Advances in Anatomic Pathology:
Well-Differentiated Adenocarcinoma—Bronchioloalveolar Carcinoma—In Situ Adenocarcinoma: A Conundrum
Weissferdt, Annikka MD, FRCPath; Kalhor, Neda MD; Moran, Cesar A. MD
Department of Pathology, M.D. Anderson Cancer Center, Houston, TX
The authors have no funding or conflicts of interest to disclose.
Reprints: Annikka Weissferdt, MD, FRCPath, Department of Pathology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: firstname.lastname@example.org).
Over the last decade, considerable changes have been made to the classification of pulmonary adenocarcinoma, mainly with respect to the classification of small solitary tumors. The main goal seems to have been the identification of tumors that not only follow an indolent clinical course but that can also be treated more conservatively. Thus, the most important change to the classification of lung adenocarcinoma was proposed for a tumor no greater than 3.0 cm in size with a pure lepidic growth pattern and lacking stromal, vascular, or pleural invasion, which should now be categorized as in situ adenocarcinoma. At the same time, a category of minimally invasive adenocarcinoma was proposed for tumors with a predominantly lepidic growth pattern, <3 cm in size, and with <5 mm invasion in greatest dimension in any 1 focus. What is interesting about all these developments is the fact that all the publications on this issue have been presented under the terms of small adenocarcinomas or bronchioloalveolar carcinoma. Unfortunately, the literature reviews that have proposed the change in nomenclature to in situ adenocarcinoma have not offered a more in-depth assessment of these neoplasms. More recently, a publication of a large series of cases of small adenocarcinomas has offered a different view and underscored some of the important issues that need to be taken into account before a serious change in the nomenclature can be considered.
More than 130 years have passed since the initial publication of Malassez1 describing a pulmonary neoplasm under the term cancer encephaloide du poumon (epithelioma) that seems to be in keeping with what has subsequently become known as bronchioloalveolar carcinoma. Twenty-five years later, Musser2 described a similar tumor under the designation of primary cancer of the lung. Judging from the illustrations provided in those publications, it is apparent that the histologies of those neoplasms shared similar features; however, it was the extension of these tumors within the lung parenchyma that was the major difference. In Malassez’ case the tumor was a multinodular lesion, whereas in Musser’s case, the tumor had a diffuse growth pattern. These 2 publications formed the basis of what Liebow3 later coined as bronchioloalveolar carcinoma. However, Liebow’s designation of the tumor was that of a well-differentiated adenocarcinoma. Furthermore, Liebow clearly defined 3 different growth patterns for this tumor: (1) the single tumor nodule pattern, (2) the multinodular pattern, and (3) the diffuse or so-called pneumonic type pattern. Nevertheless, the basic tumor distribution was essentially the same.
Although recently the main focus has been on small solitary adenocarcinomas with a lepidic growth pattern, which are believed to be the equivalent of in situ adenocarcinoma,4 a more recent publication5 on the subject of early-stage adenocarcinomas has cast some concern as to whether such designation is warranted or at least whether such a designation has any clinical significance.
After the initial descriptions by Malassez1 and Musser,2 the literature is filled with a myriad of publications on similar tumors for which the authors used different names including alveolar cell cancer, primary multiple carcinoma, diffuse lung carcinoma, alveolar carcinoma, carcinosis, carcinomatoides alveogenica multicentrica, alveolar cell tumor, pulmonary alveolar cell adenomatosis, and bronchioloalveolar carcinoma.6–15 It is important to recognize that much of the discussion in these early publications concentrated more on the origin of the neoplasm, namely whether it originated from the terminal airways or from the alveolar cells. In this context, it is important to highlight that in the majority of cases reported, the tumor was not confined to the lung proper, but invasion of pleura and lymph nodes, and even extrathoracic involvement was documented. Judging from the literature, it is difficult to unequivocally determine how many of those cases represented single tumor nodules, multinodular tumors, or had a diffuse growth pattern. Nevertheless, the histologic characteristics of the tumors described seem to be similar.
It was not until 1961 that Liebow3 coined the term bronchioloalveolar carcinoma as a well-differentiated adenocarcinoma and unified the different growth patterns that had already been described in the earlier literature. This definition remained the same until 2004 when the authors of the World Health Organization (WHO) publication on Tumours of the Lung, Pleura, Thymus and Heart16 redefined bronchioloalveolar carcinoma as a small adenocarcinoma with lepidic growth but without stromal, lymphatic, or pleural invasion. Essentially what the authors of this publication were referring to was an in situ adenocarcinoma, although this fact was not explicitly stated in the definition.
By definition, these tumors measure no more than 3 cm in greatest diameter. The tumors are well circumscribed and generally situated subpleurally. They are light brown to tan in color and do not show any necrosis or hemorrhage.
