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T1 pulmonary adenocarcinoma

Tuesday 19 August 2014

early-stage pulmonary adenocarcinoma (T1N0M0 and Stage I)

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 can be translated into improved survival rates.

Definition

In an attempt to more accurately identify tumor characteristics that may differentiate lung adenocarcinomas with better outcome, a new classification schema has been suggested in 2004 by the WHO 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 ≤5-mm invasion.

Even though at first glance these new terms appear “catchy,” their true meaning when applied to clinical practice 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.

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, a “new” proposal for the classification of lung adenocarcinoma was introduced describing similar histological characteristics as those previously presented in the WHO publication.

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.

Prognosis

The proposed IASLC/ATS/ERS classification of lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in identifying candidates for adjunctive therapy. (21252858)

In a study (21252858), three overall prognostic groups were identified:
- low grade: adenocarcinoma in situ (n=1) and minimally invasive adenocarcinoma (n=8) had 100% 5-year disease-free survival;
- intermediate grade: non-mucinous lepidic predominant (n=29), papillary predominant (n=143) and acinar predominant (n=232) with 90, 83 and 84% 5-year disease-free survival, respectively;
- high grade: invasive mucinous adenocarcinoma (n=13), colloid predominant (n=9), solid predominant (n=67) and micropapillary predominant (n=12), with 75, 71, 70 and 67%, 5-year disease-free survival, respectively (P < 0.001).

Among the clinicopathological factors, stage 1B versus 1A (P < 0.001), male sex (P < 0.008), high histological grade (P < 0.001), vascular invasion (P=0.002) and necrosis (P < 0.001) were poorer prognostic factors on univariate analysis. (21252858)

Both gross tumor size (P=0.04) and invasive tumor size adjusted by the percentage of lepidic growth (P < 0.001) were significantly associated with disease-free survival with a slightly stronger association for the latter. (21252858)

The slightly stronger association with survival for invasive size versus gross size raises the need for further studies to determine whether this adjustment in measuring tumor size could impact TNM staging for small adenocarcinomas. (21252858)

However, in a study (23542459), none of the clinical parameters of a patient population (type of surgery, age, gender, tumor size, and comorbidities) showed any statistically significant correlation with outcome, except for associated malignancies, which not surprisingly appeared to have a negative impact on survival. Statistical analyses of the histological characteristics to include tumor differentiation and the percentage of a lepidic or bronchioloalveolar component did not show any statistically significant values in terms of survival. (23542459) These results failed to show any statistically significant difference of survival between those T1N0M0 adenocarcinomas with a lepidic component and those without, thus questioning the use of terms such as "in situ" or "minimally invasive adenocarcinoma". (23542459) For these authors, the outcome for patients with T1N0M0 disease is still best determined by appopriate staging rather than by changes in the pathology nomenclature of adenocarcinoma. (23542459)

Open references

- Early-stage pulmonary adenocarcinoma (T1N0M0): a clinical, radiological, surgical, and pathological correlation of 104 cases. The MD Anderson Cancer Center Experience. Weissferdt A, Kalhor N, Marom EM, Benveniste MF, Godoy MC, Correa AM, Swisher SG, Moran CA. Mod Pathol. 2013 Aug;26(8):1065-75. doi : 10.1038/modpathol.2013.33 PMID: 23542459 [Free]

- Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, Park BJ, Rusch VW, Travis WD. Mod Pathol. 2011 May;24(5):653-64. doi : 10.1038/modpathol.2010.232 PMID: 21252858"