Bronchiolar Carcinoma (Alveolar Cell), Another Great Imitator; A Review of 41 Cases*

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1 Bronchiolar Carcinoma (Alveolar Cell), Another Great Imitator; A Review of Cases* Louis G. Ludington, M.D., F.C.C.P.;oo Joseph J. Verska, M.D., F.C.C.P.;t Thora Howard, M.D.;:!: George Kypridakis, M.D.; and Lyman A. Brewer III, M.D., F.C.C.P.II Forty-one cases of bronchiolar carcinoma in years were studied for incidence, symptomatology, methods for diagnosis, treatment, and survival. This disease, once considered rare and incurable, now appears to have clear-cut characteristics and a hopeful outcome. It is unicentric in origin, slow growing, but can spread early by air embolization, lymphatics or blood stream, and can mimic any acute or chronic pulmonary disease. As early surgery offers the only cure, aggressive diagnostic work-up for suspicious pulmonary infiltrate is imperative. Half of our cases were considered inoperable at the time of admission; these have au died. Ten showed diffuse but operable lesions and palliative resections were performed; two are living, one over four years, and a third survived two years before succumbing. Ten cases had localized disease and curative resections were attempted; seven are still living and six have reached the two-year survival mark. Bronchiolar carcinoma, once a rare and misunderstood neoplasm, today emerges as a hopeful and increasingly important entity. Hopeful, because the cure rate is improving, and important, because growing awareness and improved diagnostic techniques are increasing its apparent statistical incidence. Malassez' gave the earliest description (876) of the multiple nodular form of bronchiolar carcinoma, and 7 years later Musser described the diffuse, or pneumonic form. Skorpil" made the first diagnosis during life by performing a lobectomy on a patient with hilar metastasis in 936, and the patient survived five years. The multiplicity of terms used to identify bronchiolar carinoma emphasizes its controversial From White Memorial Medical Center, Los Angeles. Assistant Clinical Professor of Surgery, Lorna Linda University School of Medicine, Lorna Linda, California; and Thoracic Surgeon, White Memorial Medical Center. t Assistant Clinical Professor of Surgery, Lorna Linda University School of Medicine; and Chief of Thoracic Surgery, White Memorial Medical Center. :t:radiologist, White Memorial Medical Center. Associate Clinical Professor of Pathology, Lorna Linda University School of Medicine; and Chairman, Department of Pathology, White Memorial Medical Center. IIProfessor of Surgery, Lorna Linda University School of Medicine; Clinical Professor of Surgery, University of Southern California School of Medicine, Los Angeles; and Thoracic Surgeon, White Memorial Medical Center. Reprint requests: Dr. Ludington, 7 Brooklyn Avenue, Los Angeles aspects. Knudson and co-workers," listed 30 different names; Liebow" reported 36 equivalent or related terms. DESCRIPTION Like tuberculosis, bronchiolar carcinoma is a great imitator, able to mimic many types of pulmonary disease. Basically, it is a well-differentiated adenocarcinoma, usually originating in the periphery of the lung and tending to grow predominantly within it, supported in part by the stroma of the distal air spaces.ii Some have classified it as a subdivision of adenocarcinoma.f but most consider its distinctive pathologic picture and clinical course as meriting a separate classification. INCIDENCE Of 30 cases of primary lung cancer seen at the White Memorial Medical Center during the last years, 69 percent were cases of epidermoid or undifferentiated carincoma, percent adenocarcinoma, and 9 percent bronchiolar (alveolar cell) carcinoma. The literature usually reports a. percent to 6. percent incidence for bronchiolar carcinoma.v-jr" Our incidence, analyzed in five-year periods, reveals 3 percent occurrence during the first five years of our study, percent during the second, and 7 percent during the last five years. A similar trend was noted by Watson'' in his 3-year study at the Memorial Hospital for Cancer and Allied Diseases in New York. Pathologists are probably more aware of this neoplasm, and these figures may not represent a true increase in incidence. Bronchiolar carcinoma can no longer be considered a rare disease, however. 6

