection line. The final resection line of the bronchus is shown in Fig. 5 as line B. Lower and middle lobe resection and hilar and mediastinal lymph node dissection were carried out. Bronchi of the resected lobes were opened and two separate lesions were found. One was at the orifice of the superior segmental
Suspicious cells (sputum following bronchoscopy, Class V) Slight increase in number of goblet cells; no malignancy Squamous-cell carcinoma
bronchus of the lower lobe, where the mucosa was slightly rough or granular for 5 mm. along its long axis (Fig. 6), and another was just distal to the orifice of the middle lobe bronchus, where a 4 by 4 rnrn. slightly congested, slightly depressed, area was noted (Fig. 7). Histologically the lesion of the superior segmental bronchus was composed of layers of polygonal cells with oval or irregular and hyperchromatic nuclei, small nucleoli, a moderate amount of eosinophilic cytoplasm, and occasional mitotic figures, ending abruptly at the pseudostratified ciliated columnar epithelium of the bronchus, infiltrating superficially into the underlying layer with scalloped borders. Intercellular bridges and occasional dyskeratotic cells were present (Figs. 8A and 8B). A small nest of neoplastic cells was seen which appeared to be a duct of a bronchial gland. The lesion of the middle lobe bronchus was a carcinoma in situ, which was 7 mm. long along the longitudinal axis of the bronchus, and composed of short spindle to cuboidal cells with pleomorphic and hyperchromatic nuclei, intercellular bridges, and occasional mitotic figures (Fig. 9). The neoplastic focus was covered by the ciliated cells at the periphery of the lesion, indicating lateral infiltra-
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Fig. 4. A small polypoid lesion at the orifice of the superior segmental bronchus of the right lower lobe, photographed through the flexible bronchofiberscope.
Fig. 6. Surgical specimen with a minute granular lesion in the orifice of superior segmental bronchu s of the lower lobe (arrow) .
(
Fig. 5. Resection lines of the bronchus and loca tions of carcinomas or dysplastic epithelia found by bron choscopic biopsies and in the resected specimen. A , First transection line; B , second resection line; a, "severely dysplastic epithelium" obtained in February and Mar ch, 1970; b, positive biopsy obtained in July, 1970; c, positive biopsy obtained in June , 1970; d, squa mous-cell carcinoma in situ found in the surgical specimen; e, early invasive squamous-cell carcinoma found in the surgical specimen; t, squamou s-cell carcinoma in situ of a prob able bronchial gla nd duct found in the surgical specimen.
tion. A few minute nests of similar neoplastic cells were found in the subepithelial layer of the membranou s portion of the intermediate bronchus , probably repre senting bronchial gland duct with carcinoma in situ (Fig. 10). Altogether there were three neoplastic foci in the resected specimen, which were proved to be independent on step sections. No focus with atypical metaplasia or dyspla sia was found . Dissected lymph node s contained no meta stasis. The postoperative course was une ventful. One yea r after the operation the patient returned to the United State s. In the beginning of January , 1972, he experienced some dysphagia. Esoph agoscopy and bronchoscopy were done at a hospital in the United States . It was reported that esophagoscopy revealed an obstructing lesion, 33 em. from the upper incisor teeth, which appe ared to be a carcinoma; bronchoscopy revealed a soft, suspicious lesion just distal to the carina; biopsies from the bronchus and esophagus were both reported to be epidermoid carcinomas. Detailed information was not obt ained from the hospital, but it was stated that the patient
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Thorocic ond Cordiovoscular Surgery
Fig. 7. Surgical specimen with a slightly depressed and blood-stained lesion in the middle lobe bronchus (arrow).
-..... . -, ,,•-'
\
r .. -
..
. .. "' ; ~
... "
J
~
-1. _~
Fig. 8D. View of Fig. SA at higher magnification. (x200.)
