Bronchioloalveolar Cell Carcinoma of the Lung: A Clinicopathological Study

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1 Bronchioloalveolar Cell Carcinoma of the Lung: A Clinicopathological Study Daniel Dunn, M.D., Bruce Hertel, M.D., William Norwood, M.D., and Demetre M. Nicoloff, M.D. ABSTRACT Thirty-nine patients with bronchioloalveolar carcinoma were reviewed. The primary lung tumor from 27 patients was examined and divided by histological criteria into three categories. The type 1 pattern was associated with a mean survival of 4.7 years. A mean survival of 3.8 years was attained in patients with type 2. Patients with the type 3 pattern had an average survival of 1.4 years. Thlere was a statistically significant difference in survival when types 1 and 2 together were compared with type 3 (p < 0.05). Another statistically significant finding was a mean survival of 5.2 years in patients with negative lymph nodes after surgical resection and a 2.2 year mean survival in patients with positive nodes. The tumor histology of bronchioloalveolar carcinoma should be examined carefully to obtain helpful information in predicting survival. We recommend that these tumors be classified as well-differentiated or poorly differentiated bronchioloalveolar carcinoma. Bronchioloalveolar carcinoma of the lung is a rare tumor comprising approximately 2% of all primary pulmonary malignancies [16]. Since 1876 when it was described, several articles disputing its existence as a distinct pathological entity have been written [2, 201. Some investigators have found histological and clinical features that distinguish this tumor from adenocarcinoma [15, 17, 18, 231; others have not [2, 221. Because of the controversial nature of this lesion, many studies have been done to try to determine the cell of origin [8, 10, 11, 153, whether the tumor is unicentric or multicentric in origin [6, 9, 141, and which factors, From the Departments of Surgery and Pathology, University of Minnesota Hospitals, Minneapolis, MN, and the Division of Cardiac Surgery, Boston Children s Hospital, Baston, MA. Presented at the Fourteenth Annual Meeting of The Society of Thoracic Surgeons Jan 23-25, 1978, Orlando, FL. Address reprint requests to Dr. Nicoloff, Box 280 Mayo- University Hospitals, 420 Delaware St, SE, Minneapolis, M:V if any, are important in predicting survival [l, 13, 181. None of these studies investigated the influence of cell differentiation on survival of patients with bronchioloalveolar carcinoma. We reviewed our series of patients with this tumor to determine the effect of tumor histology on prognosis. Materials and Methods Thirty-nine patients with bronchioloalveolar carcinoma were seen at the University of Minnesota Hospitals from 1950 to All were followed either until death or for a minimum of 5 years, with 1 exception. This patient was operated on in 1975 and, at the time of writing, is alive with no evidence of disease. Twenty of the 39 patients (51%) were women. They ranged in age from 30 to 78 years (average, 61 years). The symptoms at examination, the location of the primary tumor, the type of tumor (single, multinodular, or a diffuse pulmonary infiltrate), and the treatment were recorded. The presence of regional lymph node metastases in patients with pulmonary resection was also correlated with survival. Pulmonary specimens were available for examination from 27 of the 39 patients (69%). The pathologist (B. H.) was not given clinical information on any patient. Patients with a previous or concurrent carcinoma were excluded from the study. The absence of another carcinoma was confirmed by long-term follow-up or postmortem examination. To be included in the study, all lesions had to show malignant cells distributed in a uniform pattern along alveolar septa and ducts. All specimens were stained with hematoxylin and eosin as well as mucicarmine and alcian bluelperiodic acid-schiff (PAS) stains for mucin. The tumors were divided into three histological groups and the mean survivals for the groups were compared. A comparison was also made of the survival of patients who had pulmonary resection in each group, excluding by Daniel Dunn

