Screening for lung cancer. A critique of the Mayo Lung Project.

The National Cancer Institute of the United States recently sponsored three large-scale, randomized controlled trials of screening for early lung cancer. The trials were conducted at the Johns Hopkins Medical Institutions, the Memorial Sloan-Kettering Cancer Center, and the Mayo Clinic. Participants were middle-aged and older men who were chronic heavy cigarette smokers and thus at high risk of developing lung cancer. Screening procedures were chest radiography and sputum cytology, the only screening tests of established value for detecting early stage, asymptomatic lung cancer. In the Hopkins and Memorial trials the study population was offered yearly chest radiography plus sputum cytology every 4 months. The control population was offered yearly chest radiography only. In these trials the addition of sputum cytology appeared to confer no lung cancer mortality rate advantage. The Mayo Clinic trial compared offering chest radiography and sputum cytology every 4 months to offering advice that the two tests be obtained once a year. This trial demonstrated significantly increased lung cancer detection, resectability, and survivorship in the group offered screening every 4 months compared with the control group. However, there was no significant difference in lung cancer mortality rate between the two groups. The statistical power of these trials was somewhat limited. Nevertheless, results do not justify recommending large-scale radiologic or cytologic screening for early lung cancer at this time.

Fifty-year trend in incidence rates of bronchogenic carcinoma by cell type in Olmsted County, Minnesota.

An earlier report suggested that incidence rates of primary bronchogenic carcinoma had leveled off for men in Olmsted County, MN. Extension of that study to cover 50 years in this midwestern community now shows that lung cancer incidence continues to increase in both sexes, with rates in women approaching those found in men 20 years ago. This increase was seen for all cell types of bronchogenic carcinoma. Because one pathologist reevaluated tissues, changing histologic classifications were not responsible for secular trends; nor were the results influenced by referral bias inasmuch as the study was population based.

Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome.

We performed a retrospective study of 859 patients with papillary thyroid cancer, who had received their primary treatment at the Mayo Clinic during the period 1946 through 1970. The maximal follow-up was 39 years. All but 2 patients underwent a thyroid operation; 319 (37%) had metastatic cervical nodes. Of the 800 patients without distant metastatic lesions on initial examination who underwent a potentially curative surgical procedure, postoperatively 7% had nodal metastatic lesions, 6% had a local tumor recurrence, and 5% had a distant metastatic lesion. In patients who had intrathyroidal tumors initially, postoperative local recurrences or distant metastatic lesions resulted in a 10-year cancer mortality of 17 and 41%, respectively; in those with extrathyroidal tumors, postoperative recurrences were associated with significantly higher death rates. Death from thyroid cancer was highly associated with the following factors: age more than 50 years, male sex, tumor size, tumor grade, initial extent of disease, and absence of Hashimoto's disease. Earlier studies of Mayo patients treated between 1926 and 1960 described no deaths due to thyroid cancer in patients with occult tumors (1.5 cm or less). Four such patients were identified among our 859 patients; all had been examined and treated after 1961. To date, 56 (6.5%) of the 859 patients have died as a result of papillary thyroid cancer. In this study, in which 16% of patients underwent total thyroidectomy and 3% had radioiodine ablation, the overall mortality observed at 30 years was only 3% above that expected.

Lung cancer screening: the Mayo program.

The National Cancer Institute has sponsored three randomized controlled trials of screening for early lung cancer in large, high-risk populations to determine whether lung cancer detection can be improved by adding sputum cytological screening every 4 months to chest roentgenography done either yearly or every 4 months; and lung cancer mortality can be significantly reduced by this type of screening program, followed by appropriate treatment. Results of the three trials suggest that sputum cytology alone detects 15% to 20% of lung cancers, almost all of which are squamous cancers with a favorable prognosis; and chest roentgenography may be a more effective test for early-stage lung cancer than previous reports have suggested. Nevertheless, results of the randomized trial conducted at the Mayo Clinic showed that offering both procedures to high-risk outpatients every 4 months conferred no mortality advantage over standard medical practice that included recommended annual testing.

