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Ann Thorac Surg 2002;74:1640-1647
© 2002 The Society of Thoracic Surgeons
a Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. USA
b Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
c Biostatistics Service, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
d Division of Thoracic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
* Address reprint requests to Dr Rusch, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY, 10021, USA.
e-mail: ruschv{at}mskcc.org
Presented at the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.
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Abstract |
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 Top Abstract IntroductionPatients and methodsResultsCommentDiscussionReferences |
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METHODS: Between 1989 and 2000, 100 consecutive surgically treated patients with adenocarcinomas exhibiting various degrees of BAC features were retrospectively studied. Histology was reviewed; tumors were classified as pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features. Clinical and radiologic pattern were classified as unifocal, multifocal, or pneumonic. Demographic data, tumor stage, and outcome were recorded. Survival was analyzed by the Kaplan-Meier method, and prognostic factors were determined by the log-rank test.
RESULTS: Patient median age was 65, and 74% of the patients were female. Pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features occurred in 47, 21, and 32 patients, respectively. Unifocal disease occurred in 64 patients, multifocal in 29, and pneumonic in 7. Seventy-one patients had stage I/II tumors, 22 had stage III/IV, and 7 patients had Stage X tumors. Overall 5-year survival was 74%. There was no significant difference in survival among the three histologic subtypes. The pneumonic pattern had significantly worse survival compared with unifocal and multifocal patterns. Pathologic stage predicted survival, with 5-year survivals for I/II and III/IV of 83.7% and 59.6%, respectively.
CONCLUSIONS: Clinical pattern and pathologic stage, but not the degree of invasion on histologic examination predict survival. Multifocal disease is associated with excellent long-term survival after resection. The favorable survival of stage III/IV BAC indicates that the current staging system does not fully describe this disease in patients undergoing resection because of its distinct tumor behavior.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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A recent revision in the World Health Organization (WHO) criteria has restricted the definition of BAC to include only those tumors with a pure alveolar growth pattern without any evidence of invasion [1]. However, the bronchioloalveolar growth pattern occurs most frequently in conjunction with focal, or even dominant, areas of invasion. There have been a few studies comparing tumors displaying varying degrees of the bronchioloalveolar component [2, 3]. By grouping tumors displaying bronchioloalveolar features according to the degree of invasion, we sought to determine the significance of this factor on clinical outcome.
Controversy also exists about the impact of clinical and radiologic disease pattern and pathologic tumor stage on prognosis. This may be due, in part, to the rarity of this entity, resulting in relatively small-scale studies. Inconsistencies regarding the definition of bronchioloalveolar carcinoma further complicate matters. Therefore we retrospectively examined the experience of Memorial Hospital with surgically treated patients with tumors displaying bronchioloalveolar features of varying degrees. These analyses were assisted by pathologic re-review as well as staging according to consistent criteria.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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Histologic review
The cases consisted of paraffin blocks and slides, fixed, cut, and stained with hematoxylin and eosin in the routine manner. The original surgical diagnoses were reviewed and the cases were categorized into four new categories. At least three slides from each case were reviewed. In some cases, mucin stains were also reviewed. No additional slides from the surgical blocks were prepared, and no additional special stains were performed.
The histologic categories used for diagnosis included pure bronchioloalveolar carcinoma (PBAC), either mucinous or nonmucinous; bronchioloalveolar carcinoma with focal invasion (BWFI); adenocarcinoma with bronchioloalveolar features (AWBF); and adenocarcinoma, not bronchioloalveolar (Fig 1). Those cases diagnosed with invasive adenocarcinoma only, with no bronchioloalveolar component, were not further analyzed.
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Tumors categorized as BWFI consisted of tumor growth in a predominantly BAC pattern with a small, focal, single, or multiple area of invasion comprising less than 10% of the total tumor mass.
