Heterozygous Men1(+/T) Knockout Mice Do Not Develop Bronchopulmonary Neuroendocrine Hyperplasia or Neoplasia but Bronchial Adenocarcinoma

Abstract

Introduction: Bronchopulmonary Neuroendocrine Neoplasms (NEN) occur in 2-7% of patients with multiple endocrine neoplasia type 1 (MEN1). Precursor lesions have been identified for MEN1-related pancreatic, duodenal, and gastric NEN. The aim of the current study using a MEN1 mouse model was to define the precursor lesions of bronchopulmonary NEN and evaluate the potential prophylactic antitumor effects of somatostatin analogues in a transgenic MEN1 mouse model.

Methods: Fifteen mice, germline heterozygous for Men1(+/T), were treated with subcutaneous injections of lanreotide autogel (Somatuline Autogel^®, IPSEN Pharma), while 15 mice were treated with subcutaneous injections of physiologic sodium chloride as the control group. Five mice from each group were euthanized after 12, 15, and 18 months, respectively. The complete lungs were resected and evaluated after hematoxylin and eosin staining and immunohistochemistry for synaptophysin and chromogranin A.

Results: In the lungs of the 30 evaluated mice, whether treated or placebo treated, no bronchopulmonary neuroendocrine cell hyperplasia nor neuroendocrine neoplasia was detected through histopathology. However, pulmonary adenocarcinoma developed in 2 (13%) of the 15 untreated mice and in 1 (7%) of the 15 lanreotide-treated mice.

Conclusions: Heterozygous Men1(+/T) knockout mice do not develop bronchopulmonary NEN or precursor lesions, but pulmonary adenocarcinoma. This surprising result needs to be investigated in more detail.

Keywords: MEN1; bronchial adenocarcinoma; bronchial neuroendocrine neoplasia; multiple endocrine neoplasia.

Figure 1

General histopathological findings: Hematoxylin and Eosin staining of a section from the lung of a 12-month-old mouse at 10× magnification shows lymphocytic infiltration around the bronchi (#) and bronchioles (*) (A) as well as rarefication of alveolar septa (B), indicative of chronic bronchitis and emphysema. Hemosiderin deposits among smooth muscle cells of the bronchial walls (arrows) as seen on slides with immunostaining for Chromogranin A (C) could be distinguished from immunostaining by the pattern of distribution and by Prussian blue staining ((D), 40×)).

Figure 2

Adenocarcinoma of a 15-month-old placebo-treated mouse at 10× magnification. Hematoxylin and Eosin staining (A) shows typical acinar and papillary morphology. Immunohistochemistry showed no expression of Chromogranin A (B) or Synaptophysin (C), which was strongly expressed in the islets of Langerhans in a pancreatic on-slide control of the same mouse (D).