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EXOPHYTIC ENDOBRONCHIAL CARCINOMA
EXOPHYTIC E N D O B R O N C H I A L CARCINOMA Russell P. Sherwin, AID.,* Eugene G. Laforet, M.D.,** John W. Strieder, M.D.***
Boston,
and
Mass.
NE of the obviously important factors influencing the prognosis of lung cancer is the aggressiveness of the tumor. The pathologist evaluates tumor behavior by a study of cellular appearance, tumor architecture, and the manner of tumor spread. However, classifications of lung tumors have been based essentially on cellular appearance with little or no emphasis on architecture. 1 '"' :i Invasion studies have stressed involvement of lymph nodes or vessels,4 relatively little attention being paid to the nature of the advancing tumor margin. In a study of 85 cases of lung cancer,5 emphasizing tumor architecture and infiltration pattern, nine lung carcinomas with a unique structure were encoun tered. All were characterized by a predominantly endobronchial carcinomatous growth of a papillomatous, polypoid, or vcrrucous nature. In addition, certain aspects of tumor invasion were remarkable. Of great importance is the presump tive favorable prognosis of these tumors.
O
MATERIALS AND METHODS
Eighty-five patients with lung cancer suitable for definitive resection and under the care of a single thoracic surgical group at one hospital were reviewed. Individuals who did not survive operation were not included. Within these limits the series was consecutive and unselected. A 16 year period was covered, extending from 1945 to the early part of 1961. The microscopic sections of the tumors were reviewed without prior clinical knowledge, and estimates of prog nosis, based on the microscopic sections, were recorded. In most cases paraffin blocks were available to supplement the slides. In some instances formalin-fixed tissue was re-examined. Seven of the nine exophytic carcinomas had not been recognized as such. The eighth and ninth were anticipated bronchoscopically after the study of this group had begun. CASE REPORTS CASE 1.—In May, 1945, a 60-year-old Caucasian exceutive had a chest x-ray examination because of loss of weight and productive cough following a tuberculosis contact. The roentProm the Departments of Pathology and Surgery, Massachusetts Memorial Hospitals and Boston University Medical Center, Boston, Mass. Received for publication June 15, 1961. ♦Associate Pathologist, Massachusetts Memorial Hospitals; Assistant Clinical Professor of Pathology, Boston University School of Medicine. ** Assistant in Surgery (Thoracic), Massachusetts Memorial Hospitals; Clinical Instructor in Surgery, Boston University School of Medicine. ♦"Visiting Surgeon (Thoracic), Massachusetts Memorial Hospitals; Professor of Clinical Surgery, Boston University School of Medicine. 716
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E X O P H Y T I C ENDOBRONCHIAL CANCER
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genogram exhibited partial atelectasis of the right upper lobe and further study was advised. (The smoking history was not determined.) Bronchoscopy showed injection and friability of the inferior carina of the right upper lobe bronchus without marked outcropping of tissue. Biopsy specimen of this area was interpreted as being ' ' epidermoid carcinoma.'' Bight pneumonectomy was performed on June 6, 1945. At operation the right upper lobe was found to be atelectatic and fixed to the chest wall by inflammatory adhesions, but the hilar struc tures were mobile and free of gross tumor involvement. The postoperative course was un complicated. The patient progressed satisfactorily until April, 1949, when he complained of cough, dyspnea, and weight loss. X-ray examination showed a mass in the left lower lobe consistent with a metastatic lesion. Radiation therapy was instituted but proved ineffective. After a rapidly downhill course, the patient died on June 13, 1949, 4 years after pneumonec tomy. Autopsy was not performed. Pathology.—The gross appearance of the operative specimen was described as follows: ' ' The bronchus to the lower portion of the right upper lobe is completely obstructed by a mass of firm, gray-white, somewhat papillary tissue, the center of which is hemorrhagic. The tumor involves approximately 3 cm. of bronchus and produces up to 4 mm. of mucosal thicken ing. At no point does it invade the surrounding l u n g . " The diagnosis was epidermoid car cinoma, grade 2 to 3. Lymph nodes were negative for tumor. An associated finding was a marked organizing granulomatous pneumonitis of the cholesterol type with bronchiectasis, secondary to obstruction of the bronchus. CASE 2.—A 61-year-old Caucasian laborer was admitted to Massachusetts Memorial Hospitals on Dec. 16, 1947, because of a productive cough for the preceding 18 months. The cough had been associated with a vague " p r e s s i n g " sensation in the lower right chest. (A smoking history was not elicited.) The patient was well nourished. There was early clubbing of the fingers. Chest x-ray demonstrated a density at the right cardiohepatic angle. On Dec. 17, 1947, bronchoscopy showed a bloody secretion originating in the right lower lobe bronchus; on coughing, a " s m a l l succulent t u m o r " came into view in the right lower lobe bronchus distal to the origin of the superior segmental bronchus. Biopsy specimen of the intraluminal mass was reported as "undifferentiated carcinoma." Right thoracotomy on Dec. 20, 1947, disclosed a mass in the right lower lobe with many enlarged mediastinal lymph nodes. Right pneumonectomy with node dissection was performed. Although an extremely poor prognosis seemed likely on clinical grounds, the patient survived without evidence of recurrent tumor until March, 1959, 11 years and 3 months after pneumonectomy. Although autopsy was not obtained, there was no evidence that death was due to carcinoma. The pathologist's report follows: The specimen is that of the right lung, the right lower lobe of which is the site of a moderately firm mass measuring 10 by 11 by 5 cm. on palpation. On cut section an irregular tumor mass is found within the bronchus to the right lower lobe at a point where its three main branches arise. The tumor mass measures 2.5 by 1.7 by 1.5 cm., is grayish-pink, is coarsely granular, and is fairly firm. The mass completely blocks the anterolateral and posterolateral bronchial branches. The bronchi distal to the tumor mass are greatly dilated. The distal lung parenchyma is firm, noncrepitant, and on cut section shows numerous small yellow-grayish areas (see Fig. 11). On microscopic examination the entire bronchial lumen is filled by well-differentiated epidermoid carcinoma. Interesting cytologic features are the presence of oosinophilic, greatly enlarged nucleoli, frequent but typical mitotic figures, and infrequent areas of keratinization. The presence of well-formed prickle cells justifies the diagnosis of squamous carcinoma, although an epidermoid (basal cell) type of neoplastic epithelium predominates. The stroma shows abundant lymphocytic and plasmocytic infiltrate, particularly in response to tumor necrosis. Foreign body type giant cells are often noted in areas of cellular debris. The over-all tumor pattern is papillomatous with infiltration limited to penetration of the wall a short distance beyond the bronchial cartilage. I n a few instances tumor extends close to small pulmonary arteries. An occasional small and organizing venous thrombus is noted. All lymph nodes were free of tumor. CASE 3.—A 74-year-old Caucasian tailor had smoked 20 cigarettes daily for most of his adult life. In February, 1949, he developed cough, fever, and hemoptysis. Chest x-ray studies
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showed left lower lobe atelectasis. Bronchoscopy was performed on April 24, 1949, and demonstrated narrowing and fixation of the left lower lobe bronchus but without visible endobronchial tumor. The aspirate was unsatisfactory for cytologic study. On May 7, 1949, left lower lobectomy was performed because of the finding of atelectasis, but there was no unequivocal evidence of tumor. The anesthetist aspirated partieulato material from the bronchus during operation, however, and this was histologically similar to the parent tumor which was found in the superior segment of the resected lower lobe on patliologic study. The patient was discharged 13 days after operation. His subsequent course was entirely satis factory until July, 1950, when he noted recurrence of hemoptysis. On July 12, bronchoscopy showed a definite recurrence of tumor in the bronchial stump; biopsy specimen was inter preted as being "undifferentiated carcinoma." Between July 25 and August 23, the patient received a tumor dose of approximately 4,000 r to the area of recurrence, with the use of a 2 million volt machine. Bronchoscopy was repeated on Oct. 6, 1950, and the mucosa of the bronchial stump was smooth and intact, there being no evidence of the recurrent tumor previously noted. The patient's condition progressed satisfactorily until December, 1950, when lie complained of left chest pain. X-ray examination showed a large mass in the left upper lobe. Despite an additional 2,000 r of supervoltage x-ray therapy directed to the obvious recurrence, this continued to enlarge. However, the patient was able to remain active and in fair comfort until March, 1951, when his condition started to deteriorate, with in creasing dyspnea, weakness, and weight loss. Pleural effusion developed on the left side and required thoracentesis. In July, 1951, there was clinical evidence of tumor involvement of the pericardium with effusion. On Aug. 14, 1951, the patient died, 27 months after operation. Permission for autopsy was not granted. Pathology.—The gross findings of the resected specimen were: " T h e dorsal bronchus of the left lower lobe displays an area of mucosal thickening that is grayish-white and granular; the bronchial wall is thickened in this area. The involved segment extends up to the proximal line of excision." The final diagnosis was poorly differentiated epidermoid carcinoma. All lymph nodes were negative for tumor. CASE 4.—A 64-year-old Caucasian florist was admitted on July 16, 1951, because of a productive cough for 7 months. (The smoking history was not determined.) He had been in excellent health until one year previously when he was hospitalized for " p n e u m o n i a . " Cough then developed and was associated with intermittent fever and malaise. Chest x-ray studies on admission showed atelectasis of the right upper lobe. Bronchoscopy on July .17, 1951, revealed a firm white nodule in the right upper lobe orifice, a specimen of which was inter preted as being "epidermoid carcinoma." At operation on J u l y 24, 1951, the right upper lobe was found to be atelectatic and indurated, but there was no evidence of tumor involve ment of the chest wall or mediastinal structures. Upper lobectomy was readily accomplished. The patient was discharged 12 days after operation. His subsequent course was entirely satisfactory until February, 1959, when the onset of malaise, anorexia, productive cough, and weight loss was noted. Chest x-ray examination in March, 1959, showed a tumor in the posterior basal segment of the left lower lobe. At bronchoscopy, no tumor excrescence was seen, but there was blood in the left lower lobe bronchus. The bronchoscopic aspirate from this site was positive for malignant cells. Adrenal insufficiency due to metastatic tumor was thought to be present clinically, and this impression was strengthened by a good response to corticosteroid therapy. A course of nitrogen mustard was administered. After some improve ment the patient's condition again began to deteriorate, and he was hospitalized in June, 1959. At this time, hepatomegaly was noted which suggested the presence of liver metastasis. The patient died on June 10, 1959, almost 8 years after lobectomy. Permission for autopsy was not granted. Pathology,—The gross description of the operative specimen was described as follows: " T h e main stem bronchus is the site of an elevated, friable, gray tumor measuring 1.0 x 0.5 cm. On section the tumor is seen to extend to the bronchial cartilage, but the underlying pulmonary parenchyma and adjacent bronchial lymph node are grossly uninvolved. The tumor extends to within one millimeter of the line of resection.'' Final diagnosis was bronchogenic epidermoid carcinoma. All lymph nodes were negative for tumor.