Tumors classified as AWBF consisted of invasive pulmonary adenocarcinomas with a peripheral component of the tumor growing along bronchioles and alveolar septae in a typical BAC pattern. The majority of the tumor in these cases was invasive, and the BAC pattern was noted only at the periphery and comprised a minor component of the tumor, usually less than 15%. The WHO classification of adenocarcinoma with mixed subtypes was not used.
In cases of multiple tumors, each tumor was analyzed separately. Two or more tumors of different histologic types were grouped according to the most invasive lesion. For instance, a case of two tumors (one PBAC and the other AWBF) was considered AWBF for the purpose of analysis.
Clinical data acquisition
Clinical information obtained from patient charts included age at the first thoracotomy, smoking history, cancer history, clinical disease pattern, type and extent of resection, time of relapse or new cancer, and disease status at last follow-up.
Characterization of clinical pattern
Patients were classified according to their radiologic and clinical presentation into three categories: (1) unifocal disease, (2) multifocal disease, or (3) pneumonic pattern. Unifocal disease was defined as a single tumor nodule on gross inspection and imaging studies, whereas multifocal disease was defined as two or more distinct tumor nodules in one or more lobes. If a patient had a single tumor on gross inspection with microscopic satellite lesions, the patient was still considered unifocal, but was staged as T4. The pneumonic pattern was characterized radiographically, presenting as a diffuse infiltrate, often involving an entire lobe.
Staging
Pathologic staging (p stage) was determined according to the guidelines of the fifth edition of the American Joint Committee on Cancer (AJCC) Staging Manual [4]. The extent of the primary tumor (T status) and the nodal involvement (N status) were determined by operative findings and pathologic reports. During the period of this study, complete mediastinal lymph dissection was performed at our institution as a routine part of pulmonary resection for lung cancer. Patients who had the pneumonic form of BAC with an indeterminate tumor size were staged as Tx and therefore stage X. In patients with multiple tumors, the Martini–Melamed criteria were used to distinguish synchronous tumors from intrapulmonary metastases [5]. Patients with two or more tumors in separate lobes with no positive intervening lymph nodes were judged to have multiple primary tumors and were staged according to the most advanced TNM system. If intervening lymph nodes were involved, the patient was judged to have metastatic disease. Finally, if a patient had two or more lesions of similar histology within the same lobe, then the tumor stage was considered T4, and therefore stage IIIB.
Definition of second events
Second events after the initial cancer were defined as either relapse or new cancer. A relapse was defined as either a locoregional recurrence (tumor along a staple line or pleura), or a distant recurrence (bone, brain, or adrenal disease, or diffuse and clearly metastatic disease within the lung parenchyma with lesions too numerous to count). A new cancer was defined as one or more new lesions detected within the lung parenchyma in an area anatomically distinct from the original primary tumor. Classification of these events was made by joint review of all records by two authors (MIE and VWR).
Data analysis
All statistical analyses were performed using SPSS software, version 10.0 (SPSS Inc, Chicago, IL). Continuous variables were analyzed by Student’s t test, categorical variables by Pearson’s 
2 or Fischer’s exact test. Survival and disease-free survival curves were calculated according to the method of Kaplan-Meier, and prognostic factors were determined by log rank analysis. A p value of 0.05 or less was considered significant.
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Results |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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2 = 12.8; p = 0.002). Nodal metastases (N1 or N2) were infrequent and occurred in 2 of the PBAC patients, 2 of the BWFI patients, and 3 of the AWBF patients, respectively. None of the 7 patients who had the pneumonic form of BAC had nodal metastases.
Clinical pattern classification
Sixty-four patients had unifocal disease, 29 had multifocal disease, and 7 patients had the pneumonic disease pattern. Of the 29 cases of multifocal disease, 41% were bilateral. However, because of the small sample size, unilateral and bilateral cases were grouped together for further analysis. Differences in age, gender, smoking history, and cancer history were not significant among the three groups. Patients with nodal disease (N1 or N2) included 6 in the unifocal group and 1 in the multifocal group. Four of the 29 patients in the multifocal group did not have nodal staging performed and were therefore categorized as Nx. No patients within the pneumonic pattern group had nodal disease. The comparison of clinical and radiologic patterns to histologic subtype is shown in Table 2.
