- Email: [email protected]
Pulmonary adenocarcinoma T1N0M0 and its classification
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semdp
Pulmonary adenocarcinoma T1N0M0 and its classification Annikka Weissferdt, MD, FRCPatha,n, Garrett Walsh, MDb, Larry Kaiser, MDc, Cesar A. Moran, MDa a
Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030 Department of Thoracic Surgery, MD Anderson Cancer Center, Houston, TX c Temple University School of Medicine, Philadelphia, PA b
article info
abstract Over the last decade, use of the term bronchioloalveolar carcinoma (BAC) has come under constant scrutiny as some consider it an anachronism or a term that provides incorrect information about this neoplasm. To that extent, it has recently been suggested to replace the term BAC with that of in situ adenocarcinoma (AIS) or minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure bronchioloalveolar growth (AIS) or predominant bronchioloalveolar growth and r5-mm invasion (MIA). However, as of today, there is no comprehensive study of these tumors, and most of what has been published in this context is based on a review of the literature that focused on scattered short series of cases describing either small adenocarcinomas or BAC. More recently, a large series of cases of a more comprehensive nature that included all early-stage adenocarcinomas (T1N0M0) has cast some doubt regarding the need for the proposed change in nomenclature. At the same time, it was suggested that if indeed that notion is maintained, a more serious and comprehensive study of actual cases must be undertaken. The details of the issues surrounding this subject are presented in this review. & 2014 Elsevier Inc. All rights reserved.
Introduction Epidemiological studies have shown that the morbidity and mortality due to lung carcinoma is considerable (SEERS; http://www.cdc.gov/cancer/lung/statistics/index.html and http:// seer.cancer.gov/csr/1975_2008); thus, every effort must be made to not only detect the disease in its early stage but to also try to identify parameters that can help distinguish those tumors with better outcome from those that may follow a more aggressive clinical course. In that regard, the use of molecular studies has provided meaningful information leading to more precise and individualized treatment protocols, which in turn
n
Corresponding author. E-mail address: [email protected] (A. Weissferdt).
http://dx.doi.org/10.1053/j.semdp.2014.06.002 0740-2570/& 2014 Elsevier Inc. All rights reserved.
can be translated into improved survival rates.1 In an attempt to more accurately identify tumor characteristics that may differentiate lung adenocarcinomas with better outcome, a new classification schema has recently been suggested in which the main emphasis was to replace the term bronchioloalveolar carcinoma (BAC) with new terminology such as “adenocarcinoma in situ” (AIS) for tumors with a pure bronchioloalveolar growth pattern and near 100% survival and “minimally invasive adenocarcinoma” (MIA) for tumors with predominant bronchioloalveolar growth and r5-mm invasion.2 Even though at first glance these new terms appear “catchy,” their true meaning when applied to clinical practice
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may lead to untoward consequences, although this is certainly not their intended purpose. Although there are no meaningful publications dealing with early pulmonary adenocarcinoma in general, there are several studies that have focused exclusively on those tumors with a bronchioloalveolar growth pattern and that have been used as justification to warrant the change in the classification system. Alternatively, it can be argued that if one is to analyze only tumors with a bronchioloalveolar growth pattern, one will likely miss the extent of the problem as there are many more adenocarcinomas that even in early pathologic stage (T1N0M0) do not show the bronchioloalveolar growth pattern and that have been excluded from comparison and statistical analysis to determine whether this change in nomenclature is justified. At the same time, it can be argued that if in general terms T1N0M0 pulmonary adenocarcinomas are treated in the same way—complete surgical resection plus staging— then what is to be gained from such action? In addition, one can further argue that the overall survival rate of T1N0M0 pulmonary adenocarcinoma is not statistically different regardless of the pattern of growth. Unfortunately, such analysis has been missing from the proposal in support of this “new” classification system.
