Lung Neuroendocrine Tumors: How Does Molecular Profiling Help?

PURPOSE OF REVIEW: Lung neuroendocrine tumors (NETs)-typical carcinoids and atypical carcinoids-have unique molecular alterations that are distinct from neuroendocrine carcinomas of the lung and non-small cell lung cancers. Here, we review the role of molecular profiling in the prognosis and treatment of lung NETs. RECENT FINDINGS: There have been no recently identified molecular prognostic factors for lung NETs and none that have been routinely used to guide management of patients with lung NETs. Previous findings suggest that patients with loss of chromosome 11q may have a worse prognosis along with upregulation of anti-apoptotic pathways (e.g., loss of CD44 and OTP protein expression). Lung NETs rarely harbor driver mutations commonly found in non-small cell lung cancer (NSCLC) or TP53/RB1 mutations found universally in small cell lung cancer. Lung NETs also have low tumor mutation burden and low PD-L1 expression. Everolimus, an mTOR inhibitor and the only FDA approved therapy for unresectable lung NETs, is an effective treatment but the presence of a molecular alteration in the PI3K/AKT/mTOR pathway is not known to predict treatment response. The predominant mutations in lung NETs occur in genes regulating chromatin remodeling and histone modification, with potential targeted therapies emerging in clinical trials. Lung NETs have recurring alterations in genes that regulate the epigenome. Future targeted therapy interfering with epigenetic pathways may hold promise.

An Update on the Management of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH).

OPINION STATEMENT: DIPNECH is caused by an idiopathic proliferation of pulmonary neuroendocrine cells which can lead to bronchiolitis and multifocal lung neuroendocrine tumors. Patients often present with chronic cough and dyspnea. Larger NETs may develop malignant potential. Somatostatin analogs can palliate chronic symptoms, particularly cough. Surgical resection can be considered for relatively large (e.g. >1 cm), progressive tumors.

COEXISTENCE OF PULMONARY FIBROSIS AND PROLIFERATION OF PULMONARY NEUROENDOCRINE CELLS FORMING TUMORLET.

Tumorlet is a disease rarely diagnosed in clinical practice. It is characterized by pulmonary neuroendocrine cell (PNEC) proliferation which invades the bronchiolar basement membrane and forms nodules with a diameter smaller than 5 mm. Case report: 72-year-old female patient was suffered for many years from progressive dyspnea and coughing with evidence of pulmonary fibrosis on high resolution computed tomography (HRCT). As a result of a lung biopsy, based on immunohistochemical tests, a 2 mm cluster of neuroendocrine cells (NEC) was found and it was diagnosed as tumorlet. Due to a long-term, insidious progress of the disease, as well as sex and age of the patient, the case emphasizes that differential diagnosis should include tumorlet as well as diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) as a more extensive manifestation of neuroendocrine cell proliferation in the respiratory tract.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: Imaging and Clinical Features of a Frequently Delayed Diagnosis.

OBJECTIVE. The purpose of this study was to assess features of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) on CT, clinical presentation, and delays in radiologic and clinical diagnosis in a series of 32 patients. MATERIALS AND METHODS. Medical records of patients with DIPNECH from the years 2000-2017 were obtained from an institutional data warehouse. Inclusion criteria were an available CT examination and either a pathologic diagnosis of DIPNECH or pathologic findings of multiple carcinoid tumorlets or carcinoid tumor with CT features suggesting DIPNECH. Two thoracic radiologists with 10 and 14 years of experience reviewed CT examinations and scored cases in consensus. RESULTS. All 32 patients were women, and most had never smoked (69%). The mean age at presentation was 61 years. Symptoms included chronic cough (59%) or dyspnea (28%), and the initial clinical diagnosis was asthma in 41%. DIPNECH was clinically suspected at presentation in only one case and was mentioned by the interpreting radiologist in only 31% of cases. CT characteristics included numerous nodules with a lower zone and peribronchiolar predominance, mosaic attenuation, and nodular bronchial wall thickening. Number of nodules at least 5 mm in diameter showed strong inverse correlations with the percentage predicted for both forced vital capacity and forced expiratory volume in 1 second and a moderate inverse correlation with total lung capacity percentage predicted. In cases with a follow-up CT interval of 3 years or longer, 85% of patients showed an increase in size of the largest nodule, and 70% had an increase in size in multiple nodules. CONCLUSION. Many cases of DIPNECH are originally missed or misdiagnosed by radiologists and clinicians. Awareness of the typical clinical and imaging features of DIPNECH may prompt earlier diagnosis of this condition.

Management of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: Review and a Single Center Experience.