2 242 The Annals of Thoracic Surgery Vol 26 No 3 September 1978 those patients who died of the operation. Survival data were compared using the Student f test. Results Eighteen patients were asymptomatic at the time of diagnosis, the presence of a chest mass was discovered on routine chest roentgenogram. Seventeen patients were seen with pulmonary symptoms of cough, chest pain, or dyspnea. Back pain, headache, and hoarseness were the chief complaints of 4 patients with symptoms from distant metastases. The mean survival for the 18 asymptomatic patients was 4.2 years, while that for the symptomatic patients was eighteen months. In addition, only l patient with symptoms from metastatic disease lived a year. Although dyspnea was an uncommon symptom at examination (5%), it usually denoted a carcinoma that was far advanced with impending respiratory failure and poor prognosis. The tumor was located in the upper lobes in 18 patients (46%) and in the lower lobes in 10 (26%). Six patients (15%) had involvement of more than 1 lobe, and 5 (13%) had extensive involvement of both lungs. There was no correlation between the site of the lesion and survival, but there was an increased survival rate in patients with less extensive lesions. Twenty-two patients were found to have a single pulmonary mass by roentgenogram or exploration. Included in this group are those lesions that could be considered coin lesionsthat is, peripheral nodules less than 2 cm in diameter-and those that were larger but were single masses without satellite nodules. The mean survival in this group was 3 years. As might be expected, patients with a single tumor mass had a higher resectability rate (86% or 19 out of 22 patients) and an improved mean survival after resection of 4 years. Seventeen patients had either multiple nodules in l lung or both lungs or diffuse parenchymal involvement by tumor. Mean survival was eighteen months. Only 4 of these (23%) were amenable to resection, with a mean survival of 3 years. Although it appeared that patients with a single mass or nodule had a better prognosis, no statistical difference could be ascertained. Of the 39 patients, 30 (77%) had a thoracotomy, and 23 (77%) of them were resected for cure. Early in the series 5 patients had pneumonectomy as the original operative procedure. One patient had a lobectomy and 5 years later, pneumonectomy for recurrent disease. Of the 6 patients who had pneumonectomy, 3 died of the operation. The remaining 3, including the patient who had pneumonectomy as a second operative procedure, had a mean survival of 3 years. One patient was a 5-year survivor. Lobectomy was the operative procedure in 17 patients. There were 2 operative deaths. Of the 17,4 were 5-year survivors (24%). The mean survival was 3.9 years. Wedge resection was performed in 1 patient who lived for 6 years. Seven patients underwent exploratory thoracotomy but were judged unresectable because of mediastinal lymph nodes involved with tumor or extensive parenchymal involvement not appreciated preoperatively. Only a lung biopsy was performed in these patients. One survived 5 years; the mean survival was 1.9 years. Nine patients were seen with disease that was far advanced, and therefore they received no operative treatment. The longest survivor lived eighteen months; the mean survival was three months. Several of these patients had a relatively short duration of symptoms while others neglected symptoms of productive cough or chest pain for up to a year. All of the patients had extensive bilateral disease, respiratory failure, or distant metastases when first seen. In total, 31 operative procedures were performed on 30 patients. There were 6 operative deaths for an overall operative mortality of 19%. Four of the 6 deaths occurred before There were no operative deaths after The improvement in surgical techniques, in preoperative and postoperative care, and in selection of patients has undoubtedly affected the operative mortality rates. A 72-year-old woman had a cerebral vascular accident while recuperating from pneumonectomy. A 68-yearold woman with a history of previous myocardial infarction died of massive myocardial infarction one month after operation. Another patient had a bronchopleural fistula following lobectomy and died while undergoing ir-