Definition In 2004, the World Health Organization (WHO)3 in its publication on Tumors of the Lung, Pleura, Thymus, and Heart introduced changes to the definition and diagnosis of BAC by defining such a tumor as one that shows growth of neoplastic cells along pre-existing alveolar structures and lacks any stromal, vascular, or pleural invasion or nodal involvement. In other words, even though not clearly stated in this publication, what the authors described was an in situ adenocarcinoma. In a review of the literature,4 a “new” proposal for the classification of lung adenocarcinoma was introduced describing similar histological characteristics as those previously presented in the WHO publication.3 One important fact that needs mentioning is that this classification is applicable only to tumors up to 3 cm in greatest dimension. If a tumor exceeds 3 cm—although with similar histological findings—it may belong to a different category. Such concept implies that when tumors with a pure bronchioloalveolar pattern and no stromal, pleural, lymphatic, or nodal invasion occur (i.e., the newly proposed category of AIS), by definition they have to be smaller than 3 cm in greatest diameter, otherwise the concept of AIS ceases to exist. It has to be acknowledged that tumors with a pure bronchioloalveolar growth pattern are unusual and if encountered will have to be submitted in their entirety with careful evaluation to rule out stromal, pleural, lymphatic, or nodal invasion. The most important question, however, is as to whether such cases truly exist or how to classify tumors that fall short of the proposed criteria for AIS. The likely answer is the use of the conventional term of “adenocarcinoma with bronchioloalveolar growth pattern” in addition to addressing any structure that shows invasion.
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Historical aspects Historically, tumors with a bronchioloalveolar pattern have been recognized in the literature for more than a century. In 1876, Malassez5 first described a pulmonary neoplasm with similar characteristics to BAC, which was followed by a report by Musser6 who described a similar case under the name “primary cancer of the lung.” The histopathological characteristics of both tumors as described were similar, namely a bronchioloalveolar growth pattern. The difference between these tumors was not their histology but rather the extent of their growth. Nevertheless, the tumors showed the same bronchioloalveolar growth pattern that we know today. In the 50 years following the above descriptions, a myriad of publications7–15 describing similar tumors were presented in the literature. Despite appearing under various diverse names, the most consistent factor was their lack of stromal invasion. Needless to say, in many of these cases, metastatic disease was documented. However, the main controversy in these early publications was whether the tumors were derived from the alveolar epithelium or from the terminal airway. In 1960, Liebow16 defined BAC as well-differentiated adenocarcinomas and emphasized the presence of three distinct presentations: (1) the single nodular pattern, (2) disseminated nodular pattern, and (3) diffuse pattern. In addition, he stated that this neoplasm is capable of invading other structures within the lung or even outside of the lung parenchyma. In the recent proposal for a change in the nomenclature,2 it is evident that the main focus is on the single nodule pattern and not on the other types, even though the histology can be similar in all those tumors.
Pathological features As stated before, the morphological features of these tumors are similar irrespective of solitary, disseminated, or diffuse growth. For the purpose of this discussion, however, only the single nodule pattern will be discussed as this appears to be the pattern for which the change in terminology has been suggested. The macroscopic findings of this tumor are those of a solitary pulmonary nodule that cannot measure more than 3 cm in greatest dimension. Histologically, the tumor is characterized by growth along the alveolar walls, which can be partially or completely replaced by a low cuboidal or cylindrical epithelium (Fig. 1A). The cells have oval or round nuclei, which may show inconspicuous or prominent nucleoli (Fig. 1B). Even though mitotic activity is not prominent, rare mitotic figures can be seen in some cases. By definition, the tumor should not show any stromal, pleural, lymphatic, or nodal invasion.
Discussion The controversy on BAC is nothing new as this entity has been debated for decades. There have been many studies in the literature with different points of view as well as different findings, which unfortunately have generated even more controversy on this subject.7–23 Since the occurrence of metastatic disease to the lung with a bronchioloalveolar
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Fig. 1 – (A) Adenocarcinoma with bronchioloalveolar growth pattern showing tumor cell growth along the alveolar walls. (B) High-power view of adenocarcinoma with bronchioloalveolar growth pattern. The alveolar walls are lined by cuboidal epithelium showing prominent hobnailing. growth pattern has been described, it has been argued that BAC represents a growth pattern rather than a true entity. In a report of 30 cases of BAC, Bennett and Sasser22 stated that there is no morphological, histogenetic, or clinical basis to separate BAC from conventional adenocarcinoma. In a reappraisal of BAC, Delarue et al.23 insisted on the validity of the entity and outlined some criteria for its diagnosis, which are fairly similar to the ones currently offered by the proponents of the “new” classification,2 namely an absence of stromal invasion. Nevertheless, it was also stated that metastatic disease and malignant pleural effusion might occur. In addition, some authors have attempted to correlate different histopathological features of BAC with survival rate. Manning et al.24 separated these tumors into mucinous and nonmucinous types, concluding that non-mucinous BAC has a 5-year survival rate of 72%. Needless to say, the number of reports dealing with this entity is vast, and their results are controversial. One of the main issues with this subject is that some studies have included tumors not only of the solitary type but also those with disseminated or diffuse growth