Fig. SA. Histology of the lesion shown in Fig. 6, interpreted as early invasive squamous-cell carcinoma rather than in situ carcinoma. Note absence of metaplasia or dysplasia of the bronchial epithelium. (x50.)
received 5,600 rads of irradi ation to the whole mediastinum, including the lower esophagus, since both esophageal and bronchial lesions were considered to be secondary from the lung carcinomas removed in our hospital. Following radiotherapy the bronchial lesion disappeared but that of the lower esophagus showed no improvement. He returned to Japan and was readmitted to our hospital on June 20, 1972. Additional irradiation of 4,200 rads was given to the lesion of the lower esophagus and jejuno stomy was performed. The stenosi s of the esophagus was improved but its margin was still irregular. A perforation into the mediastinum was noted . The patient died on No v. 3, 1972. The cause of death was acute peritonitis due to the perfora-
tion of the esophageal carcinoma into the peritoneal cavity. Autop sy revealed no carcinomatous lesion in the lung or in the bronchial tree including the stump of the right main bronchus. No metastases were found in intrathoracic lymph nodes. Thorough histologic examinations of the epithelium from trachea to subsegmental bronchi did not reveal foci of dysplasia or carc inoma in situ but atypical basal cells scattered in the main and in several segmental bronchi. The esophageal carcinoma was considered to be an independent primary carcinoma, which invaded the stomach and liver , metastasized to perigastric and peripancreatic lymph nodes, and perforated into the peritoneal cavity .
Discussion This case of multiple minute lung cancers of the major bronchi showed no abnormalities on the chest x-ray films and was diagnosed by endoscopic examination preoperatively. Twelve cases of in situ or equivocally invasive carcinoma similar to the case reported herein were collected from the
Volume 68 Number 4 October, 1974
Multiple minute cancers of major bronchi
English literature>" (Table II). Eight were symptomatic and four asymptomatic. Among the symptomatic group, three patients complained of hemoptysis and the remainder of productive or nonproductive cough. Seven cases presented some abnormal findings on chest x-ray films such as infiltration or pneumonitis. These findings were considered as secondary parenchymal changes due to stenosis of the bronchus. There were five cases with negative chest x-ray. It should be noted that many of the cases with in situ or equivocally invasive carcinoma presented unexpected symptoms and abnormal chest x-ray findings . Valaitis and associates- investigated sputum cytology of smokers and nonsmokers and stated that, among 3,123 smokers, three were positive for tumor cells, two of which were proved to be carcinoma in situ. There were only four patients whose findings could be related to smoking among the 12, all of whom were moderate to heavy smokers. The patient reported herein had been a heavy cigarette smoker for many years. All of the 12 patients were male; 11 were in the fifth or sixth decade, as was our patient, and one was in the forties. Male patients of cancer age, with heavy smoking habits and respiratory symptoms, especially hemoptysis or bloody sputum, and with minimal or no x-ray findings, are very likely to have cancer of the major bronchus in the early stage and should be examined in detail. Lung cancer of the major bronchi in the early stage can be very difficult to locate. Bronchoscopy is most useful for localization. Among the 12 cases collected with in situ or equivocally invasive carcinoma , six showed some mucosal abnormalities which were described as granular surface, roughness, or redness corresponding to the lesion. In the remaining six, with no visible abnormality at the time of bronchoscopic examination, the tumors were localized by the examinations of separate bronchoscopic smears or by aspiration cytology, and then the lesions were successfully removed. On the other hand, Neuhof and Aufses? reported two cases in which bronchoscopic
669
Fig. 9. Histology of the lesion shown in Fig. 7, showing features of in situ squamous-cell carcinoma. (xlOO.)
Fig. 10. branous vealing placing (x50 .)
Histology of the lesion found in the memportion of the truncus intermedius, reneoplastic squamous cells probably rethe lining of the bronchial gland duct.
biopsy was positive preoperatively and no carcinoma was found in the surgically resected specimens. Meyer, Bechtold, and Jones ' reported a case in which a pneumonitis-like shadow was seen in the upper lobe on chest x-ray films and positive sputum cytology was obtained but the resected right upper lobe contained no carcinomatous lesion. One patient reported by Aufses and Neuhof" became a long-term survivor and another developed a hilar mass, 4 by 3 cm., 5 years after operation. In the case of Meyer, Bechtold, and Jones ' a tumor was found at the entrance to the right lower lobe bronchus 6 years after operation. In the present case locations of the abnormal mucosa and histologically veri-
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Table II. Cases of early in situ or equivocally invasive cancers of major bronchus collected
ISmoking I
X-ray findings
Authors Ref. No.
Age
Sex
1
58
M
+
2 4
43 50
M M
+
4
64
M
Cough
5 5 5
55 63 62
M M M
Cough Cold, hemoptysis Pneumonia, hemoptysis
5 5
67 58
M M
5
52
M
3
57
M
+
3
51
M
+
habit
Symptoms
No findings Weakness, cough, sputum No findings Cough, hemoptysis Fever, cough, sputum Infiltration Obstructive pneumonitis Local emphysema Infiltration No findings
Pneumonitis Widening of mediastinum Cold, yellow sputum Enlarged hilum; infiltration No findings
tied lesions did not coincide very well in the course of several endoscopic examinations performed at different times, so that we felt uneasy until the surgical specimen was thoroughly inspected, whether or not the carcinomatous foci were in the suspected site. Among the 12 cases collected from the literature, seven patients underwent pneumonectomy, four lobectomy, and one no operation. In the follow-up study of two cases previously cited, in which the carcinoma could not be found in the resected specimens, Aufses and Neuhof" stated that if the pathologist made an unequivocal diagnosis of malignancy upon examination of a specimen obtained from a major bronchus, the surgeon should have performed a pneumonectomy even though no gross evidence of malignancy was found at operation. In our case, inspection through the bronchial stump, quick cytology, and frozen sections were carried out during the operation and the bilobectomy was done. If the focus of carcinoma found in the bronchial stump at a hospital in the United States one year and four months postoperatively had been a recurrence from the submucosal focus
No findings
Sputum cytology
I
Bronchoscopic findings
+
No findings
+
Granular area Roughness
+
No findings
+ + +
No findings No findings Roughness Nodular Blood Mucosal abnormality
+
No findings
+
No findings
found in the intermediate bronchus in the resected specimen pneumonectomy might have been preferable, but it could well have been another focus of carcinoma. The histologic type of the present case was squamous-cell carcinoma, as was that of most of the cases collected. In our case there were three separate foci of minute carcinomas in the resected specimen, one in the superior segmental bronchus of the lower lobe, one in the middle lobe bronchus, and the other in the intermediate bronchus. Fig. 5 is a schematic representation of the location of neoplastic or severely dysplastic epithelia found by several endoscopic biopsies and in the resected specimen. Foci a, b, and f were situated close to the entrance of the intermediate bronchus. It is possible that the superficial part of a minute carcinoma was completely removed by repeated biopsies and only a ductal lesion was found in the resected specimen. In no case collected were multiple primary lesions found. It has been reported that only 2.7 per cent of 37 cases of carcinoma in situ of the uterine cervix regressed spontaneously," and that the "spontaneous" regression observed
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Multiple minute cancers of major bronchi
Number 4
67 1
October, 1974
from English literature Bronchoscopic IBrOllcllOSCOPiCI
cytology
biopsy
+
+
±
+ +
Histology
Operation
Location
±
Pneumonectomy
Epidermoid cell carciLower trunk noma Neoplastic epithelium Segmental branches of lower trunk Squamous-cell carcinoma Main bronchus, upper, intermediate, and lower trunk Squamous-cell carcinoma Segmental bronchus of upper trunk
+
Lobectomy Pneumonectomy Pneumonectomy
Squamous-cell carcinoma Segmental bronchus of upper lobe Carcinoma Upper trunk, its segmental branches Squamous-cell carcinoma Main bronchus, upper trunk
+
Pneumonectomy Pneumonectomy
Carcinoma Carcinoma
Upper trunk, its segmental branches Segmental bronchus of upper lobe
+
Pneumonectomy
Carcinoma
Main bronchus
Lobectomy
Squamous-cell carcinoma Segmental and subsegmental bronchi of upper lobe Squamous-cell carcinoma Segmental bronchus of upper lobe
+ +
+
+
+ +
+
+
Lobectomy Pneumonectomy
Lobectomy