3 243 Dunn et al: Bronchioloalveolar Cell Carcinoma rigation of the fistulous tract. Three patients had extensive lesions at the time of operation. Two of these patients had pneumonectomy and extensive chest wall and diaphragm resections to remove all tumor. Both died of progressive pulmonary failure. The third had extensive involvement of both lungs and died two days after an open biopsy was performed. At the time of writing, 7 of the 39 patients are alive 5 years after operation, an overall survival of 18%. If those who died of operation and those who had no definitive treatment because of the far advanced stage of the disease are excluded, then the "operative" 5-year survival is Our overall survival is low because we included terminal patients; in many series such patients are not considered in survival statistics. Three of the 7 5-year survivors died of metastatic disease 5, 8, and 9 years after the initial operative treatment. One patient alive 12 years after the initial pulmonary resection had an epidermoid carcinoma of the tonsil and then an epidermoid carcinoma of the lung. Two patients died of unknown causes 6 and 9'years after lung resection. One patient is alive with positive hilar lymph nodes and with no evidence of disease 6 years following lobectomy. The incidence of regional (hilar or mediastinal) lymph node metastases in those patients who had curative resection was evaluated and found to correlate with survival (Fig 1). This was one of the most prognostic indicators to come from our series. Of the 23 patients who had curative resection, 13 had positive regional nodes and 10 had negative nodes. Three patients with positive regional nodes died of the operation. One patient in this group is still living 6 years after resection; the mean survival was 2.2 years. The mean survival for those patients with negative regional nodes, excluding 2 operative deaths, was 5.2 years. This difference is significant (p < 0.05). Pathological examination of the 27 specimens available indicated that the lesions could be categorized in three histological patterns. The first pattern was characterized by cells with abundant mucin-producing cytoplasm, which lined the alveolar spaces and alveolar ducts in a very organized fashion (Fig 2). These tumor cells had relatively bland nuclei with sparse la, I Negative Regional Nodes Positive Regional Nodes Fig 1. Mean survival of 18 patients with bronchioloalveolar carcinoma who had curative resection. Fig 2. Type 1 histological pattern of bronchioloalveolar carrinornn. (HbE; origiiinl tnqiiificntioii ~40.) mitoses and little if any pleomorphism. The nuclei were basally oriented. The cytoplasm was abundant with PAS and mucicarmine-positive material. The alveolar spaces in some areas were filled with mucin as well as exfoliated tumor cells. Because of the pattern of growth along alveoli, the periphery of the tumor showed frond-like projections into the lung parenchyma. The architecture of this pattern was maintained throughout the tumor. There were no undifferentiated areas or areas of focal lung destruction. The anatomy of the alveolar spaces was maintained. This pattern was designated type 1. The second histological pattern had essen-

4 244 The Annals of Thoracic Surgery Vol 26 No 3 September 1978 Fig 3. Type 2 histological pattern of bronchioloalveolar cnrririown. (Ha ; ori,piml rnngnifirntiori X40J Fig 4. Type 3 histological pattern of bronchioloalveolar cnrcinortia. (HaE; origirinl rnnpzificntiori ~40.) Fig 5. Survival according to histological type in 22 patients with bronchioloalveolar carcinoma. tially the same growth pattern, but, the tumor cells were much smaller and little mucin production was obvious when they were stained with hematoxylin and eosin (Fig 3). The mucicarmine and PAS stains were positive. The cells were very similar to the granular pneumocyte or alveolar type I1 cell. None of the tumors with this histological pattern had undifferentiated areas, and normal alveolar anatomy was maintained throughout the tumor. This pattern was designated type 2. The third pattern or type 3 was characterized by most Of the Same features as type 2. In Some sections, however, more solid areas of tumor were recognized (Fig 4). In these areas, normal anatomy was not maintained and focal lung destruction was obvious. The cells were less differentiated than in the previous two patterns, and there was less mucin production. It should be stressed that even in this type of tumor the predominant histological pattern was similar to type 2. Six patients had type 1 lesions (Fig 5). There was 1 operative death in this group. The mean survival of the remaining 5 patients, including 1 patient living 2 years after lobectomy, was 4.7 years. Eight patients had type 2 lesions. There was 1 operative death. The other 7 patients had a mean survival of 3.8 years. Type 3 lesions were present in 13 patients. Excluding 3 operative deaths, the mean survival for this group was 1.4 years. Three of the patients had far-advanced carcinoma with a relatively short duration of symptoms when they were first seen. T 7 *L/vmg Survival Mea.7 3 Byears 0 -