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patterns. Thus, it is very difficult to draw valid conclusions from those publications. In the more recent literature on this subject, Rena et al.25 presented a study of 28 patients with stage I BAC with a 5-year disease-free survival rate of 81%. However, the main issue with this report lies in the fact that many cases were diagnosed by cytology, casting some doubt as to the true histology of the tumors. Finally, Ebright et al.26 concluded that the most important parameters in the evaluation of BAC are the clinical features and pathologic staging of these tumors rather than histological assessment. In 2006, Travis et al.4 presented a review of BAC stating that there is existing evidence that patients with solitary small peripheral BAC have 100% survival at 5 years and claiming that the basis for the proposed “new” classification of BAC derives from that experience.27 The study that forms the basis for this proposal involved 236 cases of resected peripheral adenocarcinomas of the lung less than 2 cm in greatest diameter.27 The authors separated different types of adenocarcinomas into categories ranging from A to F, with 28 of the ones designated as types A and B representing the localized form of BAC; however, on closer examination of the article, the authors account for a total of 34 of these tumors, with some of these showing not only lymphatic but also pleural invasion, thus disqualifying these tumors as BAC according to the 2004 WHO schema. More important, by describing small tumors (r2 cm) with BAC growth pattern, the authors have acknowledged that these tumors have the potential to show lymphatic invasion and pleural involvement. In the recent proposal for the “new” classification of adenocarcinoma, which introduced the terms AIS and MIA, the authors claimed to have reviewed 312 selected references of 11 thousand citations.2 Of these, the authors based their suggested name change on approximately a dozen publications on the subject of “small adenocarcinomas” or BAC.28–37 Interestingly, critical review of those publications identified tumors that ranged in size from 0.2 cm to 3 cm in greatest diameter with the majority of these measuring less than 2 cm in diameter. More important is the fact that none of those publications specifically stated how many tumors were smaller or larger than 0.5 cm, this being the current size limit for calling lesions atypical adenomatous hyperplasia (AAH) versus BAC. Perhaps even more intriguing about the recent proposal is the lack of any attempt to critically compare all pulmonary adenocarcinomas in terms of survival rate to determine whether the suggested change in the nomenclature is warranted. Regardless of the histological grade of the tumor, a T1N0M0 adenocarcinoma of the lung is treated by complete surgical resection; thus, the emphasis should be placed not on the histology of the tumor but on tumor staging at the time of diagnosis. Staging is the single most important factor that determines the need for additional medical treatment leaving histological subtyping of adenocarcinomas secondary and not particularly critical in decisions regarding additional treatment. If one is to argue that histology plays an important role in determining outcome for these patients, then a comparative study of these tumors is needed. A recent study of 104 cases of T1N0M0 adenocarcinoma from a single institution attempted to determine whether there was a statistically significant difference between tumors with pure bronchioloalveolar growth pattern and so-called
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conventional adenocarcinomas.38 The initial results showed that associated malignancies, not surprisingly, had a significant impact on patient survival. In patients without an additional malignancy, the tumors were separated by grade into well, moderately, and poorly differentiated tumors, a distinction that showed no statistical differences in survival. Further analysis separated tumors based on their bronchioloalveolar component (o25%, 25–50%, and 450%), and once again, no statistically significant difference was noted when compared to conventional adenocarcinomas (Fig. 2A). Finally, the tumors were separated into pure bronchioloalveolar growth (BAC) versus other types, and again, the results failed to show any statistically significant survival difference (Fig. 2B). There was merely a trend toward better outcome in tumors with a BAC component (Fig. 2C). Thus, if all T1N0M0 adenocarcinomas show similar survival rates the question as to what is to be gained from re-naming BAC must be asked. Perhaps, the true AIS reflects what currently is labeled “atypical adenomatous hyperplasia” and which represents a lesion with bronchioloalveolar growth pattern but a size r0.5 cm in greatest dimension. Another interesting fact is that in that same study, none of the 104 cases was classified as MIA casting doubt on the usefulness of such a category. Based on the current literature, we contend that the suggested change in terminology of lung adenocarcinoma is premature. In addition, it may send a false sense of security to the treating physicians as the term AIS can easily be taken out of context, and patients may end up not being fully staged, which would be a disservice to the patient and potentially dangerous. In that regard, studies of small adenocarcinomas have documented metastatic disease to lymph nodes in as many as 22% of patients.39,40 Hence, the treatment of patients with small adenocarcinomas should not be based on the histological features of the tumor but rather on the stage of the disease at the time of diagnosis. Basing treatment decisions on changes in nomenclature such as AIS may be misleading. We suggest that the diagnosis of adenocarcinoma should include not only the grade of the tumor and the pattern of growth but also the presence of tumor spread or the lack thereof. We therefore suggest the following terminology for adenocarcinomas with a bronchioloalveolar component:
Fig. 2 – (A) Kaplan–Meier survival curves comparing tumors with a bronchioloalveolar pattern when divided by the percentage of the bronchioloalveolar component (o25%, 25– 50%, and 450%). (B) Kaplan–Meier curve for tumors with a pure bronchioloalveolar pattern (proposed “in situ adenocarcinoma”). (C) Survival curves comparing tumors with any bronchioloalveolar component to those without. (Reproduced with permission from Weissferdt et al.38)
For biopsy specimens: ○ Adenocarcinoma with bronchioloalveolar growth pattern (tumors Z 0.5 cm) For surgical resections: ○ Adenocarcinoma in situ (r0.5 cm; formerly AAH) ○ Adenocarcinoma (growth pattern(s) in approximate %) ○ Size of the tumor ○ Pleural integrity ○ Lymph node status
refere nces
1. Moran CA. Importance of molecular features of non-small cell lung cancer for choice of treatment. Am J Pathol. 2011;178(5): 1940–1948.
