Continuing with the last post, Chilosi and Murer in the January 2010 Arch Pathol Lab Med also argue for the need of a new classification of mixed adenocarcinoma of the lung based on morphology, immunophenotyping, and molecular features.
Chilosi M, Murer B. Mixed adenocarcinoma of the lung: place in new proposals in classification, mandatory for target therapy. Arch Pathol Lab Med 2010;134:55-65.
Currently, we do not know the clinical relevance of distinguishing between different subtypes of ACa--let alone the significance of assigning percentages of different recognizable subtypes. And the latter is of much more practical significance since 80% or so of lung ACa are "mixed." The article by Okudela et al previously posted could be helpful in reproducibly recognizing these different pattern-clusters but still doesn't answer the problem of the mixed type. Moreover, we know that not only are the EGFR mutations associated with response to TKIs differentially distributed amongst histological types, but survival differences are also seen by histologic type in patients treated with pemetrexed-based therapy.
The authors' argument that "the morphologic characterization of adenocarcinoma" (using the current WHO classification) "does not adequately address the new clinical needs" may be true but it would be more accurate to say that it is unknown. I have to agree with the authors that the diagnostic relevance of the "mixed" is questionable and that the mixed category is a wastebasket. It is a relatively easy to "pick off" and publish small series of pure but uncommon well-characterized subtype of lung ACa.
But what is desperately needed in this field is to carefully define the different histologic patterns of lung ACa, construct a protocol for examining resected tumors, systematically apply defined patterns to the examination of mixed ACa, use image analysis to accurately calculate percentages of different patterns, systematically examine mixed ACa with an IHC panel and correlate various percentages of patterns with IHC marker expression, EGFR/KRAS/ALK mutations, and traditional clinicopathologic factors. Only then, we could go back and look at reproducibility between pathologists, the applicability of subtyping in small biopsy specimens, the sensitivity/specificity/PPV/NPV of various IHC markers, etc.
One thing that Chilosi and Murer have contributed to the field in this paper is calling attention to lung ACa expressing "intestinal" markers, such as, cdx-2, CK20, villin, and MUC2, in contrast to the morphologically recognized "intestinal-type" adenocarcinoma characterized by enteric differentiation. This leads to the most interesting part of their paper discussing the heterogeneity of lung ACa in relation to the stem cell theory of cancer development.
Here they contrast the different maintenance and renewal strategies between bronchial and bronchiolar epithelium (key:basal cells) versus distal lung epithelium (type 2 pneumocytes) and relate these strategies to carcinogenesis of different histologic types. This section alone is worth reading.