2 BRONCHIOLAR CARCINOMA, ANOTHER GREAT IMITATOR 63 ETIOLOGY As with most other malignancies, the etiology of bronchiolar carcinoma has not been specifically determined. The frequent relationship between bronchiolar carcinoma and chronic pulmonary disease is noteworthy. We were able to show an incidence of previous chronic pulmonary disease or fibrosis in about one-third of our cases (Fig, ). Beaver and Shapirot> reported a positive history of previous pulmonary disease in 6 percent of patients, and microscopic evidence of old inflammatory changes in 8 percent of the specimens. Hewlett and co-workersts reported a significant history of previous disease in percent of their cases, and verified it pathologically in 7 percent of specimens. A history of smoking is less evident among these patients. Only 0 percent had smoking histories in our series; this was consistent with other reports. Environmental pollution is an unknown factor yet to be fully studied. SYMPTOMATOLOGY FIGURE. Chronic pulmonary scarring, fibrosis, bronchiectasis two years prior to development of bronchiolar carcinoma. No race predilection has been noted, and most reports indicate a fairly equal distribution in sexes. The age range in our study was 37 to 83 years, with the highest incidence (onethird) in the sixth decade. HISTOGENESIS The early studies of bronchiolar carcinoma were done on far advanced cases with bilateral dissemination, the diagnosis being determined at autopsy or by surgical biopsy in a late stage. This led to the concept of its multicentric origin, a theory vigorously taught by the great Evarts Craham.t? Consequently, it was believed to be uniformly fatal, and surgical intervention was thought pointless. In 93, comprehensive studiest l demonstrated a unicentric origin, starting in the lining cells of the terminal bronchioles. The most common symptoms of cough, chest pain, dyspnea and weight loss do not differ from other acute and chronic pulmonary diseases (Table ). Only two of our patients exhibited the voluminous frothy sputum sometimes described as typical. Two others presented with thrombophlebitis, and three with hemoptysis. Two-thirds of our patients had symptoms less than six months, and approximately one-third reported symptoms from six to twelve months. One patient was completely asymptomatic on admission, four had symptoms for only two weeks, and one for over two years. DIAGNOSIS The diagnosis can be made with certainty only on the typical microscopic appearance of the disease. We agree and adhere to the four criteria as outlined by Storey and associatesl! in their important paper. The following steps are important in arriving at a diagnosis:. High Degree of Suspicion. Lung scars, persistent infiltrates or unresolved pneumonias should not be ignored or regarded as benign. Any expanding nodule or persistent undiagnosed pulmonary lesion should be considered as cancer until proved otherwise.. Aggressive Work-up. Passive follow-up with time-consuming serial films permits an operable lesion to become Table l-symptoms on Admission 0/ Patients..,ith Bronchiolar Carcinoma. Symptom No. Cases Percent FIGURE. Same patient as Figure (two years later) showing new areas of infiltration and nodularity, Biopsy showed bronchiolar carcinoma. Chest pain Cough Dyspnea Weight loss Hoarseness Hemoptysis Shoulder pain Copious sputum Dysphagia Swelling face Headache Neck mass Tightness in chest Facial paralysis No symptoms CHEST, VOL. 6, NO.7, JUNE 97

3 6 LUDINGTON ET AL Table -':"'Methods by Which DefiniriIJe Diagnosis liias Made. Method Cytolugy Bronchial washings 6 Sputum Pleural fluid 3 Scalene and mediastinal node biopsy Thoracotomy and biopsy Bone marrow Autopsy No. Cases Percent 7 inoperable. 3. Cytology. Because of this tumor's tendency to profuse exfoliation, cytology of its exudates is a most promising diagnostic tool. Single cells or clusters of cells containing large multinucleated giant cells are characteristic. One quarter of our cases were diagnosd by cytology: six from bronchial washings, two from sputum cytology, and three from pleural fluid.. Bronchoscopy. Since this tumor seldom involves major bronchi, it is usually not possible to visualize or biopsy it at the time of bronchoscopy. However, every patient should be bronchoscoped prior to surgery, and bronchial washings are extremely valuable in the diagnosis.. Scalene and mediastinal node biopsy. These procedures yield additional diagnoses and help decide operability. Our series produced four positive node biopsies in nine procedures performed. 6. Needle biopsy. Though rarely done, it may save thoracotomy in disseminated poor risk cases where a tissue diagnosis cannot be obtained otherwise. 