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CASE 5.—A 50-year-old Caucasian truck driver, who customarily had smoked 20 to 40 cigarettes daily for 30 years, was seen because of exacerbation of a chronic cough and hemoptysis. Chest x-ray studies showed an irregular density in the superior segment of the right lower lobe. Bronehoscopy on June 4, 1952, disclosed a fungating mass protruding from the superior segmental orifice of the right lower lobe. Biopsy was readily accomplished but the specimen was interpreted as being negative for tumor, as was cytologic study of the aspirate. Right thoracotomy on June 11, 1952, revealed inflammatory adhesions involving the upper lobe and superior segment of the lower lobe but these were easily lysed. The superior segment of the lower lobe was indurated but no definite tumor was palpable. The intermediate bronchus was therefore exposed and a posterior bronchotomy done in the membranous portion. Tissue was seen extruding from the superior segmental bronchus of the lower lobe and was curetted for diagnosis, together with tissue removed from the interlobar fissure. Frozen section was negative for tumor. I t was elected to perform middle and lower lobectomy but, in developing a fissure between the upper and lower lobes, apparent tumor tissue was encountered. A frozen section was interpreted as being ' ' undifferentiated carcinoma.'' Right pneumonectomy was therefore performed. All visible subcarinal and periesophageal lymph nodes were removed. The postoperative course was uneventful. I n March, 1959, bronehoscopy was performed because of hemoptysis which was found to be due to inflammatory changes involving the right bronchial stump. There was no evidence of recurrent tumor. The patient was last examined on Sept. 22, 1960, 8 years and 3 months after pneu monectomy, at which time he was well and clinically and radiologically free of tumor. Pathology.—The gross findings in the operative specimen were: " I n the dorsal division of the bronchus to the right lower lobe, there is a mass of gray-white fungating tumor which measures 2.5 x 0.8 x 0.5 cm. Tumor extended into the bronchial wall and lung parenchyma both grossly and microscopically.'' The final diagnosis was anaplastic carcinoma. All lymph nodes were free of tumor. CASE 6.—A 59-year-old Caucasian attorney had customarily smoked 4 to 6 cigars and several pipefuls of tobacco daily for 30 years. Recurring mild hemoptysis began in May, 1953. Roentgenogram of the chest revealed an ill-defined density in the right lower lobe. Bronehoscopy on June 4, 1953, showed a fungating, friable, easily bleeding tumor immedi ately beyond the origin of the right middle lobe bronchus. Biopsy specimen was interpreted as being ' ' epidermoid carcinoma,'' but the aspirate was negative for malignant cells. Right thoracotomy on June 19, 1953, disclosed a palpable mass in the right lower lobe with no gross involvement of chest wall or mediastinal structures. Pneumonectomy was done and paratracheal and subcarinal lymph nodes were removed in continuity with the lung. The post operative course was entirely satisfactory. In March, 1961, 7 years and 9 months after pneumonectomy, he was actively engaged in his law practice and free of clinical evidence of disease. Pathology.—The gross findings in the operative specimen were: " G r a y tumor is en countered at the opening of one of the right lower lobe bronchi and is contiguous with the bronchial wall. Tumor tissue extends into the peripheral divisions of the bronchi.'' The final diagnosis was epidermoid carcinoma. All lymph nodes were free of tumor. CASE 7.—In July, 1959, a 53-year-old Caucasian lumber salesman, who customarily had smoked 30 cigarettes daily for at least 20 years, noted the onset of a productive cough, fatigability, malaise, and fever. One month later, blood-streaking of the sputum occurred and persisted. In October, 1959, an x-ray examination showed right middle lobe atelectasis. He was admitted to Massachusetts Memorial Hospitals, and bronehoscopy on October 26 showed only slight redness about the right middle lobe orifice. Cytologic study of the bronchoscopic aspirate was unremarkable. A right thoracotomy on October 28, revealed a shrunken middle lobe which on palpation was the consistency of liver. I t was decided to perform middle lobectomy because of findings suggesting middle lobe syndrome. However, in dissect ing the major fissure, nodular material was encountered and frozen section diagnosis was "epidermoid carcinoma." Since there was then found to be extension of tumor across the minor fissure to involve the upper lobe as well, pneumonectomy was the least resection that
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was technically feasible and this was done. A few subearinal and periesophageal lymph nodes were removed separately. The postoperative course was uneventful, and the patient was discharged 10 days after operation. On March 16, 1961, 17 months later, he was clinically well and free of tumor. Pathology.—Gross findings of significance were: " O n opening the bronchi of the right middle lobe, the main stem shows irregular thickening of the wall for a distance of 5 cm. and a nodular congested mucosa with ulceration. On cut section of the bronchus, the tumorous infiltration is seen t o extend into the parenchyma in a very localized area for a distance of 2 cm. [approximately 1 em. on r e a p p r a i s a l ] . ' ' The final diagnosis was epidermoid carcinoma of the lung. All lymph nodes were negative for tumor. CASE 8.—For approximately 18 months a 50-year-old Caucasian executive had complained of a nonproductive cough. However, this was not sufficiently severe to induce him to reduce his daily consumption of 30 to 40 cigarettes. In March, 1961, the cough became more severe and was associated with fever of 101° F . A chest roentgenogram showed opacification of the right upper lobe and a tentative diagnosis of virus pneumonia was made. Because of no improvement, bronchoscopy was done, with negative findings. Bight scalene node biopsy yielded 17 lymph nodes negative for tumor. Eight thoraeotomy was performed on March 16, 1961, because of the probability of underlying carcinoma. Bronchoscopy was repeated im mediately prior to operation and no tumor was visualized. However, with coughing, a frag ment of the tumor was loosened and recovered with the suction tip. Histologic examination later showed it to be identical with the tumor found in the resected specimen. The right upper lobe was completely atelectatic, and there were a few firm apical adhesions. Many large firm lymph nodes were seen in the subearinal and paratracheal regions, but none showed gross tumor involvement. There was a mass which appeared to arise in the angle between the origin of the right upper lobe bronchus and the right main-stem bronchus. Bight pneumonectomy and en bloc resection of all visualized paratracheal and subearinal lymph nodes were accomplished readily. The patient was discharged on March 27, 1961, 11 days after operation. Pathology.—The gross findings in the resected specimen were: " A small mass is seen growing at the base of the apical segment bronchus in the right upper main stem bronchus. I t is papillary in character, white, firm in consistency, and measures 1.5 x 1.0 x 0.3 cm. The extent of the erosion into the bronchus by tumor cannot be determined." The final diagnosis was polypoid squamous carcinoma of bronchus with deep invasion of bronchial wall and with tumor necrosis and lymphoid stroma. Thirty-two lymph nodes were negative for tumor. CASE 9.—A 68-year-old man with basilar artery insufficiency and diabetes mellitus was first seen in August, 1961. He had smoked two or more packages of cigarettes daily since adolescence. I n May, 1960, he was hospitalized for " p n e u m o n i a . " Chest x-ray examination showed a left hilar density. Bronehoscopically there was widening of the carina and stenosis of the left upper lobe orifice. Biopsy from the periphery of the left upper lobe orifice was negative for tumor. The aspirate yielded atypical cells but no definite evidence of carcinoma. At exploratory thoraeotomy on May 31, 1960, adhesions over the left upper lobe with thicken ing of its anterior segment were seen. The bronchus to this segment was beaded but no tumor mass could be felt. Eleven lymph nodes draining the area were removed and all showed inflammatory changes but no carcinoma. I t was elected, therefore, not to perform resection for what was apparently a purely inflammatory process in an elderly, poor-risk patient. After discharge, however, cough persisted and the sputum was occasionally blood tinged. In November, 1960, hospitalization was again required because of a 2 week history of fever and chills. Sputum cultures yielded Hemophilus inf/wenzae. X-ray examination showed left upper lobe pneumonitis. On laminography there was narrowing of the left upper lobe bronchus with incomplete collapse of this lobe. Bronchoscopy was repeated with the finding of inflammatory changes involving the left main-stem and lower lobe bronchi; the left upper lobe orifice could not be visualized because of blood. Sulfadiazine therapy resulted in symptomatic and radiographic improvement and the patient was discharged. Becurrence of fever and chills prompted rehospitalization in May, 1961, and there was again roentgen evidence of left