BACKGROUND: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary condition, characterized by diffuse proliferation of neuroendocrine cells in the respiratory epithelium. DIPNECH lesions are less than 5 mm in size and are limited to the basement membrane with no invasion. There is limited information regarding epidemiology, natural history of disease progression, or the management of this rare entity. We present the experience of a center with extensive expertise in neuroendocrine disease. METHODS: A cohort of patients (N = 13) with DIPNECH treated and followed at our institution was identified. We describe the our approach to their care, our disease management and also provide a review of DIPNECH pathophysiology. RESULTS: Our patient cohort consisted of twelve females and one male with a mean age of 63 years at the time of diagnosis. Dyspnea on exertion and dry cough were the most common presenting symptoms. Two patients were under surveillance without treatment; three patients were treated with a short-acting somatostatin analog; three patients were treated with azithromycin alone; four were treated with a combination of long-acting monthly somatostatin analogs and azithromycin; one patient received a combination of long-acting somatostatin analog and everolimus. Five patients had concomitant bronchial carcinoids. CONCLUSIONS: DIPNECH is a rare pathology that can profoundly affect a patient's quality of life. Paroxysmal coughing episodes can be difficult to treat. Our limited single center experience shows encouraging response to use of somatostatin analogs, azithromycin, and everolimus in the management of debilitating DIPNECH associated symptoms.

[Pulmonary neuroendocrine tumors and preneoplasic lesions]. / Tumeurs neuroendocrines pulmonaires et lésions prénéoplasiques.

In the recently published 2015 World Health Organization (WHO) classification of tumors of the lungs, all neuroendocrine tumors of the lungs are presented for the first time in one single chapter. In this classification, high-grade small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are differentiated from intermediate grade atypical carcinoids (AC) and low-grade typical carcinoids as well as from preinvasive lesion diffuse neuroendocrine hyperplasia DIPNECH. In the 2004 WHO classification, SCLC and carcinoids each had a separate chapter and LCNEC was listed in the chapter on large cell carcinoma of the lungs. The new WHO classification also gives some recommendations for the diagnosis on small biopsies. This review describes morphological, immunohistochemical, and genomic characteristic of these tumors according to the new classification.

A case of DIPNECH presenting as usual interstitial pneumonia.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disease that is classically described as presenting with cough, dyspnea, and wheezing in non-smoker middle aged females. Pulmonary function tests commonly demonstrate an obstructive pattern and CT of chest usually reveals diffuse air trapping with mosaic pattern. We present a case of patient with DIPNECH manifesting with restrictive pattern and as usual interstitial pneumonia on imaging.

Diffuse Neuroendocrine Hyperplasia with Obliterative Bronchiolitis and Usual Interstitial Pneumonia: An Unusual "Headcheese Pattern" with Nodules.

A 74-year-old non-smoker female presented to our attention with a history of dyspnea and cough. CT scan revealed multiple areas of patchy ground glass attenuation associated to a diffuse mosaic oligoemia. Scattered bilateral subcentimetric pulmonary nodules were also present. Patient underwent a surgical lung biopsy. Specimens showed features of diffuse neuroendocrine hyperplasia, microhoneycombing, fibroblast foci. A final diagnosis of diffuse neuroendocrine hyperplasia with obliterative bronchiolitis and UIP was rendered.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia of the Lung (DIPNECH): Current Best Evidence.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is recognized as a preneoplastic condition by the World Health Organization. We reviewed our experience with 30 patients and performed a systematic review of the English literature to collect best evidence on the clinical features and disease course in 169 additional patients. Some patients presented with one or more carcinoid tumors associated with multiple small pulmonary nodules on imaging studies and showed DIPNECH as a somewhat unexpected pathologic finding. Others presented with multiple small pulmonary nodules that raised suspicion of metastatic disease on imaging. A third subset was presented with previously unexplained respiratory symptoms. In most patients, DIPNECH was associated with a good prognosis, with chronological progression into a subsequent carcinoid tumor noted in only one patient and death attributed directly to DIPNECH in only two patients. There is no best evidence to support the use of octreotide, steroids, or bronchodilators in DIPNECH patients.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH).

