We have adopted subtyping adenocarcinoma routinely as part of the examination of lung resections along the lines suggested in the recent "comprehensive histologic subtyping" article by Motoi et al. (Am J Surg Pathol 2008;32:810-827). A recent case exposed an unexpected issue with such subtyping. The primary tumor measured 8.0 cm and appeared to show an exclusively solid pattern (6 blocks of tumor submitted):
Final stage was IIIA (T3N2). The primary tumor is EGFR wild-type but showed the KRAS mutation Gly12Cys. The case demonstrates a significant morphological discrepancy in histological subtypes between the primary tumor and lymph node metastases. What is the significance of this? What does this phenomenon suggest about the relationship between the primary tumor and its metastases?
A key question in lung adenocarcinoma currently is the association between histological subtypes and outcomes and mutational profiles.
I call your attention to the timely and thoughtful editorial by Dr. Sanja Dacic from UPMC, Pittsburgh published in last month's Archives of Pathology and Laboratory Medicine which touches on the issues and problems concerning adenocarcinoma subtyping. Dr. Dacic's own excellent study published in Modern Pathology last year showed a large morphologic overlap between tumors with/without KRAS and EGFR mutations. I found this to be an especially provocative quote:
At this point, there are not enough data to prove an independent prognostic significance of detailed histologic subtyping, and it is uncertain whether histologic subtype of adenocarcinoma is an independent predictor of therapy response.
On the research side, I have been retrospectively annotating our cases in several large databases at Rush University Medical Center. One critical issue in archival specimens is sampling--there is a wide range in the number of sections taken of tumor. I think it reasonable (and practical) to entirely submit T1 tumors for histological exam. But currently, there are no guidelines or protocols (or even suggestions!) for what constitutes adequate sampling to be "representative" of tumors in the T2-T3 categories. The Motoi study only included 101 cases and included stage I to III cases. Of note, cases were selected on the basis of available frozen tumor not as part of a consecutive series (!). The range of H&E stained slides reviewed was 1 to 23 with a average of 6.8.
From the clinician's and patient's points-of-view, adenocarcinoma subtype is meaningful if it provides some prognostic and predictive information. The data are just not out there right now that subtyping provides this. So should we bother? Long enough post for a Friday afternoon--I'll give my answer next week.