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upper lobe pneumonitis. Symptoms regressed with drug therapy and the patient was dis charged, only to be readmitted for recurrence of fever in August, 1961. Thoracentesis was attempted because of the possibility of a loculated empyema in the region of the completely opacified left upper lobe. I t yielded 1 ml. of pus which showed E. influenzae on culture. ( I n retrospect, the exploring needle had entered a small intrapulmonary abscess, a possibility strongly considered at the time.) Although the fever disappeared with treatment, it was decided to perform left upper lobectomy since the lobe was obviously destroyed and would undoubtedly continue to produce symptoms. Bronchoscopy immediately prior to left thoracotomy showed friable, indurated mucosa about the left upper lobe orifice but no definite tumor. At operation there was pleural symphysis involving the upper lobe, which was sub sequently mobilized with extreme difficulty. Pus escaped from several abscess cavities which were ruptured during the arduous dissection. The lower lobe could be expanded satisfactorily but the upper was shrunken and indurated. As the left upper lobe bronchus was transected, a small fragment of apparent tumor tissue was recovered from its lumen by the aspirating tip. The pathologic report on the fragment and the resected upper lobe stated that it was exophytie carcinoma. I t was decided, therefore, to extend the operation to pneumonectomy and the remaining lower lobe was rapidly resected. Postoperatively the patient progressed satisfactorily and was discharged 2 weeks after operation. Pathologic study of the resected specimen showed a polypoid moderately firm mass within the main-stem bronchus (see Fig. 12). The mass measured 2.0 by 1.0 by 0.6 cm., and its base, which measured 1.7 by 0.5 cm. in cross diameters, was 0.8 cm. from the margin of resection. The involved bronchus was greatly dilated and the lumen completely filled by the tumor mass. On cut section there was very little necrosis within the mass. Cut section of the base of the tumor revealed focal penetration of the bronchial wall by tumor but there was no penetration of peribronchial tissue. Five lymph nodes within the hilar area were free of tumor. The bronchi distal to the tumor were greatly dilated and filled with mucinous greenish-yellow exudate. The lung parenchyma revealed an extensive organizing pneumonitis. Microscopic examination showed large confluent nests of epidermoid cells with fairly marked pleomorphism and focal keratinization. A moderate amount of fibrous tissue stroma was present, associated with a moderate, widespread lymphocytic and plasmocytie infiltrate. The necrosis found was sometimes associated with a foreign body type giant cell reaction. CLINICAL AND RADIOGRAPHIC FEATURES
Discussion.—The symptoms have been primarily due to bronchial obstruc tion, with distressing cough occurring as a presenting complaint in 7 of the 9 patients. Distal suppuration was manifested by significant fever in 5 in dividuals. In 4 patients, brisk hemoptysis was a prominent feature. The x-ray appearance was usually that of lobar atelectasis, again mirroring the endobronchial growth of the tumor. Bronchoscopic biopsy was positive in 4 of the 5 instances in which a suspicious area was seen endoscopically. However, cytologic study was unrewarding in all 6 cases in which it was employed. Scalene node biopsy was undertaken in only one patient and it was negative. The initial findings at operation were principally those of atelectasis and an obstructive type of inflammation, without gross evidence of cancer; this again reflects the exophytie, noninvasive characteristics of the tumor. The hilar vessels were invariably mobile and uninvolved by the lesion. Pneumonectomy was performed in 7 of the cases and lobectomy in the remaining 2. The patients treated by lobectomy represent 2 of the 3 who died of their malignancy. The significance of this is not clear, but there is at least an implication that pneumonectomy may be preferable to lobectomy in the treatment of these particular tumors when clinical circumstances permit. X-ray therapy proved effective for a local endo-
S H E R W I N , LAFORET, S T R I E D E R
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J. Thoracic and Cardiovas. Surg.
bronchial recurrence but not for metastatic parenchymal deposits. Although cytologie studies were negative, the massive intraluminal growth of these tumors enhances the possibility of fragmentation and subsequent implantation in other lobes. Therefore, operative manipulation should be reduced to a minimum, and it is probably desirable that bronchial occlusion be achieved early in the course of the procedure. Although lymph nodes were sometimes enlarged, metastases were invariably absent. TABLE I.
EXOPHYTIC ENDOBRONCHIAL
CARCINOMA—CLINICAL
FEATURES
SMOKING
DU RA TION NO. OP OF CIGA NO. S Y M P RETTES OF TOMS DAILY YEARS ( M O . )
VISUAL IZED AT BRON CHOSCOPY
HEMOP TYSIS
COUGH
GROSS TUMOR FRAG MENT
3-6
0
+
0
0
18
0
+
0
+
50
2
+
+
+
0
20-40
30
12 6
0 +
+ +
0 0
+ +
30
1
+
0
0
+
M
Cigar and pipe 30
20
3
+
+
0
0
50
M
30-40
30
18
0
+
+
0
68
M
40
50
15
0
0
+
0
CASE NO.
AGE
SEX
1
60
M
2
61
M
3
74
M
20
4 5
64 50
M M
6
59
M
7
53
8 9
—
—
OPERATION
SUR VIVAL TIME POSTOP
"WITH DISEASE
4 yr.* Pneumonectomy Pneumo11% nectomy yr.* Lobectomy 2 % yr.* Lobectomy 8 yr.* Pneumo8% nectomy Pneumo7% nectomy yrPneumonectomy Pneumonectomy Pneumonectomy
+ 0 + + 0 0
2 yr.
0
9 mo.
0
3 mo.
0
•Patient died .
Pathology.—In a study of cancer of the oral cavity and throat, architectural features, such as exophytic growth, superficial invasion, and a broad, sharply demarcated tumor margin, strongly suggest a more favorable prognosis.6 These same characteristics are present in the cases of this series, particularly the unique property of growing into the lumen of a bronchus as a warty or poly poid mass. Case 7 is the only instance of fairly deep tumor invasion into the alveolar sacs adjacent to the involved bronchus. It also differs from the others in that the tumor pattern is not as orderly nor as papillary, and there is lym phatic invasion. These factors suggest an intermediate prognosis, less favorable than the other 8 but better than the usual epidermoid bronehogenic carcinoma. However, the predominance of tumor within the bronchial wall, the long (5 cm.) segment of bronchus involved, and the very limited area of lung invasion war rants its inclusion in this series. In 2 cases the full thickness of the bronchial wall was penetrated by focally invasive tumor. In one of these 2 patients there was partial invasion of the adventitia of an adjacent pulmonary artery but the patient is still free of disease clinically almost 8 years postoperatively. Invasion in the remaining 6 cases was relatively superficial and in 2 of these the tumor had spread primarily by involvement of adjacent ducts and glands. . Case 1 (Fig. 1) is unusual in that the tumor growth pattern is essentially
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that of a superficially spreading carcinoma which has replaced the entire mucosal circumference of a bronchus. Since little invasion is present, the presence of tumor in the opposite lung 4 years later is more likely the result of multicentric cancer formation than metastasis from the initial growth. Case 2 (see Fig. 11) showed invasion involving the full thickness of the bronchial wall but the bulk of the tumor was intraluminal and host resistance
Fig. 1.—Case 1. A division of the tumor-containing bronchus, showing essentially in situ acanthotic carcinoma. At "5 o'clock" there is a remnant of mucosal epithelium, other wise the entire mucosa has been replaced by tumor.
Fig. 2.—Case 3. The mucosal lining on the left has been replaced by polypoid tumor tissue. Note the stalk-like stromal structure, reminiscent of papillomatosis in the breast. Case 6 showed a similar picture.
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factors were prominent. The patient died of unrelated disease over 11 years after resection. Case 3 (Fig. 2) had a well-localized, essentially in situ, carcinoma which grew into the bronchial lumen as a polypoid mass. The clinical problem was clearly one of local recurrence rather than metastatic disease. The same type of tumor pattern was found in Case 6. Although the tumor of Case 6 had
Fig. 3.—Case 4. The verruciform carcinoma of Case 4. Note the cartilage at the base of the lesion, illustrating the superficial nature of the carcinoma. Fig. i.—Case 4. Two "fronds" of the verruciform carcinoma (Case 4), one of which (top) is denuded of carcinomatous epithelium, and the other intact. Even at this relatively low magnification it is apparent that the anaplasia present is not prominent.