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pre-invasive generalized proliferation of pulmonary neuroendocrine (PNE) cells, which has been described in combination with carcinoid tumorlets, obliterative bronchiolitis, and other fibrotic lung changes. Since its first recognition as a distinct syndrome in 1992, variable clinico-pathologic features have been used to diagnose DIPNECH in small case series and case reports. We recently proposed the use of the following criteria for the pathologic diagnosis of the syndrome on lung resection specimens: the presence of multifocal neuroendocrine cell hyperplasia, as defined by the presence of 5 or more PNE cells in at least 3 separate small airways combined with 3 or more carcinoid tumorlets. At diagnosis, 53% of DIPNECH patients present with a synchronous carcinoid tumor and 24% have obliterative bronchiolitis. To our knowledge, only 1 patient has been diagnosed with a carcinoid tumor subsequent to a DIPNECH diagnosis and the syndrome is not associated with an increased incidence of high-grade neuroendocrine neoplasms. Patients have usually a stable disease and only 26% experience clinical and/or radiographic deterioration. There is no evidence that treatment with octreotide or other medications improves the prognosis of DIPNECH patients.

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

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disease characterized by the diffuse proliferation of neuroendocrine cells in the bronchial epithelium. It is considered a preinvasive precursor to carcinoid tumors and usually presents with obstructive symptoms. We present the case of a 71-year-old female, non-smoker, with a past medical history of asthma, osteoarthritis, allergic rhinitis, and hyperlipidemia who was referred to the pulmonology clinic in view of incidental chest CT findings of multiple pulmonary nodules. Physical examination and labs were unremarkable. CT of the chest showed scattered multiple noncalcified pulmonary nodules with a 10 mm dominant nodule in the inferior right middle lobe and several subcentimeter hypodensities in the left and right lobes of the lung. A PET scan confirmed the CT findings along with no abnormal hypermetabolic activity to suggest malignancy. The patient was followed up in the pulmonology clinic at six months, 12 months, and then 18 months. At 18 months owing to a slight increase in the size of the largest lung nodule, a CT-guided biopsy done was conclusive of a carcinoid. The tumor cells were positive for synaptophysin, chromogranin, insulinoma-associated protein 1 (INSM-1), and thyroid transcription factor 1 (TTF-1). The Ki-67 (Keil) index was <1%. A video-assisted thoracic surgery with right middle lobectomy along with mediastinal lymph node dissection was then done, and the patient was found to have stage pT1aN0 typical carcinoid tumor (1.0 cm), with multiple carcinoid tumors and neuroendocrine hyperplasia, consistent with DIPNECH. She has been under clinical follow-up for over three years at present and continues to be asymptomatic with complete remission following surgery. DIPNECH primarily affects middle-aged, non-smoking females who present with cough and dyspnea, and diagnosis is often delayed due to clinical features overlapping with those of obstructive lung disease. Imaging shows lung nodules, ground-glass opacities, and/or mosaic attenuation. Due to the rarity of the conditions, there are no established clinical trials, and therefore, there is a need to establish guidelines.

Rare Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) Finding in a 9/11 World Trade Center Survivor: A Case Report.

Bronchial carcinoid tumors represent a relatively uncommon category within lung neoplasms, originating from neuroendocrine cells. The exact cause of these pulmonary tumors remains not fully understood. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterized by widespread hyperplasia of these neuroendocrine cells, essential for regulating air and blood flow in response to stimuli such as hypoxia, dyspnea, and chronic obstructive pulmonary disease (COPD). The prognosis for bronchial carcinoid tumors hinges on factors such as grade and stage, with lung resection being the preferred treatment. A chest computed tomography (CT) scan unveiled diffuse bilateral pulmonary nodules with ground-glass opacities, leading to a right video-assisted thoracoscopic surgery (VATS) wedge resection. Immunohistochemical examination confirmed neuroendocrine differentiation, describing a lung wedge measuring 9 × 4 × 1.5 cm with spongy parenchyma and scattered white nodules.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognized entity-a report of two cases.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary disorder that is classified as a pre-invasive lesion. It can also be present in association with chronic lung diseases. We present two cases of DIPNECH, which were picked up incidentally only on histopathology. A 29-year-old male presented with a history of longstanding cough with expectoration. A computed tomography (CT) scan showed bronchiectasis in the left lung. Histopathological evaluation of the pneumonectomy specimen revealed nests of proliferating, non-infiltrating neuroendocrine cells. Our second patient was a 38-year-old female with chronic cough and expectoration with recent exacerbation. CT scan showed cystic bronchiectasis in the left lower lobe; hence, a lobectomy was performed. On histopathology, nests of non-infiltrating neuroendocrine cells were noted. A diagnosis of DIPNECH with bronchiectasis was offered to both patients, and they have been on follow-up ever since. DIPNECH is a diagnostic and therapeutic quandary requiring a high index of suspicion for its detection and effective surveillance.

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

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is 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 mechanistic target of rapamycin inhibitors are the 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 (DIPNECH): An Underrecognized Cause of Multiple Lung Nodules and Mosaic Perfusion Pattern.

