Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with a central and peripheral carcinoid and multiple tumorlets: a case report emphasizing the role of neuropeptide hormones and human gonadotropin-alpha.

We report a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). We performed immunohistochemical analysis of 17 neuropeptides and human gonadotropin-alpha (hCGα), a trophoblastic peptide that promotes the proliferation of neuroendocrine cells. A 51-year-old woman with no history of smoking was found to have a nodule in the right middle lobe. Upon examination, the nodule was found to comprise diffuse linear and nodular neuroendocrine cell hyperplasia (NECH), numerous pulmonary tumorlets merging with one peripheral carcinoid, and an additional central carcinoid. Immunohistochemical analysis revealed diffuse but intense expression of the general neuroendocrine markers CD56, synaptophysin, and chromogranin A, together with gastrin-releasing peptide (GRP), calcitonin, and hCGα throughout the carcinoids, tumorlets, and NECH. Positive staining was also noted for adrenocorticotropic hormone, corticotropin-releasing hormone, met-enkephalin, vasoactive intestinal polypeptide, neurotensin, and growth hormone-releasing hormone in a few isolated cells of the carcinoids and the tumorlets, but staining for these proteins was entirely negative in the NECH lesions. The presence of these neuropeptides in neuroendocrine tumors might explain the presence of neuropeptide-producing tumors of the lungs, cases of which have been reported over the last 30 years. The preoperative serum proGRP level was high but returned to normal after surgical intervention, indicating that GRP was produced and secreted by carcinoids, tumorlets, and/or NECH lesions. It is also probable that neuroendocrine cells secreted GRP into the interstitium in a paracrine manner, leading to the development of dense fibrosis around the tumorlets. During the preoperative and postoperative periods, no evidence of bronchiolitis obliterans was noted, in contrast to some previously reported cases of DIPNECH.