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invaded the outer coat of a pulmonary artery, the patient was clinically free of disease 7 years and !) months postoperatively. Case 4 (Pigs. 3 and 4) is extraordinary in that the tumor pattern is very similar to the verrucous carcinoma of the oral cavity described by Ackerman. 7 Although the patient died with evidence of tumor in the opposite lung and
Fi K 5—Case 5. The bronchial wall has been greatly thinned and the lumen dilated by a "cauliflower" mass. The base of the polypoid mass (upper right hand corner) was attached by a slightly broad stalk to the mucosa, at a point just beyond the edge of the photograph. The dark areas of the upper half of the tumor represent invasive carcinoma. Invasion ex tended into the mucosa of the bronchus. Note the fingerlike projections of the tumor pe riphery, composed of myxomatous stroma and orderly epithelium. Fig 6 —Case 5. Higher magnification of Pig. 5 which shows epithelial lining, a small amount of stroma, and invasive spindle-cell carcinoma resembling the surface epithelium. The ominous appearance of the tumor inflltrate was contradicted by the good clinical course.
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probably widespread metastatic disease, the long survival period, the sudden onset of symptoms after 8 years of good health, and the obviously warty nature of the original cancer strongly favor a second primary tumor. In regard to the warty structure, it should be noted that the verrucous carcinoma of the oral cavity often recurs locally but rarely metastasizes. We believe this is the first report of this type of tumor in the lung.
Figr. 7.—Case 8. The polypoid carcinoma of Case 8 closely resembles the structure of ,. a denomatous polyp of the large bowel. Note the long, slender, tumor-free stalks and the well-differentiated squamous epithelium. In the lower left hand corner of the photograph there are small submucosal nodules of invasive squamous carcinoma.
an
The tumor of Case 5 (Pig. 5) resembles a myxomatous fibroadenoma or cystosarcoma of the breast in that both the epithelium and the stroma of the tumor are proliferating. In addition, the relatively benign looking epithelium has given rise to a spindle cell carcinoma (Fig. 6) which mimics a carcinosarcoma. We are calling the tumor a "polypoid fibroepithelial carcinoma." The tumor pattern of Case 8 (Figs. 7 and 8) is unquestionably unique and warrants an optimistic outlook despite the inadequate follow-up period. The majority of the tumor lies within multiple mucosal polyps, all of which have long, slender stalks. Although the stalks are free of carcinoma, a small focus of invasive cancer is present in the bronchial wall. Possibly the invasive area is tumor left behind as the main tumor was pulled into the respiratory stream, in
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the same fashion as adenomatous polyps of the bowel. Of course, direct con tinuity and lymphatic metastases are also plausible explanations, but are un likely in view of the negative multiple sections through the area in question. Cases 2, 7, and 9 are similar microscopically, in that the squamous car cinomas had generally broad advancing margins but also focal infiltration by small cellular islands. A promising facet to the problem of predicting tumor aggressiveness is host resistance, as demonstrated histologically by tumor necrosis, leukocytic response, and a foreign body type granulomatous response. Little, however, is known concerning the nature of intrinsic tumor growth properties.
Fig. 8.—Case 8. An intriguing feature of the invasive carcinoma in Case 8 is the ap parent "host resistance" as shown by the marked lymphocytic response and tumor necrosis. Note the poorly defined tumor within a large "ring" of lymphocytes in the right half of the photograph. The tumor on the left shows neutrophil infiltration of its periphery.
Cases 2, 4, 6, 8, and 9 showed a marked lymphocytic-plasmacytic reaction to invading tumor in association with focal foreign body type giant cells (Figs. 8 and 9). Keratin production was not often an obvious factor in the attraction of the giant cells; also keratin production was not always associated with a giant cell response. Tumor necrosis with neutrophil infiltration was also prominent. In Case 4 an intriguing finding was the destruction of cartilage without apparent cause. Examination of multiple levels, however, revealed that within the leuko cytic aggregates adjacent to eroded cartilage there were remnants of tumor cells. In other words, invasion by tumor was much more extensive than realized, but a large proportion of the invading tumor had undergone almost complete necrosis. The extensive lymphocytic reaction to the tumor in this case, as well as in the others, is well recognized as a favorable prognostic sign.8 The granulomatous response requires further study, but a preliminary report strongly suggests that it is useful in evaluating prognosis.0 Of additional interest is the dramatic response of lymph node metastases to x-ray therapy in one case of epidermoid
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J. Thoracic and Cardiovas. Surg.
carcinoma of the tongue with granulomatous response.9 The resemblance of the giant cell reaction about the tumor to the fate of homografts is supporting evi dence for a relationship to good host resistance. An exception to the rule was found in one of the nonexophytic carcinomas of this series. The tumor exhibited a marked granulomatous reaction but, shortly after operation, the patient de veloped carcinoma in the operative incision and died 6 months postoperatively with extensive skin involvement and visceral metastases. The precipitous course
Pig-. 9.—Case 4. Epidermoid carcinoma of Case 4. Note the foreign body type giant cells adjacent to a mass, top left. The tumor in the advancing- margin, lower part of picture, is undergoing necrosis and there is an associated dense lymphocytic infiltrate. Fig. 10.—Case 7. Note the polypoid mass on the right, most of which projects into the lumen. The mucosa, which is clearly shown centrally, extends to the right almost as far as the marginal cartilage. The tumor infiltrate can be seen between the two cartilaginous masses on the right involving the full thickness of the bronchial wall.
Vol. 43, No. 6 June, 1962
EXOPHTTIC ENDOBRONCHIAL CANCER
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Fig. 11.—A cauliflower-shaped mass completely occludes the bronchus supplying the con solidated and fleshy appearing lobe. Note the sharpness and circumscription of the base of the mass.
Pig. 12.—The mass is composed of three polypoid structures sharing a common base. The divisions of the polypoid mass are clearly related to the branches of the main-stem bronchus. On cutting through the base of the carcinoma, penetration of tumor through the bronchial wall but not into the peribronchial tissue was noted. The tumor within the bronchial wall represents a very small portion of the tumor.
730
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STRIEDER
J. Thoracic and Cardiovas. Surg.
and the manner of tumor spread imply a dramatic alteration in the host resist ance balance. From this study of 9 cases, derived from a relatively small series of 85 lung resections, it is clear that a detailed report of the pathology must be avail able before survival figures can be correlated with other factors. More effort must be made to obtain detailed pathologic information, such as tumor pattern and growth behavior, the presence and extent of in situ carcinoma, multicentric cancer foci 12 ' 13 and, particularly, the cause of death as verified by autopsy. I t is interesting to note that the case reported by Henry and Miscall seems to be an example of an exophytic endobronchial tumor. 10 Although the lesion was called an anaplastic carcinoma, the patient was asymptomatic and ap parently free of tumor 20 months after left upper lobectomy.11 SUMMARY
A clinicopathologic study of 85 lung carcinomas revealed 9 exophytic tumors, characterized by endobronchial proliferation and superficial, focal in vasion of the bronchial wall. Unique growth patterns were found, including polypoid and papillomatous masses, superficially spreading in situ carcinomas, verruciform neoplasia, and a distinctive "polypoid fibroepithelial carcinoma." Six of the 9 patients have had adequate follow-up periods. Two of these are living and well approximately 8 years after resection. One died 11 years after resection from a nonrelated disease. One died 8 years after resection with late appearing clinical evidence of cancer in the opposite lung. Another died 4 years after resection with cancer of the opposite lung. A sixth patient died 27 months after resection following recurrence of tumor in the bronchial stump. Reasons are given for optimism in the prognosis of the remainder with shortterm follow-up. REFERENCES
1. Doll, R., Bradford Hill, A., and Kreyberg, L.: Significance of Cell Type in Relation to Etiology of Lung Cancer, Brit. J . Cancer 1 1 : 43-48, 1957. 2. Kirklin, J . W., McDonald, J . R., Clagett, O. T., Moersch, H. J., and Gage, R. P . : Bronchogenic Carcinoma: Cell Type and Other Factors Relating to Prognosis, Surg. Gynec. & Obst. 100: 429-438, 1955. 3. Olcott, C. T.: Cell Types and Histologic Patterns in Carcinoma of the L u n g : Observa tions on the Significance of Tumors Containing More Than One Type of Cell, Am. J . Path. 3 1 : 975-995, 1955. 4. Nohl, H . C.: Investigation Into Lymphatic and Vascular Spread of Carcinoma of Bronchus, Thorax 1 1 : 172-185, 1956. 5. Sherwin, R. P., and Laforet, E. G.: Unpublished data. 6. Sherwin, R. P., and Zovickian, A.: Squamous Carcinomas of the Oral Cavity and Throat and Their Clinicopathological Correlation, Am. J . Surg. 102: 823-829, 1962. 7. Ackerman, L. V., and McGavran, M. H . : Proliferating Benign and Malignant Epithelial Lesions of the Oral Cavity, J . Oral Surg. 16: 400-413, 1958. 8. Berg, J . W.: Inflammation and Prognosis in Breast Cancer: Search for Host Resistance, Cancer 12: 714-720, 1959. 9. Sherwin, R. P., and Zovickian, A.: Unpublished data. 10. Henry, W. J., and Miscall, L.: Rapidly Reversible Atelectasis Due to Change in Position, J . THORACIC SURG. 4 1 : 686-688,
1961.
11. Miscall, L.: Personal communication, 1961. 12. Hartsock, R. J., and Fisher, E. R.: Bilateral Primary Invasive Carcinoma of the Lungs, Dis. Chest 39: 421-424, 1961. 13. Hughes, R. K., and Blades, B . : Multiple Primary Bronchogenic Carcinoma, J . THORACIC SURG. 4 1 : 421,
1961.
