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Screening for bronchogenic carcinoma
J
THoRAc CARDIOV ASC SURG
78:876-882, 1979
Screening for bronchogenic carcinoma The surgical experience A screening project consisting of 10.362 men was designed to detect early lung cancer. Half (if the subjects had sputum cytologic studies and chest radiographs. and the other half had chest radiographs. Seventy cases (if bronchogenic carcinoma were detected. Eight patients had malignant cells in their sputum and normal chest radiographs. and 62 patients had radiographic evidence (if bronchogenic carcinoma. After clinical assessment including bronchoscopy. percutaneous needle biopsy. mediastinoscopy. and mediastinotomy in selected cases. 48 of the patients underwent exploratory thoracotomies. Six patients had benign disease. Thirty-nine of the remaining 42 patients had tumors resected for cure. an overall resectability rate of 55%. Staging was accomplished after resection and histologic examination (if the operative specimens. Five patients with Stage 0 carcinoma have survived a median (if 36 months without evidence of recurrence. Twenty-six patients had Stage I disease. and 77% have survived a median of 36 months without recurrence. Four of these patients have developed second primary tumors. Of the seven patients with Stage Il disease. three are alive 40 to 50 months following operation. Seventeen patients had Stage III disease. two of whom have survived. Nine patients with oat cell carcinoma were treated by irradiation and chemotherapy, and all are dead. The median survival was 8 months. The results (if this study are encouraging. However, long-term follow-up is necessary to demonstrate whether early detection by sputum cytologic studies and chest radiographs and the apparently improved survival (if these paitents will result in a decreased death rate from bronchogenic carcinoma. The high initial survival rates may be due simply to earlier intervention in the natural history (if the disease.
R. Robinson Baker, M.D., Melvyn S. Tockman, M.D. (by invitation), Bernard R. Marsh, M.D. (by invitation), Frederick P. Stitik, M.D. (by invitation), Wilmot C. Ball, Jr., M.D. (by invitation), Joseph C. Eggleston, M.D. (by invitation), Yener S. Erozan, M.D. (by invitation), Morton L. Levin, M.D. (by invitation), and John K. Frost, M.D. (by invitation), Baltimore. Md.
Two-hundred fifty people die of bronchogenic carcinoma every day in the United States. Hopefully this death rate can be decreased by prevention or possibly by detection of these extraordinarily malignant tumors before metastases have occurred. Prevention is the most effective and logical of these possibilities, but thus far the modest decrease in cigarette consumption From the Departments of Surgery, Medicine, Otolaryngology, Radiology, and Pathology, The Johns Hopkins University School of Medicine, Baltimore, Md. Supported by National Institutes of Health and National Cancer Institute Research Contract NOl-CN-45037. Read at the Fifty-ninth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass., April 30 to May 2, 1979. Address for reprints: R. Robinson Baker, M.D., Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Md. 21205.
876
since the Surgeon General's message of 1964 and efforts to reduce air pollution have not been reflected in lower lung cancer incidence. This report describes our experience with a project designed to determine if early detection can significantly decrease the death rate from bronchogenic carcinoma. Two methods of early detection were employed: serial cytologic examination of the sputum for malignant cells combined with serial chest radiographs versus chest radiographs alone. Our preliminary experience with this project, demonstrating that cytologically positive, radiologically occult lesions could be successfully localized and treated, was reported in 1974. 1 Two other institutions are involved in similar projects, the Mayo Clinic" and the Memorial SloanKettering Institute." This report describes the experience at The Johns
0022-5223/79/120876+07$00.70/0 © 1979 The C. V. Mosby Co.
Volume 78 Number 6 December, 1979
Hopkins Hospital with the cases detected by the initial screening procedures. The clinical management, staging, and treatment of these prevalence cases are described and correlated with the subsequent clinical courses of the patients.
Methods This study was initiated in January, 1974. Since that time 10,362 men between 45 and 76 years of age have volunteered for the project. All of these individuals smoked at least one pack of cigarettes per day or had stopped smoking a pack or more per day within the past year. The patients were randomly assigned into two groups prior to their initial screening. Those men assigned to Group A (study group) reported to the Pulmonary Screening Unit for sputum induction. Sputum samples were obtained after the person being screened had spent 15 to 20 minutes inhaling a nebulized mist of Hanks solution or hypertonic saline. On the following three mornings, the subject coughed a spontaneous sputum specimen into a jar of Saccomanno's preservative that was subsequently mailed back to the study office. These men also had posteroanterior and lateral chest radiographs. Most chest radiographs were obtained at 140 kVp. The films were reviewed by two radiologists, and if a disagreement occurred a third radiologist acted as referee. Subjects assigned to Group B (control group) received similar chest radiographs, but their sputum was not examined for malignant cells.
Results Seventy prevalence cases of bronchogenic carcinoma were detected in the initial screen, 34 from Group A and 36 from Group B. The patients' age range was from 45 to 76 years with a median age of 60. If malignant cells were detected by the initial cytologic studies of the sputum or if a lesion probably caused by cancer was detected on the chest radiographs, the patients were called in for further evaluation. The initial physical examination was supplemented with three successive urine and stool examinations for occult blood. Screening for occult metastases was accomplished by a serum alkaline phosphatase determination. Further clinical assessment was accomplished by tomography, sputum cytologic studies, and bronchoscopy. Percutaneous needle biopsies were performed in selected patients who had radiographic lesions which were not characteristic of malignancy, who were poor operative risks, or who refused any other diagnostic procedures. Transcervical mediastinoscopy and parasternal explorations were performed in selected cases, usually prior to thoracotomy in patients with primary tumors 3 cm in
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Table I. Total number of bronchogenic carcinomas detected correlated with method of therapy Treatment Stage 0 Thoracotomy plus resection Stage I Thoracotomy plus resection Irradiation No treatment Stage II Thoracotomy plus resection Irradiation Stage III Thoracotomy plus resection Exploratory thoracotomy Irradiation Small cell carcinoma Chemotherapy plus irradiation Total
'--N-O-.o->t-p-a-tie-n-ts-5 5 32*
26 4 2 7 5 2
17 4 2 II
9 9 70
'Three radiographically occult.