5 ~ 245 Dunn et al: Bronchioloalveolar Cell Carcinoma 1 n '" I c- "1 Survival - ( yecirs) c 6l- 4 t 2 I 0- Mean 4 'years 1. Fig 6. Mean survival of 15 patients with curative resectiori arid pathological examination of resected specinicns. There is no statistically significant difference in survival between patients with types 1 and 2. There is a significant difference in survival, however, when types 1 and 2 are compared with type 3 (p < 0.05). To determine if there was a correlation between lymph node metastases and histological type, patients who had curative resection were compared (Fig 6). Fifteen of the 23 patients who survived curative resection and had pathological examination of resected specimens were compared. Three patients had type 1 pattern, negative nodes, and a mean survival of 4.2 years. This includes 1 patient living 2 years after lobectomy with no evidence of disease. Seven patients had type 2 histology and a mean survival of 4.0 years. This includes 4 patients witlh positive regional lymph nodes and 3 with negative lymph nodes. Of the 5 patients who had curative resections and type 3 histology, 4 had positive lymph nodes. Excluding 1 patient with type 3 pattern and negative nodes, the mean survival for this group was ten months. Turnor histology appears to be important in predicting survival and incidence of lymph node metastases. Comments There have been many articles written about the controversial aspects of bronchioloalveolar carcinoma of the lung [241. Those questions causing the most discussion are as yet unanswered. Since there is strong contradictory evidence to dispute most of the theories about this disease, the best that can be achieved is a consensus of opinion. For example, Coalson and co-workers [4] believe that the cell or origin of this tumor is the alveolar type I1 cell or granular pneumocyte, other researchers are unsure [5, 16, 231, and still others offer electron and light microscopic evidence for a bronchiolar origin of the tumor [7, 8, 15, 211. The controversy has little if any clinical importance since the terminal bronchiole and alveolus are in such close proximity. Thus the term bronchiozoazveozar carcinoma is the one most commonly used to designate this tumor. While most investigators believe that bronchioloalveolar carcinoma is a distinct clinicopathological entity [6, 16, 171, others [3, 12, 191 present data indicating that it behaves no differently from adenocarcinoma and has many of the same clinical features-peripheral location, high incidence in women, and frequent association with scar. They think that bronchioloalveolar carcinoma is merely a growth pattern of adenocarcinoma. We believe that the majority of evidence now available, including survival rates [17, 181, tumor morphology on both light microscopy and electron microscopy [8, 151, and distinguishing roentgenographic findings, indicates that this carcinoma should be classified separately from adenocarcinoma. Furthermore, there is marked variability of

6 246 The Annals of Thoracic Surgery Vol 26 No 3 September 1978 tumor morphology within the group of lesions satisfying the criteria for bronchioloalveolar carcinoma. Therefore, pathological specimens should be examined carefully if helpful prognostic information is to be gained. The question of the greatest clinical importance is whether this tumor is of unicentric or multicentric origin. If it is multicentric in origin, then little is to be gained by any type of operative procedure short of removing both lungs. If, however, the tumor is unicentric and has a propensity to spread by aerogenous, lymphatic, and hematogenous routes to other parts of the lung and distant organs, operative procedures to remove it with a good margin are justified. Since one-third of these