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2. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma. J Thorac Oncol. 2011;6(2):244–285. 3. Travis WD, Brambilla E, Müller-Hermelink K, Harris CC, eds. Tumours of the Lung, Pleura, Thymus, and Heart. In: Pathology & Genetics, World Health Organization, IARC Press: Lyon, France; 2004; p38. 4. Travis WD, Garg K, Franklin WA, et al. Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 World Health Organization pathologic criteria. J Thorac Oncol. 2006;1(9 Suppl):S13–S19. 5. Malassez L. Examen histologique d’un cas de cancer encephaloide du poumon (epithelioma). Arch Physiol Norm Pathol. 1876;3:352–372. 6. Musser JH. Primary cancer of the lung. Univ Pa Med Bull. 1903;16:289–296. 7. Sweany HC. A so-called alveolar cell cancer of the lung. Arch Pathol. 1935;19:203–207. 8. Casilli AR, White HJ. Rare forms of primary malignant lung tumors. Am J Clin Pathol. 1940;10:623–641. 9. Geever KT. Alveolar cell tumor of the human lung. Arch Pathol. 1942;33:551–569. 10. Herbut PA. Bronchiolar origin of “Alveolar Cell Tumor” of the lung. Am J Pathol. 1944;20:911–929. 11. Wood DA, Pierson PH. Pulmonary alveolar adenomatosis in man. Am Rev Tuberc. 1945;51:205–223. 12. Ikeda K. Alveolar cell carcinoma of the lung. Am J Clin Pathol. 1945;15:50–63. 13. Osserman KE, Neuhof H. Mucocellular papillary adenocarcinoma of the lung. J Thorac Surg. 1946;15:272–278. 14. Drymalski GW, Thompson R, Sweany HC. Pulmonary adenomatosis. Am J Pathol. 1948;20(5):1083–1093. 15. Delarue NC, Graham EA. Alveolar cell carcinoma of the lung (pulmonary adenomatosis, jaagsiekte?). J Thorac Surg. 1949;18 (2):237–251. 16. Liebow AA. Bronchioloalveolar carcinoma. Adv Int Med. 1960;10:329–358. 17. Overholt RH, Meissner WA, Delmonico E. Favorable bronchiolar carcinoma. Chest. 1955;27(4):403–413. 18. Watson I, Farppour A. Terminal bronchiolar or “alveolar cell” cancer of the lung: two hundred sixty-five cases. Cancer. 1966;19(6):776–780. 19. Belgrad R, Good A, Woolner LB. Alveolar cell carcinoma (terminal bronchiolar carcinoma): a study of surgically excised tumors with special emphasis on localized lesions. Radiology. 1962;79:789–798. 20. Munell ER, Lawson RC, Keller DF. Solitary bronchiolar (alveolar cell) carcinoma of the lung. J Thorac Cardiovasc Surg. 1966;52(2):261–270. 21. Rosenblatt MB, Lisa JR, Collier F. Primary and metastatic bronchioloalveolar carcinoma. Chest. 1967;52(2):147–152. 22. Bennett DE, Sasser WF. Bronchiolar carcinoma: a valid clinicopathologic entity? A study of 30 cases. Cancer. 1969;24(5): 876–887. 23. Delarue NC, Anderson W, Sanders D, Starr J. Bronchioloalveolar carcinoma: a reappraisal after 24 years. Cancer. 1972;29(1):90–97. 24. Manning JT, Spjut HJ, Tsechen JA. Bronchioloalveolar carcinoma: the significance of two histopathologic types. Cancer. 1984;54(3):525–534.