Teaching Point: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is an underrecognized and misdiagnosed cause of multiple lung nodules in combination with mosaic attenuation.

A multidisciplinary approach to the work up and management of pulmonary carcinoid tumors and DIPNECH: a narrative review.

Background and Objective: Low and intermediate grade neuroendocrine tumors of the lung are uncommon malignancies representing 2% of all lung cancers. These are termed typical and atypical pulmonary carcinoid tumors. These can arise in the setting of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). The presentation, workup, management and outcomes of patients with these tumors can overlap with more common lung cancers but differ in that many of these patients have a prolonged clinical course. The objective of this narrative review is to summarize the literature and provide evidence and expert-based algorithms for work up and treatment of pulmonary carcinoids and DIPNECH. Methods: A search of PubMed and Web of Science databases ending April 15, 2022, with the following keywords "lung carcinoid", "DIPNECH", "lung neuroendocrine," and "bronchopulmonary carcinoid". Key Content and Findings: Pulmonary carcinoid tumors benefit from a multidisciplinary approach. Pre-treatment imaging with contrast-enhanced computed tomography, and DOTATATE positron emission tomography is required. Surgical resection is the gold standard for curative intent, and possibly including sublobar resections. Patients can recur or develop new primaries thus emphasizing the importance of surveillance; national guidelines recommend at least a 10-year follow up. A growing body of literature support the use of endobronchial therapy, with long responses documented. Systemic therapy consists of everolimus, somatostatin analogs, peptide receptor radionuclide therapy, and chemotherapy. Diffuse idiopathic pulmonary neuroendocrine tumor cell hyperplasia is rare, but series suggest somatostatin analogs may confer clinical benefit. Conclusions: Pulmonary carcinoid tumors and DIPNECH are rare. Despite lack of regulatory approvals for advanced disease, multiple options are available but should be sequenced according to the clinical status and disease biology. Each patient should be discussed in a multidisciplinary setting and clinical trials should be considered if available.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): Prevalence, clinicopathological characteristics and survival outcome in a cohort of 311 patients with well-differentiated lung neuroendocrine tumours.

INTRODUCTION: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is considered to be a rare condition associated with lung neuroendocrine tumours (NET), and its natural history is poorly described. We aimed to assess the prevalence and clinicopathologic characteristics of DIPNECH in the lung NET population, and to investigate predictors of time-to-progression (TTP) and overall survival (OS). METHODS: We retrospectively identified patients diagnosed with DIPNECH between April 2005 and December 2020. Clinical data were collected from medical records. The relationship between baseline characteristics and TTP and OS was analysed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazards model. RESULTS: Of 311 patients with well-differentiated lung NETs, 61 (20%) had DIPNECH and were included in the study. Baseline demographics described 95% female, 59% never smokers and mean body mass index 34.4 kg m-2 ; 77% were typical carcinoids (TC), 13% atypical carcinoids (AC), and 10% both TC and AC (multicentric). At presentation, 54% of patients were asymptomatic. Multicentric NETs were demonstrated in 16 (26%) on histopathology, and a further 32 (52%) had synchronous NETs suggested on imaging (multiple nodules ≥ 5 mm). Seven (11%) patients developed metastases and the median OS from time of first metastasis was 37 months. AC histopathology and NET TNM stage ≥ IIA were associated with poorer TTP and OS. Of the DIPNECH cohort, the 15-year survival rate was 86%. CONCLUSIONS: DIPNECH may be more prevalent in the lung NET population than previously appreciated, especially in women. Although our results confirm that DIPNECH is predominantly an indolent disease associated with TC, 23% developed AC and these patients may warrant closer observation.

Quantitative Airway Assessment of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) on CT as a Novel Biomarker.