By definition, the tumor grows along the alveolar walls without involving the interstitium. In general, the tumor nodules appear well demarcated but not encapsulated. The alveolar lining is replaced by either cuboidal or cylindrical type of epithelium that lines the alveolar wall either partially or entirely and follows the normal alveolar architecture (Figs. 1A, B). The tumor cells show mild cellular atypia but mitotic figures are rare. Areas of necrosis and/or hemorrhage are not a feature of these tumors. The uninvolved lung parenchyma adjacent to the tumors does not show any particular histologic changes and most of the time is within normal limits.
The controversy surrounding the entity known as bronchioloalveolar carcinoma has generated numerous publications in which the authors have addressed differing points of view spanning from being merely a growth pattern to a specific entity and from an indolent type of tumor to a conventional adenocarcinoma. Needless to say, the many variations have brought considerable controversy to this topic.6–15
In 2004, the authors of the WHO publication on Tumours of the Lung, Pleura, Thymus and Heart,16 without alluding to the term in situ adenocarcinoma, defined bronchioloalveolar carcinoma as a small adenocarcinoma with lepidic growth but without stromal, pleural, or lymphatic invasion, which essentially left the reader to interpret such a tumor as an in situ lesion. Important to note is that the original term bronchioloalveolar carcinoma was maintained; only the definition was modified. In the wake of the WHO publication, reviews of the literature attempted to link the new definition of bronchioloalveolar carcinoma to current practice, when some authors17 suggested that solitary bronchioloalveolar carcinomas as per the new definition had a survival rate of 100% at 5 years. The basis for such an argument was provided in a publication by Noguchi et al18 studying 236 cases of peripheral adenocarcinomas. It is important to highlight that in this publication all tumors measured <2 cm in greatest diameter. It is even more important to carefully address some of the features that have largely been ignored about this particular publication: (1) of the 236 cases of peripheral adenocarcinomas, the authors separated 28 cases with a lepidic growth pattern into those with alveolar collapse and those without by dividing them into 2 groups A and B comprising 14 cases each; (2) even though in the general information it is stated that all tumors measured ≤2 cm, there is no specific information of the size for those tumors included as types A or B, and the authors only state that these lesions are “usually larger than 1 cm”; (3) scrutinizing the data more carefully, one discerns that the authors account for 34 cases with a lepidic growth pattern (not the 28 initially reported) with some of them showing pleural or vascular invasion. This clearly documents that such cases can occur in regular practice and not necessarily fulfill the requirements of the WHO definition. This seems to be the reason why these cases were excluded from the group of 28 cases finally referred to in this publication. In a different study using the WHO’s new definition of bronchioloalveolar carcinoma, Zell et al19 identified 1909 patients from the California Cancer Registry between the years 1999 and 2003 with a histologically confirmed diagnosis of bronchioloalveolar carcinoma and complete TNM staging. In this group, 33% of tumors were stage I, whereas 30% were stage II, once again demonstrating that tumors with a pure lepidic growth pattern may be encountered in stages higher than stage I. Nevertheless, the data from this study show that stage I bronchioloalveolar carcinoma have survival rates of 94% and 65% at 1 and 5 years, respectively. Such an analysis clearly contradicts not only Noguchi’s data but also that of the WHO publication. Similar data were collected by Grover and Piantadosi20 in a series of 235 cases diagnosed as pure bronchioloalveolar carcinoma between the years 1977 and 1988. The authors determined a mortality rate for stage I bronchioloalveolar carcinoma (T1N0) of 7% per year. In a more recent review on this topic,4 the authors stated that they found 312 references of 11,000, which they determined to be the basis for their suggested change in the nomenclature of adenocarcinoma. This time, in addition to Noguchi’s publication on the subject,18 the authors also included 12 additional references, one of which included the so-called minimally invasive adenocarcinoma.21–30
Critical review of these publications shows that the majority of tumors presented were of small size (<2 cm in diameter). However, it is important to highlight that in many of these reports the tumors were as small as 0.2 cm. The exact number of lesions measuring ≤0.5 cm is difficult to determine, as no specific size was provided for each of the tumors described. Therefore, it is possible that many of these tumors should not have been called bronchioloalveolar carcinoma as lesions <0.5 cm would today fall into a category which is called atypical adenomatous hyperplasia. Theoretically speaking, it would probably make some sense to reserve the term of in situ adenocarcinoma to those particular lesions that have been designated as atypical adenomatous hyperplasia.
Another vital argument is the fact that there has not been a detailed statistical analysis of tumors suggested to be in situ adenocarcinoma, which would critically compare these tumors to the conventional early-stage adenocarcinomas (T1N0M0) to determine whether the term in situ adenocarcinoma would actually be clinically relevant. In this context, it is important to underscore that the treatment of choice for T1N0M0 adenocarcinoma is complete surgical resection and staging. Furthermore, to make a diagnosis of in situ adenocarcinoma, one must not only submit the entire tumor for histologic evaluation but evaluation of lymph nodes and pleural integrity has to be undertaken for staging purposes. Thus, if the treatment of T1N0M0 will be determined by the stage of the patient’s tumor, then what is the clinical significance for the change in nomenclature? Of course, it can be argued that the clinical course of these so-called in situ adenocarcinomas is different than that of conventional early-stage adenocarcinomas. In that regard, a recent publication on the subject has raised some doubt about the clinical significance of such a change in the nomenclature.