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25. Rena O, Papalia E, Ruffini E, et al. Stage I pure bronchioloalveolar carcinoma: recurrences, survival and comparison with adenocarcinoma. Eur J Cardiothorac Surg. 2003;23(3): 409–414. 26. Ebright MI, Zakoski MF, Martin J, et al. Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma. Ann Thorac Surg. 2002;74(5): 1640–1647. 27. Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung: histologic characteristics and prognosis. Cancer. 1995;75(12):2844–2852. 28. Yamamoto Y, Tsuchida M, Watanabe T, et al. Early resection of a prospective study of limited resection for bronchioloalveolar adenocarcinoma of the lung. Ann Thorac Surg. 2001;71(3): 971–974. 29. Watanabe S, Watanabe T, Arai K, Kasai T, Haratake J, Urayama H. Results of wedge resection for focal bronchioloalveolar carcinoma showing pure ground-glass attenuation on computed tomography. Ann Thorac Surg. 2002;73(4): 1071–1075. 30. Suzuki K, Asamura H, Kusumoto M, Kondo H, Tsuchiya R. “Early” peripheral lung cancer: prognostic significance of ground glass opacity on thin-section computed tomography scan. Ann Thorac Surg. 2002;74(5):1635–1639. 31. Sakurai H, Dobashi Y, Mizutani E, et al. Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: a retrospective assessment. Ann Thorac Surg. 2004;78(5): 1728–1733. 32. Yamada S, Kohno T. Video-assisted thoracic surgery for pure ground-glass opacities 2 cm or less in diameter. Ann Thorac Surg. 2004;77(6):1911–1915. 33. Yoshida J, Nagai K, Yokose T, et al. Limited resection trial for pulmonary ground-glass opacity nodules: fifty-case experience. J Thorac Cardiovasc Surg. 2004;129(5):991–996. 34. Koike T, Togashi K, Shirato T, et al. Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination. Ann Thorac Surg. 2009;88(4): 1106–1111. 35. Vazquez M, Carter D, Brambilla E, et al. Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: Histopathologic features and their prognostic implications. Lung Cancer. 2009;64(2):148–154. 36. Yim J, Zhu LC, Chiriboga L, Watson HN, Goldberg JD, Moreira AL. Histological features are important prognostic indicators in early stages lung adenocarcinoma. Mod Pathol. 2007;20(2): 233–241. 37. Borczuk AC, Qian F, Kazeros A, et al. Invasive size is an independent predictor of survival in pulmonary adenocarcinoma. Am J Surg Pathol. 2009;33(3):462–469. 38. Weissferdt A, Kalhor N, Marom E, et al. Early pulmonary adenocarcinoma (T1N0M0): a clinical, radiological, surgical, and pathological correlation of 104 cases. The MD Anderson Cancer Center Experience. Mod Pathol. 2013;26(8): 1065–1075. 39. Takizawa T, Terashima M, Koike T, et al. Lymph node metastasis in small peripheral adenocarcinoma of the lung. J Thorac Cardiovasc Surg. 1998;116(2):276–280. 40. Konaka C, Ikeda N, Hiyoshi T, et al. Peripheral non-small lung cancers 2.0 cm or less in diameter: proposed criteria for limited pulmonary resection based upon clinicopathological presentation. Lung Cancer. 1998;21(3):185–191.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semdp
Pulmonary adenocarcinoma T1N0M0 and its classification Annikka Weissferdt, MD, FRCPatha,n, Garrett Walsh, MDb, Larry Kaiser, MDc, Cesar A. Moran, MDa a
Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030 Department of Thoracic Surgery, MD Anderson Cancer Center, Houston, TX c Temple University School of Medicine, Philadelphia, PA b
article info
abstract Over the last decade, use of the term bronchioloalveolar carcinoma (BAC) has come under constant scrutiny as some consider it an anachronism or a term that provides incorrect information about this neoplasm. To that extent, it has recently been suggested to replace the term BAC with that of in situ adenocarcinoma (AIS) or minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure bronchioloalveolar growth (AIS) or predominant bronchioloalveolar growth and r5-mm invasion (MIA). However, as of today, there is no comprehensive study of these tumors, and most of what has been published in this context is based on a review of the literature that focused on scattered short series of cases describing either small adenocarcinomas or BAC. More recently, a large series of cases of a more comprehensive nature that included all early-stage adenocarcinomas (T1N0M0) has cast some doubt regarding the need for the proposed change in nomenclature. At the same time, it was suggested that if indeed that notion is maintained, a more serious and comprehensive study of actual cases must be undertaken. The details of the issues surrounding this subject are presented in this review. & 2014 Elsevier Inc. All rights reserved.