7. Thoracotomy. Open surgery is often necessary to establish a diagnosis, and was resorted to in of our patients. Table indicates the method of diagnosis in these cases. ROUTES OF SPREAD FIGURE. Planigram shows "Cocklebur" appearance. of this disease. Lymphatic and blood stream spread also occur. Dissemination was present in 7 percent of our cases, with 3 percent to regional nodes and adjacent structures of the lung, 3 percent to distant organs only, and 7 percent to both pulmonary regional nodes and pleura and distant organs. RADIOGRAPHIC PIcruRE There is no typical x-ray picture of bronchiolar carcinoma. Its protean manifestations enable it to mimic almost any pulmonary disease on film as well as symptomatically. If diagnosed early, the x-ray pattern is most often a small solitary peripheral nodule or infiltrate (Fig 3), usually with The tendency to excessive desquamation probably accounts for the bronchial or air embolization so characteristic FIGURE 3. Solitary pulmonary nodule. FIGURE. Solitary pulmonary nodule with central bronchus. CHEST, VOL. 6, NO.7, JUNE 97

4 BRONCHIOLAR CARCINOMA, ANOTHER GREAT IMITATOR 6 FIGURE 6. Planigram of Figure showing nodular lesion surrounding central bronchus. ill-defined borders which seem to fade into adjacent normal tissues. Radiating spicules of fibrous tissue can give the mass a cocklebur appearance (Fig,, 6). Rarely cavitation may be present, suggesting a granulomatous cavity (Fig 7, 8). There were ten patients with this favorable picture in our series, Another frequent x-ray pattern is multiple nodular lesions, varying in size and involving one or both lungs or hilar areas (Fig ). Ten of our patients demonstrated this picture and in six the lesions were bilateral. The third type of presenting film is that of a pneumonic infiltration which spreads through a segment or lobe, and which mimics a patchy or confluent pneumonia, or a granulomatous process. Thirteen in our series presented this way. Four patients had massive pleural effusions on their first x ray, another had pneumothorax with a pneumonic area. FIGURE 7. Cavitating solitary pulmonary nodule-may mimic tuberculosis. FIGURE 8. Planigram of Figure 7 showing cavitating pulmonary nodule. Over half of our cases were referred to us in disseminated or advanced stages. In those cases where earlier x-rays were available, many had shown small operable lesions. Some of these patients had been treated for tuberculosis despite negative sputum. Others were diagnosed as unresolved pneumonias, fibrosis, or other chronic inflammatory problems, and had been observed with serial films until they were beyond the operable stage., The difficulties our own radiology department encountered underscore again the magnitude of the diagnostic challenge. On the initial films, a tuberculous cavity was suggested in two, another was reported as far advanced tuberculosis, while two more were read as fibrocalcific lesions of the apices. One case appeared to be pulmonary emboli and another pulmonary sequestration. Two patients whose original radiographs appeared normal, demonstrated lesions on follow-up planigrams. Planigrams are extremely important and should be a part of the work-up of any suspicious pulmonary lesion. Aware of these hazards, our department consistently includes Table 3--Presenting X.ray Picture on Hospital Admission.* X-ray Picture No. cases Percent Negative x-ray Single nodule With cavitation Multiple nodules Pneumonic infiltration With pneumothorax With pleural effusion Hilar mass Fibroapical scarring 3 *Routine posterior-anterior and lateral films of chest. 3 CHEST, VOL. 6, NO.7, JUNE 97

5 66 LUDINGTON ET AL Author Overholt and co-workers-! 93 Fitzpatrick and associates'< 96 Belgrad and co-workers'? 96 Hewlett and colleagues'! 