tumors are seen as solitary masses or coin lesions [Z] and have a good prognosis if resected [17, 181, a multicentric origin is certainly unlikely. Again tumor histology is helpful in answering this question. A characteristic histological finding is alveolar spaces filled with exfoliated tumor cells and prominent papillary projections of tumor extending from the alveolar septa. This, together with multiple tumor implants in close proximity to the primary tumor, justifies the theory that these tumor cells are transmitted along aerogenous pathways. In addition, if there are microscopic implants in close proximity to the gross tumor and if lymphatic invasion is common [16, 251, wedge resection will be inadequate treatment. If, however, a peripherally located lesion has extended to involve an entire lobe or 2 lobes, then the chances of having aerogenous metastases to the opposite lung are much higher and pneumonectomy in most cases is not justified. Lymph node metastases from bronchioloalveolar carcinoma are an important prognostic indicator. Another important aid in predicting survival of patients with this tumor is the tumor histology. Since there was no significant difference in our series between types 1 and 2, we suggest that these tumors may have a very similar biology. If either of these patterns is present, a mean survival of 3% to 4% years can be expected. If the tumor has a type 3 pattern in several areas, a much poorer prognosis is likely. This difference could account for the wide disparity in survival figures reported for bron- chioloalveolar carcinoma. We recommend that all pathology specimens be examined carefully and that they be designated as well (types 1 and 2) or poorly (type 3) differentiated bronchioloalveolar carcinoma. Thirty-nine patients with bronchioloalveolar carcinoma were reviewed. Noteworthy indicators of the prognosis were the presence or absence of symptoms, lymph node metastases, and tumor histology. Patients with welldifferentiated tumors, types 1 and 2, had a significantly better survival than those with the more undifferentiated type 3 tumor. We recommend designating these tumors as welldifferentiated or poorly differentiated according to our criteria. We believe that this grading system will be helpful in predicting survival for patients with this tumor. References 1. Bell JW, Knudtson KP: Observations on the natural history of bronchiolo-alveolar carcinoma: experience with twenty-one cases. Am Rev Respir Dis 83:660, Bennett DE, Sasser WF: Bronchiolar carcinoma: a valid clinicopathologic entity?: a study of 30 cases. Cancer 24:876, Bennett DE, Sasser WF, Ferguson TB: Adenocarcinoma of the lung in men: a clinicopathologic study of 100 cases. Cancer 23:431, Coalson JJ, Mohr JA, Pirtle JK, et al: Electron microscopy of neoplasms in the lung with special emphasis on the alveolar cell carcinoma. Am Rev Respir Dis 101:181, Delarue ND, Anderson W, Sanders D, et al: Bronchiolo-alveolar carcinoma: a reappraisal after 24 years. Cancer 29:90, Delarue NC, Graham E: Alveolar cell carcinoma of the lung (pulmonary adenomatosis Jagziekte?): a multicentric tumor of epithelial origin. J Thorac Surg 18:237, Geller SA, Toker C: Pulmonary adenomatosis and peripheral adenocarcinoma of the lung: an ultrastructural demonstration of common morphologic features. Arch Pathol 88:148, Greenberg SD, Smith MN, Spjut HJ: Bronchioloalveolar carcinoma+ell of origin. Am J Clin Pathol 63:153, Hawkins JA, Hansen JE, Howbert J: A clinical study of bronchiolar carcinoma: a clue to unicentricity or multicentricity. Am Rev Respir Dis 88:1, Herbut PA: Bronchiolar origin of alveolar cell tumor of the lung. Am J Pathol 20:911, Herbut PA: Alveolar cell tumor of the lung:

7 247 Dunn et al: Bronchioloalveolar Cell Carcinoma further evidence of its bronchiolar origin. Arch Pathol 41:175, Hukill PB, Stern H: Adenocarcinoma of the lung: histological factors affecting prognosis: a study of 38 patients with resection and 5-year follow up. Cancer 15:504, Jackman RJ, Good CA, Clagett OT, et al: Survival rates in peripheral bronchogenic carcinomas up to four centimeters in diameter presenting as solitary pulmonary nodules. J Thorac Cardiovasc Surg 57:1, Knudson RJ, Hatch HB, Mitchell WT, et al: Unusual cancer of the lung: 11. Bronchiolar carcinoma of the lung. Dis Chest 48:628, Kuhn C: Fine structure of bronchiolo-alveolar cell carcinoma. Cancer 30:1107, Liebow AA: Bronchiolo-alveolar carcinoma. Adv Intern Med 10:329, Munnell ER, Lawson RC, Keller DF: Solitary bronchiolar (alveolar cell) carcinoma of the lung. J Thorac Cardiovasc Surg 52:261, Overholt RH, Meissner WA, Delmonico JE: Favorable bronchiolar carcinoma. Dis Chest 27:403, Raeburn C: Lung scar cancers. Br J Dis Chest 51:237, Rosenblatt MD, Lisa JR, Collier F: Primary and metastatic bronchiolo-alveolar carcinoma. Dis Chest 52:147, Sherwin RP, Laforet EG: The enigma of bronchiolar carcinoma: histopathologic clues in fifty-three cases. Dis Chest 43:504, Steele JD, Kleitsch WP, Dunn JE, et al: Survival in males with bronchogenic carcinomas resected as asymptomatic solitary pulmonary nodules. Ann Thorac Surg 2:368, Storey CF, Knudtson KP, Lawrence BJ: Bronchiolar ( alveolar cell ) carcinoma of the lung. J Thorac Surg 26:331, Vincent TN, Satterfield JV, Ackerman LV: Carcinoma of the lung in women. Cancer 18:559, Watson WL, Farpour A: Terminal bronchiolar or alveolar cell cancer of the lung: two hundred sixty-five cases. Cancer 19:776, 1966 Discussion DR CLIFTON F. MOUNTAIN (Houston, TX): Two major points are made in the study: (1) bronchioloalveolar carcinoma is a unique clinicopathological entity, and (2) histological grading is an important prognostic predictor. With respect to the first point, two lines of inquiry may be used to test the hypothesis. First, is the clinical and biological behavior of bronchioloalveolar carcinoma notably different from that of adenocarcinoma, with which it is commonly grciuped? Second, can histological differences be cataloged and the probable cell of origin of this tumor identified? In our experience with 113 patients classified as having bronchioloalveolar carcinoma, proportionately fewer patients were resected, but the survival of those was very similar to that for adenocarcinoma. Dr. Dunn s data emphasized the markedly adverse effects of tumor burden, especially metastases to regional lymph nodes. This was also true in our experience with adenocarcinoma: only 2% of the patients with positive mediastinal lymph nodes who underwent resection survived 5 years. We both observed several apparently unique clinical characteristics: (1) the extreme peripheral location of the tumors; (2) the relative absence of atelectasis and obstructive pneumonitis, which we think supports our belief in airborne metastases; (3) the tendency to visceral pleural involvement; and (4) intrapulmonary spread, especially to the contralateral lung. We believe aerometastases is a more tenable concept than that of multicentric origin for this tumor. The unequivocal diagnosis of this tumor by light microscopy is regarded as difficult by many pathologists. In studying its ultrastructure by electron microscopy, my colleague, Dr. Bruce McKay, found two types of cells to be present. Clara cells, arising in the terminal bronchioles, predominate. These are characterized by granular, membranelimited, neurosecretory granules, which tend to accumulate on the lumen side of the cell. There are large lakes of cytoplasmic glycogen, and in many cells mucin is present. Less common are type I1 pneumocytes of the alveolar walls, which are distinguished by lamellar bodies. Not a pathologist, I find it interesting that in sputum cytological specimens adenocarcinoma cells are most often large and single, while bronchioloalveolar carcinoma cells appear in clusters. Basing my agreement on results in our own studies, therefore, I concur with Dr. Dunn that this is a distinct clinicopathological entity. However, I am not persuaded that there is a necessity to catalog our experience by grading these tumors. Because the survival experience in his type I and I1 is similar, they can be brought together, and the poorer experience with type 111 can be accounted for by the preponderance of patients with positive mediastinal lymph nodes. DR. EDWARD R. MUNNELL (Oklahoma City, OK): In our experience, attention to cell type for classification and prognosis may be confusing. One example is a 66-year-old woman who had an infiltrate in the right midlung in 1962 and was treated by middle lobectomy. Tissue section showed a growth pattern typical of bronchiolar carcinoma with extension over the existing alveolar network and little fibrosis. Chest roentgenograms were made yearly, and in May of 1974, 12 years later, a new lesion was seen in the right lower lung field in the lateral view. A right lower lobectomy was done, and a mass with a simi-