Objectives: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) occurs due to abnormal proliferation of pulmonary neuroendocrine cells. We hypothesized that performing a quantitative analysis of airway features on chest CT may reveal differences to matched controls, which could ultimately help provide an imaging biomarker. Methods: A retrospective quantitative analysis of chest CTs in patients with DIPNECH and age matched controls was carried out using semi-automated post-processing software. Paired segmental airway and artery diameters were measured for each bronchopulmonary segment, and the airway:artery (AA) ratio, airway wall thickness:artery ratio (AWTA ratio) and wall area percentage (WAP) calculated. Nodule number, size, shape and location was recorded. Correlation between CT measurements and pulmonary function testing was performed. Results: 16 DIPNECH and 16 control subjects were analysed (all female, mean age 61.7 +/− 11.8 years), a combined total of 425 bronchopulmonary segments. The mean AwtA ratio, AA ratio and WAP for the DIPNECH group was 0.57, 1.18 and 68.8%, respectively, compared with 0.38, 1.03 and 58.3% in controls (p < 0.001, <0.001, 0.03, respectively). DIPNECH patients had more nodules than controls (22.4 +/− 32.6 vs. 3.6 +/− 3.6, p = 0.03). AA ratio correlated with FVC (R2 = 0.47, p = 0.02). A multivariable model incorporating nodule number, AA ratio and AWTA-ratio demonstrated good performance for discriminating DIPNECH and controls (AUC 0.971; 95% CI: 0.925−1.0). Conclusions: Quantitative CT airway analysis in patients with DIPNECH demonstrates increased airway wall thickness and airway:artery ratio compared to controls. Advances in knowledge: Quantitative CT measurement of airway wall thickening offers a potential imaging biomarker for treatment response.

A case of multiple lung carcinoid tumors localized in the right lower lobe.

Typical pulmonary carcinoid (TC) tumors are low-grade neuroendocrine tumors and usually detected as indolent solitary tumors. We herein report a case of multiple pulmonary carcinoid tumors and tumorlets localized in the right lower lobe with no underlying lung disorders suggesting diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). A 28-year-old man with multiple 1-to-8-mm pulmonary nodules in the peripheral pulmonary parenchyma of the right lower lobe was referred to our hospital. The patient underwent a surgical biopsy. Pathological examination revealed multiple nodules composed of spindle cells, and immunohistochemistry revealed staining for chromogranin A, synaptophysin, and CD56, suggesting neuroendocrine tumors. He was diagnosed as having multiple TC tumors and tumorlets. Neuroendocrine cell hyperplasia (NECH) was also observed on some bronchioles. A follow-up CT scan after 6 months showed no changes in the sizes of the nodules and no new lesions. The present case was histopathologically compatible with DIPNECH but it occurs mainly in elderly women. The patient might be in an early stage of DIPNECH before progression to symptomatic DIPNECH. In conclusion, clinicians should consider the possibility of carcinoid tumors and tumorlets in cases with multiple pulmonary nodules even if they are localized in one lobe.

Is the combination of bilateral pulmonary nodules and mosaic attenuation on chest CT specific for DIPNECH?

BACKGROUND: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterized by multifocal proliferation of pulmonary neuroendocrine cells. On chest CT, DIPNECH exhibits bilateral pulmonary nodules and mosaic attenuation in most patients. We sought to: (1) assess the specificity of this pattern (i.e., bilateral pulmonary nodules together with mosaic attenuation) for DIPNECH; (2) describe its differential diagnosis; and (3) identify the clinico-radiologic features that may help prioritize DIPNECH over other diagnostic considerations. METHODS: We searched the Mayo Clinic records from 2015 to 2019 for patients with bilateral pulmonary nodules and mosaic attenuation on CT who had a diagnostic lung biopsy. A thoracic radiologist reviewed all CT scans. Chi-square test was used for categorical variables, and odds ratios were utilized to measure the association between certain variables and DIPNECH. RESULTS: Fifty-one patients met our inclusion criteria; 40 (78%) were females and 34 (67%) were never-smokers. Median age was 65 (interquartile range 55-73) years. Lung biopsy was surgical in 21 patients (41%), transbronchial in 17 (33%), and transthoracic in 12 (24%); explanted lungs were examined in 1 (2%). Metastatic/multifocal cancer was the most common diagnosis, and was found in 17 (33%) cases. Bronchiolitis was diagnosed in 12 patients (24%), interstitial lung disease in 10 (20%), and DIPNECH in 5 (10%). Previous diagnosis of an obstructive lung disease (odds ratio 15.8; P = 0.002), and peribronchial nodular distribution on CT (odds ratio 14.4; P = 0.006) were significantly correlated with DIPNECH. Although statistical significance was not reached, DIPNECH nodules were more likely to display solid attenuations (80% vs. 67%, P = 0.45), and were more numerous; > 10 nodules were seen in 80% of DIPNECH cases vs. 52% in others (P = 0.23). Because DIPNECH primarily affects women, we analyzed the women-only cohort and found similar results. CONCLUSIONS: Various disorders can manifest the CT pattern of bilateral pulmonary nodules together with mosaic attenuation, and this combination is nonspecific for DIPNECH, which was found in only 10% of our cohort. Previous diagnosis of an obstructive lung disease, and peribronchial distribution of the nodules on CT increased the likelihood of DIPNECH vs. other diagnoses.