In a recent study of 104 cases5 surgically treated at M.D. Anderson Cancer Center, the authors included all histologic types of early-stage adenocarcinoma (T1N0M0). As expected from a Cancer Center, 48 of these patients had an associated malignancy, which statistically was found to be significant for survival. However, when the remaining 56 patients without an associated malignancy were analyzed, the results were quite different. From a histopathologic point of view, when the tumors were separated by grade into well, moderately, and poorly differentiated adenocarcinomas, the statistical analysis regarding survival rate was not significant. Then, when the tumors were separated into percentages of lepidic growth (<25%; 25% to 50%; >50%), the results were not statistically significant either. Furthermore, when tumors with pure lepidic growth were separated from the rest of the tumors, the statistical analysis still did not provide any significant difference in outcome compared with other types of adenocarcinomas (Figs. 2A–C). The results outlined in this report state that univariable and multivariable statistical analyses of clinical aspects such as type of surgery, age, sex, tumor size (only tumors up to 3 cm were analyzed), and comorbidities in this group of patients did not show any significant statistical significance in reference to outcome. The only exception was found in patients in whom another associated malignancy was documented. In addition, similar univariable and multivariable statistical analyses of histologic characteristics such as tumor differentiation and percentage of lepidic component did not show any significance in reference to outcome either.
Also important to highlight are other important aspects that have been ignored or neglected by the proponents of the new nomenclature: (1) according to the proponents of the new terminology, the diagnosis of in situ adenocarcinoma is only possible when the tumors measure no more than 3 cm in greatest diameter, thus, if a tumor with similar histologic characteristics is >3 cm the term in situ adenocarcinoma seizes to exist, thus limiting such diagnosis to only small tumors; (2) it is a common occurrence that these types of tumors are multifocal. Therefore, do the authors of this new nomenclature believe that these cases would represent in situ adenocarcinomatosis? Or in contrast as has been documented extensively, would this rather represent a lepidic growth pattern of a well-differentiated adenocarcinoma? As stated by the proponents of the new classification in their latest review,4 the rationale for a change in the approach to these tumors is “the need to assist in determining patient therapy and predicting outcome.” In that case the bigger question is what their treatment proposal for early-stage adenocarcinomas of the lung would entail? It is well known that today the best treatment for small adenocarcinomas is complete surgical resection and corresponding staging. Do the proponents of this new classification suggest a change in this treatment approach? It is becoming increasingly clear that this “new approach” can be interpreted as a cosmetic change to the usage of the term bronchioloalveolar carcinoma. However, to substitute such a term for one that implies benign behavior (in situ carcinoma) may lead to unforeseen consequences for the patients and may not be the best way to advance patient care.
On the basis of the results of our analysis, a change in the nomenclature of pulmonary adenocarcinoma will not offer the clinical importance or relevance that one would expect, especially when taking into consideration that the treatment for tumors of up to 3 cm in diameter is complete surgical resection with concurrent lymph node resection for staging purposes. In contrast, as many of the current publications include lesions under 0.5 cm in size, one cannot advocate that patients with these small lesions be treated surgically and staged. However, that remains a clinical decision. In that regard, previous publications on small adenocarcinomas (tumor up to 2 cm) have shown that the rate of metastasis to lymph nodes can be as high as 22%,31,32 once again speaking in favor of proper staging as the single most important parameter in the prognosis of patients with small adenocarcinomas of the lung.
In short, it is arguable that the new proposed nomenclature for pulmonary adenocarcinoma offers statistically significant differences from the conventional nomenclature of these tumors. We consider that as of today, appropriate diagnosis is highly important, but more important is the issue of surgical staging, which is still the most important parameter to predict prognosis in this group of patients. Any change in the nomenclature should be carefully analyzed, as it may offer a false sense of security and may even have unforeseen consequences for patient care, as tumors diagnosed as in situ adenocarcinoma may not be fully surgically staged.
Hence, we suggest the following when dealing with either biopsy material or a resection specimen of pulmonary adenocarcinomas with a lepidic growth pattern:
- Biopsy material
- Adenocarcinoma with lepidic/bronchioloalveolar growth pattern (for tumors over 0.5 cm).
- Adenocarcinoma with lepidic/bronchioloalveolar growth pattern (determine the percentage of the lepidic component).
- Tumor size.
- Status of pleura integrity.
- Status of lymph nodes.
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well-differentiated adenocarcinoma; bronchioloalveolar carcinoma; in situ adenocarcinoma; lung; lepidic
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