Boston,
and
Mass.
NE of the obviously important factors influencing the prognosis of lung cancer is the aggressiveness of the tumor. The pathologist evaluates tumor behavior by a study of cellular appearance, tumor architecture, and the manner of tumor spread. However, classifications of lung tumors have been based essentially on cellular appearance with little or no emphasis on architecture. 1 '"' :i Invasion studies have stressed involvement of lymph nodes or vessels,4 relatively little attention being paid to the nature of the advancing tumor margin. In a study of 85 cases of lung cancer,5 emphasizing tumor architecture and infiltration pattern, nine lung carcinomas with a unique structure were encoun tered. All were characterized by a predominantly endobronchial carcinomatous growth of a papillomatous, polypoid, or vcrrucous nature. In addition, certain aspects of tumor invasion were remarkable. Of great importance is the presump tive favorable prognosis of these tumors.
O
MATERIALS AND METHODS
Eighty-five patients with lung cancer suitable for definitive resection and under the care of a single thoracic surgical group at one hospital were reviewed. Individuals who did not survive operation were not included. Within these limits the series was consecutive and unselected. A 16 year period was covered, extending from 1945 to the early part of 1961. The microscopic sections of the tumors were reviewed without prior clinical knowledge, and estimates of prog nosis, based on the microscopic sections, were recorded. In most cases paraffin blocks were available to supplement the slides. In some instances formalin-fixed tissue was re-examined. Seven of the nine exophytic carcinomas had not been recognized as such. The eighth and ninth were anticipated bronchoscopically after the study of this group had begun. CASE REPORTS CASE 1.—In May, 1945, a 60-year-old Caucasian exceutive had a chest x-ray examination because of loss of weight and productive cough following a tuberculosis contact. The roentProm the Departments of Pathology and Surgery, Massachusetts Memorial Hospitals and Boston University Medical Center, Boston, Mass. Received for publication June 15, 1961. ♦Associate Pathologist, Massachusetts Memorial Hospitals; Assistant Clinical Professor of Pathology, Boston University School of Medicine. ** Assistant in Surgery (Thoracic), Massachusetts Memorial Hospitals; Clinical Instructor in Surgery, Boston University School of Medicine. ♦"Visiting Surgeon (Thoracic), Massachusetts Memorial Hospitals; Professor of Clinical Surgery, Boston University School of Medicine. 716
Vol. 43, No. 6 June, 1962
E X O P H Y T I C ENDOBRONCHIAL CANCER
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genogram exhibited partial atelectasis of the right upper lobe and further study was advised. (The smoking history was not determined.) Bronchoscopy showed injection and friability of the inferior carina of the right upper lobe bronchus without marked outcropping of tissue. Biopsy specimen of this area was interpreted as being ' ' epidermoid carcinoma.'' Bight pneumonectomy was performed on June 6, 1945. At operation the right upper lobe was found to be atelectatic and fixed to the chest wall by inflammatory adhesions, but the hilar struc tures were mobile and free of gross tumor involvement. The postoperative course was un complicated. The patient progressed satisfactorily until April, 1949, when he complained of cough, dyspnea, and weight loss. X-ray examination showed a mass in the left lower lobe consistent with a metastatic lesion. Radiation therapy was instituted but proved ineffective. After a rapidly downhill course, the patient died on June 13, 1949, 4 years after pneumonec tomy. Autopsy was not performed. Pathology.—The gross appearance of the operative specimen was described as follows: ' ' The bronchus to the lower portion of the right upper lobe is completely obstructed by a mass of firm, gray-white, somewhat papillary tissue, the center of which is hemorrhagic. The tumor involves approximately 3 cm. of bronchus and produces up to 4 mm. of mucosal thicken ing. At no point does it invade the surrounding l u n g . " The diagnosis was epidermoid car cinoma, grade 2 to 3. Lymph nodes were negative for tumor. An associated finding was a marked organizing granulomatous pneumonitis of the cholesterol type with bronchiectasis, secondary to obstruction of the bronchus. CASE 2.—A 61-year-old Caucasian laborer was admitted to Massachusetts Memorial Hospitals on Dec. 16, 1947, because of a productive cough for the preceding 18 months. The cough had been associated with a vague " p r e s s i n g " sensation in the lower right chest. (A smoking history was not elicited.) The patient was well nourished. There was early clubbing of the fingers. Chest x-ray demonstrated a density at the right cardiohepatic angle. On Dec. 17, 1947, bronchoscopy showed a bloody secretion originating in the right lower lobe bronchus; on coughing, a " s m a l l succulent t u m o r " came into view in the right lower lobe bronchus distal to the origin of the superior segmental bronchus. Biopsy specimen of the intraluminal mass was reported as "undifferentiated carcinoma." Right thoracotomy on Dec. 20, 1947, disclosed a mass in the right lower lobe with many enlarged mediastinal lymph nodes. Right pneumonectomy with node dissection was performed. Although an extremely poor prognosis seemed likely on clinical grounds, the patient survived without evidence of recurrent tumor until March, 1959, 11 years and 3 months after pneumonectomy. Although autopsy was not obtained, there was no evidence that death was due to carcinoma. The pathologist's report follows: The specimen is that of the right lung, the right lower lobe of which is the site of a moderately firm mass measuring 10 by 11 by 5 cm. on palpation. On cut section an irregular tumor mass is found within the bronchus to the right lower lobe at a point where its three main branches arise. The tumor mass measures 2.5 by 1.7 by 1.5 cm., is grayish-pink, is coarsely granular, and is fairly firm. The mass completely blocks the anterolateral and posterolateral bronchial branches. The bronchi distal to the tumor mass are greatly dilated. The distal lung parenchyma is firm, noncrepitant, and on cut section shows numerous small yellow-grayish areas (see Fig. 11). On microscopic examination the entire bronchial lumen is filled by well-differentiated epidermoid carcinoma. Interesting cytologic features are the presence of oosinophilic, greatly enlarged nucleoli, frequent but typical mitotic figures, and infrequent areas of keratinization. The presence of well-formed prickle cells justifies the diagnosis of squamous carcinoma, although an epidermoid (basal cell) type of neoplastic epithelium predominates. The stroma shows abundant lymphocytic and plasmocytic infiltrate, particularly in response to tumor necrosis. Foreign body type giant cells are often noted in areas of cellular debris. The over-all tumor pattern is papillomatous with infiltration limited to penetration of the wall a short distance beyond the bronchial cartilage. I n a few instances tumor extends close to small pulmonary arteries. An occasional small and organizing venous thrombus is noted. All lymph nodes were free of tumor. CASE 3.—A 74-year-old Caucasian tailor had smoked 20 cigarettes daily for most of his adult life. In February, 1949, he developed cough, fever, and hemoptysis. Chest x-ray studies
718
SHERW1N, LAFOBET,
STRIEDEK
.1. Thoracic and Cardiovas. Surg.
showed left lower lobe atelectasis. Bronchoscopy was performed on April 24, 1949, and demonstrated narrowing and fixation of the left lower lobe bronchus but without visible endobronchial tumor. The aspirate was unsatisfactory for cytologic study. On May 7, 1949, left lower lobectomy was performed because of the finding of atelectasis, but there was no unequivocal evidence of tumor. The anesthetist aspirated partieulato material from the bronchus during operation, however, and this was histologically similar to the parent tumor which was found in the superior segment of the resected lower lobe on patliologic study. The patient was discharged 13 days after operation. His subsequent course was entirely satis factory until July, 1950, when he noted recurrence of hemoptysis. On July 12, bronchoscopy showed a definite recurrence of tumor in the bronchial stump; biopsy specimen was inter preted as being "undifferentiated carcinoma." Between July 25 and August 23, the patient received a tumor dose of approximately 4,000 r to the area of recurrence, with the use of a 2 million volt machine. Bronchoscopy was repeated on Oct. 6, 1950, and the mucosa of the bronchial stump was smooth and intact, there being no evidence of the recurrent tumor previously noted. The patient's condition progressed satisfactorily until December, 1950, when lie complained of left chest pain. X-ray examination showed a large mass in the left upper lobe. Despite an additional 2,000 r of supervoltage x-ray therapy directed to the obvious recurrence, this continued to enlarge. However, the patient was able to remain active and in fair comfort until March, 1951, when his condition started to deteriorate, with in creasing dyspnea, weakness, and weight loss. Pleural effusion developed on the left side and required thoracentesis. In July, 1951, there was clinical evidence of tumor involvement of the pericardium with effusion. On Aug. 14, 1951, the patient died, 27 months after operation. Permission for autopsy was not granted. Pathology.—The gross findings of the resected specimen were: " T h e dorsal bronchus of the left lower lobe displays an area of mucosal thickening that is grayish-white and granular; the bronchial wall is thickened in this area. The involved segment extends up to the proximal line of excision." The final diagnosis was poorly differentiated epidermoid carcinoma. All lymph nodes were negative for tumor. CASE 4.—A 64-year-old Caucasian florist was admitted on July 16, 1951, because of a productive cough for 7 months. (The smoking history was not determined.) He had been in excellent health until one year previously when he was hospitalized for " p n e u m o n i a . " Cough then developed and was associated with intermittent fever and malaise. Chest x-ray studies on admission showed atelectasis of the right upper lobe. Bronchoscopy on July .17, 1951, revealed a firm white nodule in the right upper lobe orifice, a specimen of which was inter preted as being "epidermoid carcinoma." At operation on J u l y 24, 1951, the right upper lobe was found to be atelectatic and indurated, but there was no evidence of tumor involve ment of the chest wall or mediastinal structures. Upper lobectomy was readily accomplished. The patient was discharged 12 days after operation. His subsequent course was entirely satisfactory until February, 1959, when the onset of malaise, anorexia, productive cough, and weight loss was noted. Chest x-ray examination in March, 1959, showed a tumor in the posterior basal segment of the left lower lobe. At bronchoscopy, no tumor excrescence was seen, but there was blood in the left lower lobe bronchus. The bronchoscopic aspirate from this site was positive for malignant cells. Adrenal insufficiency due to metastatic tumor was thought to be present clinically, and this impression was strengthened by a good response to corticosteroid therapy. A course of nitrogen mustard was administered. After some improve ment the patient's condition again began to deteriorate, and he was hospitalized in June, 1959. At this time, hepatomegaly was noted which suggested the presence of liver metastasis. The patient died on June 10, 1959, almost 8 years after lobectomy. Permission for autopsy was not granted. Pathology,—The gross description of the operative specimen was described as follows: " T h e main stem bronchus is the site of an elevated, friable, gray tumor measuring 1.0 x 0.5 cm. On section the tumor is seen to extend to the bronchial cartilage, but the underlying pulmonary parenchyma and adjacent bronchial lymph node are grossly uninvolved. The tumor extends to within one millimeter of the line of resection.'' Final diagnosis was bronchogenic epidermoid carcinoma. All lymph nodes were negative for tumor.