96 Watson and co-workers'' 966 Munnell and colleagues'" 966 Ludington and co-workers WMMC 970 Table --Re8ult8 0 Surgery lor Bronchiolar Carcinoma Comparing Literature with Our Study. Total Cases Not reported Percent Resected favorable resections 0 Percent 8 resections (II localized) (7 diffuse) 7 Percent 3 Percent 6 Percent 8 Percent ( localized) (IO diffuse) *Includes recent cases not yet reaching and year survivals. neoplasm in the differential diagnosis of any suspicious pulmonary lesion. TREATMENT AND RESULTS Early surgery is the only proved treatment of benefit. In institutions where patients are seen early and referred promptly to the surgeon, two year Percent Still Living* 80 Percent 68 Percent 0 Percent 70 Percent localized 0 Percent diffuse Percent Reaching Year Survival 60 Percent 30 Percent 63 Percent localized.3 Percent diffuse 8 Percent Percent 8 Percent 60 Percent localized 0 Percent diffuse Percent Reaching Year Survival 0 Percent 8 Percent survival rates are as good as for other primary carcinomas of the lung (Table ). The senior author of this paper has previously showri'" that the location of a neoplasm is probably more important prognostically than its histology; midlung neoplasms give a better prognosis than subpleural or hilar lesions. Because bronchiolar carcinoma usually Table --Follow-up on Patienu Ha"ing Reseetione for Locali.zed Disease,* Patient No. Sex Age Type Resection Date Follow-up Survival Time F 68 Left lower lobe November 6, 968 Living and well years, 8 months M Right middle lobe January 6, 969 Living and well years, 6 months 3 M 67 Left upper lobe November, 963 Living and well 7 years, 8 months F 76 Left upper lobe March, 966 Living and well years, months M Right upper lobe July, 969 Living and well years 6 F 7 Right pneumonectomy August 3, 96 February, 96 Died after Distant metastases years, months 7 M 6 Left upper lobe December 9, 96 Died days PO Died days Myocardial infarct PO 8 M 63 Left upper lobe September, 970 Living and well months 9 M 9 Left upper lobe April 6, 96 November, 966 Died after Brain metastases 3 years F 7 Right middle and July, 966 Living and well years right lower lobes *No supraclavicular or mediastinal or hilar node involvement or evidence of distant spread. CHEST, VOL. 6, NO.7, JUNE 97

6 BRONCHIOLAR CARCINOMA, ANOTHER GREAT IMITATOR 67 Table 6----Cases with Diffuse Disease and Palliative Resection.* Patient ~o. Sex Age Type Resection M 6 Right upper lobe M 6 Right upper lobe 3 F 7 Left upper lobe M 77 Left lower lobe M F M M Left upper lobe Right pneumonectomy Left pneumonectomy Right pneumonectomy 9 F 76 Right upper and right middle lobes IO M 73 Right upper lobe and superior segment right lower lobe "Spread to hilar, mediastinal, or supraclavicular nodes. starts unicentrically in a midlung or peripheral location, it should give a better prognosis than other types of primary carcinoma if diagnosed and treated early. Though this tumor grows slowly, it can still spread early. To be effective, surgery must be performed solely on the basis of suspicious x-ray findings, preferably in an asymptomatic or minimally symptomatic stage with negative bronchoscopic or neck node examinations. Only two of our ten favorable cases had positive cytology on bronchial washings, and all were negative on bronchoscopic examination, and had negative scalene and mediastinal node biopsies. Resectional Surgery: Thoracotomy was performed on 3 patients in this series. Ten were found to have localized favorable disease, ten diffuse but Follow-up Living with recurrent disease, right hilar nodes and RML Died October 8, 96 Metastases RLL and spine Died December 7, 967 Massive pulmonary artery thrombosis Died June 30, 96 Respiratory failure secondary to extensive bronchopneumonia ~o autopsy Living and well, no evidence of recurrence Died day PO Respiratory failure Regional nodes and distant metastases Died October 3, 96 Regional and distant metastases Died September 9, 969 Pulmonary insufficiency possibly due to radiation effect, second primary tumor of brain (subependymoma) No evidence of metastatic lung tumor Died February 3, 969 Distant metastases Died November, 969 Pulmonary insufficiency No autopsy Survival Living year, month Died after IO months Died month PO Died 3 days PO Living years, 9 months Died day PO Died after 7 months Died after Yz months Died after years Died after year, 3 months operable disease (hilar or mediastinal nodes involved ), and were considered inoperable, only biopsy being performed. Our criteria for localized disease which can lead to favorable results from surgical resection are: ) no pleural involvement as indicated by absence of malignant cells in aspirated pleural fluid; ) no mediastinal or supraclavicular node metastases, and 3) no distant metastases. In the ten patients with localized disease, eight lobectomies, one right and middle lobectomy and one pneumonectomy were performed (Table ). Seven of these patients are still living, ten months to n years following surgery. Of the three who died, one was an operative death two days after surgery, and two others succumbed to their original disease, although one of these lived for three years. CHEST, VOL. 6, NO.7, JUNE 97