size or greater. Operability was assessed by history and physical examination supplemented with the following studies: electrocardiogram, vital capacity, forced expiratory volume in I second, and arterial Po 2, PC02, and pH. Following the clinical evaluation, 48 patients had a thoracotomy. At thoracotomy, the mediastinum was assessed by palpation but the mediastinal pleura was not opened and routine mediastinal lymph node biopsies were not taken. Final staging in these patients was based on histologic examination of the operative specimens. In the remaining 28 patients, final staging was accomplished by clinical findings, radiographic studies, and staging procedures. A summary of the clinical management of the 70 patients with bronchogenic carcinoma correlated with the stage of disease is presented in Table I. Eight patients from Group A were found to have cells shed from a squamous cell carcinoma in their sputum in the presence of normal chest radiographs. In all eight cases a fiberoptic bronchoscopy was used to localize the presence of endobronchial lesions to a specific segmental, lobar, or main-stem bronchus. In all instantces, the presence of squamous cell carcinoma in situ was documented by histologic section prior to operation. In one patient bilateral lesions were detected by the fiberoptic bronchoscope. Five patients subsequently underwent a lobectomy, two patients had a sleeve resection (one of the right upper lobe and right main-stem bronchus, the other of the left upper 'lobe and left main-stem bronchus), and one patient had a pneumonectomy. Stage O. Following histologic examination of the
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Thoracic and Cardiovascular Surgery
o I
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CJ FREE OF DISEASE ALIVE DISEASE t DEATH SECOND LESION
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Fig. I. Stage I. Surgical resection.
operative specimens, five patients were found to have squamous cell carcinoma in situ with extensive glandular involvement but no evidence of invasion. These patients were classified as having Stage 0 disease. 4 One of these patients died of multiple pulmonay emboli 8 days following a left pneumonectomy. The remaining four patients are alive without clinical, radiographic, or cytologic evidence of recurrence 36 to 40 months postoperatively. The one patient with bilateral lesions had a tumor of the left upper lobe resected. The other lesion in the right upper lobe was destroyed with the cautery. He has survived 36 months without evidence of recurrence. The remaining three patients had invasive squamous cell carcinoma and were classified as having Stage I disease. The bronchial anastomosis of the patient undergoing a sleeve resection of the left upper lobe and left main-stem bronchus became disrupted on the fifth postoperative day and a left pneumonectomy was completed; the patient survived. The survival of these three patients with radiographically occult cancers is summarized in the section on Stage I lesions. Sixty-eight patients had abnormal chest radiographs which demonstrated lesions varying in size from 0.5 to 8 ern. Ninety-five percent of these patients had lesions 5 cm in size or less (TI and T2 lesions).
Stage I. Twenty-six patients were classified as having Stage I disease (TI NO MO, 21; TI NI MO, one; T2 NO MO, four patients) following histologic examination of the operative specimens. The histologic types of Stage I tumors resected are listed in Table II. One of these patients died 14 days postoperatively, I day after discharge from the hospital. Death apparently was due to a pulmonary embolus; no autopsy was obtained. The subsequent courses of the remaining 22 patients and the three patients with radiographically occult Stage I lesions are summarized in Fig. I. Six patients with clinical and radiographic evidence of Stage I disease were not operated upon. Five patients with squamous cell carcinoma refused operation. Four of these patients were treated by irradiation. One died 6 months following the diagnosis, and the remaining three patients are alive with evidence of disease 14 to 38 months after the diagnosis was established. The remaining patient with a squamous cell carcinoma refused treatment and died 12 months after the diagnosis was established. One patient was not treated because he had a cardiac arrest during a diagnostic procedure and became decerebrate. He died of metastatic large cell undifferentiated carcinoma 6 months later. Stage II. Five patients were found to have Stage II disease (T2 N 1 MO) following thoracotomy and resec-
Volume 78 Number 6 December, 1979
tion. All of these lesions were squamous cell carcinomas. They were resected by pneumonectomy in four instances and by lobectomy in one instance. Two of these patients died of metastatic carcinoma II and 21 months postoperatively. The remaining three patients are alive without evidence of recurrence 40, 42, and 50 months postoperatively. Two additional patients had x-ray evidence of Stage II lesions. One refused operation and the other was thought to be a poor candidate for operation because of associated pulmonary and cardiovascular disease. Both of these patients were treated by irradiation and died 4 and 18 months later with evidence of metastatic and persistent primary bronchogenic carcinoma. Stage III. Seventeen patients were eventually classified as having Stage III disease. The histologic types of tumor are presented in Table III. Six of these patients underwent thoracotomy. The tumor was unresectable because of direct extension into the mediastinum in one instance. This patient was subsequently treated by irradiation and died 12 months later. In two instances, the chest wall was excised in continuity with the tumor. Both of these patients have survived for 42 and 56 months after operation. Two patients were treated by preoperative irradiation after transcervical mediastinoscopy had detected mediastinal lymph node metastases. The primary tumor and mediastinal nodes were subsequently resected in one patient; the other patient had an unresectable tumor at thoracotomy and was treated by additional postoperative irradiation. These patients died 23 and 26 months after the diagnosis was established. Another patient was found to have posterior mediastinal lymph node metastases at operation. He died 18 months following a right lower lobectomy and excision of mediastinal nodes. The remaining 11 patients were classified as having Stage III disease because of bronchoscopic evidence of tumor within 2 em of the carina (one case), supraclavicular lymph node metastases (three cases), mediastinal lymph node metastases detected by transcervical mediastinoscopy and parasternal exploration (four cases), a cytologically positive pleural effusion (one case), and clinical or radiographic evidence of mediastinal extension (two cases-left recurrent nerve palsy and phrenic nerve palsy). These 11 patients with Stage III disease were treated by irradiation of the primary tumor and regional lymph nodes. All of these patients died within 19 months of the diagnosis (median survival 12 months). Small cell carcinoma. Nine patients with abnormalities on the chest radiograph had small cell carcinomas. In six of these patients the diagnosis was established by bronchoscopy. In the remaining three patients the diagnosis was established by supraclavicular lymph
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Table II. Histologic types of tumors resectedStage I Histologic type
No. of cases
Squamous cell carcinoma Adenocarcinoma Large cell undifferentiated carcinoma
10 13 3
Table III. Histologic types of tumorsStage III Histologic type
No. of cases
Squamous cell carcinoma Adenocarcinoma Large cell undifferentiated carcinoma
5
6 6
Table IV. Nonmalignant lesions resected correlated with number of cases and operative procedure Lesion Tuberculosis Hamartoma Nonspecific necrosis Nonspecific scar Inflammatory pseudotumor
I
No. of cases
2 1
1 I
1
I
Operation Lobectomy Wedge resection Lobectomy Multiple biopsies Lobectomy
node biopsy, parasternal exploration on the left side, and thoracotomy. These patients were treated with a combination of radiotherapy and chemotherapy. All of the patients subsequently died of small cell carcinoma within 4 to 22 months of the diagnosis (median survival 8 months). Nonmalignant lesions. Six patients underwent thoracotomy with a clinical diagnosis of bronchogenic carcinoma and proved to have benign lesions. The histologic type of lesions correlated with operative procedures is presented in Table IV. Discussion The results of this study demonstrate that cytologic examination of the sputum for malignant cells and 14 by 17 inch posteroanterior and lateral chest radiographs complement each other as screening procedures in the detection of bronchogenic carcinoma. Cytologic screening of the sputum for malignant cells was the sole means of detection in 22.8% of the patients who were screened by this mode. All of these radiographically occult tumors were resected. Five proved to have histologic evidence of Stage 0 squamous cell carcinoma, and three patients had microscopic evidence of invasive carcinoma. All of the patients surviving operation have
