Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia

Introduction

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is an uncommon lung disorder. It is a benign cell proliferative condition that is considered a precancerous lesion of the lungs. It is considered a precancerous lesion for carcinoid tumors of the lungs by the World Health Organization (WHO). It is seen in nonsmoking middle-aged females with a history of asthma or chronic cough.

What Does Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Mean?

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is an uncommon lung disorder that causes abnormal proliferation of bronchiolar and bronchial pulmonary neuroendocrine cells in the lungs. The neuroendocrine cells receive signals from neurons (nerve cells) and produce hormones. The abnormal proliferation can be a generalized proliferation of the scattered single cells and small neuroendocrine bodies or linear proliferation of the pulmonary neuroendocrine cells of the bronchial and bronchiolar epithelium. The reason for the occurrence of this disorder is not known. It can be associated with chronic conditions like hypoxia, pulmonary interstitial fibrosis, bronchopulmonary dysplasia, cystic fibrosis, asthma, bronchiectasis, high altitude exposure, tobacco smoke, and chronic obstructive pulmonary disease.

What Is the Pathology of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia?

DIPNECH's condition is regarded as idiopathic, and its cause is not well understood. However, it is frequently linked to chronic inflammation or other pre-existing pulmonary disorders. It may also extend into other more prominent neuroendocrine tumors, for example, carcinoid tumors.

Histologically, DIPNECH is identified by the presence of:

• Proliferating Neuroendocrine Cells: These cells are immunoreactive for neuroendocrine markers such as chromogranin, synaptophysin, and CD 56.

• Tumorlets: These are small clusters of neuroendocrine cells that are less than 5 mm in diameter and are located in the airway walls only.

• Associated Fibrosis: There can be related changes in the form of fibrosis around the small airways.

How Does Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Present?

The patients are usually asymptomatic. The common symptoms are:

• Chronic nonproductive cough.

• Shortness of breath.

• Dyspnea during exercises.

• Wheezing.

• Hemoptysis.

The symptoms are usually misdiagnosed as asthma or chronic obstructive pulmonary disease (COPD).

What Are the Signs and Symptoms of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia?

DIPNECH also presents several symptoms that are quite similar to other chronic lung diseases and are fairly non-specific. They may include:

• Chronic Cough: This is the most frequent sign, and it may be chronic.

• Wheezing: Wheezing is associated with airflow obstruction, but it is commonly confused with asthma.

• Dyspnea (Shortness of Breath): This can range from mild to severe and is frequently so.

• Pulmonary Nodules: These may be seen as incidental findings in investigations, especially in patients with no symptoms.

What Are the Effects of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia?

Pulmonary neuroendocrine cells are the epithelial cells that line the large and the small airways.

They play a role in hypoxia detection, regulating pulmonary blood flow, controlling bronchial tonus, modulation of immune responses, and maintenance of the stem cell niche. This disorder causes abnormal growth of pulmonary neuroendocrine cells along the small airways. This extends through the basement membrane of the bronchiolar epithelium and results in the formation of carcinoid tumorlets. Tumorlets are hyperplasia of neuroendocrine cells smaller than 5mm in diameter. They lack mitotic activity and necrosis. If the tumorlets are larger than 5mm, they are considered bronchial carcinoids. These tumorlets are considered precancerous lesions of the lungs.

What Are the Complications of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia?

It can cause respiratory failure, which cannot be treated and requires lung transplantation. It can become malignant with lymph node involvement and metastases to the bone, liver, adrenal gland, and eyes. It results in constrictive bronchiolitis due to fibrosis.

What Are the Other Conditions Similar to Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia?

This disorder is associated with multiple small airway-centered solid nodules that cause air trapping. The following disorders have similar characteristics, which include:

• Pulmonary Adenocarcinoma - Consists of irregular and sub-solid nodules showing greater interval growth.

• Hematogenous Metastases or Infections - These result in random nodules. Metastatic lung cancer is a primary and systemic disease. The nodules are variable in size, with a preference for the lower and periphery regions of the lungs.

