Pulmonary adenocarcinoma Issues, Issues and more issues. Why the - - PDF document

Pulmonary adenocarcinoma – Issues, Issues and more issues. Why the headache? Alain Borczuk In this talk, I will try to focus on three issues in pulmonary adenocarcinoma – classification, multiple nodules, and invasive size determination. Lung cancer classification has been expanded in lung adenocarcinoma to a greater extent than in other

• histologies. This is in part due to the recognition that radiologic ground glass lesions that correspond to

adenocarcinoma in situ, progress through stages of increasing invasion and in doing so increase their malignant potential. This sequence is best established for non-mucinous tumors. The radiologist encounters these nodules is ground glass opacities or ground glass nodules. Even before we discuss pathology, this has been ground breaking has many of these ground glass nodules are followed with watchful waiting rather than resection, establishing an active surveillance program in addition to a screening program in lung cancer. The ground glass nodule when in fact a carcinoma has a high degree of correlation with a lepidic pattern of growth. The gross pathology of a pure lepidic tumor

• r adenocarcinoma in situ is challenging as these lesions are often indistinct especially when the

specimen is fresh and received for frozen section. While the gross appearance does vary most challenging are such lesions without fibrosis or umbilication whose color blends in with adjacent lung but is seen mainly because of its lack of collapse relative to the rest of the lung. Histologically alveolar architecture is seen throughout the lesion but even at low magnification it can be recognized that the lining of the spaces consists of uniform type II pneumocytes which are cuboidal an enlarged. While there are airspaces to the center of the lesion and recognition of alveolar architecture in the walls of these alveoli, the alveolar walls are often thickened relative to normal alveolar walls. However the cells lining the spaces are cuboidal and would not be described as columnar; in addition stratification is generally lacking. When inflammation obscures a lesion it can be difficult to recognize an adenocarcinoma in situ and also when these cells line altered architecture such as that of emphysema, broken septal structures can resemble papillae. Minimally invasive adenocarcinoma is defined as an early invasive lesion in the background of a lepidic pattern but in which the invasive size is less than or equal to 5 mm. The radiologist may also call these ground glass nodules but may suggest that there is an emerging solid component or semisolid component spanning a few millimeters. Here again the correlation while reasonable is not perfect. When a biopsy is obtained from such a lesion, the lepidic pattern is often the predominant one but

• ccasionally there can be foci of invasion in the core. However since this is a small sample of a larger

lesion, the term lepidic pattern adenocarcinoma can be used rather than a commitment of adenocarcinoma in situ or minimally invasive adenocarcinoma. In well correlated cases, the gross appearance can suggest an area of central fibrosis corresponding to the solid area seen radiologically. A section and demonstrate the solid areas and are generally the area of invasion as in this example showing a lepidic pattern in the background of the zone of transition and an invasive tumor with a solid pattern. When invasion exceeds 5 mm in the tumor that is predominantly lepidic, the term lepidic predominant adenocarcinoma should be used. However this is the lesion in which invasive size rather than growth size becomes the focus which we will discuss later. In this case a radiologic ground glass nodule had a subtle gross appearance with perhaps a slightly greater area of density on cut surface. Sections reveal a

lipidic predominant tumor with airspaces and retained alveolar architecture with the exception of one 8mm area in which is a transition from that lepidic pattern to one of an acinar invasive pattern. It is of note that is and morphologic change in the cells in this transition from a more cuboidal population to a clearly low columnar somewhat stratified polygonal and more atypical cellular population. The remaining patterns of lung adenocarcinoma that are commonly encountered are acinar, papillary, micropapillary and solid. Solid patterns may have demonstrable mucin. These patterns are relatively reproducible and among several observers for routine case typical patterns showed a reasonable kappa value of 0.77. Interestingly solid and lepidic were the most easily recognized, while papillary versus micropapillary was the most challenging. Why enumerate these invasive patterns? There may be some molecular correlates to some patterns, and predominant patterns have been shown to have some prognostic significance. In multiple nodules unusual patterns may be evidence for metastasis rather than synchronous primaries. This an example study in which survival was linked to predominant pattern with solid and micropapillary having the worst outcome. A summary of studies in this case with varying stages at presentation show high overall survival for AIS and MIA, a reduction in overall survival for lepidic pattern adenocarcinoma with further reduction are acinar solid and then solid and micropapillary. While it is recommended that all patterns be mentioned within this estimated percentage involvement, the role of secondary patterns remains limited to micropapillary and recurrence in limited resections in which margins are less than a centimeter. The next topic of multiple nodules has become of greater headache for pathologists as both screening and longer survival in patients has led to the question of metastasis versus synchronous or metachronous primary. Once data was established for these situations it became clear that survival is better than expected in patients with multiple nodules and as a result synchronous primary and metachronous primary is more common than was initially thought. AJCC 8th edition staging developed quite a bit of space for this topic. In the table are the several situations in which we encounter multiple nodules. The 1st situation as multiple primaries can be determined by different histologies, the presence of an in situ component, excluding pneumonic type, and the overlay of molecular alterations. Examples are provided that show distinctly different nodules with different histologies, different histologies with different molecular alterations, but also raising the problem of similar patterns that just have different morphologic features which are harder to integrate into the analysis. However the conclusion is that these are unrelated tumors and should not be staged as metastatic lesions. The 2nd situation are multiple ground glass lesions. In this example, this patient has had multiple ground glass nodules over years, and when removed these have represented synchronous and metachronous adenocarcinomas without nodal metastasis. Each nodule can be assessed and given a