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remained free of disease 16 to 40 months (mean 36 months) postoperatively. The chest radiographs taken and evaluated as recently described by Stitik and Tockman" have detected a larger number of Stage I peripheral bronchogenic carcinomas. Twenty-three of these tumors have been resected and 77% of the patients surviving the operation are alive without evidence of recurrence of the primary tumor or metastases 19 to 44 months (median 36 months) following operation. Second primary tumors have developed in four of these patients within the follow-up period. We did not routinely open the mediastinal pleura and resect mediastinal lymph nodes as a staging procedure. Since there have been no local recurrences solely in the mediastinal lymph nodes, we believe that routine exploration of the mediastinum and excision of mediastinal lymph nodes, as advocated by Martini and Beattie," is not necessary in patients with lesions less than 3 em in size. In those patients with lesions greater than 3 ern, we would advocate preoperative exploration of the mediastinum by transcervical mediastinoscopy or parasternal exploration rather than mediastinal dissection at the time of thoracotomy for prognostic purposes. In addition to the 31 patients with Stage 0 and I disease, eight other patients with Stage II and III disease underwent resection for cure, a resectability rate of 55%. If the six patients with clinical and radiographic evidence of Stage I disease who did not undergo resection are included, the probable resectability rate increases to 64%. This rate of 64% compares favorably with the 25% to 40% resectability rates reported in a number of other clinical studies 7-10 and indicates that the screening procedures employed have detected these tumors at an earlier stage than does routine medical care. Several other studies relating to radiographic screening for bronchogenic carcinoma have been reported. 11,12 These studies employed 70 mm photofluorograms. Although an appreciable number of bronchogenic carcinomas were detected, these investigators were unable to demonstrate a significant decrease in the death rate. Our seemingly better results in detection of lung cancer may be due to improved methods of radiographic screening as well as the combination of radiographic and cytologic screening techniques. By recruiting subjects outside the hospital environment, we have dealt with a relatively healthy population. Thus only one of 70 patients in our study was thought to be inoperable because of associated medical illness. In contrast, similar cytologic screening projects'": 14 employing hospital populations have had a considerably higher incidence of inoperability because
Thoracic and Cardiovascular Surgery
of associated cardiovascular and pulmonary disease. However, five patients with Stage I disease in our series refused operation. One had no therapy and four were treated by irradiation. All of these patients are dead of bronchogenic carcinoma or alive with evidence of recurrence or metastases 6 to 38 months following treatment. Despite careful preoperative evaluation including fiberoptic bronchoscopy in all patients and liberal indications for percutaneous needle biopsies, six patients in this study were found to have benign lesions at the time of thoracotomy. In any type of screening project employing chest radiographs, a certain small number of unnecessary thoracotomies will be performed primarily because the lesions detected are too small to be visualized by fluoroscopy and therefore are inaccessible to percutaneous needle biopsy. A particularly high survivorship has been demonstrated in patients with Stage 0 disease and in patients with squamous cell carcinomas and adenocarcinomas 3 em or smaller who had no evidence of lymph node metastases in the operative specimen. The, indication for adjuvant therapy is difficult to determine in this type of patient, who seemingly has at least an 80% chance of survival with no additional treatment. Second primary tumors in this type of patient, in our experience, appear to be a more important and treatable problem than distant metastases from the original primary tumor. The results of this study are encouraging, but longterm follow-up is necessary to determine if the early detection by sputum cytologic study or 14 by 17 inch chest radiographs (or both) and the apparent improved survival of these cases will result in a decrease of the death rate from bronchogenic carcinoma. The high initial survival rates may be simply due to earlier intervention in the natural history of the disease. The clinical course of the six patients with unresected Stage I disease suggests, however, that excision of these tumors does significantly prolong the disease-free interval. REFERENCES Baker RR, Marsh BR, Frost JK, Stitik FP, Carter D, Lee JM: The detection and treatment of early lung cancer. Ann Surg 179:813, 1974 2 Fontanna RS, Sanderson DR, Woolner LB, Miller WE, Bernatz PE, Payne WS, Taylor WF: The Mayo Lung Project for early detection and localization of bronchogeniccarcinoma. A status report. Chest 67:511, 1975 3 Melamed M, Glehinger B, Miller D, Osborne R, Zamin M, McGinnis C, MartiniJ: Preliminary report of the lung cancer detection program in New York. Cancer 39:369, 19TI
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system for carcinoma of the lung, Chicago, 1973, The American Joint Committee for Cancer Staging and End Results Reporting Stitik FP, Tockman MS: Radiographic screening in the early detection of lung cancer. Radiol Clin North Am 16:347, 1978 Martini E, Beattie EJ: Results of surgical treatment in Stage I lung cancer. J THORAC CARDIOVASC SURG 74:499, 1977 Kirklin JW, McDonald JR, Clagett DT, Moersch HJ, Gage RP: Bronchogenic carcinoma. Cell type and other factors relating to prognosis. Surg Gynecol Obstet 100:429, 1955 Maloney JV, Bennett LR, Longmire WP, Madden SC, Rigler LG, Simmons OH, Steele JD, Stein 11, Troup GM, Weber AP: Carcinoma of the lung. The UCLA interdepartmental conference. Ann Intern Med 64: 165, 1966 Paulson DL: A philosophy of treatment for bronchogenic carcinoma. Ann Thorac Surg 5:289, 1968 Stanford W, Spivey CG, Larsen GL, Alexander JA, Besich WJ: Results of treatment of primary carcinoma of the lung. An analysis of 3,000 cases. J THORAC CARD10VASC SURG 72:441, 1976 Boucot KR, Weiss W: Is curable lung cancer detected by semi-annual screening? JAMA 244: 1361, 1973 Brett GZ: Earlier diagnosis and .survival in lung cancer. Br Med J 4:260, 1969 Gryzbowski S, Coy P: Early diagnosis of carcinoma of the lung. Simultaneous screening with chest x-rays and sputum cytology. Cancer 25: 113, 1970 Lilienfeld A, et al: An evaluation of radiologic and cytologic screening for early detection of lung cancer. A cooperative pilot study of the American Cancer Society and Veteran's Administration. Cancer Res 26:2083, 1966
Discussion DR. RICHARD H. OVERHOLT Boston. Mass.
It is certainly refreshing to hear of an effort to find early cancer. Pessimism seems to dominate much of the literature, and in the past decade we have been overwhelmed by reports of palliation by chemotherapists and radiotherapists. What surgical therapy can do for this type of cancer is minimized in the minds of the general medical profession by a continuum of references which lump all cancer cases together and repetitiously point out a dismal overall cure rate-about 10%. Dr. Baker and his associates have shown that the cure rate can be raised significantly if the time schedule for discovery is set ahead. Now, I assume that the 10,000 subjects in this survey were screened just one time. I am told that when a Gloucester fisherman pulls in his net, he catches fish of all ages. This cancer fishing expedition that Dr. Baker has done unfortunately caught old cancers as well as new cancers. He was able to operate in only half of the total number of cases found. This should make us consider a repetitive screening procedure so that earlier cancers can be caught as they pass from the occult to the discoverable stage.