8 248 The Annals of Thoracic Surgery Vol 26 No 3 September 1978 lar, although not identical, pattern to the original was removed. There was greater pleomorphism, fibrosis, and a pattern more like adenocarcinoma but called bronchiolar carcinoma by the pathologist. In 1977, a clavicular metastasis on biopsy had yet a third pattern less characteristic of bronchiolar carcinoma. In essence, the pathologist is presented with a dilemma in the differential diagnosis of bronchiolar carcinoma versus adenocarcinoma. It may be impossible to determine morphologically whether a more poorly differentiated new lesion represents metastasis from another neoplasm or less well differentiated bronchiolar carcinoma. Dr. Dunn s presentation is a bit worrisome to me since it is possible that some of their patients had adenocarcinoma of the lung and not bronchiolar carcinoma. In our studies and others, with strict adherence to instances of bronchiolar carcinoma, excluding adenocarcinoma, the results are much different, and, therefore, the prognosis is much different from that reported here. In our studies carried out over a number of years, 75% of patients with solitary bronchiolar carcinoma survived 5 years and 50% survived 10 years. I enjoyed Dr. Dunn s presentation greatly and would like to ask him three questions. (1) Were your instances of type 111, in fact, adenocarcinoma of the lung? (2) Was fibrosis seen in conjunction with the tumor, as is often reported by others? (3) Why were your survival statistics not as good as those more commonly reported in recent years? DR. F. GRIFFITH PEARSON (Toronto, Ont, Canada): I wish to present some information which Dr. Norman Delarue at the Toronto General Hospital is currently analyzing. Dr. Delarue s data do support a number of observations the authors have made relating histology to diagnosis. At the same time, it is evident from the discussion of this paper that we as surgeons are very much dependent on the interpretation of the histology by our pathologists. Differences in interpretation make comparison between institutions difficult when one is attempting to relate prognosis to histological type. During a recent 7-year period at the Toronto General Hospital, 101 patients were seen with bronchioloalveolar carcinoma. The first striking observation is the unexpectedly high incidence of this cell type; it represents close to 10% of the primary carcinomas seen in our institution during that time period. Our pathologists have come up with an identical classification to that of the authors and define three types: a well-differentiated secretory type, a welldifferentiated nonsecretory type, and a poorly differentiated type in which there are sheets of cells resembling adenocarcinoma. In January, 1972, in Cancer, Dr. Delarue reported on a group of 40 patients who had undergone resec- tion for alveolar cell carcinoma. Thirty-two of the 40 patients had localized tumors, most of which were the well-differentiated type. Sixteen of the 32 have survived 5 years, giving an absolute survival of 50% for this cell type with localized disease. We have observed a much better survival rate in this group of patients than that reported by the authors. Eight patients in this series of 40 had hilar lesions that required pneumonectomy, and in these patients the hilar lymph nodes were frequently involved. In this latter group, 4 patients were living at 3 years, but all were dead at 5 years. In these 8 patients there was a high proportion of the poorly differentiated cell type. DR. HERMES c. GRILLO (Boston, MA): A few years ago Dr. Gerald Nash who was then at the Massachusetts General Hospital, Dr. Lorenzo de la Gazza, and I reviewed our patients with alveolar cell carcinoma. We quickly discovered the problem of a spectrum of histology and the frequent variations from one part of a tumor to another if enough fields are examined. More than 200 consecutive patients with alveolar cell carcinoma and adenocarcinoma were studied. With regards to histological criteria, there were four categories of carcinoma: pure alveolar cell carcinoma, pure adenocarcinoma, alveolar cell carcinoma with mixed adenocarcinoma, and another