• histology. Using AJCC 8th edition, these are synchronous primary tumors by definition and should be T.

Staged based upon the high staged achieved in the individual lesion. Conceptually this represents similar-appearing tumors based upon the presence of an in situ component not similar-appearing tumors therefore metastatic. In this case molecular findings also corroborated the independent and separate primary tumor finding.

The 3rd situation, pneumonic type adenocarcinoma, is considered a single tumor with multi-lobar

• involvement. In contrast to the tumor that crosses the fissure by direct invasion, this is considered T3,

T4 or M1 depending on the distribution of the tumor. These tumors tend to be either mucinous or when nonmucinous, these are not lepidic. I am going to conclude with a discussion of invasive size in the setting of staging. One of the main changes in AJCC 8th edition is stratification based on size. These new strata are additionally modified to represent only invasive size. However this measurement can be very challenging. It is imperative that we pay attention to the grossing of these tumors in order to get accurate measuring. Invasive cancers

• ften have a central umbilication which corresponds to the invasion. In taking sections from such

tumors it is imperative that we do not transect the area of invasion, or if we do we do so in a way that the longest dimension is represented. If you go back to the minimally invasive example from earlier sections that highlight the full extent of the invasive component would be a good option but those that transected in a way that cannot be measured would not be. There is an example of a tumor that I recently encountered in which there was a grossly identifiable

• lesion. I find it interesting that after even a little bit of formalin fixation the lesion show up a lot better

than when they are fresh, and I believe this is largely due to the rinsing out of blood and the irregular collapse of the specimen due to formalin replacing air in the normal lung. I'm going to try to show you the steps I would take at the microscope. I would identify the areas that are lepidic and identify the areas in which is a morphologic change in both architecture and cell content that to me highlight

• invasion. I would then go to that area and with a marking pen dot around the area of putative invasion

culminating in the region in which I can take a longest linear dimension. I like this method because I find the overall correlates best with the radiology which remains a linear assessment. In lesions in which a lepidic component represents a minor degree of the entire tumor I would not correct for invasion. There has been proposed to methods to adjust for invasive size - one the linear extent method that I just showed you and the other taking the percent invasion pattern and multiplying it by the diameter of the

• tumor. In this case which is different than the prior case, I am taking you through the two methods. I

method one I have the entire tumor extent in the green circle, and I'm highlighting the area of transition at high magnification. The new green circle on the slide is my attempt to show you. The dot in method that I previously did but with a circle around the much more irregular tumor in this case which spans 1.3 cm which is the red arrow. I find the percentage approach very challenging an extremely subjective. However to make it more objective I to the area of the tumor using pixels and the area of the invasive

• component. This would come up as 13% invasion which around it up to 15% using a 5% increments

recommended by the WHO. Since the tumor was 2.8 cm grossly, this would come out to a 4.2 mm invasive size which is quite different from method one and more importantly quite different in the radiologic assessment which place the solid component at 1.2 cm. I acknowledge there are some cases in which the fragmentation of the tumor makes the percentage method the only feasible one. In summary I have taken you through the importance of classification, multiple nodules, and invasive

• size. Pulmonary adenocarcinoma remains one of the more difficult issues in pulmonary pathology, but

with each classification and staging we are getting a clearer picture of what problems need to be tackled because they are clinically significant, and which ones may in time become less important.