ΔNp63 (p40) and Thyroid Transcription Factor-1 Immunoreactivity on Small Biopsies or Cellblocks for Typing Non-small Cell Lung Cancer: A Novel Two-Hit,

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ΔNp63 (p40) and Thyroid Transcription Factor-1 Immunoreactivity on Small Biopsies or Cellblocks for Typing Non-small Cell Lung Cancer: A Novel Two-Hit, Sparing-Material Approach Giuseppe Pelosi, MD, MIAC, Alessandra Fabbri, MD, Fabrizio Bianchi, DSc, PhD, Patrick Maisonneuve, Eng, Giulio Rossi, MD, Mattia Barbareschi, MD, Paolo Graziano, MD, Alberto Cavazza, MD, Natasha Rekhtman, MD, PhD, Ugo Pastorino, MD, Paolo Scanagatta, MD, Mauro Papotti, MD Journal of Thoracic Oncology Volume 7, Issue 2, Pages 281-290 (February 2012) DOI: 10.1097/JTO.0b013e31823815d3 Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 A–D, Hierarchic unsupervised (A, C) and supervised (B, D) clustering analyses of 46 tumors showing a nonrandom distribution of the relevant markers in both surgical specimens (A, B) and biopsy/cellblock samples (C, D). Unsupervised analysis identified the same tumor clusters in both SS (clusters 1-SS to 3-SS) and BS (clusters 1-BS to 3-BS). Tumor clustering for conventional histology defined distinct profiles for AD (positivity or negativity for TTF1 with up to 1+ score for p40 and 1+ to 3+ for p63), which corresponded to clusters 1-SS/2-SS in SS and 1-BS/2-BS in BS, and for SQC (lack of TTF1 and 4+ to 5+ score for p40/p63), which corresponded to cluster 3-SS in SS and 3-BS in BS. ADSQC showed variable coexistence of AD- and SQC-related profiles (B, D), whereas the single case of SC was focally (1+) immunoreactive for p63 only (SS, surgical specimens; BS, biopsy/cellblock samples; AD, adenocarcinoma; SQC, squamous cell carcinoma; ADSQC, adenosquamous carcinoma; SC, sarcomatoid carcinoma). Journal of Thoracic Oncology 2012 7, 281-290DOI: (10.1097/JTO.0b013e31823815d3) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 A–C, Pairwise comparison for each marker between any two samples according to unsupervised (A) and supervised (B) hierarchical clustering analyses. High coefficients of correlation (C) were found for each marker between SS and BS (SS, surgical specimens; BS, biopsy/cell block samples; AD, adenocarcinoma; SQC, squamous cell carcinoma; ADSQC, adenosquamous carcinoma; SC, sarcomatoid carcinoma). Journal of Thoracic Oncology 2012 7, 281-290DOI: (10.1097/JTO.0b013e31823815d3) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 A, B, Mosaic plot diagrams (the more surface of varying colored rectangles, the more amount of cases in the different tumor subsets) confirmed a close and distinct relationship of the clusters with the diverse tumor categories in surgical specimens (A) and biopsies (B), (AD, adenocarcinoma; SQC, squamous cell carcinoma; ADSQC, adenosquamous carcinoma; SC, sarcomatoid carcinoma). Journal of Thoracic Oncology 2012 7, 281-290DOI: (10.1097/JTO.0b013e31823815d3) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 AUC-ROC analysis curves for each marker and relevant diagnosis are shown in both surgical specimens (A) and small biopsies (B). The high values of the areas under curve (AUC) in both types of material documented the high performance of IHC to correctly classify adenocarcinoma (heralded by TTF1, with clone 8G7G3/1 or SPT24) and squamous cell carcinoma (heralded by p40 and p63). Journal of Thoracic Oncology 2012 7, 281-290DOI: (10.1097/JTO.0b013e31823815d3) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 A–H, Representative pictures from two cases of adenocarcinoma (AD) from biopsy (A–D) or surgical (E–H) specimen. AD cells invading a fragment of bronchial mucosa as seen with hematoxylin and eosin (H&E)-stained sections (A) were also immunoreactive for TTF1 (B) and p63 (C) but not p40, except for an erratic and faint labeling of few tumor cells (D). Similarly, another sample of poorly differentiated AD with solid growth pattern (E) showed strong and diffuse immunoreactivity for both TTF1 (F) and p63 (G) but not p40 (H). Note in the panel C and D (right upper corner) and H (left lower corner) the internal positive control for p63 or p40, which are represented by the normal basal cell layer of the bronchial epithelium. Journal of Thoracic Oncology 2012 7, 281-290DOI: (10.1097/JTO.0b013e31823815d3) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 Diagnostic algorithm constructed starting from p40 for predicting diverse diagnostic combinations on surgical specimens. Of the five p40+/TTF1+ or p40+/TTF1−ADSQC, four were missed in biopsy/cellblock for the exclusive presence of the squamous (three cases) or glandular (one case) component. In ADSQC samples, TTF1 and p40 could be expressed within the same tumor cells or in mutually exclusive elements (see text for detail). Additional characterization of the two p40−/TTF1−AD for CK7, CK5/6, napsin-A, surfactant and desmocollin-3 (DSC-3) confirmed such a diagnosis, whereas the case of SC showed strong and diffuse labeling for vimentin (AD, adenocarcinoma; SQC, squamous cell carcinoma; ADSQC, adenosquamous carcinoma; SC, sarcomatoid carcinoma). Journal of Thoracic Oncology 2012 7, 281-290DOI: (10.1097/JTO.0b013e31823815d3) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions