A pre-vertebrate endodermal origin of calcitonin-producing neuroendocrine cells.

Vertebrate calcitonin-producing cells (C-cells) are neuroendocrine cells that secrete the small peptide hormone calcitonin in response to elevated blood calcium levels. Whereas mouse C-cells reside within the thyroid gland and derive from pharyngeal endoderm, avian C-cells are located within ultimobranchial glands and have been reported to derive from the neural crest. We use a comparative cell lineage tracing approach in a range of vertebrate model systems to resolve the ancestral embryonic origin of vertebrate C-cells. We find, contrary to previous studies, that chick C-cells derive from pharyngeal endoderm, with neural crest-derived cells instead contributing to connective tissue intimately associated with C-cells in the ultimobranchial gland. This endodermal origin of C-cells is conserved in a ray-finned bony fish (zebrafish) and a cartilaginous fish (the little skate, Leucoraja erinacea). Furthermore, we discover putative C-cell homologs within the endodermally-derived pharyngeal epithelium of the ascidian Ciona intestinalis and the amphioxus Branchiostoma lanceolatum, two invertebrate chordates that lack neural crest cells. Our findings point to a conserved endodermal origin of C-cells across vertebrates and to a pre-vertebrate origin of this cell type along the chordate stem.

It Is Time to Get to Know the Neuroendocrine Cell Hyperplasia of Infancy.

In the two decades that have elapsed since the initial proposal of neuroendocrine cell hyperplasia of infancy (NEHI), several hundred cases have been reported and researched. However, a comprehensive analysis of research progress remains absent from the literature. The present article endeavors to evaluate the current progress of NEHI research and offer a reference for the clinical management of this condition.

Rare presence and function of neuroendocrine cells in the nasal mucosa.

There is growing evidence that neurogenic inflammation contributes to the pathophysiology of upper airway diseases, with nasal hyperreactivity (NHR) being a key symptom. The rare neuroendocrine cells (NECs) in the epithelium have been linked to the pathophysiology of bronchial and intestinal hyperreactivity, however their presence in the nasal mucosa and their potential role in NHR remains unclear. Therefore, we studied the presence of NECs in the nasal epithelium of controls, allergic rhinitis patients and chronic rhinosinusitis with nasal polyps patients, and their link to NHR. The expression of typical NECs markers, CHGA, ASCL1 and CGRP, were evaluated on gene and protein level in human samples using real-time quantitative PCR (RT-qPCR), western blot, immunohistochemistry fluorescence staining, RNA scope assay, flow cytometry and single cell RNA-sequencing. Furthermore, the change in peak nasal inspiratory flow after cold dry air provocation and visual analogue scale scores were used to evaluate NHR or disease severity, respectively. Limited gene expression of the NECs markers CHGA and ASCL1 was measured in patients with upper airway diseases and controls. Gene expression of these markers did not correlate with NHR severity nor disease severity. In vitro, CHGA and ASCL1 expression was also evaluated in primary nasal epithelial cell cultures from patients with upper airway disease and controls using RT-qPCR and western blot. Both on gene and protein level only limited CHGA and ASCL1 expression was found. Additionally, NECs were studied in nasal biopsies of patients with upper airway diseases and controls using immunohistochemistry fluorescence staining, RNA scope and flow cytometry. Unlike in ileum samples, CHGA could not be detected in nasal biopsies of patients with upper airway diseases and control subjects. Lastly, single cell RNA-sequencing of upper airway tissue could not identify a NEC cluster. In summary, in contrast to the bronchi and gut, there is only limited evidence for the presence of NECs in the nasal mucosa, and without correlation with NHR, thereby questioning the relevance of NECs in upper airway pathology.

Impact of Neuroendocrine Differentiation (NED) on Enzalutamide and Abiraterone Efficacy in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Retrospective Analysis.