Bronchogenic carcinoma in Olmsted County, 1935-1979.

The incidence rates of bronchogenic carcinoma based upon 414 cases that occurred in Olmsted County, Minnesota, over a period of 45 years are described. Histologic preparations were available for 97% of cases and were reviewed by one pathologist. The overall average annual age-adjusted rates per 100,000 person-years for the most recent 5 years were 45.6 and 14.0 for men and women, respectively. Squamous cell carcinoma was most common among men and adenocarcinoma was the most common cell type among women. Incidence rates for women have risen to approximately those of men 30 years ago, whereas the incidence for men in the last 5 years has ceased to increase. Age-specific rates show increases for women in all age groups 55 years and older, and for men 65 years and older, whereas the incidence in men younger than 65 years has declined. Survival for 5 years is best for women for all cell types except small cell carcinoma, and is essentially unchanged from the earlier 40-year report.

Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic study.

The initial (prevalence) radiologic and cytologic screening for lung cancer in the Mayo Clinic study (Mayo Lung Project) involved 10,933 outpatients. All were men at high risk for lung cancer, but none were suspected of having it when they entered the Mayo Clinic. Screening identified 91 lung cancers (8.3 per 1,000 screened). Nearly two thirds of the prevalence lung cancers were detected by chest roentgenography alone. Half of these cancers were resected. Only a fifth of the cancers were detected by sputum cytologic examination alone; however, all but 1 of these were resected. Compared with a group of lung cancers encountered in contemporary clinical practice at the Mayo Clinic, the prevalence cancers were more than twice as likely to be (1) resectable, (2) postsurgical Stage I or II (AJCC), and (3) associated with survival 5 yr after treatment.

Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period.

During the first 10 years of the Mayo Lung Project, 68 roentgenographically inapparent ("occult") lung cancers were localized and apparently completely resected. A pathologic classification was developed based on depth of tumor infiltration. The five categories were (1) in situ carcinoma confined to surface epithelium or ducts of mucous glands or acini (23 cancers), (2) intramucosal invasion not greater than 0.1 cm from mucosal surface (12 cancers), (3) invasion to bronchial cartilages (11 cancers), (4) invasion to full thickness of bronchial wall (10 cancers), and (5) extrabronchial invasion (12 cancers). Multicentricity of lung cancer was studied in 54 patients, none of whom had a history of cancer of the respiratory tract, and all of whom had had "complete" surgical resection of the initial occult lung cancer (or cancers). Neoplasms that were initially multicentric occurred in 4 patients, and a subsequent primary lung cancer developed in 11. The rate of detection of second primary lesions was 42 per 1,000 person-years of observation. A high incidence of unresectable cancers and a low survival rate were noted among patients who had a subsequent primary tumor. These findings were primarily attributable to invasiveness of the subsequent primary cancer or to respiratory insufficiency that resulted from obstructive lung disease or previous pulmonary resection. Because of the high risk of development of a second primary cancer after initial surgical resection, it is important to treat the initial occult cancer as conservatively as possible consistent with "cure."

Roentgenographically occult lung cancer. A ten-year experience.

During the past 10 years, 54 patients, all men, were found to have roentgenographically occult lung cancer. The mean age was 61 years (range 45 to 76 years). All patients had abnormal findings on sputum cytologic study (carcinoma in 41 patients and squamous cell atypia in 13). The cancer was localized by bronchoscopy in all patients (range one to five examinations, mean 1.5). Seventy-five percent of the tumors were localized within 169 days of the abnormal sputum cytologic examination. Pulmonary resection for cure was performed in all patients: lobectomy in 38, pneumonectomy in nine, and bilobectomy in seven. Operative mortality was 5.6% (three patients). Fifty-eight cancers were resected, all squamous cell carcinomas (two had a component of large cell cancer). Tumor TNM classification (AJC) was TIS N0 M0 in 19 patients, T1 N0 M0 in 25, T1 N1 M0 in five, T2 N1 M0 in four, and T3 N0 M0 in one. Overall 5 year actuarial survival rate (lung cancer deaths only) was 90%. Five-year survival rate for the 44 patients with TIS N0 M0 and T1 N0 M0 neoplasms was 91%. Currently, 21 patients have died, but only 10 of lung cancer. Subsequent additional lung cancer developed in 12 patients (22%). Eleven of these patients had a second primary squamous lung cancer, six of which again were occult. We conclude that patients with occult lung cancer have a strong likelihood of long-term survival if treated early. Close surveillance is indicated because of the high incidence of a second primary lung cancer.