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Survival analyses
The median overall survival for all patients was not reached during this study, but was greater than 145.9 months. When patients are analyzed by histologic subtype, there is no significant difference among the groups (Fig 2).
When grouped by clinical pattern, the pneumonic subtype had a significantly shorter survival than the unifocal and multifocal patients combined (p = 0.005), with a median survival of 48.7 months (Fig 3).
Mucin-positive tumors were associated with a worse overall survival (p = 0.006). However when the 7 pneumonic type tumors, which were all mucin producing, were excluded from this analysis, the overall survival difference did not achieve statistical significance (p = 0.06). There was no significant difference between the unifocal and multifocal groups (p = 0.202). Considering pathologic stage, stage X appears to have the worst prognosis again (Fig 4).
A statistical difference also exists between the stage I/II patients and the stage III/IV patients (p = 0.019).
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Relapses and new cancers
Information about sites of relapse and the frequency of new lung cancers is shown in Table 4.
Briefly, of the 100 patients, 22 had relapses and 22 had new cancers develop during the period of this study. Of the 47 patients with the PBAC histologic subtype, 9 had new cancers develop and 12 had recurrent disease develop. Of these 12 relapses, 8 were intrathoracic, 2 were extrathoracic, and 2 patients were both intra- and extrathoracic. Of the patients with the pneumonic clinical pattern, 3 had new cancers develop and 2 suffered from relapse, 1 intrathoracic and the other 1 extrathoracic. The intrathoracic disease was diffuse lung metastases and distant sites of relapse were bone and brain.
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Comment |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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Although the revised WHO definition strictly defines BAC as having absolutely no evidence of invasion, adenocarcinoma can display a range of BAC features from predominant BAC with only a small focal area of invasion to a lesion that has BAC features only at the periphery of the tumor. Few studies explore the significance of these differences. Higashiyama and colleagues [2] grouped tumors into four types based on the percentage of the BAC component, corresponding to 0% BAC, 1% to 49% BAC, 50% to 99% BAC, and 100% BAC. He reported that the 17 tumors that were type IV or pure BAC had no nodal involvement and 100% overall survival at 5 years. The less extensive the BAC involvement among these four adenocarcinoma tumor subgroups, the worse the prognosis. Noguchi and colleagues [3] classified patients with small adenocarcinomas into six types, A through F. It is difficult to correlate directly our groups with Noguchi and colleagues’ [3] subtypes, because they were not primarily investigating the BAC pattern. Only their types A through C included tumors with at least a partial bronchioloalveolar pattern.
However, both Higashiyama and colleagues [2] and Noguchi and colleagues [3] studied only small tumors (< 2 cm in size), necessarily excluding those of the pneumonic clinical pattern. Both studies showed that BAC pattern tumors with invasive components had a worse prognosis than pure BAC tumors, and that stage I pure BAC tumors were associated with a 100% survival at 5 years after resection. Our patients with stage I PBAC tumors had a 5-year survival of 83.3%, which is similar to that found by Breathnach and colleagues [11] and to the T1N0 mol/L0 category of Hsu and colleagues [16]. Unfortunately it is difficult to compare results across most studies because of the revision of the WHO definition of BAC.
Both the published literature and our experience suggest that BAC presents in an extremely heterogenous manner, has a variable clinical behavior, and is distinct from other subsets of NSCLC [17, 18]. The new WHO classification of BAC and adenocarcinoma eliminates confusion in pathologic diagnosis but does not fully describe histologic admixtures, which in turn appear to have unique clinical behaviors. Although we certainly do not suggest a change in pathologic classification, the grouping of tumors into three distinct histologic categories (PBAC, BWFI, AWBF) and three clinical patterns (unifocal, multifocal, pneumonic) allow us to analyze outcome in ways that are meaningful to clinicians. These tumor groupings were arrived at after much consideration as the heterogenous presentations and behavior of BAC or BAC-containing adenocarcinoma became evident in our review.