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I was surprised that not one of his patients was treated by segmental resection. Screening programs ought to pick up early small infiltrates or small, strictly localized coin lesions. These can best be handled by a conservative resection, which eliminates thoughts of pneumonectomy, lobectomy, sleeve resection, or preoperative radiation. Over the years the pendulum in our own clinic has swung from the extensive resections to a more conservative type. In the last 2 years we have explored 154 cases and performed resections in 138 of them. Segmental resections were done in 64 cases, lobectomy in 51, and pneumonectomy in only 23 cases. Survey cases ought to yield higher cure rates. The survey salvage at 5 years in our clinic has been 66%, and if we correct that for life tables, it would rise to almost 75%. I should like to ask Dr. Baker several questions: First, what is the incidence of false negative results in your examination of the sputum by cytologic means? Second, what is the incidence of false positive results? Third, if an asymptomatic patient presents himself with a coin lesion or infiltrate that is peripherally located and there is no evidence of calcific deposits, what do you recommend-needle biopsy, bronchial brushing and bronchoscopy, or a total biopsy? I think we will increase our cure rate if we concentrate on efforts to do a total biopsy rather than to try to determine ways not to treat people who have such a fatal disease. DR. F. GRIFFITH PEARSON Toronto. Ontario. Canada
I wish to bring to your attention information on a special group of patients identified in Dr. Baker's review of his screening program. These are patients who have a radiologically occult lesion-the carcinoma being identified only by the evidence of malignancy on sputum cytologic studies. In Dr. Baker's presentation this represents only 8 of 10,000 cases screened, an incidence of less than 0.01%. A group at The Mayo Clinic has been conducting a similar survey since 1971. At initial screening, they identified lung cancer in 86 individuals-these are the 86 "prevalence cases. " This leaves a group of just over 9,000 patients, who had normal chest x-ray films, no evidence of malignancy in the sputum cells on initial screening, and a satisfactory subsequent follow-up. In this group of patients 140 new lung cancers have been identified. These are the "incidence cases. " Only 105 (three quarters) of the incidence cases were actually detected by the screening modalities. Presumably, the others presented with signs or symptoms in their own communities. Of the 105 cases identified by the screening process, only 21 were identified by cytologic examination of the sputum alone-that is, a normal chest x-ray film and abnormal sputum cells. Thus, 21 of close to 10,000 patients, followed for an average of 4 112 years, have developed a radiologically occult lung cancer. This is a detection rate of less than 0.03%. The observations from Dr. Baker's screening program and the Mayo lung project both suggest that screening by cytologic examination of the sputum in a general population of male smokers is not yet practical. I would now like to draw your attention to the generally
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favorable biologic characteristics of this subgroup of patients with radiologically occult primary lung cancer. At the Toronto General Hospital between 1963 and 1979, we have encountered 27 patients with chest x-ray negative, sputum positive lung cancer. These patients were identified for the most part because they presented with symptoms which were actually due to their tiny tumors. Hemoptysis was a presenting complaint in 16 of the 27. Segmental pneumonitis was present in six. Three of the 27 patients were picked up in a screening program which we conducted in 1965 in smoking men over 45 years of age, from our out-patient population. Of the 27 tumors, 25 were squamous, one adenocarcinoma, and one small cell carcinoma. Despite their small size, 22 of the tumors were invasive. Five were at an in situ stage. Not one of the 27 patients had a nodal metastasis. In 18 of the 21 patients who were treated by resection, the tumor was not palpable by the surgeon at operation. The results are startling. No patient has died of recurrent tumor, no patient is living with local recurrence and, still more surprising, no patient as yet has a second primary carcinoma. Finally, we have some interesting data from a group of 268 men who worked in a nickel smelting operation between 1948 and 1963, which exposed them to a nickel compound which is carcinogenic. These patients were screened by annual chest x-ray and sputum cytologic studies beginning in 1973 and 1974 and have been followed regularly since. The mean follow-up is now 5Yz years. In 12 of these 268 men, cytologic studies of the sputum have revealed malignancy while the chest x-ray film was still normal. A primary respiratory cancer was identified in all 12 by subsequent investigationone in the maxillary sinus, one in the larynx, and the remainder in the lung. Nine of the 10 pulmonary lesions were resected. Again, all of them were squamous cell tumors. The biologic characteristics of these carcinogen-induced cancers, however, appears much less favorable that that of similar occult tumors which develop in cigarette smokers without any additional industrial risk. At resection, nodal metastases were identified in one patient and multiple synchronous primary tumors in another. Within 2 years of resection, local recurrence has developed in two patients, and one has died of the disease. Second primary tumors have developed in two patients. In conclusion, screening by sputum cytology in a general population of smoking men appears unrewarding. Screening by sputum cytology in selected high-risk groups who are exposed to an industrial carcinogen such as occurs in the nickel
Thoracic and Cardiovascular Surgery
smelting, uranium, asbestos industries does appear practical at the present time. If primary lung cancer is identified at a radiologically occult stage, the results of surgical resection appear to be excellent. These results, however, are less favorable in patients subjected to the combined effects of an industrial carcinogen and cigarette smoking. DR. B A K E R (Closing) I would like to thank Dr. Overholt and Dr. Pearson for their comments. In answer to Dr. Overholt's questions, I am reporting solely the prevalence experience. We have also had an incidence experience of approximately the same number of patients. All of the patients in the study will be followed for 5 years and additional incidence cases will be detected. We have done two sleeve resections in patients with radiographically occult tumors. Both patients were found to have Stage I cancer after pathological staging. I would agree that segmental resection should be performed when technically feasible because these patients are apt to have second primary tumors. We have had no false-positive sputum results, which is a credit to our very competent cytologists. We are not aware of any false-negative cases. I did not mean to imply that needle biopsies were employed in every case. We have employed needle biopsies only if the lesion was not radiographically characteristic of malignancy or if the patient simply refused to be operated upon until a definitive diagnosis was established. For a peripheral lesion, we have found needle biopsy to be far more efficient than transbronchial biopsies even with sophisticated techniques including use of a biplane fluoroscope. In answer to Dr. Pearson's questions, we also have found a relatively low incidence of sputum-positive cases in the incidence group. I think that similar results will probably be observed both at the Mayo Clinic and at The Memorial Sloan-Kettering Institute. We will report the incidence experience in a year or so. I think it is important to emphasize a point to which Dr. Pearson alluded: If there are malignant cells in the sputum but a normal chest x-ray film, those cells are not necessarily coming from the tracheobronchial tree. The upper aerodigestive tract should be examined carefully for evidence of tumor before fiberoptic bronchoscopy is done.
