DIPNECH: pragmatic approach, uncertainties, notable associations, and a proposal for an improved definition

Abstract

DIPNECH is an increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course, and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mTOR inhibitors are most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms “diffuse” and “idiopathic”. We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: A Blanked Out Pulmonary Neuroendocrine Tumor

“…This allows for a comprehensive approach to managing the disease, addressing symptoms, and monitoring for potential progression to carcinoid tumors or other complications. Regular follow-up visits, imaging studies, and pulmonary function tests are typically recommended to monitor disease progression and response to treatment [ 5 , 6 ]. The available evidence for the management of DIPNECH is limited to case reports, case series, and retrospective studies.…”

A Rare Case of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: A Case Report

“…When the symptoms require pharmacological intervention, the initial approach involves the initiation of inhaled beta-2 agonists (80%), inhaled corticosteroids (49%), antitussive agents, and systemic steroids(49%) [9]. In some studies, systemic corticosteroids are discouraged due to their ineffectiveness and significant toxicity [15]. If symptoms persist despite these interventions, the possibility of conducting a trial with somatostatin analogs (SSAs) may be considered.…”

“…Nonetheless, considering their notable toxicity, including pulmonary effects, some studies suggest that initiating mTOR inhibitors solely for relieving respiratory symptoms may not be advisable. Instead, it is preferable to reserve their use for DIPNECH patients facing progressive respiratory failure [15].…”

Survival outcomes for lung neuroendocrine tumors in California differ by sociodemographic factors

“…The contribution of chronic inflammation, underlying pulmonary conditions like asthma or chronic obstructive pulmonary disease, or environmental factors like smoking are poorly understood. Some patients develop diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to lung NETs but not a majority ( Samhouri et al 2023 ). Both the underlying mechanisms driving NET pathogenesis and clinical outcomes may vary by case.…”