Introduction Epidemiological studies have shown that the morbidity and mortality due to lung carcinoma is considerable (SEERS; http://www.cdc.gov/cancer/lung/statistics/index.html and http:// seer.cancer.gov/csr/1975_2008); thus, every effort must be made to not only detect the disease in its early stage but to also try to identify parameters that can help distinguish those tumors with better outcome from those that may follow a more aggressive clinical course. In that regard, the use of molecular studies has provided meaningful information leading to more precise and individualized treatment protocols, which in turn
n
Corresponding author. E-mail address: [email protected] (A. Weissferdt).
http://dx.doi.org/10.1053/j.semdp.2014.06.002 0740-2570/& 2014 Elsevier Inc. All rights reserved.
can be translated into improved survival rates.1 In an attempt to more accurately identify tumor characteristics that may differentiate lung adenocarcinomas with better outcome, a new classification schema has recently been suggested in which the main emphasis was to replace the term bronchioloalveolar carcinoma (BAC) with new terminology such as “adenocarcinoma in situ” (AIS) for tumors with a pure bronchioloalveolar growth pattern and near 100% survival and “minimally invasive adenocarcinoma” (MIA) for tumors with predominant bronchioloalveolar growth and r5-mm invasion.2 Even though at first glance these new terms appear “catchy,” their true meaning when applied to clinical practice
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may lead to untoward consequences, although this is certainly not their intended purpose. Although there are no meaningful publications dealing with early pulmonary adenocarcinoma in general, there are several studies that have focused exclusively on those tumors with a bronchioloalveolar growth pattern and that have been used as justification to warrant the change in the classification system. Alternatively, it can be argued that if one is to analyze only tumors with a bronchioloalveolar growth pattern, one will likely miss the extent of the problem as there are many more adenocarcinomas that even in early pathologic stage (T1N0M0) do not show the bronchioloalveolar growth pattern and that have been excluded from comparison and statistical analysis to determine whether this change in nomenclature is justified. At the same time, it can be argued that if in general terms T1N0M0 pulmonary adenocarcinomas are treated in the same way—complete surgical resection plus staging— then what is to be gained from such action? In addition, one can further argue that the overall survival rate of T1N0M0 pulmonary adenocarcinoma is not statistically different regardless of the pattern of growth. Unfortunately, such analysis has been missing from the proposal in support of this “new” classification system.
Definition In 2004, the World Health Organization (WHO)3 in its publication on Tumors of the Lung, Pleura, Thymus, and Heart introduced changes to the definition and diagnosis of BAC by defining such a tumor as one that shows growth of neoplastic cells along pre-existing alveolar structures and lacks any stromal, vascular, or pleural invasion or nodal involvement. In other words, even though not clearly stated in this publication, what the authors described was an in situ adenocarcinoma. In a review of the literature,4 a “new” proposal for the classification of lung adenocarcinoma was introduced describing similar histological characteristics as those previously presented in the WHO publication.3 One important fact that needs mentioning is that this classification is applicable only to tumors up to 3 cm in greatest dimension. If a tumor exceeds 3 cm—although with similar histological findings—it may belong to a different category. Such concept implies that when tumors with a pure bronchioloalveolar pattern and no stromal, pleural, lymphatic, or nodal invasion occur (i.e., the newly proposed category of AIS), by definition they have to be smaller than 3 cm in greatest diameter, otherwise the concept of AIS ceases to exist. It has to be acknowledged that tumors with a pure bronchioloalveolar growth pattern are unusual and if encountered will have to be submitted in their entirety with careful evaluation to rule out stromal, pleural, lymphatic, or nodal invasion. The most important question, however, is as to whether such cases truly exist or how to classify tumors that fall short of the proposed criteria for AIS. The likely answer is the use of the conventional term of “adenocarcinoma with bronchioloalveolar growth pattern” in addition to addressing any structure that shows invasion.