THoRAc CARDIOV ASC SURG
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Screening for bronchogenic carcinoma The surgical experience A screening project consisting of 10.362 men was designed to detect early lung cancer. Half (if the subjects had sputum cytologic studies and chest radiographs. and the other half had chest radiographs. Seventy cases (if bronchogenic carcinoma were detected. Eight patients had malignant cells in their sputum and normal chest radiographs. and 62 patients had radiographic evidence (if bronchogenic carcinoma. After clinical assessment including bronchoscopy. percutaneous needle biopsy. mediastinoscopy. and mediastinotomy in selected cases. 48 of the patients underwent exploratory thoracotomies. Six patients had benign disease. Thirty-nine of the remaining 42 patients had tumors resected for cure. an overall resectability rate of 55%. Staging was accomplished after resection and histologic examination (if the operative specimens. Five patients with Stage 0 carcinoma have survived a median (if 36 months without evidence of recurrence. Twenty-six patients had Stage I disease. and 77% have survived a median of 36 months without recurrence. Four of these patients have developed second primary tumors. Of the seven patients with Stage Il disease. three are alive 40 to 50 months following operation. Seventeen patients had Stage III disease. two of whom have survived. Nine patients with oat cell carcinoma were treated by irradiation and chemotherapy, and all are dead. The median survival was 8 months. The results (if this study are encouraging. However, long-term follow-up is necessary to demonstrate whether early detection by sputum cytologic studies and chest radiographs and the apparently improved survival (if these paitents will result in a decreased death rate from bronchogenic carcinoma. The high initial survival rates may be due simply to earlier intervention in the natural history (if the disease.
R. Robinson Baker, M.D., Melvyn S. Tockman, M.D. (by invitation), Bernard R. Marsh, M.D. (by invitation), Frederick P. Stitik, M.D. (by invitation), Wilmot C. Ball, Jr., M.D. (by invitation), Joseph C. Eggleston, M.D. (by invitation), Yener S. Erozan, M.D. (by invitation), Morton L. Levin, M.D. (by invitation), and John K. Frost, M.D. (by invitation), Baltimore. Md.
Two-hundred fifty people die of bronchogenic carcinoma every day in the United States. Hopefully this death rate can be decreased by prevention or possibly by detection of these extraordinarily malignant tumors before metastases have occurred. Prevention is the most effective and logical of these possibilities, but thus far the modest decrease in cigarette consumption From the Departments of Surgery, Medicine, Otolaryngology, Radiology, and Pathology, The Johns Hopkins University School of Medicine, Baltimore, Md. Supported by National Institutes of Health and National Cancer Institute Research Contract NOl-CN-45037. Read at the Fifty-ninth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass., April 30 to May 2, 1979. Address for reprints: R. Robinson Baker, M.D., Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Md. 21205.
876
since the Surgeon General's message of 1964 and efforts to reduce air pollution have not been reflected in lower lung cancer incidence. This report describes our experience with a project designed to determine if early detection can significantly decrease the death rate from bronchogenic carcinoma. Two methods of early detection were employed: serial cytologic examination of the sputum for malignant cells combined with serial chest radiographs versus chest radiographs alone. Our preliminary experience with this project, demonstrating that cytologically positive, radiologically occult lesions could be successfully localized and treated, was reported in 1974. 1 Two other institutions are involved in similar projects, the Mayo Clinic" and the Memorial SloanKettering Institute." This report describes the experience at The Johns
0022-5223/79/120876+07$00.70/0 © 1979 The C. V. Mosby Co.
Volume 78 Number 6 December, 1979
Hopkins Hospital with the cases detected by the initial screening procedures. The clinical management, staging, and treatment of these prevalence cases are described and correlated with the subsequent clinical courses of the patients.
Methods This study was initiated in January, 1974. Since that time 10,362 men between 45 and 76 years of age have volunteered for the project. All of these individuals smoked at least one pack of cigarettes per day or had stopped smoking a pack or more per day within the past year. The patients were randomly assigned into two groups prior to their initial screening. Those men assigned to Group A (study group) reported to the Pulmonary Screening Unit for sputum induction. Sputum samples were obtained after the person being screened had spent 15 to 20 minutes inhaling a nebulized mist of Hanks solution or hypertonic saline. On the following three mornings, the subject coughed a spontaneous sputum specimen into a jar of Saccomanno's preservative that was subsequently mailed back to the study office. These men also had posteroanterior and lateral chest radiographs. Most chest radiographs were obtained at 140 kVp. The films were reviewed by two radiologists, and if a disagreement occurred a third radiologist acted as referee. Subjects assigned to Group B (control group) received similar chest radiographs, but their sputum was not examined for malignant cells.
Results Seventy prevalence cases of bronchogenic carcinoma were detected in the initial screen, 34 from Group A and 36 from Group B. The patients' age range was from 45 to 76 years with a median age of 60. If malignant cells were detected by the initial cytologic studies of the sputum or if a lesion probably caused by cancer was detected on the chest radiographs, the patients were called in for further evaluation. The initial physical examination was supplemented with three successive urine and stool examinations for occult blood. Screening for occult metastases was accomplished by a serum alkaline phosphatase determination. Further clinical assessment was accomplished by tomography, sputum cytologic studies, and bronchoscopy. Percutaneous needle biopsies were performed in selected patients who had radiographic lesions which were not characteristic of malignancy, who were poor operative risks, or who refused any other diagnostic procedures. Transcervical mediastinoscopy and parasternal explorations were performed in selected cases, usually prior to thoracotomy in patients with primary tumors 3 cm in
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Table I. Total number of bronchogenic carcinomas detected correlated with method of therapy Treatment Stage 0 Thoracotomy plus resection Stage I Thoracotomy plus resection Irradiation No treatment Stage II Thoracotomy plus resection Irradiation Stage III Thoracotomy plus resection Exploratory thoracotomy Irradiation Small cell carcinoma Chemotherapy plus irradiation Total
'--N-O-.o->t-p-a-tie-n-ts-5 5 32*
26 4 2 7 5 2
17 4 2 II
9 9 70
'Three radiographically occult.
size or greater. Operability was assessed by history and physical examination supplemented with the following studies: electrocardiogram, vital capacity, forced expiratory volume in I second, and arterial Po 2, PC02, and pH. Following the clinical evaluation, 48 patients had a thoracotomy. At thoracotomy, the mediastinum was assessed by palpation but the mediastinal pleura was not opened and routine mediastinal lymph node biopsies were not taken. Final staging in these patients was based on histologic examination of the operative specimens. In the remaining 28 patients, final staging was accomplished by clinical findings, radiographic studies, and staging procedures. A summary of the clinical management of the 70 patients with bronchogenic carcinoma correlated with the stage of disease is presented in Table I. Eight patients from Group A were found to have cells shed from a squamous cell carcinoma in their sputum in the presence of normal chest radiographs. In all eight cases a fiberoptic bronchoscopy was used to localize the presence of endobronchial lesions to a specific segmental, lobar, or main-stem bronchus. In all instantces, the presence of squamous cell carcinoma in situ was documented by histologic section prior to operation. In one patient bilateral lesions were detected by the fiberoptic bronchoscope. Five patients subsequently underwent a lobectomy, two patients had a sleeve resection (one of the right upper lobe and right main-stem bronchus, the other of the left upper 'lobe and left main-stem bronchus), and one patient had a pneumonectomy. Stage O. Following histologic examination of the
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Fig. I. Stage I. Surgical resection.
operative specimens, five patients were found to have squamous cell carcinoma in situ with extensive glandular involvement but no evidence of invasion. These patients were classified as having Stage 0 disease. 4 One of these patients died of multiple pulmonay emboli 8 days following a left pneumonectomy. The remaining four patients are alive without clinical, radiographic, or cytologic evidence of recurrence 36 to 40 months postoperatively. The one patient with bilateral lesions had a tumor of the left upper lobe resected. The other lesion in the right upper lobe was destroyed with the cautery. He has survived 36 months without evidence of recurrence. The remaining three patients had invasive squamous cell carcinoma and were classified as having Stage I disease. The bronchial anastomosis of the patient undergoing a sleeve resection of the left upper lobe and left main-stem bronchus became disrupted on the fifth postoperative day and a left pneumonectomy was completed; the patient survived. The survival of these three patients with radiographically occult cancers is summarized in the section on Stage I lesions. Sixty-eight patients had abnormal chest radiographs which demonstrated lesions varying in size from 0.5 to 8 ern. Ninety-five percent of these patients had lesions 5 cm in size or less (TI and T2 lesions).
Stage I. Twenty-six patients were classified as having Stage I disease (TI NO MO, 21; TI NI MO, one; T2 NO MO, four patients) following histologic examination of the operative specimens. The histologic types of Stage I tumors resected are listed in Table II. One of these patients died 14 days postoperatively, I day after discharge from the hospital. Death apparently was due to a pulmonary embolus; no autopsy was obtained. The subsequent courses of the remaining 22 patients and the three patients with radiographically occult Stage I lesions are summarized in Fig. I. Six patients with clinical and radiographic evidence of Stage I disease were not operated upon. Five patients with squamous cell carcinoma refused operation. Four of these patients were treated by irradiation. One died 6 months following the diagnosis, and the remaining three patients are alive with evidence of disease 14 to 38 months after the diagnosis was established. The remaining patient with a squamous cell carcinoma refused treatment and died 12 months after the diagnosis was established. One patient was not treated because he had a cardiac arrest during a diagnostic procedure and became decerebrate. He died of metastatic large cell undifferentiated carcinoma 6 months later. Stage II. Five patients were found to have Stage II disease (T2 N 1 MO) following thoracotomy and resec-
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tion. All of these lesions were squamous cell carcinomas. They were resected by pneumonectomy in four instances and by lobectomy in one instance. Two of these patients died of metastatic carcinoma II and 21 months postoperatively. The remaining three patients are alive without evidence of recurrence 40, 42, and 50 months postoperatively. Two additional patients had x-ray evidence of Stage II lesions. One refused operation and the other was thought to be a poor candidate for operation because of associated pulmonary and cardiovascular disease. Both of these patients were treated by irradiation and died 4 and 18 months later with evidence of metastatic and persistent primary bronchogenic carcinoma. Stage III. Seventeen patients were eventually classified as having Stage III disease. The histologic types of tumor are presented in Table III. Six of these patients underwent thoracotomy. The tumor was unresectable because of direct extension into the mediastinum in one instance. This patient was subsequently treated by irradiation and died 12 months later. In two instances, the chest wall was excised in continuity with the tumor. Both of these patients have survived for 42 and 56 months after operation. Two patients were treated by preoperative irradiation after transcervical mediastinoscopy had detected mediastinal lymph node metastases. The primary tumor and mediastinal nodes were subsequently resected in one patient; the other patient had an unresectable tumor at thoracotomy and was treated by additional postoperative irradiation. These patients died 23 and 26 months after the diagnosis was established. Another patient was found to have posterior mediastinal lymph node metastases at operation. He died 18 months following a right lower lobectomy and excision of mediastinal nodes. The remaining 11 patients were classified as having Stage III disease because of bronchoscopic evidence of tumor within 2 em of the carina (one case), supraclavicular lymph node metastases (three cases), mediastinal lymph node metastases detected by transcervical mediastinoscopy and parasternal exploration (four cases), a cytologically positive pleural effusion (one case), and clinical or radiographic evidence of mediastinal extension (two cases-left recurrent nerve palsy and phrenic nerve palsy). These 11 patients with Stage III disease were treated by irradiation of the primary tumor and regional lymph nodes. All of these patients died within 19 months of the diagnosis (median survival 12 months). Small cell carcinoma. Nine patients with abnormalities on the chest radiograph had small cell carcinomas. In six of these patients the diagnosis was established by bronchoscopy. In the remaining three patients the diagnosis was established by supraclavicular lymph
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Table II. Histologic types of tumors resectedStage I Histologic type
No. of cases
Squamous cell carcinoma Adenocarcinoma Large cell undifferentiated carcinoma
10 13 3
Table III. Histologic types of tumorsStage III Histologic type
No. of cases
Squamous cell carcinoma Adenocarcinoma Large cell undifferentiated carcinoma
5
6 6
Table IV. Nonmalignant lesions resected correlated with number of cases and operative procedure Lesion Tuberculosis Hamartoma Nonspecific necrosis Nonspecific scar Inflammatory pseudotumor
I
No. of cases
2 1
1 I
1
I
Operation Lobectomy Wedge resection Lobectomy Multiple biopsies Lobectomy
node biopsy, parasternal exploration on the left side, and thoracotomy. These patients were treated with a combination of radiotherapy and chemotherapy. All of the patients subsequently died of small cell carcinoma within 4 to 22 months of the diagnosis (median survival 8 months). Nonmalignant lesions. Six patients underwent thoracotomy with a clinical diagnosis of bronchogenic carcinoma and proved to have benign lesions. The histologic type of lesions correlated with operative procedures is presented in Table IV. Discussion The results of this study demonstrate that cytologic examination of the sputum for malignant cells and 14 by 17 inch posteroanterior and lateral chest radiographs complement each other as screening procedures in the detection of bronchogenic carcinoma. Cytologic screening of the sputum for malignant cells was the sole means of detection in 22.8% of the patients who were screened by this mode. All of these radiographically occult tumors were resected. Five proved to have histologic evidence of Stage 0 squamous cell carcinoma, and three patients had microscopic evidence of invasive carcinoma. All of the patients surviving operation have
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remained free of disease 16 to 40 months (mean 36 months) postoperatively. The chest radiographs taken and evaluated as recently described by Stitik and Tockman" have detected a larger number of Stage I peripheral bronchogenic carcinomas. Twenty-three of these tumors have been resected and 77% of the patients surviving the operation are alive without evidence of recurrence of the primary tumor or metastases 19 to 44 months (median 36 months) following operation. Second primary tumors have developed in four of these patients within the follow-up period. We did not routinely open the mediastinal pleura and resect mediastinal lymph nodes as a staging procedure. Since there have been no local recurrences solely in the mediastinal lymph nodes, we believe that routine exploration of the mediastinum and excision of mediastinal lymph nodes, as advocated by Martini and Beattie," is not necessary in patients with lesions less than 3 em in size. In those patients with lesions greater than 3 ern, we would advocate preoperative exploration of the mediastinum by transcervical mediastinoscopy or parasternal exploration rather than mediastinal dissection at the time of thoracotomy for prognostic purposes. In addition to the 31 patients with Stage 0 and I disease, eight other patients with Stage II and III disease underwent resection for cure, a resectability rate of 55%. If the six patients with clinical and radiographic evidence of Stage I disease who did not undergo resection are included, the probable resectability rate increases to 64%. This rate of 64% compares favorably with the 25% to 40% resectability rates reported in a number of other clinical studies 7-10 and indicates that the screening procedures employed have detected these tumors at an earlier stage than does routine medical care. Several other studies relating to radiographic screening for bronchogenic carcinoma have been reported. 11,12 These studies employed 70 mm photofluorograms. Although an appreciable number of bronchogenic carcinomas were detected, these investigators were unable to demonstrate a significant decrease in the death rate. Our seemingly better results in detection of lung cancer may be due to improved methods of radiographic screening as well as the combination of radiographic and cytologic screening techniques. By recruiting subjects outside the hospital environment, we have dealt with a relatively healthy population. Thus only one of 70 patients in our study was thought to be inoperable because of associated medical illness. In contrast, similar cytologic screening projects'": 14 employing hospital populations have had a considerably higher incidence of inoperability because
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of associated cardiovascular and pulmonary disease. However, five patients with Stage I disease in our series refused operation. One had no therapy and four were treated by irradiation. All of these patients are dead of bronchogenic carcinoma or alive with evidence of recurrence or metastases 6 to 38 months following treatment. Despite careful preoperative evaluation including fiberoptic bronchoscopy in all patients and liberal indications for percutaneous needle biopsies, six patients in this study were found to have benign lesions at the time of thoracotomy. In any type of screening project employing chest radiographs, a certain small number of unnecessary thoracotomies will be performed primarily because the lesions detected are too small to be visualized by fluoroscopy and therefore are inaccessible to percutaneous needle biopsy. A particularly high survivorship has been demonstrated in patients with Stage 0 disease and in patients with squamous cell carcinomas and adenocarcinomas 3 em or smaller who had no evidence of lymph node metastases in the operative specimen. The, indication for adjuvant therapy is difficult to determine in this type of patient, who seemingly has at least an 80% chance of survival with no additional treatment. Second primary tumors in this type of patient, in our experience, appear to be a more important and treatable problem than distant metastases from the original primary tumor. The results of this study are encouraging, but longterm follow-up is necessary to determine if the early detection by sputum cytologic study or 14 by 17 inch chest radiographs (or both) and the apparent improved survival of these cases will result in a decrease of the death rate from bronchogenic carcinoma. The high initial survival rates may be simply due to earlier intervention in the natural history of the disease. The clinical course of the six patients with unresected Stage I disease suggests, however, that excision of these tumors does significantly prolong the disease-free interval. REFERENCES Baker RR, Marsh BR, Frost JK, Stitik FP, Carter D, Lee JM: The detection and treatment of early lung cancer. Ann Surg 179:813, 1974 2 Fontanna RS, Sanderson DR, Woolner LB, Miller WE, Bernatz PE, Payne WS, Taylor WF: The Mayo Lung Project for early detection and localization of bronchogeniccarcinoma. A status report. Chest 67:511, 1975 3 Melamed M, Glehinger B, Miller D, Osborne R, Zamin M, McGinnis C, MartiniJ: Preliminary report of the lung cancer detection program in New York. Cancer 39:369, 19TI
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system for carcinoma of the lung, Chicago, 1973, The American Joint Committee for Cancer Staging and End Results Reporting Stitik FP, Tockman MS: Radiographic screening in the early detection of lung cancer. Radiol Clin North Am 16:347, 1978 Martini E, Beattie EJ: Results of surgical treatment in Stage I lung cancer. J THORAC CARDIOVASC SURG 74:499, 1977 Kirklin JW, McDonald JR, Clagett DT, Moersch HJ, Gage RP: Bronchogenic carcinoma. Cell type and other factors relating to prognosis. Surg Gynecol Obstet 100:429, 1955 Maloney JV, Bennett LR, Longmire WP, Madden SC, Rigler LG, Simmons OH, Steele JD, Stein 11, Troup GM, Weber AP: Carcinoma of the lung. The UCLA interdepartmental conference. Ann Intern Med 64: 165, 1966 Paulson DL: A philosophy of treatment for bronchogenic carcinoma. Ann Thorac Surg 5:289, 1968 Stanford W, Spivey CG, Larsen GL, Alexander JA, Besich WJ: Results of treatment of primary carcinoma of the lung. An analysis of 3,000 cases. J THORAC CARD10VASC SURG 72:441, 1976 Boucot KR, Weiss W: Is curable lung cancer detected by semi-annual screening? JAMA 244: 1361, 1973 Brett GZ: Earlier diagnosis and .survival in lung cancer. Br Med J 4:260, 1969 Gryzbowski S, Coy P: Early diagnosis of carcinoma of the lung. Simultaneous screening with chest x-rays and sputum cytology. Cancer 25: 113, 1970 Lilienfeld A, et al: An evaluation of radiologic and cytologic screening for early detection of lung cancer. A cooperative pilot study of the American Cancer Society and Veteran's Administration. Cancer Res 26:2083, 1966
Discussion DR. RICHARD H. OVERHOLT Boston. Mass.
It is certainly refreshing to hear of an effort to find early cancer. Pessimism seems to dominate much of the literature, and in the past decade we have been overwhelmed by reports of palliation by chemotherapists and radiotherapists. What surgical therapy can do for this type of cancer is minimized in the minds of the general medical profession by a continuum of references which lump all cancer cases together and repetitiously point out a dismal overall cure rate-about 10%. Dr. Baker and his associates have shown that the cure rate can be raised significantly if the time schedule for discovery is set ahead. Now, I assume that the 10,000 subjects in this survey were screened just one time. I am told that when a Gloucester fisherman pulls in his net, he catches fish of all ages. This cancer fishing expedition that Dr. Baker has done unfortunately caught old cancers as well as new cancers. He was able to operate in only half of the total number of cases found. This should make us consider a repetitive screening procedure so that earlier cancers can be caught as they pass from the occult to the discoverable stage.
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I was surprised that not one of his patients was treated by segmental resection. Screening programs ought to pick up early small infiltrates or small, strictly localized coin lesions. These can best be handled by a conservative resection, which eliminates thoughts of pneumonectomy, lobectomy, sleeve resection, or preoperative radiation. Over the years the pendulum in our own clinic has swung from the extensive resections to a more conservative type. In the last 2 years we have explored 154 cases and performed resections in 138 of them. Segmental resections were done in 64 cases, lobectomy in 51, and pneumonectomy in only 23 cases. Survey cases ought to yield higher cure rates. The survey salvage at 5 years in our clinic has been 66%, and if we correct that for life tables, it would rise to almost 75%. I should like to ask Dr. Baker several questions: First, what is the incidence of false negative results in your examination of the sputum by cytologic means? Second, what is the incidence of false positive results? Third, if an asymptomatic patient presents himself with a coin lesion or infiltrate that is peripherally located and there is no evidence of calcific deposits, what do you recommend-needle biopsy, bronchial brushing and bronchoscopy, or a total biopsy? I think we will increase our cure rate if we concentrate on efforts to do a total biopsy rather than to try to determine ways not to treat people who have such a fatal disease. DR. F. GRIFFITH PEARSON Toronto. Ontario. Canada
I wish to bring to your attention information on a special group of patients identified in Dr. Baker's review of his screening program. These are patients who have a radiologically occult lesion-the carcinoma being identified only by the evidence of malignancy on sputum cytologic studies. In Dr. Baker's presentation this represents only 8 of 10,000 cases screened, an incidence of less than 0.01%. A group at The Mayo Clinic has been conducting a similar survey since 1971. At initial screening, they identified lung cancer in 86 individuals-these are the 86 "prevalence cases. " This leaves a group of just over 9,000 patients, who had normal chest x-ray films, no evidence of malignancy in the sputum cells on initial screening, and a satisfactory subsequent follow-up. In this group of patients 140 new lung cancers have been identified. These are the "incidence cases. " Only 105 (three quarters) of the incidence cases were actually detected by the screening modalities. Presumably, the others presented with signs or symptoms in their own communities. Of the 105 cases identified by the screening process, only 21 were identified by cytologic examination of the sputum alone-that is, a normal chest x-ray film and abnormal sputum cells. Thus, 21 of close to 10,000 patients, followed for an average of 4 112 years, have developed a radiologically occult lung cancer. This is a detection rate of less than 0.03%. The observations from Dr. Baker's screening program and the Mayo lung project both suggest that screening by cytologic examination of the sputum in a general population of male smokers is not yet practical. I would now like to draw your attention to the generally
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favorable biologic characteristics of this subgroup of patients with radiologically occult primary lung cancer. At the Toronto General Hospital between 1963 and 1979, we have encountered 27 patients with chest x-ray negative, sputum positive lung cancer. These patients were identified for the most part because they presented with symptoms which were actually due to their tiny tumors. Hemoptysis was a presenting complaint in 16 of the 27. Segmental pneumonitis was present in six. Three of the 27 patients were picked up in a screening program which we conducted in 1965 in smoking men over 45 years of age, from our out-patient population. Of the 27 tumors, 25 were squamous, one adenocarcinoma, and one small cell carcinoma. Despite their small size, 22 of the tumors were invasive. Five were at an in situ stage. Not one of the 27 patients had a nodal metastasis. In 18 of the 21 patients who were treated by resection, the tumor was not palpable by the surgeon at operation. The results are startling. No patient has died of recurrent tumor, no patient is living with local recurrence and, still more surprising, no patient as yet has a second primary carcinoma. Finally, we have some interesting data from a group of 268 men who worked in a nickel smelting operation between 1948 and 1963, which exposed them to a nickel compound which is carcinogenic. These patients were screened by annual chest x-ray and sputum cytologic studies beginning in 1973 and 1974 and have been followed regularly since. The mean follow-up is now 5Yz years. In 12 of these 268 men, cytologic studies of the sputum have revealed malignancy while the chest x-ray film was still normal. A primary respiratory cancer was identified in all 12 by subsequent investigationone in the maxillary sinus, one in the larynx, and the remainder in the lung. Nine of the 10 pulmonary lesions were resected. Again, all of them were squamous cell tumors. The biologic characteristics of these carcinogen-induced cancers, however, appears much less favorable that that of similar occult tumors which develop in cigarette smokers without any additional industrial risk. At resection, nodal metastases were identified in one patient and multiple synchronous primary tumors in another. Within 2 years of resection, local recurrence has developed in two patients, and one has died of the disease. Second primary tumors have developed in two patients. In conclusion, screening by sputum cytology in a general population of smoking men appears unrewarding. Screening by sputum cytology in selected high-risk groups who are exposed to an industrial carcinogen such as occurs in the nickel
Thoracic and Cardiovascular Surgery
smelting, uranium, asbestos industries does appear practical at the present time. If primary lung cancer is identified at a radiologically occult stage, the results of surgical resection appear to be excellent. These results, however, are less favorable in patients subjected to the combined effects of an industrial carcinogen and cigarette smoking. DR. B A K E R (Closing) I would like to thank Dr. Overholt and Dr. Pearson for their comments. In answer to Dr. Overholt's questions, I am reporting solely the prevalence experience. We have also had an incidence experience of approximately the same number of patients. All of the patients in the study will be followed for 5 years and additional incidence cases will be detected. We have done two sleeve resections in patients with radiographically occult tumors. Both patients were found to have Stage I cancer after pathological staging. I would agree that segmental resection should be performed when technically feasible because these patients are apt to have second primary tumors. We have had no false-positive sputum results, which is a credit to our very competent cytologists. We are not aware of any false-negative cases. I did not mean to imply that needle biopsies were employed in every case. We have employed needle biopsies only if the lesion was not radiographically characteristic of malignancy or if the patient simply refused to be operated upon until a definitive diagnosis was established. For a peripheral lesion, we have found needle biopsy to be far more efficient than transbronchial biopsies even with sophisticated techniques including use of a biplane fluoroscope. In answer to Dr. Pearson's questions, we also have found a relatively low incidence of sputum-positive cases in the incidence group. I think that similar results will probably be observed both at the Mayo Clinic and at The Memorial Sloan-Kettering Institute. We will report the incidence experience in a year or so. I think it is important to emphasize a point to which Dr. Pearson alluded: If there are malignant cells in the sputum but a normal chest x-ray film, those cells are not necessarily coming from the tracheobronchial tree. The upper aerodigestive tract should be examined carefully for evidence of tumor before fiberoptic bronchoscopy is done.