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E X O P H Y T I C ENDOBRONCHIAL CANCER
710 ' ±a
CASE 5.—A 50-year-old Caucasian truck driver, who customarily had smoked 20 to 40 cigarettes daily for 30 years, was seen because of exacerbation of a chronic cough and hemoptysis. Chest x-ray studies showed an irregular density in the superior segment of the right lower lobe. Bronehoscopy on June 4, 1952, disclosed a fungating mass protruding from the superior segmental orifice of the right lower lobe. Biopsy was readily accomplished but the specimen was interpreted as being negative for tumor, as was cytologic study of the aspirate. Right thoracotomy on June 11, 1952, revealed inflammatory adhesions involving the upper lobe and superior segment of the lower lobe but these were easily lysed. The superior segment of the lower lobe was indurated but no definite tumor was palpable. The intermediate bronchus was therefore exposed and a posterior bronchotomy done in the membranous portion. Tissue was seen extruding from the superior segmental bronchus of the lower lobe and was curetted for diagnosis, together with tissue removed from the interlobar fissure. Frozen section was negative for tumor. I t was elected to perform middle and lower lobectomy but, in developing a fissure between the upper and lower lobes, apparent tumor tissue was encountered. A frozen section was interpreted as being ' ' undifferentiated carcinoma.'' Right pneumonectomy was therefore performed. All visible subcarinal and periesophageal lymph nodes were removed. The postoperative course was uneventful. I n March, 1959, bronehoscopy was performed because of hemoptysis which was found to be due to inflammatory changes involving the right bronchial stump. There was no evidence of recurrent tumor. The patient was last examined on Sept. 22, 1960, 8 years and 3 months after pneu monectomy, at which time he was well and clinically and radiologically free of tumor. Pathology.—The gross findings in the operative specimen were: " I n the dorsal division of the bronchus to the right lower lobe, there is a mass of gray-white fungating tumor which measures 2.5 x 0.8 x 0.5 cm. Tumor extended into the bronchial wall and lung parenchyma both grossly and microscopically.'' The final diagnosis was anaplastic carcinoma. All lymph nodes were free of tumor. CASE 6.—A 59-year-old Caucasian attorney had customarily smoked 4 to 6 cigars and several pipefuls of tobacco daily for 30 years. Recurring mild hemoptysis began in May, 1953. Roentgenogram of the chest revealed an ill-defined density in the right lower lobe. Bronehoscopy on June 4, 1953, showed a fungating, friable, easily bleeding tumor immedi ately beyond the origin of the right middle lobe bronchus. Biopsy specimen was interpreted as being ' ' epidermoid carcinoma,'' but the aspirate was negative for malignant cells. Right thoracotomy on June 19, 1953, disclosed a palpable mass in the right lower lobe with no gross involvement of chest wall or mediastinal structures. Pneumonectomy was done and paratracheal and subcarinal lymph nodes were removed in continuity with the lung. The post operative course was entirely satisfactory. In March, 1961, 7 years and 9 months after pneumonectomy, he was actively engaged in his law practice and free of clinical evidence of disease. Pathology.—The gross findings in the operative specimen were: " G r a y tumor is en countered at the opening of one of the right lower lobe bronchi and is contiguous with the bronchial wall. Tumor tissue extends into the peripheral divisions of the bronchi.'' The final diagnosis was epidermoid carcinoma. All lymph nodes were free of tumor. CASE 7.—In July, 1959, a 53-year-old Caucasian lumber salesman, who customarily had smoked 30 cigarettes daily for at least 20 years, noted the onset of a productive cough, fatigability, malaise, and fever. One month later, blood-streaking of the sputum occurred and persisted. In October, 1959, an x-ray examination showed right middle lobe atelectasis. He was admitted to Massachusetts Memorial Hospitals, and bronehoscopy on October 26 showed only slight redness about the right middle lobe orifice. Cytologic study of the bronchoscopic aspirate was unremarkable. A right thoracotomy on October 28, revealed a shrunken middle lobe which on palpation was the consistency of liver. I t was decided to perform middle lobectomy because of findings suggesting middle lobe syndrome. However, in dissect ing the major fissure, nodular material was encountered and frozen section diagnosis was "epidermoid carcinoma." Since there was then found to be extension of tumor across the minor fissure to involve the upper lobe as well, pneumonectomy was the least resection that
720
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STBIEDER
J. Thoracic and Cardiovas. Surg.
was technically feasible and this was done. A few subearinal and periesophageal lymph nodes were removed separately. The postoperative course was uneventful, and the patient was discharged 10 days after operation. On March 16, 1961, 17 months later, he was clinically well and free of tumor. Pathology.—Gross findings of significance were: " O n opening the bronchi of the right middle lobe, the main stem shows irregular thickening of the wall for a distance of 5 cm. and a nodular congested mucosa with ulceration. On cut section of the bronchus, the tumorous infiltration is seen t o extend into the parenchyma in a very localized area for a distance of 2 cm. [approximately 1 em. on r e a p p r a i s a l ] . ' ' The final diagnosis was epidermoid carcinoma of the lung. All lymph nodes were negative for tumor. CASE 8.—For approximately 18 months a 50-year-old Caucasian executive had complained of a nonproductive cough. However, this was not sufficiently severe to induce him to reduce his daily consumption of 30 to 40 cigarettes. In March, 1961, the cough became more severe and was associated with fever of 101° F . A chest roentgenogram showed opacification of the right upper lobe and a tentative diagnosis of virus pneumonia was made. Because of no improvement, bronchoscopy was done, with negative findings. Bight scalene node biopsy yielded 17 lymph nodes negative for tumor. Eight thoraeotomy was performed on March 16, 1961, because of the probability of underlying carcinoma. Bronchoscopy was repeated im mediately prior to operation and no tumor was visualized. However, with coughing, a frag ment of the tumor was loosened and recovered with the suction tip. Histologic examination later showed it to be identical with the tumor found in the resected specimen. The right upper lobe was completely atelectatic, and there were a few firm apical adhesions. Many large firm lymph nodes were seen in the subearinal and paratracheal regions, but none showed gross tumor involvement. There was a mass which appeared to arise in the angle between the origin of the right upper lobe bronchus and the right main-stem bronchus. Bight pneumonectomy and en bloc resection of all visualized paratracheal and subearinal lymph nodes were accomplished readily. The patient was discharged on March 27, 1961, 11 days after operation. Pathology.—The gross findings in the resected specimen were: " A small mass is seen growing at the base of the apical segment bronchus in the right upper main stem bronchus. I t is papillary in character, white, firm in consistency, and measures 1.5 x 1.0 x 0.3 cm. The extent of the erosion into the bronchus by tumor cannot be determined." The final diagnosis was polypoid squamous carcinoma of bronchus with deep invasion of bronchial wall and with tumor necrosis and lymphoid stroma. Thirty-two lymph nodes were negative for tumor. CASE 9.—A 68-year-old man with basilar artery insufficiency and diabetes mellitus was first seen in August, 1961. He had smoked two or more packages of cigarettes daily since adolescence. I n May, 1960, he was hospitalized for " p n e u m o n i a . " Chest x-ray examination showed a left hilar density. Bronehoscopically there was widening of the carina and stenosis of the left upper lobe orifice. Biopsy from the periphery of the left upper lobe orifice was negative for tumor. The aspirate yielded atypical cells but no definite evidence of carcinoma. At exploratory thoraeotomy on May 31, 1960, adhesions over the left upper lobe with thicken ing of its anterior segment were seen. The bronchus to this segment was beaded but no tumor mass could be felt. Eleven lymph nodes draining the area were removed and all showed inflammatory changes but no carcinoma. I t was elected, therefore, not to perform resection for what was apparently a purely inflammatory process in an elderly, poor-risk patient. After discharge, however, cough persisted and the sputum was occasionally blood tinged. In November, 1960, hospitalization was again required because of a 2 week history of fever and chills. Sputum cultures yielded Hemophilus inf/wenzae. X-ray examination showed left upper lobe pneumonitis. On laminography there was narrowing of the left upper lobe bronchus with incomplete collapse of this lobe. Bronchoscopy was repeated with the finding of inflammatory changes involving the left main-stem and lower lobe bronchi; the left upper lobe orifice could not be visualized because of blood. Sulfadiazine therapy resulted in symptomatic and radiographic improvement and the patient was discharged. Becurrence of fever and chills prompted rehospitalization in May, 1961, and there was again roentgen evidence of left