Neuroendocrine differentiation (NED) represents a possible androgen receptor pathway inhibitors (ARPI) resistance mechanism in metastatic castration resistance prostate cancer (mCRPC). As mCRPC with NED has been excluded from clinical trials evaluating ARPI efficacy, this study investigates the prognostic impact of NED in mCRPC patients treated with ARPIs. Methods: We retrospectively analyzed 327 mCRPC patient data treated with Enzalutamide or Abiraterone in the first and second or successive lines of treatment. NED was assessed using prostate biopsy samples through immunohistochemical staining. Results: NED was confirmed in 32/327 (9.8%) mCRPC patients. In the overall population, mCRPC with NED showed worse PFS (4.38 vs. 11.48 months HR 2.505 [1.71-3.68] p < 0.05), disease control rate (DCR), and PSA response. In the first line setting, mCRPC with NED demonstrated worse PFS (8.5 vs. 14.9 months HR 2.13 [1.18-3.88], p < 0.05). Similarly, in the second or successive lines, mCRPC with NED showed worse PFS (4.0 vs. 7.5 months HR 2.43 [1.45-4.05] p < 0.05), DCR, PSA response and OS (12.53 vs. 18.03 months HR 1.86 [1.12-3.10] p < 0.05). The adverse impact of NED on PFS was consistence across all subgroups; we also noted a trend of worse PFS in patients with high vs. low NED. Conclusions: In our study, mCRPC with NED treated with Enzalutamide or Abiraterone showed worse clinical outcomes. NED assessment should be considered to optimize treatment decisions in the mCRPC setting.

Comprehensive analysis of single-cell transcriptomics and genetic factors reveals the mechanisms and preventive strategies for the progression from pulmonary fibrosis to lung cancer.

BACKGROUND: Pulmonary fibrosis (PF) leads to excessive deposition of fibrous connective tissue in the lungs, increasing the risk of lung cancer due to the enhanced activity of fibroblasts (FBs). Fibroblast-mediated collagen fiber deposition creates a tumor-like microenvironment, laying the foundation for tumorigenesis. Clinically, numerous cases of lung cancer induced by pulmonary fibrosis have been observed. In recent years, the study of nucleotide point mutations, which provide more detailed insights than gene expression, has made significant advancements, offering new perspectives for clinical research. METHODS: We initially employed Mendelian randomization to ascertain that the initial stage of lung cancer induced by PF belongs to small cell lung cancer (SCLC). Subsequently, pulmonary neuroendocrine cells (PNECs) were identified by using pseudo-time series analysis as cell clusters with carcinogenic potential. We categorized FBs into four groups according to their cellular metabolism, and then analyzed the cellular communication between FBs and PNECs, as well as changes in intracellular pathways of PNECs. Additionally, we examined the characteristic genome of FBs which is significantly associated with PF and investigated the impact of FBs on immune cells in the PF microenvironment. Finally, we explored strategies for preventing the progression from PF to lung cancer. RESULTS: The genetic features of cells with carcinogenic potential in PF tissues were revealed, characterized by upregulation of Achaete-Scute Family BHLH Transcription Factor 1 (ASCL1), Homeobox B2 (HOXB2), Teashirt Zinc Finger Homeobox 2 (TSHZ2), Insulinoma-associated 1 (INSM1), and reduced activity of RE1 Silencing Transcription Factor (REST). FBs characterized by high glycolysis and low tricarboxylic acid (TCA) cycling played a key role in the progression of PF. The microenvironment of PF resembles the tumor microenvironment, providing a conducive immunosuppressive environment for the occurrence of cancer cells. In dendritic cells, rs9265808 is a susceptibility locus for progression from pulmonary fibrosis to lung cancer, mutations at this locus increase the expression of Complement Factor B (CFB), and excessive activation of the complement pathway is a crucial factor leading to lung cancer development in patients with pulmonary fibrosis. Ensuring adequate nutritional supply and physical function is one of the effective measures to prevent progression from pulmonary fibrosis to lung cancer. CONCLUSION: CFB promotes lung cancer occurrence by inducing the accumulation and polarization of a large number of monocytes/macrophages in the lungs, driving disease progression by reducing the physical fitness of patients with pulmonary fibrosis.

Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer.

Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers. This was accompanied by upregulation of MHC and type I IFN and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of NE differentiation in advanced prostate cancer and provide insights into how Notch signaling influences lineage plasticity and the tumor microenvironment (TME).

Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities.

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.

MCTP1 increases the malignancy of androgen-deprived prostate cancer cells by inducing neuroendocrine differentiation and EMT.

Neuroendocrine prostate cancer (PCa) (NEPC), an aggressive subtype that is associated with poor prognosis, may arise after androgen deprivation therapy (ADT). We investigated the molecular mechanisms by which ADT induces neuroendocrine differentiation in advanced PCa. We found that transmembrane protein 1 (MCTP1), which has putative Ca2+ sensing function and multiple Ca2+-binding C2 domains, was abundant in samples from patients with advanced PCa. MCTP1 was associated with the expression of the EMT-associated transcription factors ZBTB46, FOXA2, and HIF1A. The increased abundance of MCTP1 promoted PC3 prostate cancer cell migration and neuroendocrine differentiation and was associated with SNAI1-dependent EMT in C4-2 PCa cells after ADT. ZBTB46 interacted with FOXA2 and HIF1A and increased the abundance of MCTP1 in a hypoxia-dependent manner. MCTP1 stimulated Ca2+ signaling and AKT activation to promote EMT and neuroendocrine differentiation by increasing the SNAI1-dependent expression of EMT and neuroendocrine markers, effects that were blocked by knockdown of MCTP1. These data suggest an oncogenic role for MCTP1 in the maintenance of a rare and aggressive prostate cancer subtype through its response to Ca2+ and suggest its potential as a therapeutic target.

