The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung Adi F. Gazdar, MD, Trisha K. Savage, MS, Jane.

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The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung Adi F. Gazdar, MD, Trisha K. Savage, MS, Jane E. Johnson, PhD, Anton Berns, PhD, Julien Sage, PhD, R. Ilona Linnoila, MD, David MacPherson, PhD, David G. McFadden, MD, PhD, Anna Farago, MD, PhD, Tyler Jacks, PhD, William D. Travis, MD, Elisabeth Brambilla, MD Journal of Thoracic Oncology Volume 10, Issue 4, Pages 553-564 (April 2015) DOI: 10.1097/JTO.0000000000000459 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 SCLC tumors. A and C, Berns laboratory, (p53/Rb1 double CKO); B and D, Sage laboratory, (p53/Rb/p130 triple CKO). A, Whole lung section demonstrating multiple in situ lesions arising in large airways and a few small invasive carcinomas. Bar 10 microns. B, SCLC with area of necrosis and Azzopardi effect adjacent to a focus of LCNEC. C, High power view of SCLC morphology. D, Combined SCLC carcinoma, with focal areas of poorly differentiated NSCLC. NSCLC, non–small-cell lung carcinoma; SCLC, small-cell lung carcinoma. Journal of Thoracic Oncology 2015 10, 553-564DOI: (10.1097/JTO.0000000000000459) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Metastases from SCLC. In all models examined, the metastatic tumors usually had SCLC morphology irrespective of the GEMM or the dominant pulmonary tumor phenotype. A and C, Berns laboratory, (B) Sage laboratory, (D) Jacks laboratory (p53/Rb1/Pten triple CKO). A, Extensive mediastinal spread, modest intrapulmonary tumor. B, Intrapulmonary perivascular lymphatic spread with focal invasion of BV wall. C, Metastasis to mediastinal node. D, Metastases to liver. Horizontal bars Distance in microns as indicated. SCLC, small-cell lung carcinoma; GEMM, genetically engineered mouse model; BV, blood vessel. Journal of Thoracic Oncology 2015 10, 553-564DOI: (10.1097/JTO.0000000000000459) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 LCNECs. A and B, Johnson laboratory; (C and D) Sage laboratory (both laboratories used the same p53/Rb1/p130 triple CKO). A, Intrabronchial in situ lesion with underlying invasive component. B, A lesion similar to the one illustrated in A, CGRP immunostain. Strong cytoplasmic expression of the NE cell product CGRP in both the in situ and invasive tumor components. C, High power view of LCNEC morphology. D, Both LCNEC (left field) to SCLC (right field) morphologies are present within a single lesion. SCLC, small-cell lung carcinoma; NE, neuroendocrine; LCNEC, large-cell NE cell carcinoma. Journal of Thoracic Oncology 2015 10, 553-564DOI: (10.1097/JTO.0000000000000459) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 NSCLC tumors. A and B, Johnson laboratory; (C and D) MacPherson laboratory (p53/Rb1/PTEN triple CKO). A and B, Adjacent LCNEC (left field) and NSCLC (right field) tumors in the p130 triple knockout model. CGRP immunostaining (B) is limited to the LCNEC tumor and an adjacent NEB within a bronchus separating the two tumors. C and D, In situ SCLC and adjacent invasive NSCLC-NE arising in a Ptenlox/+ triple knockout mouse. CGRP immunostaining (D) demonstrates that the NE cell marker expression is limited to the in situ SCLC component and to a NEB in the same bronchus. NSCLC, non–small-cell lung carcinoma; SCLC, small-cell lung carcinoma; NE, neuroendocrine; LCNEC, large-cell NE cell carcinoma; NSCLC-NE, NSCLC with NE features; NEB, neuroepithelial body. Journal of Thoracic Oncology 2015 10, 553-564DOI: (10.1097/JTO.0000000000000459) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 NSCLCs with expression of NE cell markers (NSCLC-NE). A and B, MacPherson Laboratory; (C and D) Linnoila laboratory (SV40/ASCL1 driven by CC10 promoter). A, Adenocarcinoma. B, Same tumor as A immunostained for CGRP expression. C and D, Poorly differentiated NSCLC immunostained for Cgrp (C) or Ascl1 (D). There is focal and variable NE marker expression in the tumor. Immunostaining of the foci of NE cell hyperplasia in adjacent bronchi show more intense and uniform expression of Ascl1. NSCLC, non–small-cell lung carcinoma; NE, neuroendocrine; NSCLC-NE, NSCLC with NE features. Journal of Thoracic Oncology 2015 10, 553-564DOI: (10.1097/JTO.0000000000000459) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions