Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is defined as an idiopathic neuroendocrine cell hyperplasia located in the small bronchi and bronchioles. Since Aguayo and colleagues first described 6 DIPNECH patients in 1992 and recognition of the entity by WHO in 2004,1 several series2–6 have comprehensively reviewed this newly recognized disease and >100 cases have been reported to date. Patients with DIPNECH were predominantly female with no association with smoking. The pulmonary symptoms commonly consisted of a nonproductive cough and dyspnea. Patients at early stage of the disease are often asymptomatic and are often referred for incidental finding of pulmonary nodules on imaging studies. The findings of obstructive pattern on pulmonary function tests and multiple small pulmonary nodules on high-resolution computed tomography (HRCT) are the best clues to the diagnosis of DIPNECH.5 Despite the increasing number of case reports and series, information about the disease is still limited, especially with regard to patient management and prognosis.3,6 Here we report 2 patients with DIPNECH who were treated with double lung transplantation at our institution.
Both of the patients had chronic obstructive pulmonary disease (COPD)/emphysema without clear etiology. The transplantations were performed due to deteriorating pulmonary function. DIPNECH was first diagnosed upon histologic examination of the resected native lungs and was an unexpected diagnosis in both cases.
Patient 1 was a 59-year-old African American woman with a history of severe COPD. She was a nonsmoker. Pulmonary function tests showed: forced expiratory volume in 1 second (FEV1) (% predicted) of 400 mL (20%), forced vital capacity (FVC) of 1330 mL (55%), and FEV1/FVC of 36. HRCT demonstrated emphysematous lungs with bilateral scattered small nodules up to 7 mm (Fig. 1). Mild diffuse bronchial thickening and bronchiectasis were present bilaterally. She had progressive shortness of breath on exertion with New York Heart Association class 3 (NYHA3) symptoms (marked limitation in activity due to symptoms, comfortable only at rest). In view of progression of the disease and irreversible loss of pulmonary function, the patient was assessed for double lung transplantation and underwent a successful surgery in January 2010.
The pathologic examination of the native lungs showed multiple parenchymal nodules varying from 2 to 11 mm in diameter through bilateral lungs. A distinct histologic feature was diffuse proliferation of neuroendocrine cells involving the bronchiolar epithelium (Fig. 2A). The neuroendocrine cells formed intraepithelial clusters that replaced part of or the entire epithelium and resulted in luminal narrowing or complete obliteration (Fig. 2B). Extraluminal extension of the proliferative neuroendocrine cells formed small nodules (tumorlets). Multiple carcinoid tumors are also defined in both lungs (up to 7 mm typical carcinoid tumor in the left lung and up to 11 mm typical carcinoid tumor in the right lung). Associated with the diffuse neuroendocrine cell hyperplasia, typical carcinoid tumors were focally observed in the left upper and lower lobes and the right upper lobe. Microscopic features of emphysema were also observed.
The patient remained well at her most recent follow-up in November 2012. Posttransplantation HRCT of the thorax was unremarkable. No evidence of rejection or recurrent DIPNECH was detected on follow-up transbronchial biopsies.
Patient 2 was a 67-year-old white woman with a clinical history of COPD. She was also a nonsmoker. Pulmonary function tests showed: FEV1 (% predicted) of 600 mL (30%), FVC of 1660 mL (68%), and FEV1/FVC of 45. HRCT showed hyperinflated lungs with multiple bilateral nodules up to 5 mm. No significant air trapping was observed. She had dyspnea on exertion with NYHA3 symptoms. The patient was assessed for double lung transplantation and underwent a successful surgery in January 2012.
The native lungs contained multiple parenchymal nodules varying from 2 to 6 mm in diameter with similar microscopic features as that of patient 1, including microscopic evidence of emphysema. Of note, the distribution of the neuroendocrine hyperplasia, tumorlets, or carcinoid tumors does not have preference either centrally or peripherally in these 2 patients. Patient 2 was most recently followed up in January 2013 and remained well. No recurrent disease was detected in posttransplantation HRCT of the thorax. Surveillance transbronchial biopsies showed no evidence of graft rejection or recurrent disease.
DIPNECH is an indolent but slowly progressive disease. Patients are diagnosed by either nonspecific pulmonary symptoms or workup with incidental pulmonary nodules.5 The histopathologic evaluation of surgical lung biopsy remains the gold standard for diagnosis of DIPNECH. The classic histologic feature of DIPNECH is multifocal proliferation of neuroendocrine cells within the epithelium of the distal bronchi or terminal bronchioles with immunoreactivity to neuroendocrine differentiation markers such as Chromogranin, Synaptophysin, or CD56. DIPNECH-related peribronchiolar fibrosis and obliterative bronchiolitis are thought to be associated with stimulation of fibroblasts by neuroendocrine cell–released fibrogenic cytokines.7 The progression of intraluminal PNEC proliferation, obliterative bronchiolitis, and peribronchiolar fibrosis often leads to narrowing and eventual obstruction of the small airways. This fundamental pathology dictates the abnormalities in pulmonary function tests and imaging studies. The majority of DIPNECH patients show obstructive abnormality on pulmonary function tests. HRCT typically shows thickening of bronchiolar walls and mosaic pattern of air trapping caused by incomplete small airway obstruction. The nodules detected on chest CT usually represent tumorlets or carcinoid tumor commonly associated with DIPNECH.2,8 Bronchoscopy is generally nondiagnostic or inconclusive and diagnosis typically requires surgical lung biopsy.9,10 Octriotide scanning is usually used to evaluate the nodules in DIPNECH cases and many cases have a positive scan.3,6
Carcinoid tumor or tumorlets are consistent findings in almost all reported DIPNECH cases, presumably a result of uncontrolled proliferation of pulmonary neuroendocrine cells. Metastatic disease should be ruled out when multiple nodules are observed on imaging studies in cases eventually diagnosed as DIPNECH.11 However, the progression of the nodules in DIPNECH is very slow.
The course of DIPNECH progression is slow and patients may have pulmonary symptoms for 3 to 30 years.6 As a result, there is a high health care cost over the long disease course. Although most of the cases remain stable over many years,5 progression of the disease in some patients causes severe damage to the pulmonary function which necessitates clinical intervention. Clinical observation without active treatment has been proposed as the first course of action for patients without symptoms.5 Trials of steroid therapy or even chemotherapy were advocated in cases with deteriorating pulmonary function.5,7 A recent study has shown that patients treated with somatostatin analogs for progressive respiratory symptoms experienced disease stabilization and improved pulmonary function.6 However, the treatment options for DIPNECH are heterogenous and limited. There is no effective therapy or clinical trial currently available.2,5,12,13
Nearly 2 decades ago, single lung transplantation was reportedly performed on a DIPNECH patient with deteriorating pulmonary function and the patient expired 5 years later due to presumed chronic rejection.5,14 Since then, no cases of lung transplantation have been reported for DIPNECH patients.
DIPNECH is considered a preneoplastic condition in the lung.5 Although most of the cases are indolent in nature and the patients can be clinically stable for many years, some cases do progress with irreversible pulmonary function deterioration. Considering the diffuse nature of this disease, we believe surgical intervention with lung transplantation is a valid treatment choice. We report here the first 2 cases of double lung transplantation for treating DIPNECH with worsening pulmonary function. The patients are in stable condition under regular surveillance protocol after transplantation surgery, and no transplantation rejection or recurrent DIPNECH has so far occurred.
In conclusion, lung transplantation may be a life-saving treatment for DIPNECH patients with deteriorating pulmonary function. Considering the rarity of the disease, a multicenter registry for DIPNECH patients and coordinated studies will be essential to generate data for prognosis and potential clinical trials.
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