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261
Historical aspects Historically, tumors with a bronchioloalveolar pattern have been recognized in the literature for more than a century. In 1876, Malassez5 first described a pulmonary neoplasm with similar characteristics to BAC, which was followed by a report by Musser6 who described a similar case under the name “primary cancer of the lung.” The histopathological characteristics of both tumors as described were similar, namely a bronchioloalveolar growth pattern. The difference between these tumors was not their histology but rather the extent of their growth. Nevertheless, the tumors showed the same bronchioloalveolar growth pattern that we know today. In the 50 years following the above descriptions, a myriad of publications7–15 describing similar tumors were presented in the literature. Despite appearing under various diverse names, the most consistent factor was their lack of stromal invasion. Needless to say, in many of these cases, metastatic disease was documented. However, the main controversy in these early publications was whether the tumors were derived from the alveolar epithelium or from the terminal airway. In 1960, Liebow16 defined BAC as well-differentiated adenocarcinomas and emphasized the presence of three distinct presentations: (1) the single nodular pattern, (2) disseminated nodular pattern, and (3) diffuse pattern. In addition, he stated that this neoplasm is capable of invading other structures within the lung or even outside of the lung parenchyma. In the recent proposal for a change in the nomenclature,2 it is evident that the main focus is on the single nodule pattern and not on the other types, even though the histology can be similar in all those tumors.
Pathological features As stated before, the morphological features of these tumors are similar irrespective of solitary, disseminated, or diffuse growth. For the purpose of this discussion, however, only the single nodule pattern will be discussed as this appears to be the pattern for which the change in terminology has been suggested. The macroscopic findings of this tumor are those of a solitary pulmonary nodule that cannot measure more than 3 cm in greatest dimension. Histologically, the tumor is characterized by growth along the alveolar walls, which can be partially or completely replaced by a low cuboidal or cylindrical epithelium (Fig. 1A). The cells have oval or round nuclei, which may show inconspicuous or prominent nucleoli (Fig. 1B). Even though mitotic activity is not prominent, rare mitotic figures can be seen in some cases. By definition, the tumor should not show any stromal, pleural, lymphatic, or nodal invasion.
Discussion The controversy on BAC is nothing new as this entity has been debated for decades. There have been many studies in the literature with different points of view as well as different findings, which unfortunately have generated even more controversy on this subject.7–23 Since the occurrence of metastatic disease to the lung with a bronchioloalveolar
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Fig. 1 – (A) Adenocarcinoma with bronchioloalveolar growth pattern showing tumor cell growth along the alveolar walls. (B) High-power view of adenocarcinoma with bronchioloalveolar growth pattern. The alveolar walls are lined by cuboidal epithelium showing prominent hobnailing. growth pattern has been described, it has been argued that BAC represents a growth pattern rather than a true entity. In a report of 30 cases of BAC, Bennett and Sasser22 stated that there is no morphological, histogenetic, or clinical basis to separate BAC from conventional adenocarcinoma. In a reappraisal of BAC, Delarue et al.23 insisted on the validity of the entity and outlined some criteria for its diagnosis, which are fairly similar to the ones currently offered by the proponents of the “new” classification,2 namely an absence of stromal invasion. Nevertheless, it was also stated that metastatic disease and malignant pleural effusion might occur. In addition, some authors have attempted to correlate different histopathological features of BAC with survival rate. Manning et al.24 separated these tumors into mucinous and nonmucinous types, concluding that non-mucinous BAC has a 5-year survival rate of 72%. Needless to say, the number of reports dealing with this entity is vast, and their results are controversial. One of the main issues with this subject is that some studies have included tumors not only of the solitary type but also those with disseminated or diffuse growth
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patterns. Thus, it is very difficult to draw valid conclusions from those publications. In the more recent literature on this subject, Rena et al.25 presented a study of 28 patients with stage I BAC with a 5-year disease-free survival rate of 81%. However, the main issue with this report lies in the fact that many cases were diagnosed by cytology, casting some doubt as to the true histology of the tumors. Finally, Ebright et al.26 concluded that the most important parameters in the evaluation of BAC are the clinical features and pathologic staging of these tumors rather than histological assessment. In 2006, Travis et al.4 presented a review of BAC stating that there is existing evidence that patients with solitary small peripheral BAC have 100% survival at 5 years and claiming that the basis for the proposed “new” classification of BAC derives from that experience.27 The study that forms the basis for this proposal involved 236 cases of resected peripheral adenocarcinomas of the lung less than 2 cm in greatest diameter.27 The authors separated different types