We observed no difference in nodal status between the histologic subgroups. It appears that tumors with a bronchioloalveolar pattern, regardless of degree of invasion, are less likely to involve lymph nodes. Even among our 29 multifocal cases, only one patient had nodal disease. Daly and colleagues [14] also found a low incidence of lymph node metastasis, even in patients with multifocal disease. Several studies report a decreased incidence of extrathoracic metastases in patients with BAC when compared with general adenocarcinoma [10–12]. However extrathoracic metastases are occasionally seen in all three histologic subgroups. In fact, 1 of our 7 patients of the pneumonic subtype died as a result of a brain metastasis. Feldman and colleagues [19] demonstrated that when BAC is metastatic, the prognosis is similar to that of metastatic adenocarcinoma of the lung.
We found no difference in either survival or disease-free interval among our defined histologic subtypes. In fact, even when we eliminate the seven pneumonic pattern patients from the PBAC subtype, we still observe no difference. It appears from this data that the presence of a bronchioloalveolar pattern of any degree is a positive prognostic factor within adenocarcinoma.
With respect to disease pattern, the pneumonic pattern is clearly an ominous sign, predicting both a decreased disease-free and overall survival, even though these tumors were composed solely of PBAC. All seven of the tumors were mucin producing; these characteristics have been reported by other investigators [7, 9, 13, 16, 20]. However, it should be noted that 3 of our 7 patients with the pneumonic pattern survived 2 years or more after an operation, and therefore survival in this poor prognosis subgroup is variable. It is noteworthy that we did not find a significant difference in survival between the unifocal pattern and the multifocal pattern. This supports the theory that BAC is often a multifocal disease in which synchronous tumors should, in the absence of disease in common lymphatics or extrapulmonary sites, be treated as separate primaries.
It is important that the criteria of Martini and Melamed [5] be invoked when staging this disease. Daly and colleagues [14] found bilateral multifocal disease to be ominous, and advised patients with this disease to receive an operation for diagnostic purposes only. However, of our 12 patients with bilateral multifocal disease, the mean survival was 75 months. If two tumors arose within the same lobe, we were unable to distinguish unequivocally between synchronicity and satellite metastasis. Therefore these cases would be considered T4N0 mol/L0, stage IIIb, categorizing them within our stage III/IV group. Pathologic stage, as defined here, predicted both disease-free and overall survival. The median survival was 116 and 83 months for stages I/II and III/IV, respectively. This translates into 5-year survivals of 83.7% and 59.6%, respectively. Even though there was a significant difference between these two groups, the survival of the III/IV group was still markedly higher than what would be expected from other NSCLC types. Values published by Mountain [21] show 5-year survival for stages cIIIA, cIIIB, and cIV as 13%, 5%, and 1%, respectively. Data from other studies show advanced stage BAC with a somewhat less favorable survival than the present study, but there were critical differences in staging techniques [14, 16, 22]. Our data suggest that the current staging system for NSCLC does not accurately describe the behavior of stage III and IV patients with BAC or BAC-containing tumors who undergo surgical resection.