• Follicular Bronchiolitis - It is a broncho-centric lymphoproliferative disorder that causes air trapping. It is also related to Sjogren syndrome or rheumatoid arthritis.

• Pulmonary Hypertension - Pulmonary hypertension is similar to diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

What Are the Diagnostic Criteria for Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia?

This disease is diagnosed as an unexpected finding during lung surgery or the evaluation of a patient with symptoms. A biopsy plays a significant role in the diagnosis of this disorder. Other diagnostic criteria include:

• Clinical Findings - Cough and shortness of breath are commonly seen.

• Pulmonary Function Tests - Pulmonary function tests identified fixed airway obstruction with a decreased forced expiratory volume and reduced forced expiratory volume or vital capacity. Air trapping increases the residual volume. The disease progresses and results in airway obstruction and restriction. The pulmonary function test demonstrates increased total lung capacity, increased residual volume, fixed obstruction, and reduced diffusion capacity of the lungs for carbon monoxide, which corrects with the alveolar volume.

• High-resolution CT (Computed Tomography) Scan - CT scan shows bilateral and diffuse imaging. It demonstrates multiple peribronchovascular and endobronchial smoothly lobulated primary nodules or masses on a mosaic attenuation background with thickening of the airway wall. The masses are airway-centric and cause thickening of the proximal airway and mucus plugging in the distal airway. It shows an irregular thickening and beaded appearance of the bronchial wall. The nodules are found in the entire lungs with a lazy pattern of growth. The nodules appear round and well-defined.

• Transbronchial Biopsy - Biopsy is done to demonstrate the proliferation of neuroendocrine cells. It shows inflammatory infiltration with thickening and fibrosis of the airway.

• Serum Markers - Elevated serum chromogranin A level confirms the presence of this disorder. It also expresses synaptophysin, CD56 (neural cell adhesion molecule), CD10, and less specific antibodies for neuron-specific enolase, PGP9.5 (protein gene product), and thyroid transcription factor - 1. It also expresses gastrin-releasing peptide (bombesin), BCL-2 (b cell lymphoma-2), retinoblastoma protein, p27 (phosphorylation), and calcitonin in variable amounts. It also expresses somatostatin receptor type 2 and the mammalian target of rapamycin (mTOR).

How Is Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Treated?

The treatment involves using oral and inhaled steroids, chemotherapy, surgical resection, and lung transplantation for severe cases, and clinical observation for mild cases. Symptomatic patients are managed with steroids. Corticosteroids help to reduce the inflammatory response stimulated by the neuropeptides secreted by neuroendocrine cells. A somatostatin analog, Octreotide, is used to reduce the hormonal hypersecretion of neuroendocrine cells in gastrointestinal and bronchial carcinoids.

What Is the Prognosis of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia?

The outcome of DIPNECH is determined by the extent of the disease and the presence of other diseases such as carcinoid tumors. DIPNECH as a condition on its own is often characterised as a slow progressive disease. However, it may cause severe respiratory dysfunction because of airflow limitation and fibrosis in some circumstances.

• Benign Course: In most of the affected individuals, the condition is relatively chronic or only changes at a very slow rate and is usually characterized by mild symptoms.

• Progression to Neuroendocrine Tumors: It has been shown that there is potential development of carcinoid tumors, which are dangerous and demand surgical operation.

• Management: Management is more or less supportive with the aim of treating complications relating to respiratory function. Sometimes, only localized neoplasms or lung transplantation can be performed in severe conditions.

What to Expect With Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia?

The disease slowly progresses and results in respiratory failure, which requires oxygen therapy. It requires lung transplantation in the end stages of respiratory failure. In rare cases, it causes complications due to airway obstruction. It may progress to malignant lung cancer.

Conclusion

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is an uncommon disorder that usually affects nonsmoking middle-aged women. This rare lung disorder can be easily misdiagnosed. It is a slowly progressive disease that can cause complications. Early diagnosis and treatment are vital parts of managing patients with symptoms and preventing the risk of complications.