Vol. 43, No. 6 June, 1962
E X O P H Y T I C ENDOBRONCHIAL CANCER
721
upper lobe pneumonitis. Symptoms regressed with drug therapy and the patient was dis charged, only to be readmitted for recurrence of fever in August, 1961. Thoracentesis was attempted because of the possibility of a loculated empyema in the region of the completely opacified left upper lobe. I t yielded 1 ml. of pus which showed E. influenzae on culture. ( I n retrospect, the exploring needle had entered a small intrapulmonary abscess, a possibility strongly considered at the time.) Although the fever disappeared with treatment, it was decided to perform left upper lobectomy since the lobe was obviously destroyed and would undoubtedly continue to produce symptoms. Bronchoscopy immediately prior to left thoracotomy showed friable, indurated mucosa about the left upper lobe orifice but no definite tumor. At operation there was pleural symphysis involving the upper lobe, which was sub sequently mobilized with extreme difficulty. Pus escaped from several abscess cavities which were ruptured during the arduous dissection. The lower lobe could be expanded satisfactorily but the upper was shrunken and indurated. As the left upper lobe bronchus was transected, a small fragment of apparent tumor tissue was recovered from its lumen by the aspirating tip. The pathologic report on the fragment and the resected upper lobe stated that it was exophytie carcinoma. I t was decided, therefore, to extend the operation to pneumonectomy and the remaining lower lobe was rapidly resected. Postoperatively the patient progressed satisfactorily and was discharged 2 weeks after operation. Pathologic study of the resected specimen showed a polypoid moderately firm mass within the main-stem bronchus (see Fig. 12). The mass measured 2.0 by 1.0 by 0.6 cm., and its base, which measured 1.7 by 0.5 cm. in cross diameters, was 0.8 cm. from the margin of resection. The involved bronchus was greatly dilated and the lumen completely filled by the tumor mass. On cut section there was very little necrosis within the mass. Cut section of the base of the tumor revealed focal penetration of the bronchial wall by tumor but there was no penetration of peribronchial tissue. Five lymph nodes within the hilar area were free of tumor. The bronchi distal to the tumor were greatly dilated and filled with mucinous greenish-yellow exudate. The lung parenchyma revealed an extensive organizing pneumonitis. Microscopic examination showed large confluent nests of epidermoid cells with fairly marked pleomorphism and focal keratinization. A moderate amount of fibrous tissue stroma was present, associated with a moderate, widespread lymphocytic and plasmocytie infiltrate. The necrosis found was sometimes associated with a foreign body type giant cell reaction. CLINICAL AND RADIOGRAPHIC FEATURES
Discussion.—The symptoms have been primarily due to bronchial obstruc tion, with distressing cough occurring as a presenting complaint in 7 of the 9 patients. Distal suppuration was manifested by significant fever in 5 in dividuals. In 4 patients, brisk hemoptysis was a prominent feature. The x-ray appearance was usually that of lobar atelectasis, again mirroring the endobronchial growth of the tumor. Bronchoscopic biopsy was positive in 4 of the 5 instances in which a suspicious area was seen endoscopically. However, cytologic study was unrewarding in all 6 cases in which it was employed. Scalene node biopsy was undertaken in only one patient and it was negative. The initial findings at operation were principally those of atelectasis and an obstructive type of inflammation, without gross evidence of cancer; this again reflects the exophytie, noninvasive characteristics of the tumor. The hilar vessels were invariably mobile and uninvolved by the lesion. Pneumonectomy was performed in 7 of the cases and lobectomy in the remaining 2. The patients treated by lobectomy represent 2 of the 3 who died of their malignancy. The significance of this is not clear, but there is at least an implication that pneumonectomy may be preferable to lobectomy in the treatment of these particular tumors when clinical circumstances permit. X-ray therapy proved effective for a local endo-
S H E R W I N , LAFORET, S T R I E D E R
722
J. Thoracic and Cardiovas. Surg.
bronchial recurrence but not for metastatic parenchymal deposits. Although cytologie studies were negative, the massive intraluminal growth of these tumors enhances the possibility of fragmentation and subsequent implantation in other lobes. Therefore, operative manipulation should be reduced to a minimum, and it is probably desirable that bronchial occlusion be achieved early in the course of the procedure. Although lymph nodes were sometimes enlarged, metastases were invariably absent. TABLE I.
EXOPHYTIC ENDOBRONCHIAL
CARCINOMA—CLINICAL
FEATURES
SMOKING
DU RA TION NO. OP OF CIGA NO. S Y M P RETTES OF TOMS DAILY YEARS ( M O . )
VISUAL IZED AT BRON CHOSCOPY
HEMOP TYSIS
COUGH
GROSS TUMOR FRAG MENT
3-6
0
+
0
0
18
0
+
0
+
50
2
+
+
+
0
20-40
30
12 6
0 +
+ +
0 0
+ +
30
1
+
0
0
+
M
Cigar and pipe 30
20
3
+
+
0
0
50
M
30-40
30
18
0
+
+
0
68
M
40
50
15
0
0
+
0
CASE NO.
AGE
SEX
1
60
M
2
61
M
3
74
M
20
4 5
64 50
M M
6
59
M
7
53
8 9
—
—
OPERATION
SUR VIVAL TIME POSTOP
"WITH DISEASE
4 yr.* Pneumonectomy Pneumo11% nectomy yr.* Lobectomy 2 % yr.* Lobectomy 8 yr.* Pneumo8% nectomy Pneumo7% nectomy yrPneumonectomy Pneumonectomy Pneumonectomy
+ 0 + + 0 0
2 yr.
0
9 mo.
0
3 mo.
0
•Patient died .
Pathology.—In a study of cancer of the oral cavity and throat, architectural features, such as exophytic growth, superficial invasion, and a broad, sharply demarcated tumor margin, strongly suggest a more favorable prognosis.6 These same characteristics are present in the cases of this series, particularly the unique property of growing into the lumen of a bronchus as a warty or poly poid mass. Case 7 is the only instance of fairly deep tumor invasion into the alveolar sacs adjacent to the involved bronchus. It also differs from the others in that the tumor pattern is not as orderly nor as papillary, and there is lym phatic invasion. These factors suggest an intermediate prognosis, less favorable than the other 8 but better than the usual epidermoid bronehogenic carcinoma. However, the predominance of tumor within the bronchial wall, the long (5 cm.) segment of bronchus involved, and the very limited area of lung invasion war rants its inclusion in this series. In 2 cases the full thickness of the bronchial wall was penetrated by focally invasive tumor. In one of these 2 patients there was partial invasion of the adventitia of an adjacent pulmonary artery but the patient is still free of disease clinically almost 8 years postoperatively. Invasion in the remaining 6 cases was relatively superficial and in 2 of these the tumor had spread primarily by involvement of adjacent ducts and glands. . Case 1 (Fig. 1) is unusual in that the tumor growth pattern is essentially
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June, 1962
E X O P H Y T I C ENDOBRONCHIAL CANCER
723
that of a superficially spreading carcinoma which has replaced the entire mucosal circumference of a bronchus. Since little invasion is present, the presence of tumor in the opposite lung 4 years later is more likely the result of multicentric cancer formation than metastasis from the initial growth. Case 2 (see Fig. 11) showed invasion involving the full thickness of the bronchial wall but the bulk of the tumor was intraluminal and host resistance
Fig. 1.—Case 1. A division of the tumor-containing bronchus, showing essentially in situ acanthotic carcinoma. At "5 o'clock" there is a remnant of mucosal epithelium, other wise the entire mucosa has been replaced by tumor.
Fig. 2.—Case 3. The mucosal lining on the left has been replaced by polypoid tumor tissue. Note the stalk-like stromal structure, reminiscent of papillomatosis in the breast. Case 6 showed a similar picture.
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factors were prominent. The patient died of unrelated disease over 11 years after resection. Case 3 (Fig. 2) had a well-localized, essentially in situ, carcinoma which grew into the bronchial lumen as a polypoid mass. The clinical problem was clearly one of local recurrence rather than metastatic disease. The same type of tumor pattern was found in Case 6. Although the tumor of Case 6 had
Fig. 3.—Case 4. The verruciform carcinoma of Case 4. Note the cartilage at the base of the lesion, illustrating the superficial nature of the carcinoma. Fig. i.—Case 4. Two "fronds" of the verruciform carcinoma (Case 4), one of which (top) is denuded of carcinomatous epithelium, and the other intact. Even at this relatively low magnification it is apparent that the anaplasia present is not prominent.
