bronchioloalveolar carcinoma

Since the latest 2004 publication on lung carcinoma by the World Health Organization Committee and subsequent publications by the International Association for the Study of Lung Cancer, the introduction of terms such as “pulmonary adenocarcinoma in situ” and “minimally invasive adenocarcinoma” to replace the category of what is known as “bronchioloalveolar carcinoma.”

Over the decade 2000-2010, 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 "pulmonary in situ adenocarcinoma" (PAIS) or "minimally invasive adenocarcinoma" (MIA) for small solitary adenocarcinomas with either pure bronchioloalveolar growth (AIS) or predominant bronchioloalveolar growth and ≤5-mm invasion (MIA).

History

Historically, tumors with a bronchioloalveolar pattern have been recognized in the literature for more than a century.

In 1876, Malassez first described a pulmonary neoplasm with similar characteristics to BAC, which was followed by a report by Musser 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 publications 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, Liebow defined BAC as well-differentiated adenocarcinomas and emphasized the presence of three distinct presentations:
 (1) the single nodular pattern,
 (2) disseminated nodular pattern,
 (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 2004 proposal for a change in the nomenclature, 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.

Controversy

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.

Since the occurrence of metastatic disease to the lung with a bronchioloalveolar 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 Sasser stated that there is no morphological, histogenetic, or clinical basis to separate BAC from conventional adenocarcinoma.

In a reappraisal of BAC, Delarue et al. 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, 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. separated these tumors into mucinous BAC and non-mucinous BAC, concluding that non-mucinous BAC has a 5-year survival rate of 72%.

Some studies have included tumors not only of the solitary type but also those with disseminated or diffuse growth patterns.

Thus, it is very difficult to draw valid conclusions from those publications. In the more recent literature on this subject, Rena et al. 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. 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. 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. 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.

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 (≤2 cm) with BAC growth pattern, the authors have acknowledged that these tumors have the potential to show lymphatic invasion and pleural involvement.

In the 2004 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.

Of these, the authors based their suggested name change on approximately a dozen publications on the subject of “small adenocarcinomas” or BAC.

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 "conventional adenocarcinomas". 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 (@<@25%, 25–50%, and >50%), and once again, no statistically significant difference was noted when compared to conventional adenocarcinomas.

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.

There was merely a trend toward better outcome in tumors with a BAC component.

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 ≤0.5 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, it has been contended that the 2004 suggested change in terminology of lung adenocarcinoma is premature. For some authors, 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.

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.

It has been suggested 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.

It has been therefore suggested the following terminology for adenocarcinomas with a bronchioloalveolar component:

 For biopsy specimens:

• Adenocarcinoma with bronchioloalveolar growth pattern (tumors ≥ 0.5 cm)

 For surgical resections:

• Adenocarcinoma in situ (≤0.5 cm; formerly AAH)
• Adenocarcinoma (growth pattern(s) in approximate %)
• Size of the tumor
• Pleural integrity
• Lymph node status

Credits

 Pulmonary adenocarcinoma T1N0M0 and its classification. Weissferdt A, Walsh G, Kaiser L, Moran CA. Semin Diagn Pathol. 2014 Jul;31(4):260-4. doi : 10.1053/j.semdp.2014.06.002 PMID: 25012478

References

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