In summary, our experience with pure BAC and BAC-containing adenocarcinomas suggest that these variants of NSCLC have distinct clinical features and behavior. It is important to recognize that the current staging system and histologic classification do not fully characterize the outcome of these tumor subsets. Therefore treatment algorithms different than those used for the other more common and more invasive forms of NSCLC should be considered. These intriguing differences may be explained in the future through the molecular profiling of tumors, which could reveal whether BAC is a pre-invasive form of adenocarcinoma and whether there are specific molecular abnormalities that make these tumors more prone to intrathoracic multicentricity rather than systemic progression. Finally it is important to recognize that BAC and its variant tumor types are associated with a high risk of second primary lung cancers. Given the excellent postoperative prognosis of most of these patients after resection, and the high risk of second primary tumors, careful long-term postoperative surveillance is warranted.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsCommentDiscussionReferences |
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DR EBRIGHT: Actually, Dr Wood, I am glad you brought that up. One of the advantages of this study is that we were able to correlate clinical disease pattern with the histologic features. And, in fact, we did run that study. We took out the 7 patients that were pure BAC of the pneumonic pattern and we still had no significant difference in survival. The curves were all overlying on top of one another. So I would say that although it is a phenomenon that the pneumonic patterns were all pure BAC, still, even given with that, the histological subtypes do not predict survival.
DR MICHAEL T. JAKLITSCH (Boston, MA): The one thing that seems to be lacking in your presentation is what your actual treatment was, although we are sure that they were all surgically treated. Your results are really quite good, but I am curious about the subgroup that is the multifocal BAC. So the implication is that you are taking all of these nodules out. Is that a correct assumption? Are there some nodules that you are waiting until they start to grow, so that you have an observational period? Also, are you doing multiple lobectomies or are you treating these with wedge resections? Could you just address that particular subgroup?
DR EBRIGHT: Sure. Actually I believe we had 29 multifocal BAC patients and treatment was surgical. Depending on the patient, case by case, most patients were lobectomies, although with multifocal disease we ended up doing wedges as well. Less than a handful of patients had neoadjuvant therapy, and if it were a complete resection, they did not have therapy beyond that besides surveillance.
DR VALERIE W. RUSCH (New York, NY): I will just add a couple of points of information and emphasize what Michael has said. We are seeing more and more of these patients, as I suspect other individuals in this room are seeing, too. We are certainly also seeing more and more patients who have multifocality, and I think that we have gained a better understanding of the natural history of this disease after resection. As I think everyone here knows, this is a disease which appears to be chemotherapy–unresponsive, so it is important to recognize that there are not good nonsurgical options at the present time and also that the survival of these individuals after surgical resection is favorable. So we have certainly taken the strategy of resection of all sites of disease in patients who have multifocal BAC and have allowed lesser resections depending on tumor location and tumor size because of the better prognosis and the risk of second primary tumors. So some of these patients now have lobectomies or lobectomies and segments or lobectomies and wedge resections to try to remove all the disease.
DR WOOD: Would you actually prefer lesser resections now because of the common multifocality and common recurrence at another site in BAC?
DR RUSCH: Without saying that that is the preferred resection, it is certainly an option that we tend to use much more readily in this patient population.
DR GEORGE ZORN, JR (Birmingham, AL): Just one quick question about patients who present with bilateral lung disease. Would you comment on your strategy with this?
DR EBRIGHT: In our study we did not have the power to analyze separately multifocal unilateral patients with multifocal patients that had bilateral disease. We did have 12 patients with multifocal bilateral disease. Their mean survival time was 75 months. So we did definitely have long-term survival and these patients fared very well. Again, it is important to stage these patients with Martini-Melamed criteria if they can be considered second primaries and should be treated as such.
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V. A. Miller, M. G. Kris, N. Shah, J. Patel, C. Azzoli, J. Gomez, L. M. Krug, W. Pao, N. Rizvi, B. Pizzo, et al. Bronchioloalveolar Pathologic Subtype and Smoking History Predict Sensitivity to Gefitinib in Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., March 15, 2004; 22(6): 1103 - 1109. [Abstract] [Full Text] [PDF]
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P. F. Roberts, M. Straznicka, P. N. Lara, D. H. Lau, D. M. Follette, D. R. Gandara, and J. R. Benfield Resection of multifocal non-small cell lung cancer when the bronchioloalveolar subtype is involved J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1597 - 1601. [Abstract] [Full Text] [PDF]
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