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invaded the outer coat of a pulmonary artery, the patient was clinically free of disease 7 years and !) months postoperatively. Case 4 (Pigs. 3 and 4) is extraordinary in that the tumor pattern is very similar to the verrucous carcinoma of the oral cavity described by Ackerman. 7 Although the patient died with evidence of tumor in the opposite lung and
Fi K 5—Case 5. The bronchial wall has been greatly thinned and the lumen dilated by a "cauliflower" mass. The base of the polypoid mass (upper right hand corner) was attached by a slightly broad stalk to the mucosa, at a point just beyond the edge of the photograph. The dark areas of the upper half of the tumor represent invasive carcinoma. Invasion ex tended into the mucosa of the bronchus. Note the fingerlike projections of the tumor pe riphery, composed of myxomatous stroma and orderly epithelium. Fig 6 —Case 5. Higher magnification of Pig. 5 which shows epithelial lining, a small amount of stroma, and invasive spindle-cell carcinoma resembling the surface epithelium. The ominous appearance of the tumor inflltrate was contradicted by the good clinical course.
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probably widespread metastatic disease, the long survival period, the sudden onset of symptoms after 8 years of good health, and the obviously warty nature of the original cancer strongly favor a second primary tumor. In regard to the warty structure, it should be noted that the verrucous carcinoma of the oral cavity often recurs locally but rarely metastasizes. We believe this is the first report of this type of tumor in the lung.
Figr. 7.—Case 8. The polypoid carcinoma of Case 8 closely resembles the structure of ,. a denomatous polyp of the large bowel. Note the long, slender, tumor-free stalks and the well-differentiated squamous epithelium. In the lower left hand corner of the photograph there are small submucosal nodules of invasive squamous carcinoma.
an
The tumor of Case 5 (Pig. 5) resembles a myxomatous fibroadenoma or cystosarcoma of the breast in that both the epithelium and the stroma of the tumor are proliferating. In addition, the relatively benign looking epithelium has given rise to a spindle cell carcinoma (Fig. 6) which mimics a carcinosarcoma. We are calling the tumor a "polypoid fibroepithelial carcinoma." The tumor pattern of Case 8 (Figs. 7 and 8) is unquestionably unique and warrants an optimistic outlook despite the inadequate follow-up period. The majority of the tumor lies within multiple mucosal polyps, all of which have long, slender stalks. Although the stalks are free of carcinoma, a small focus of invasive cancer is present in the bronchial wall. Possibly the invasive area is tumor left behind as the main tumor was pulled into the respiratory stream, in
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the same fashion as adenomatous polyps of the bowel. Of course, direct con tinuity and lymphatic metastases are also plausible explanations, but are un likely in view of the negative multiple sections through the area in question. Cases 2, 7, and 9 are similar microscopically, in that the squamous car cinomas had generally broad advancing margins but also focal infiltration by small cellular islands. A promising facet to the problem of predicting tumor aggressiveness is host resistance, as demonstrated histologically by tumor necrosis, leukocytic response, and a foreign body type granulomatous response. Little, however, is known concerning the nature of intrinsic tumor growth properties.
Fig. 8.—Case 8. An intriguing feature of the invasive carcinoma in Case 8 is the ap parent "host resistance" as shown by the marked lymphocytic response and tumor necrosis. Note the poorly defined tumor within a large "ring" of lymphocytes in the right half of the photograph. The tumor on the left shows neutrophil infiltration of its periphery.
Cases 2, 4, 6, 8, and 9 showed a marked lymphocytic-plasmacytic reaction to invading tumor in association with focal foreign body type giant cells (Figs. 8 and 9). Keratin production was not often an obvious factor in the attraction of the giant cells; also keratin production was not always associated with a giant cell response. Tumor necrosis with neutrophil infiltration was also prominent. In Case 4 an intriguing finding was the destruction of cartilage without apparent cause. Examination of multiple levels, however, revealed that within the leuko cytic aggregates adjacent to eroded cartilage there were remnants of tumor cells. In other words, invasion by tumor was much more extensive than realized, but a large proportion of the invading tumor had undergone almost complete necrosis. The extensive lymphocytic reaction to the tumor in this case, as well as in the others, is well recognized as a favorable prognostic sign.8 The granulomatous response requires further study, but a preliminary report strongly suggests that it is useful in evaluating prognosis.0 Of additional interest is the dramatic response of lymph node metastases to x-ray therapy in one case of epidermoid
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carcinoma of the tongue with granulomatous response.9 The resemblance of the giant cell reaction about the tumor to the fate of homografts is supporting evi dence for a relationship to good host resistance. An exception to the rule was found in one of the nonexophytic carcinomas of this series. The tumor exhibited a marked granulomatous reaction but, shortly after operation, the patient de veloped carcinoma in the operative incision and died 6 months postoperatively with extensive skin involvement and visceral metastases. The precipitous course
Pig-. 9.—Case 4. Epidermoid carcinoma of Case 4. Note the foreign body type giant cells adjacent to a mass, top left. The tumor in the advancing- margin, lower part of picture, is undergoing necrosis and there is an associated dense lymphocytic infiltrate. Fig. 10.—Case 7. Note the polypoid mass on the right, most of which projects into the lumen. The mucosa, which is clearly shown centrally, extends to the right almost as far as the marginal cartilage. The tumor infiltrate can be seen between the two cartilaginous masses on the right involving the full thickness of the bronchial wall.
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Fig. 11.—A cauliflower-shaped mass completely occludes the bronchus supplying the con solidated and fleshy appearing lobe. Note the sharpness and circumscription of the base of the mass.
Pig. 12.—The mass is composed of three polypoid structures sharing a common base. The divisions of the polypoid mass are clearly related to the branches of the main-stem bronchus. On cutting through the base of the carcinoma, penetration of tumor through the bronchial wall but not into the peribronchial tissue was noted. The tumor within the bronchial wall represents a very small portion of the tumor.
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and the manner of tumor spread imply a dramatic alteration in the host resist ance balance. From this study of 9 cases, derived from a relatively small series of 85 lung resections, it is clear that a detailed report of the pathology must be avail able before survival figures can be correlated with other factors. More effort must be made to obtain detailed pathologic information, such as tumor pattern and growth behavior, the presence and extent of in situ carcinoma, multicentric cancer foci 12 ' 13 and, particularly, the cause of death as verified by autopsy. I t is interesting to note that the case reported by Henry and Miscall seems to be an example of an exophytic endobronchial tumor. 10 Although the lesion was called an anaplastic carcinoma, the patient was asymptomatic and ap parently free of tumor 20 months after left upper lobectomy.11 SUMMARY
A clinicopathologic study of 85 lung carcinomas revealed 9 exophytic tumors, characterized by endobronchial proliferation and superficial, focal in vasion of the bronchial wall. Unique growth patterns were found, including polypoid and papillomatous masses, superficially spreading in situ carcinomas, verruciform neoplasia, and a distinctive "polypoid fibroepithelial carcinoma." Six of the 9 patients have had adequate follow-up periods. Two of these are living and well approximately 8 years after resection. One died 11 years after resection from a nonrelated disease. One died 8 years after resection with late appearing clinical evidence of cancer in the opposite lung. Another died 4 years after resection with cancer of the opposite lung. A sixth patient died 27 months after resection following recurrence of tumor in the bronchial stump. Reasons are given for optimism in the prognosis of the remainder with shortterm follow-up. REFERENCES
1. Doll, R., Bradford Hill, A., and Kreyberg, L.: Significance of Cell Type in Relation to Etiology of Lung Cancer, Brit. J . Cancer 1 1 : 43-48, 1957. 2. Kirklin, J . W., McDonald, J . R., Clagett, O. T., Moersch, H. J., and Gage, R. P . : Bronchogenic Carcinoma: Cell Type and Other Factors Relating to Prognosis, Surg. Gynec. & Obst. 100: 429-438, 1955. 3. Olcott, C. T.: Cell Types and Histologic Patterns in Carcinoma of the L u n g : Observa tions on the Significance of Tumors Containing More Than One Type of Cell, Am. J . Path. 3 1 : 975-995, 1955. 4. Nohl, H . C.: Investigation Into Lymphatic and Vascular Spread of Carcinoma of Bronchus, Thorax 1 1 : 172-185, 1956. 5. Sherwin, R. P., and Laforet, E. G.: Unpublished data. 6. Sherwin, R. P., and Zovickian, A.: Squamous Carcinomas of the Oral Cavity and Throat and Their Clinicopathological Correlation, Am. J . Surg. 102: 823-829, 1962. 7. Ackerman, L. V., and McGavran, M. H . : Proliferating Benign and Malignant Epithelial Lesions of the Oral Cavity, J . Oral Surg. 16: 400-413, 1958. 8. Berg, J . W.: Inflammation and Prognosis in Breast Cancer: Search for Host Resistance, Cancer 12: 714-720, 1959. 9. Sherwin, R. P., and Zovickian, A.: Unpublished data. 10. Henry, W. J., and Miscall, L.: Rapidly Reversible Atelectasis Due to Change in Position, J . THORACIC SURG. 4 1 : 686-688,
1961.
11. Miscall, L.: Personal communication, 1961. 12. Hartsock, R. J., and Fisher, E. R.: Bilateral Primary Invasive Carcinoma of the Lungs, Dis. Chest 39: 421-424, 1961. 13. Hughes, R. K., and Blades, B . : Multiple Primary Bronchogenic Carcinoma, J . THORACIC SURG. 4 1 : 421,
1961.