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

Abstract

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.

Enkephalin, its precursor, processing enzymes, and receptor as part of a local opioid network throughout the respiratory system of lung cancer patients

“…5). Importantly, we demonstrated that the majority of ENK-IR cells coexpressed DOR or CgA, a marker for neuroendocrine structures [18,19], indicating that solitary PNECs within bronchial epithelium coexpressed both DOR and its ligand ENK (Fig. 6A-H).…”

“…Our findings showed colocalization of PENK with ENK and its processing enzymes within PNECs. By use of CgA, a specific marker for neuroendocrine cells, we could clearly differentiate PNECs from other cells of the bronchial epithelium [18,19]. PNECs are part of the diffuse neuroendocrine system within the bronchial epithelium, display endocrine and paracrine secretory mechanisms, and are associated with a dense network of sensory nerve fibers (see review of Nagaki et al [34]).…”

Proliferative and Nonproliferative Lesions of the Rat and Mouse Respiratory Tract

“…In neuroendocrine cells of the larynx and trachea, serotonin could not be demonstrated, whereas in the lung, serotonin-containing cells were seen. (Adriaensen et al 2001;Boorman, Morgan, and Uraih 1990;Dungworth, Ernst, et al 1992;Dungworth et al 2001;Elizegi et al 2001;Gopinath, Prentice, and Lewis 1987;Haworth et al 2007;Karube et al 1989;Kasacka and Sawicki 2004;Kerns et al 1983;Larson et al 2004;Lauweryns and Van Ranst 1988;Lauweryns et al 1987;D. Lewis 1991;Luts et al 1991;Maronpot et al 1986;McBride et al 1990;Montuenga et al 1992;Pack, Al-Ugaily, and Morris 1981;Rehm and Kelloff 1991;Shimosegawa and Said 1991;Takahashi, Iwasaki, and Ide 1985;Van Lommel 2001;Van Lommel et al 1999) Hyperplasia with Cellular Atypia (Dysplasia): Larynx, Trachea, Bronchi, Bronchioles Pathogenesis/cell of origin: Proliferation of respiratory epithelium, or submucosal glands.…”

“…Diagnosis of a malignant tumor is based on one or more features including overall size, loss of polarity of epithelium, a high degree of atypia, increased numbers of mitoses, or invasive behavior. (Haworth et al 2007;Kasacka and Sawicki 2004;Levasseur et al 2004;Reznik, Stinson, and Ward 1980;Reznik-Schüller 1983a, 1983bRouquier and Giorgi 2007;Schüller, Gregg, and Reznik 1990;Shimosegawa and Said 1991;Trinh and Storm 2004) Hyperplasia with Atypia ( Figure 40): Nasal Cavity, Nasopharynx, Paranasal Sinus Pathogenesis/cell of origin: Hyperplastic squamous, respiratory, olfactory, or glandular epithelium. Diagnostic features:…”

The respiratory system

“…The presence of clusters of neuroendocrine cells within the respiratory or olfactory epithelium of the nasal cavity and within the lungs may be observed (Haworth et al 2007). …”