Hematoporphyrin derivative in the detection and localization of radiographically occult lung cancer.

Hematoporphyrin derivative used in conjunction with the Mayo Clinic bronchofiberscopic fluorescence detection system allows accurate localization of radiographically occult early squamous cell carcinoma. Thirteen tumors were localized in 10 patients with radiographically occult lung cancer. Six were in situ with or without microinvasion and were also bronchoscopically occult. Localization of these 6 tumors was expedited by the use of hematoporphyrin derivative and the bronchoscopic fluorescence detection system. Hematoporphyrin-derivative fluorescence was not specific for carcinoma and was also detected in areas of moderate and marked squamous cellular atypia. Thus, although detection of hematoporphyrin-derivative fluorescence suggests the presence of cancer, proof depends on histologic or cytologic confirmation.

Sputum cytologic diagnosis of upper respiratory tract cancer. Second report.

Screening for cancer is a popular issue for debate because few, if any, evaluations of the screening process have been conducted on a long-term prospective basis with use of concomitant, unscreened controls. We have found that screening of high-risk persons for presymptomatic lung cancer will identify patients with cancer in the upper and lower respiratory passages. Randomly selected patients enrolled in the Mayo Lung Project have undergone sputum cytologic and chest roentgenographic screening at four-month intervals and were compared with randomly selected matched control subjects who were not intensively screened. The search for upper airway tumors in the head and neck region was instigated by abnormal findings on sputum cytology in 12 screened patients. In the same period, 12 other screened patients with abnormal results of sputum cytology were found to have roentgenographically "occult" lung cancer. This finding emphasized the importance of the otorhinolaryngologic examination in screening programs for airway cancer. It is also important to emphasize that sputum-negative patients may have obvious, symptomatic tumors of the upper aerodigestive tract that can be easily diagnosed by those who are skilled in examining this area. Contrary to our expectation, there is no definitive evidence that screening has reduced mortality from either upper or lower airway cancer.

Occult papillary carcinoma of the thyroid.

Retrospective review was undertaken of 137 patients with occult papillary carcinoma of the thyroid (lesions less than or equal to 1.5 cm in diameter) who were operated on at the Mayo Clinic, Rochester, Minn, between 1926 and 1955. Mean follow-up period was 25.3 years. Operations were conservative. No patient underwent bilateral total lobectomy. For 55 patients with lymph node involvement, lymphadenectomy generally involved selective node excision or modified neck dissection. Subsequent surgery was required in 12 patients; modified radical neck dissection was necessary in only four. No operative deaths occurred. Long-term follow-up showed that all patients were alive and without disease or were dead without proof of thyroid-related disease. Thus, occult papillary thyroid carcinoma with or without nodal metastasis is a nonlethal and curable disease when treated by conservative surgical means. Radical surgical or medical extirpation of all thyroid tissue is unnecessary in the treatment of this disease.

Clinical application of a new endoscopic technique for detection of in situ bronchial carcinoma.

Hematoporphyrin is preferentially concentrated by cancer tissue and therefore is a potentially useful chemical marker. This report demonstrates the effectiveness of a photoelectric hematoporphyrin fluorescence detector used simultaneously with flexible fiberoptic bronchoscopy as a means of detecting and localizing bronchogenic carcinoma. The detector generates an audio signal when fluorescence is within the visual field of the bronchoscope. Of interest is that an audio signal was generated which indicated hematoporphyrin fluorescence in areas where no mucosal abnormality had been seen. These areas proved to be carcinoma in situ.

Primary hyperparathyroidism with multiple parathyroid gland enlargement: review of 53 cases.

Of 53 patients who had hyperparathyroidism assocated with multiple parathyroid gland enlargement, 39 (74%) had primary hyperparathyroidism without clinical or laboratory evidence of associated endocrine gland dysfunction, 2 had documented familial primary hyperparathyroidism, and 12 had hyperparathyroidism as part of the multiple endocrine neoplasia syndrome. When last studied, 31 of the 39 patients with nonfamilial hyperparathyroidism had normal serum calcium levels, 3 had permanent hypoparathyroidism, 2 had recurrent hyperparathyroidism, and 3 were lost to follow-up. The two patients with familial hyperparathyroidism were treated by removal only of enlarged parathyroid glands, and in each, hyperparathyroidism recurred. Five patients with multiple endocrine neoplasia, type 1, were treated by removal only of enlarged parathyroid glands, and hyperparathyroidism recurred in four. Four patients with multiple endocrine neoplasia, type 1, were treated by removal of three or more parathyroid glands, and there were no instances of recurrent hyperparathyroidism. In one patient, permanent hypoparathyroidism developed. Three patients with multiple endocrine neoplasia syndrome, type 2, had total parathyroidectomies as a part of thyroidectomy for medullary thyroid carcinoma. In each patient, permanent hypoparathyroidism developed. When primary hyperparathyroidism occurs in the absence of a definite history of polyendocrine or familial disease, only the glands that are definitely enlarged should be removed, and normal-appearing glands should be tagged rather than risk the possibility of permanent hypoparathyroidism that may attend routine subtotal parathyroid gland excision.

Bronchoplastic procedures in the treatment of carcinoid tumors of the tracheobronchial tree.

Sixteen patients, aged 10 to 70 years, had carcinoid tumors of the lower respiratory tract treated by various resective tracheobronchoplastic procedures. These represent 8.8 percent of 181 patients with carcinoid lesions treated during a recent 20 year period. All 16 patients had respiratory symptoms, and one patient also had the carcinoid syndrome. Roentgenographic changes ranged from a mass or atelectasis (or both) through unilateral lung hyperinflation to clear lungs with subtle filling defects in major airways. All tumors were visualized endoscopically, and 13 patients had biopsies. Histopathologically, all tumors were "typical" carcinoids . Before operation, the patients had minimal or no respiratory insufficiency, although flow-volume and ventilation-perfusion abnormalities were noted when major airways were affected. Surgical management at thoracotomy was as follows: (1) simple wedge tracheobronchotomy without lung resection (five patients); (2) bronchial sleeve resection without lung resection (three patients); and (3) bronchial sleeve with upper lobe resection (eight patients). These 16 operations were performed with eight technical anatomic variations. No early or late deaths occurred. One patient had early transient atelectasis, and three patients required late endoscopic removal of suture granulation tissue. All patients were alive without recurrence of tumor or carcinoid syndrome or other respiratory complications 6 months to 19 years postoperatively. Pulmonary resection should be avoided unless there is histologic evidence of tumor extension into lung parenchyma or irreversible pulmonary suppuration distal to the obstructive tumor.

Adenoid cystic carcinoma (cylindroma) and mucoepidermoid carcinoma of the bronchus. Factors affecting survival.

A review was made of the presentation, treatment, and follow-up of 20 patients with adenoid cystic carcinoma and 12 patients with mucoepidermoid carcinoma of the bronchus who were seen at the Mayo Clinic during the 50 year period 1927 through 1977. Three forms of therapy were employed: complete surgical resection, radiation therapy alone, and radiation therapy after endoscopic removal of tumor tissue. Superior results were obtained in the group with adenoid cystic carcinoma, when complete resection was possible. Significant survival and palliation of sepsis was achieved with subtotal resection. The mucoepidermoid carcinomas in this series were classified on the basis of histologic differentiation. Mucoepidermoid carcinoma of Grade 1 was managed by conservative pulmonary resection. Mucoepidermoid carcinoma of Grades 2 and 3 showed a greater propensity for malignancy. Widespread dissemination caused death with unresectable high-grade mucoepidermoid carcinomas of Grades 2 and 3.

Incidence, trend, and outcome of bronchogenic carcinoma in Olmsted County, Minnesota, 1935--1974.

The 40-year incidence trends of bronchogenic carcinoma in Olmsted County, Minnesota, are presented and analyzed. The incidence in men has risen rapidly with each decade. During the last decade this increase was due to an increase of the rate among men over 65, rates in men under 65 appearing to have plateaued. The incidence in women increased for the first time in the decade 1965 to 1974. During the period 1935 through 1974, rates for all cell types increased in men, with that for squamous cell carcinoma increasing most. In women the recent overall increase was due mainly to an increase of adenocarcinoma, which has been the predominant cell type in women throughout. Among all cases together the 5-year survivorship was 11%, which comprised 24% for squamous cell carcinoma, 11% for large cell carcinoma, 12% for adenocarcinoma, and 0 for small cell carcinoma.

Sputum cytologic diagnosis of upper respiratory tract cancer.

Sputum cytologic testing has been applied in the screening of high-risk individuals for presymptomatic lung cancer. This same screening procedure sometimes identifies patients with upper respiratory tract cancers and thereby may permit earlier treatment. Patients enrolled in the Mayo Lung Project undergo sputum cytologic and chest roentgenographic screening at four-month intervals and are compared with matched controls who are not intensively screened. Experience to date indicates an incidence rate of approximately 1 per 1,000 per year of cancer in the upper respiratory and alimentary passages among males more than 45 years old who are heavy cigarette smokers. This compares with a rate of approximately 4 per 1,000 per year of lung cancer. Recognition of early cancer of the upper respiratory tract is an additional benefit of screening for lung cancer. Since cigarette smoking represents an etiologic agent common to both upper and lower respiratory tract cancers, tumors should be searched for in both sites in this high-risk population.

Transient hyperthyroidism in patients with lymphocytic thyroiditis.

We have studied seven episodes of transient hyperthyroidism in three men and one woman, aged 19 to 38 years. No patient had fever or neck tenderness. All had palpable thyroid glands. Elevated serum thyroxine values persisted for 1 to 3 months. Thyroid131I uptake at 6 and 24 hours was low (1 to 3%). Erythrocyte sedimentation rates were normal or only slightly increased. Needle biopsy in four patients and a thyroidectomy specimen in one patient, all taken during the hyperthyroid phase, showed lymphocyte infiltration and extensive follicular disruption without oxyphilia. There was no evidence of granulomatous thyroiditis. Thyroglobulin antibodies were normal in all. In three patients, transient hypothyroidism followed the hyperthyroid episode. In two patients, the condition was recurrent. The findings are compatible with transient unregulated discharge of thyroid follicle content in some patients with lymphocytic thyroiditis. Recognition permits avoidance of unnecessary treatment with surgery, radioiodine, or antithyroid drugs.

Localized mesothelioma of the pleura: benign and malignant variants.

Mesothelioma, even of the pleura alone, is a ubiquitous pathological designation. The diffuse variety is associated with an ominous prognosis. The localized mesothelioma generally has been assumed to be benign. A review of tumors from 60 patients with localized pleural mesothelioma seems to justify separation into benign (52 patients) and malignant (eight patients) variants. Histologic criteria are used primarily to make this division. No single clinical feature allowed preoperative predictability concerning benignity or malignancy, although extrathoracic osteoarthropathy was seen only with benign lesions (20 percent), usually those greater than 7 cm. Follow-up periods of as long as 24 years revealed recurrent tumor in only two of the 58 patients with benign lesions and revealed a survival curve identical to that of the general population. All of the patients with the malignant variety had recurrence or metastasis, and all but one were dead within 2 years of the initial operation. One patient died of tumor complications after 9 years. More aggressive local resection is indicated for the malignant variant.