CRACD loss induces neuroendocrine cell plasticity of lung adenocarcinoma.

Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, some lung adenocarcinoma (LUAD) cells transform into neuroendocrine (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD (capping protein inhibiting regulator of actin dynamics), a capping protein inhibitor, is frequently inactivated in cancers. CRACD knockout (KO) is sufficient to de-repress NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models, Cracd KO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed that Cracd KO-induced NE cell plasticity is associated with cell de-differentiation and stemness-related pathway activation. The single-cell transcriptomic analysis of LUAD patient tumors recapitulates that the distinct LUAD NE cell cluster expressing NE genes is co-enriched with impaired actin remodeling. This study reveals the crucial role of CRACD in restricting NE cell plasticity that induces cell de-differentiation of LUAD.

CYB561 supports the neuroendocrine phenotype in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is associated with resistance to androgen deprivation therapy, and an increase in the population of neuroendocrine (NE) differentiated cells. It is hypothesized that NE differentiated cells secrete neuropeptides that support androgen-independent tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. The cytochrome b561 (CYB561) gene, which codes for a secretory vesicle transmembrane protein, is constitutively expressed in NE cells and highly expressed in CRPC. CYB561 is involved in the α-amidation-dependent activation of neuropeptides, and contributes to regulating iron metabolism which is often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression and maintenance of the highly aggressive NE phenotype in CRPC. In our study, we found that CYB561 expression is upregulated in metastatic and NE prostate cancer (NEPC) tumors and cell lines compared to normal prostate epithelia, and that its expression is independent of androgen regulation. Knockdown of CYB561 in androgen-deprived LNCaP cells dampened NE differentiation potential and transdifferentiation-induced increase in iron levels. In NEPC PC-3 cells, depletion of CYB561 reduced the secretion of growth-promoting factors, lowered intracellular ferrous iron concentration, and mitigated the highly aggressive nature of these cells in complementary assays for cancer hallmarks. These findings demonstrate the role of CYB561 in facilitating transdifferentiation and maintenance of NE phenotype in CRPC through its involvement in neuropeptide biosynthesis and iron metabolism pathways.

Investigating pulmonary neuroendocrine cells in human respiratory diseases with airway models.

Despite accounting for only ∼0.5% of the lung epithelium, pulmonary neuroendocrine cells (PNECs) appear to play an outsized role in respiratory health and disease. Increased PNEC numbers have been reported in a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma. Moreover, PNECs are the primary cell of origin for lung neuroendocrine cancers, which account for 25% of aggressive lung cancers. Recent research has highlighted the crucial roles of PNECs in lung physiology, including in chemosensing, regeneration and immune regulation. Yet, little is known about the direct impact of PNECs on respiratory diseases. In this Review, we summarise the current associations of PNECs with lung pathologies, focusing on how new experimental disease models, such as organoids derived from human pluripotent stem cells or tissue stem cells, can help us to better understand the contribution of PNECs to respiratory diseases.

Neuroendocrine cells initiate protective upper airway reflexes.

Airway neuroendocrine (NE) cells have been proposed to serve as specialized sensory epithelial cells that modulate respiratory behavior by communicating with nearby nerve endings. However, their functional properties and physiological roles in the healthy lung, trachea, and larynx remain largely unknown. In this work, we show that murine NE cells in these compartments have distinct biophysical properties but share sensitivity to two commonly aspirated noxious stimuli, water and acid. Moreover, we found that tracheal and laryngeal NE cells protect the airways by releasing adenosine 5'-triphosphate (ATP) to activate purinoreceptive sensory neurons that initiate swallowing and expiratory reflexes. Our work uncovers the broad molecular and biophysical diversity of NE cells across the airways and reveals mechanisms by which these specialized excitable cells serve as sentinels for activating protective responses.

Three-dimensional ultrastructural and anatomical analysis of prostatic neuroendocrine cells in mice.

BACKGROUND: A few studies have examined the ultrastructure of prostatic neuroendocrine cells (NECs), and no study has focused on their ultrastructure in three dimensions. In this study, three-dimensional ultrastructural analysis of mouse prostatic NECs was performed to clarify their anatomical characteristics. METHODS: Three 13-week-old male C57BL/6 mice were deeply anesthetized, perfused with physiological saline and 2% paraformaldehyde, and then placed in 2.5% glutaraldehyde in 0.1 M cacodylate (pH 7.3) buffer for electron microscopy. After perfusion, the lower urinary tract, which included the bladder, prostate, coagulation gland, seminal vesicle, upper vas deferens, and urethra, was removed, and the specimen was cut into small cubes and subjected to postfixation and en bloc staining. Three-dimensional ultrastructural analysis was performed on NECs, the surrounding cells, tissues, and nerves using focused ion beam/scanning electron microscope tomography. RESULTS: Twenty-seven serial sections were used in the present study, and 32 mouse prostatic NECs were analyzed. Morphologically, the NECs could be classified into three types: flask, flat, and closed. Closed-shaped NECs were always adjacent to flask-shaped cells. The flask-shaped and flat NECs were in direct contact with the ductal lumen and always had microvilli at their contact points. Many of the NECs had accompanying nerves, some of which terminated on the surface in contact with the NEC. CONCLUSIONS: Three-dimensional ultrastructural analysis of mouse prostatic NECs was performed. These cells can be classified into three types based on shape. Novel findings include the presence of microvilli at their points of contact with the ductal lumen and the presence of accompanying nerves.

Molecular pathology of small cell lung cancer: Overview from studies on neuroendocrine differentiation regulated by ASCL1 and Notch signaling.

Pulmonary neuroendocrine (NE) cells are rare airway epithelial cells. The balance between Achaete-scute complex homolog 1 (ASCL1) and hairy and enhancer of split 1, one of the target molecules of the Notch signaling pathway, is crucial for NE differentiation. Small cell lung cancer (SCLC) is a highly aggressive lung tumor, characterized by rapid cell proliferation, a high metastatic potential, and the acquisition of resistance to treatment. The subtypes of SCLC are defined by the expression status of NE cell-lineage transcription factors, such as ASCL1, which roles are supported by SRY-box 2, insulinoma-associated protein 1, NK2 homeobox 1, and wingless-related integration site signaling. This network reinforces NE differentiation and may induce the characteristic morphology and chemosensitivity of SCLC. Notch signaling mediates cell-fate decisions, resulting in an NE to non-NE fate switch. The suppression of NE differentiation may change the histological type of SCLC to a non-SCLC morphology. In SCLC with NE differentiation, Notch signaling is typically inactive and genetically or epigenetically regulated. However, Notch signaling may be activated after chemotherapy, and, in concert with Yes-associated protein signaling and RE1-silencing transcription factor, suppresses NE differentiation, producing intratumor heterogeneity and chemoresistance. Accumulated information on the molecular mechanisms of SCLC will contribute to further advances in the control of this recalcitrant cancer.

Investigation of Clinical, Laboratory, Imaging Findings and Histopathological Features of Patients with Gastric Neuroendocrine Cell Hyperplasia.

BACKGROUND/AIMS: Neuroendocrine cell hyperplasia is a non-neoplastic proliferation of enterochromaffin-like cells and is considered a premalignant lesion because of their potential to progress to neuroendocrine tumor. In this study, we aimed to evaluate the demographic and clinical features, laboratory, radiological and endoscopic findings, gastric biopsy histopathological features, follow-up frequency, and histopathological findings of patients diagnosed with gastric neuroendocrine cell hyperplasia as well as to investigate the factors that play a role in the development of neuroendocrine tumors on the basis of neuroendocrine cell hyperplasia. MATERIALS AND METHODS: The study has been conducted in 2 centers with 282 patients that were grouped as those with and without neuroendocrine tumor. Individuals with control endoscopy were separated as those with regression of neuroendocrine cell hyperplasia and those without regression, and the determined parameters were evaluated between the groups. RESULTS: The most common histological subtype of neuroendocrine cell hyperplasia was linear+micronodular (50.4%). Neuroendocrine tumor developed in 4.3% (12/282) of the patients with neuroendocrine cell hyperplasia after a mean of 36 months. The presence of polyps as confirmed via endoscopy and dysplasia as confirmed via histopathological examination was significantly higher in favor of the group with neuroendocrine tumor (P = .01). In patients with neuroendocrine cell hyperplasia regressed and patients in whom it did not regress were examined, the rate of asymptomatic patients and increased sedimentation rate were found in favor of the group that did not regress (P = .02 and P = .02), but no difference was found in other parameters. CONCLUSION: Neuroendocrine tumor development rate was found to be 4.3% in the background of neuroendocrine cell hyperplasia. Two factors predicting progression from neuroendocrine cell hyperplasia to neuroendocrine tumor can be elaborated as the presence of polypoid appearance due to neuroendocrine cell hyperplasia as confirmed via endoscopy and dysplasia as confirmed via histopathological examination.

A multi-lesional analysis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a single-centre analysis.

AIM: To conduct a multi-lesional computed tomography (CT) analysis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) patients to determine volumetric changes in lesions over 5 years. MATERIALS AND METHODS: A retrospective case-note review was undertaken to identify 16 patients with histological and radiological features of DIPNECH between 2012-2021. Area and volume were calculated for 17 sets of lesions identified on high-resolution CT. Clinical data were extracted from electronic patient records, which included demographic data, outpatient clinic letters, histology reports, and imaging reports. RESULTS: One hundred and twenty-eight lesions were identified in 16 patients (one male, 15 female) and followed-up annually over a median 1,985 days (range 1,450-2,290). At year 1 follow-up, lesion area ranged from 1-48 mm2, and lesion volume ranged from 8-18,380 mm3; lesion area ranged from 1-45mm2 and lesion volume ranged from 11-17,800 mm3 and year 5. Half (8/16) of the patients had concomitant typical carcinoid tumours and one patient had an atypical carcinoid tumour. No statistically significant correlation (p<0.05) was found between lesion cross-sectional area or volume and duration of follow-up (years and days). No metastatic spread was observed at the time of analysis. CONCLUSIONS: No significant increase was observed in the size of over 100 lesions in patients with DIPNECH over a 5-year period and no metastasis occurred during the study period affirming the relatively indolent course of the disease.

Integrated analysis of single-cell and bulk transcriptomics develops a robust neuroendocrine cell-intrinsic signature to predict prostate cancer progression.

Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount significance for both research and clinical applications, yet valid NEPC biomarker remains to be defined. Methods: Leveraging 11 published NE-related gene sets, 11 single-cell RNA-sequencing (scRNA-seq) cohorts, 15 bulk transcriptomic cohorts, and 13 experimental models of prostate cancer (PCa), we employed multiple advanced algorithms to construct and validate a robust NEPC risk prediction model. Results: Through the compilation of a comprehensive scRNA-seq reference atlas (comprising a total of 210,879 single cells, including 66 tumor samples) from 9 multicenter datasets of PCa, we observed inconsistent and inefficient performance among the 11 published NE gene sets. Therefore, we developed an integrative analysis pipeline, identifying 762 high-quality NE markers. Subsequently, we derived the NE cell-intrinsic gene signature, and developed an R package named NEPAL, to predict NEPC risk scores. By applying to multiple independent validation datasets, NEPAL consistently and accurately assigned NE feature and delineated PCa progression. Intriguingly, NEPAL demonstrated predictive capabilities for prognosis and therapy responsiveness, as well as the identification of potential epigenetic drivers of NEPC. Conclusion: The present study furnishes a valuable tool for the identification of NEPC and the monitoring of PCa progression through transcriptomic profiles obtained from both bulk and single-cell sources.

Radiological-pathological correlation in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): imaging and histopathology.

AIM: To review histologically confirmed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) cases and carry out a detailed pathological-radiological correlation to see if computed tomography (CT) can be used to confidently identify DIPNECH. MATERIALS AND METHODS: Twenty-three histologically confirmed DIPNECH patients in the shared database of two NHS Trusts were reviewed. CT images were reviewed by two independent radiologists, each of them with >10 years of experience in thoracic imaging. All histological specimens were reviewed by a single pathologist with >25 years of experience. The diagnosis of DIPNECH was made according to the current World Health Organization (WHO) definition included in the WHO 2015 classification of pulmonary tumours. The results on histology were compared to the presence of nodules and air trapping on CT. Demographic information and, when available, molecular imaging studies and pulmonary function tests were also considered. RESULTS: There are prototypal clinical and radiological findings reflecting the presence of underlying histological DIPNECH: middle-aged women with multiple small and scattered nodules due to the clustering and proliferation of neuroendocrine cells. At least one larger, dominant, lung nodule reflecting a carcinoid tumour is very common and mosaic attenuation/air trapping is seen approximately in 50% of cases in inspiratory scans. Airflow obstruction is rarely associated with histological bronchial or peribronchial fibrosis, which suggests other mechanisms must be involved in its development. CONCLUSION: CT can be used to predict pathological DIPNECH in the appropriate clinical setting. It is important to consider DIPNECH to avoid overdiagnosis of more sinister conditions such as lung cancer or metastases.