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Toxicologic Pathology
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Pulmonary Neuroendocrine Cell Hyperplasia: Identification, Diagnostic Criteria and Incidence in Untreated Ageing Rats of Different Strains

Richard Haworth1, Jennie Woodfine1, Sean McCawley1, Andrew M. Pilling2, David J. Lewis1 and Tom C. Williams1

1 Department of Pathology, Safety Asssessment, GlaxoSmithKline Research and Development Ltd, Herts SG12 0DP, United Kingdom
2 Pathology Department, Huntingdon Life Sciences, Cambridgeshire PE28 4HS, United Kingdom

Correspondence: Address correspondence to: Richard Haworth, Department of Pathology, Safety Assessment, GlaxoSmithKline Research and Development Ltd., Park Road, Ware, Herts SG12 0DP, United Kingdom. e-mail:richard.i.haworth{at}gsk.com

Pulmonary Neuroendocrine Cells (PNEC) are found as clusters called neuroepithelial bodies (NEB) or as single cells scattered in the respiratory epithelium. Pulmonary neuroendocrine cell hyperplasia is recorded in humans and experimentally manipulated rodents. The objectives of this work were to identify the optimal immunohistochemical markers for PNEC in the rat for use on paraffin-embedded, formalin-fixed material and to provide the first comparative incidence of PNEC hyperplasia in untreated 2-year-old rats of different strains. Calcitonin-gene related peptide (CGRP) and protein G product 9.5 (PGP9.5) antibodies identified PNEC consistently and selectively. In contrast, PNEC did not express chromogranin-A or S-100. PNEC hyperplasia was defined as foci of PNEC with greater than 40 nuclei, excluding overlying respiratory epithelium and submucosal PNEC. PNEC hyperplasia was observed at low incidence (0–7%) in untreated 2-year-old Sprague-Dawley, Han Wistar and Wistar rats but not Fischer 344 rats. This is the first report of spontaneous PNEC hyperplasia in rats. The cause of this hyperplasia is unknown, but experimental models that induce PNEC hyperplasia by causing bronchiolar cell injury are discussed. PNEC neoplasia in the rat is unreported in the literature and was not observed in animals examined in this study.

Key Words: Rat • neuroepithelial bodies • immunohistochemistry • hyperplasia • pulmonary • neuroendocrine cells • PNEC

Abbreviations: CGRP, calcitonin gene-related peptide • GRP, gastrin-releasing peptide • IHC, immunohistochemistry • NEB, neuroepithelial bodies • NSCLC-NE, non-SCLC with neuroendocrine features • PGP9.5, protein gene product 9.5 • PNEC, pulmonary neuroendocrine cells • SCLC, small-cell lung cancer

Toxicologic Pathology, Vol. 35, No. 5, 735-740 (2007)
DOI: 10.1080/01926230701460000
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