Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) Syndrome and Carcinoid Tumors With/Without NECH

Abstract

The diagnostic criteria of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are not well defined, and DIPNECH can be mistaken for carcinoids associated with neuroendocrine cell hyperplasia (NECH). In this study, we compared clinical, radiologic, histologic, immunohistochemical, and molecular features of DIPNECH and isolated carcinoids with/without NECH. The study population included 151 cases (77 female patients and 74 male patients), 19 with DIPNECH and 132 with carcinoids with/without NECH. None of the cases displayed molecular alterations or anaplastic lymphoma kinase expression. Compared with individuals with carcinoids with/without NECH, patients with DIPNECH were more likely to be female individuals (P<0.0001), nonsmokers (P=0.021), and symptomatic, and to have an obstructive/mixed respiratory defect, peripheral location of the lesions, and air trapping (P<0.0001) on chest computed tomography, and constrictive bronchiolitis on histology (P<0.0001). Among immunohistochemical markers, DIPNECH was associated with higher expression of thyroid transcription factor-1, CD10, and gastrin-releasing peptide/bombesin-like peptide (P<0.0001). Yet, when a purely histopathologic definition of DIPNECH was applied, 40% of isolated carcinoids also met the diagnostic criteria for DIPNECH, even in the absence of symptoms and/or radiologic abnormalities. Therefore, as DIPNECH represents a distinct clinical syndrome, we suggest the term DIPNECH be limited to cases presenting with respiratory symptoms, functional and/or radiologic abnormalities, and constrictive bronchiolitis on histology.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH)

“…The current WHO definition of DIPNECH takes into account only partially the clinical, radiologic, and respiratory functional scenarios of the disease, limiting the diagnostic criteria to histology. Some authors question this concept and propose to consider DIPNECH differently from sporadic carcinoids with/without neuroendocrine hyperplasia (Mengoli et al 2018).…”

“…The epithelial nature of PNCs is highlighted by the immunoreaction for pan-cytokeratins, although the high-molecular weight cytokeratins are typically negative (Sturm et al 2003). The PNCs weakly express the thyroid transcription factor-1 and quite constantly CD10 (Mengoli et al 2018). Several works reported a variable expression of GRP, retinoblastoma protein, estrogen and progesterone receptors, calcitonin, p27, ribosomal p70S6-kinase (p70S6K), mTOR, and somatostatin receptor type 2 (SSTR2).…”

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia With Progression to Neuroendocrine Tumor

“…Its first descriptions came from incidental findings on biopsies of lung nodules, and, consequently, it was initially described as a histological entity and recognized by the World Health Organization as a premalignant disorder [1,3]. Based on accumulating evidence from case reports, DIPNECH is now considered a syndrome of unknown cause, with typical clinical, radiological, and histopathological findings [3,4].…”

“…Clinically, it has been predominantly observed in middle aged (40 to 60-years old) nonsmoking females who present with an insidious onset of exertional dyspnea, cough, or wheezing [4]. As pulmonary function tests frequently show a pure or mixed obstructive pattern, the clinical picture is usually misinterpreted as being caused by asthma or chronic obstructive pulmonary disease [2][3][4].…”

“…Neuroendocrine cell hyperplasia (NECH) can be superficial and isolated or invade the basement membrane and form tumorlets (cell aggregates <5 mm) or carcinoid tumors (if >5 mm) [1,2,4]. Histologically, DIPNECH is characterized by the presence of a variable number of tumorlets and/or carcinoid tumors [1,4]. Neuroendocrine origin is confirmed by cell expression of cluster of differentiation (CD)56, synaptophysin, and chromogranin A [3].…”