7 68 Of the ten patients having palliative resections for diffuse disease, seven had lobectomies, and three had pneumonectomies (Table 6). Two are living today, one a year and the second four years nine months. A third succumbed two years after surgery of his disease. There were two operative deaths in this group, and the other seven died within months of surgery. Of those considered to be inoperable because of bilateral lung involvement or distant spread, nine were treated with conventional radiotherapy or cobalt as their only therapy, and none is alive today. One survived ~ years, a second 0 months, but the rest died from one to ten months following treatment. Three patients in this group had a serious attempt at chemotherapy, but all died nine months or less after beginning treatment. Nine patients received palliative medical therapy only. Two lived slightly over a year, one 0 months, and the other 6 months. The rest succumbed from one to eight months following admission. To summarize, 60 percent of our patients died within months of onset of symptoms, 0 percent lived one to two years and 0 percent are still living. These figures suggest not only the slower growth rate of bronchiolar carcinoma as compared with other lung cancers, but also that longevity is probably somewhat improved even in those cases where the disease has spread beyond the scope of surgery. Table shows that 60 percent of our favorable resected patients and 3 percent of our overall resectional cases (including both localized and diffuse operable disease) have already reached the two-year survival mark. Four more are living and well to date, and hopefully will also reach the twoyear survival mark and improve these statistics. Five-year survival rates are not available because the majority of these cases have been operated on within the last five years. Watson and Farpour" show a 0 percent five-year survival, and Munnell and co-workers" a 8 percent figure for their overall resectional cases. REFERENCES Malassez L: Examen histologique d'un cas de cancer LUDINGTON ET AL encephaloide du poumon (epithelioma). Arch Physiol Norm Path 3:33-37, 876 (Cited by Watson'' ) Musser JH: Primary cancer of the lung. Univ Pa Moo Bull, Phila 6:89-96, (Cited by Watson'' ) 3 Skorpil F: Beitrage zur Pathologie und Histologie des Alveolarepithelkrebses. Frankfurt, Z Path :37-363, 9 (Cited by Liebow- ) Knudson RJ, Hatch HB, Mitchell WT, et al: Unusual cancer of the lung; II. Bronchiolar carcinoma of the lung. Dis Chest 8:68-633, 96 Liebow AA: Bronchiolo-alveolar carcinoma. Adv Intern Med :39-38, Bennett DE, Sasser WF: Bronchiolar carcinoma: A valid clinicopathologic entity? A study of 30 cases. Cancer : , McNamara n, Kingsley WB, Paulson DL, et al: Alveolar cell (bronchiolar) carcinoma of the lung. J Thorac Cardiovase Surg 7 :68-66, Watson WL, Farpour A: Terminal bronchiolar or "alveolar cell" cancer of the lung: Two hundred sixty-five cases. Cancer 9: , Clagett QT, Allen TH, Payne WS, et al: The surgical treatment of pulmonary neoplasms: A year experience. J Thorac Cardiovasc Surg 8:39-00, 96 Delarue NC, Graham EA: Alveolar cell carcinoma of the lung (pulmonary adenomatosis, jagziekte?); multicentric tumor of epithelial origin. J Thorac Cardiovasc Surg 8:37-,99 Storey CF, Knudtson KP, Lawrence BJ: Bronchiolar ("alveolar cell") carcinoma of the lung. J Thorac Cardiovasc Surg 6:33-06, 93 Beaver DL, Shapiro JL: A consideration of chronic pulmonary parenchymal inflammation and alveolar cell carcinoma with regard to a possible etiologic relationship. Amer J Med : ,96 3 Hewlett TH, Gomez AC, Aronstam EM, et al: Bronchiolar carcinoma of lung; review of 39 patients. J Thorac Cardiovasc Surg 8:6-6, 96 Brewer LA, Bai AF, Little IN, et al: Carcinoma of the lung; practical classification for early diagnosis and surgical treatment. JAMA 66:9-, 98 Overholt RH, Meissner WA, Delmonico JE Jr: Favorable bronchiolar carcinoma. Dis Chest 7 :03-3, 98 6 Fitzpatrick HF, Miller RE, Edgar MS Jr, et al: Bronchiolar carcinoma of the lung; a review of 33 patients. J Thorac Cardiovasc Surg :3-36, 96 7 Belgrad R, Good CA, Woolner LB: Alveolar-cell carcinoma (terminal bronchiolar carcinoma); a study of surgically excised tumors with special emphasis on localized lesions. Radiology 79: , 96 8 Munnell ER, Lawson RC, Keller DF: Solitary bronchiolar (alveolar cell) carcinoma of the lung. J Thorac Cardiovasc Surg :6-70, 966 CHEST, VOL. 6, NO.7, JUNE 97