of adenocarcinomas into categories ranging from A to F, with 28 of the ones designated as types A and B representing the localized form of BAC; however, on closer examination of the article, the authors account for a total of 34 of these tumors, with some of these showing not only lymphatic but also pleural invasion, thus disqualifying these tumors as BAC according to the 2004 WHO schema. More important, by describing small tumors (r2 cm) with BAC growth pattern, the authors have acknowledged that these tumors have the potential to show lymphatic invasion and pleural involvement. In the recent proposal for the “new” classification of adenocarcinoma, which introduced the terms AIS and MIA, the authors claimed to have reviewed 312 selected references of 11 thousand citations.2 Of these, the authors based their suggested name change on approximately a dozen publications on the subject of “small adenocarcinomas” or BAC.28–37 Interestingly, critical review of those publications identified tumors that ranged in size from 0.2 cm to 3 cm in greatest diameter with the majority of these measuring less than 2 cm in diameter. More important is the fact that none of those publications specifically stated how many tumors were smaller or larger than 0.5 cm, this being the current size limit for calling lesions atypical adenomatous hyperplasia (AAH) versus BAC. Perhaps even more intriguing about the recent proposal is the lack of any attempt to critically compare all pulmonary adenocarcinomas in terms of survival rate to determine whether the suggested change in the nomenclature is warranted. Regardless of the histological grade of the tumor, a T1N0M0 adenocarcinoma of the lung is treated by complete surgical resection; thus, the emphasis should be placed not on the histology of the tumor but on tumor staging at the time of diagnosis. Staging is the single most important factor that determines the need for additional medical treatment leaving histological subtyping of adenocarcinomas secondary and not particularly critical in decisions regarding additional treatment. If one is to argue that histology plays an important role in determining outcome for these patients, then a comparative study of these tumors is needed. A recent study of 104 cases of T1N0M0 adenocarcinoma from a single institution attempted to determine whether there was a statistically significant difference between tumors with pure bronchioloalveolar growth pattern and so-called
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conventional adenocarcinomas.38 The initial results showed that associated malignancies, not surprisingly, had a significant impact on patient survival. In patients without an additional malignancy, the tumors were separated by grade into well, moderately, and poorly differentiated tumors, a distinction that showed no statistical differences in survival. Further analysis separated tumors based on their bronchioloalveolar component (o25%, 25–50%, and 450%), and once again, no statistically significant difference was noted when compared to conventional adenocarcinomas (Fig. 2A). Finally, the tumors were separated into pure bronchioloalveolar growth (BAC) versus other types, and again, the results failed to show any statistically significant survival difference (Fig. 2B). There was merely a trend toward better outcome in tumors with a BAC component (Fig. 2C). Thus, if all T1N0M0 adenocarcinomas show similar survival rates the question as to what is to be gained from re-naming BAC must be asked. Perhaps, the true AIS reflects what currently is labeled “atypical adenomatous hyperplasia” and which represents a lesion with bronchioloalveolar growth pattern but a size r0.5 cm in greatest dimension. Another interesting fact is that in that same study, none of the 104 cases was classified as MIA casting doubt on the usefulness of such a category. Based on the current literature, we contend that the suggested change in terminology of lung adenocarcinoma is premature. In addition, it may send a false sense of security to the treating physicians as the term AIS can easily be taken out of context, and patients may end up not being fully staged, which would be a disservice to the patient and potentially dangerous. In that regard, studies of small adenocarcinomas have documented metastatic disease to lymph nodes in as many as 22% of patients.39,40 Hence, the treatment of patients with small adenocarcinomas should not be based on the histological features of the tumor but rather on the stage of the disease at the time of diagnosis. Basing treatment decisions on changes in nomenclature such as AIS may be misleading. We suggest that the diagnosis of adenocarcinoma should include not only the grade of the tumor and the pattern of growth but also the presence of tumor spread or the lack thereof. We therefore suggest the following terminology for adenocarcinomas with a bronchioloalveolar component:
Fig. 2 – (A) Kaplan–Meier survival curves comparing tumors with a bronchioloalveolar pattern when divided by the percentage of the bronchioloalveolar component (o25%, 25– 50%, and 450%). (B) Kaplan–Meier curve for tumors with a pure bronchioloalveolar pattern (proposed “in situ adenocarcinoma”). (C) Survival curves comparing tumors with any bronchioloalveolar component to those without. (Reproduced with permission from Weissferdt et al.38)
For biopsy specimens: ○ Adenocarcinoma with bronchioloalveolar growth pattern (tumors Z 0.5 cm) For surgical resections: ○ Adenocarcinoma in situ (r0.5 cm; formerly AAH) ○ Adenocarcinoma (growth pattern(s) in approximate %) ○ Size of the tumor ○ Pleural integrity ○ Lymph node status
refere nces
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