group of adenocarcinoma mixed with alveolar cell carcinoma. We then correlated this with the clinical picture. The patients with pure alveolar cell carcinoma had a 5-year survival of more than 50%. Those with alveolar cell carcinoma with a touch of adenocarcinoma, which ought to be lethal, had about a 24% 5-year survival. The other two groups, pure adenocarcinoma and adenocarcinoma with a little bit of alveolar cell carcinoma, were at the expected adenocarcinoma levels of 8 to 15% 5-year survival. Light microscopy may not be really keen enough to differentiate these groups. DR. WATTS WEBB (New Orleans, LA): Some years ago in reviewing our records of patients with carcinoma that was considered scar carcinoma, we found a disproportionately high incidence of bronchioloalveolar carcinoma, more than 20%, and very excellent survival in this group. I wonder if there has been a similar experience here. DR. J. w. PEABODY (Washington, DC): As a proponent of the minithoracotomy for peripheral lesions, I am impressed with the frequency with which alveolar cell carcinoma appears as a peripheral lesion. I am impressed equally with the statistics provided by Dr. Mountain in his discussion and with the fact that patients with nodal involvement do poorly in the long run. For many years, we have been satisfied with wedge resection to treat peripheral alveolar cell car-

9 249 Dunn et a]: Bronchioloalveolar Cell Carcinoma cinoma and think it an adequate operation. It avoids extension of the 6 to 8 cm incision. It is an operation that is easily performed and is superior to and more quickly done than a needle lung biopsy in many instances. I ask the author whether he would regard wedge resection as a satisfactory operation for alveolar cell carcinoma of the lung. Frequently, a gross diagnosis is made, which is confirmed easily by the pathologist, and there may be no need to extend the operation. DR. DUNN: I will answer the last question first. We have not treated enough patients by wedge resection, and I don't think anyone has, to compare it with treatment by lobectomy. However, we think that since there is evidence for aerogenous metastases, lymphatic invasion in a high percentage of patients, and microscopic satellite nodules within close proximity to the tumor, wedge resection is inadequate treatment. Lobectomy is a better procedure but we have no hard data to support that statement. Many of the questions alluded to the controversy of whether this tumor is really just a unique growth pattern of adenocarcinoma. We think that bronchioloalveolar carcinoma is a specific and distinct tumor. However, it is more important that the differentiation be recognized by the surgeon and pathologist. If a tumor is primarily type I11 or poorly differentiated, then the patient will not do as well as he would if the tumor were type I or 11, which is better differentiated. To answer the questions about fibrosis and association of scars with this tumor, we did not make a specific point of that although fibrosis was present in many of the lesions. The reason for our low survival was probably because of the inclusion of many patients who were terminal and had no definitive treatment. I was very encouraged by the work of Dr. Pearson and Dr. Delarue since they also have established a very similar grading system for bronchioloalveolar carcinoma. I thank all of the discussants, especially Dr. Mountain, for their very interesting and pertinent comments. Notice from the Southern Thoracic Surgical Association The Twenty-fifth Annual Meeting of the Southern Thoracic Surgical Association will be held at the Marco Beach Hotel, Marco Island, FL, on November 2-4, There will be a $100 registration fee for nonmember physicians except for guest speakers, authors and coauthors on the program, and residents. There will be a Postgraduate Program on Difficult Problems in Surgical Management preceding the regular program. This meeting has been approved for Category I CME credit. The Scientific Program appears at the end of this issue of The Annals of Thoracic Surgery (pp ). Manuscripts of papers accepted for the program must be submitted to The Annuls of Thoracic Surgery by October 15, Hotel reservations may be made by writing to the Marco Beach Hotel, 400 South Collier Blvd, Marco Island, FL (Phone: ). 1. Kent Trinkle, M.D. Secretary-Treasurer