might not be spontaneous in nature but the result of multiple and repeated biopsy samplings. Auerbach and associates'? stated that in some lung cancer cases there were separate carcinomas in situ in the bronchus. Ryan and McDonald" reported five cases of bronchogenic carcinoma with carcinoma in situ in the opposite lung. We also experienced a case in which carcinoma in situ was present apart from the small carcinoma confined to the bronchial wall." This patient developed later carcinomas of the larynx and of the opposite lung but was sucessfully treated and survived for 7 years after initial surgery.» These observations support the assumption that squamous-cell carcinomas of the major bronchi are probably induced by chemical carcinogens. All the minute in situ or early invasive squamous-cell carcinomas we experienced so far ended abruptly at the pesudostratified ciliated columnar epithelium. And no focus of squamous-cell metaplasia or dysplasia was observed in or adjacent to the lesions. This finding may indicate that bronchial squamous-cell carcinomas developed in some instances from the normal-appearing epithelium, not through the stage of atypical
metaplasia or dysplasia. The biopsy specimens obtained prior to operation and diagnosed as severely dysplastic epithelium elsewhere were reviewed and interpreted by one of us as squamous-cell carcinoma, supporting this assumption. Association of metaplastic or dysplastic epithelium with squamous-cell carcinoma, which is considered to be a general rule by some, may be related to potency and types of carcinogen and to the period of time during which patients are exposed to it. If the esophageal lesion had been metastatic from the lung cancer, the route of the spread could have been either a direct extension from the lung, or from the lymph node metastasis of the lower mediastinum, or blood borne. No carcinomatous continuation, however, was seen between the esophageal lesion and the remaining lung, including the bronchial stump. No metastasis was found in any of the lymph nodes removed surgically or examined at autopsy. Furthermore, it has been widely recognized that the esophagus is a very rare site of hematogenous metastasis of lung cancer. We have never seen this type of metastasis. The bronchial lesions
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were reasonably considered to be primary from the growth pattern. From the clinicopathological features and the autopsy findings, therefore, the patient was considered to have developed small lung cancers of the major bronchi which were followed by an independent primary esophageal cancer. REFERENCES
2
3
4
5
6
Papanicolaou, G. N., and Korpowska, I.: Carcinoma In Situ of the Right Lower BronchusA Case Report, Cancer 4: 141, 1951. Umiker, W., and Storey, c.: Bronchogenic Carcinoma In Situ-Report of a Case With Positive Biopsy, Cytological Examination and Lobectomy, Cancer 5: 369, 1952. Valaitis, J., McGrew, E. A., Chomet, B., CorreI, N., and Head, J.: Bronchogenic Carcinoma In Situ in Asymptomatic High-Risk Population of Smokers. Wierman, W. H., McDonald, J. R., and Clagett, O. T.: Occult Carcinoma of the Major Bronchi, Surgery 35: 335, 1954. Woolner, L. B., Andersen, H. A., and Bernatz, P. E.: Occult Carcinoma of the Bronchus: A Study of 15 Cases of in Situ or Early Invasive Bronchogenic Carcinoma. Neuhof, H., and Aufses, A H.: Cancer of the Lung. Interval and Late Results of Operation
Thorocic ond Cardiovascular Surgery
7
8
9
10
II
12 13
in Relation to Topography and Gross Pathology, J. THORAC. SURG. 17: 297, 1948. Meyer, J. A., Bechtold, E., and Jones, D. B.: Positive Sputum Cytologic Tests for Five Years Before Specific Detection of Bronchial Carcinoma, J. THORAC. CARDIOVASC. SURG. 57: 318, 1969. Aufses, A H., and Neuhof, H.: Minute Carcinoma of the Major Bronchi-A Follow-up Report, J. THoRAc. SURG. 23: 219, 1952. Kurihara, S.: Precancerous Changes in Uterine Cervix (in Japanese), 1972, Published by Kurihara, p. 22. Auerbach, 0., Gere, J. B., Pawlowski, J. M., Muehsam, G. E., Smolin, H. J., and Stout, A. P.: Carcinoma In Situ and Early Invasive Carcinoma Occurring in the Tracheobronchial Trees in Cases of Bronchial Carcinoma, J. THORAC. SURG. 34: 298, 1957. Ryan, R., and McDonald, J. R.: Bronchogenic Carcinoma With Carcinoma in Situ in the Oppositte Lung: Report of Five Cases, Proc. Staff Meet., Mayo Clin. 31: 478, 1956. Ishikawa, S.: Atlas of Lung Cancer (in Japanese), 1968, Nakayama Shoten, pp. 47-52. Miyazawa, N., Shimosato, Y., Suemasu, K., Ogata, T., Yoneyama, T., Naruka, T., Ikeda, S., and Suzuki, A: Pathological and Clinical Study of 6 Cases of Early Lung Cancer, Hilar Type, J. Jap. Assoc. Thorac Surg. 21: 688, 1973 (in Japanese).