2013 USCAP Pathologist in Training Award Winner

Jessica Munne, MD
Department of Pathology, Hospital del Mar, Parc de Salut Mar, Autonomous University of Barcelona, Spain

Abstract: Partially Differentiated Non-Small Cell Lung Carcinomas with Paradoxal Immunophenotype: A Role for Electron Microscopy in the Era of Targeted Therapy. [PDF/1.3mb]

Jessica Munne, MD; Lara Pijuan MD, PhD; Javier Gimeno, MD; Nuria Juanpere, MD; Laura Comerma, MD; Luis Magan; Mecerdes Simon; Sergi Serrano, MD, PhD; and Josep Lloreta, MD, PhD
Department of Pathology, Hospital del Mar, Parc de Salut Mar, Autonomous University of Barcelona, Spain

Background: The identification of EGFR, ALK and K-RAS mutations in some adenocarcinomas of the lung and the development of targeted drugs for these cases have increased the impact of pathological classification in non-small cell carcinomas of the lung (NSCLC). Poorly differentiated cases require the use of immunohistochemistry (IHC) for the diagnosis of adenocarcinoma, as these are the cases that are candidates for molecular testing, and eventually for targeted therapy. However, IHC may be misleading, while electron microscopy (EM) allows the easy identification of very small luminal spaces not detectable by light microscopy. The aim of this study has been to assess the value of EM in the identification of glandular phenotype in a series of poorly differentiated NSCLC with conflicting IHC findings.

Design: Eight cases of poorly differentiated NSCLC identified by bronchoscopic or core needle biopsy, and with equivocal IHC results, were selected for this retrospective preliminary study. From 1 to 5 pieces of tissue, 0.5 mm each, were retrieved from paraffin and processed for EM.

Results: The samples for EM were technically adequate and informative in all cases. Ultrastructural features of adenocarcinoma, i.e., luminal spaces with short microvilli and occasional junctional complexes, were present in 4 cases that were thus classified as poorly differentiated adenocarcinomas. Previous IHC of these cases was TTF1-/p63-, TTF1-/p63+/34BE12+, and in one case CD56+/TTF1+. This case had been initially labeled as large cell neuroendocrine carcinoma. In the remaining 4 cases, glandular differentiation was lacking. Three of them showed relatively abundant tonofilaments and occasional desmosomes and were classified as poorly differentiated squamous cell carcinomas. Their previous IHC profiles were respectively CK7+/CK5,6-/p63-/TTF1-, CK7+/CK5,6+/p63+/TTF1+, and CK7-/CK5,6-/p63-/TTF1-/34BE12-. Finally, one case did not have squamous nor glandular features and was classified as large cell carcinoma.

Conclusions: Even using small samples retrieved from paraffin, EM is an extremely sensitive and specific tool that can provide very useful information to subtype poorly differentiated NSCLC when IHC results are misleading, and even when they seem to fit. Thus, EM can have an indirect impact on therapeutic decision making in these patients. A multicentric study is currently being undertaken to further support this application of EM.