Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

Last revised by Liz Silverstone on 29 Nov 2024

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is an extremely rare but underdiagnosed pulmonary disorder at the benign end of the neuroendocrine cell proliferation spectrum of preinvasive lesions of the lungs

Symptomatic DIPNECH predominantly occurs in women (90%) from middle age onwards, many of whom have never smoked 3,10. Asymptomatic neuroendocrine cell hyperplasia can also be an incidental finding in lung specimens, more commonly when resection is performed for a peripheral carcinoid tumor, supporting the "pre-malignant" WHO classification. These conditions should not be confused with reactive neuroendocrine cell hyperplasia related to hypoxia (e.g. smoking, chronic lung disease, or living at high altitude) 12.

The diagnosis can be suggested when CT demonstrates characteristic findings, including multiple bronchocentric nodules and mosaic attenuation 10. Surgical biopsy can confirm the diagnosis, although not every nodule can be pathologically confirmed.

The diagnosis is usually not apparent from clinical features or pulmonary function tests. DIPNECH may be asymptomatic or present with dyspnea, a chronic cough or "late-onset asthma" 10. The delay in diagnosis can be 10 years or more. Progressive functional impairment rarely causes respiratory failure 5.

The WHO definition of DIPNECH refers to the histological findings regardless of clinical features. Hyperplastic neuroendocrine cells line the peripheral airway mucosa as scattered single cells, small nodules, or linear proliferation. This can be an incidental histological finding on random surgical specimens but is more commonly found in lung specimens excised for peripheral carcinoid tumors. If the basement membrane is invaded, tumourlets (<5 mm) or invasive carcinoid tumors (>5 mm) form 12. Nodules tend to slowly increase in number and size over time. Malignancy can complicate approximately 10% of cases with possible nodal and distant metastases. 

DIPNECH also causes constrictive bronchiolitis due to fibrosis exacerbated by peptide secretion. Small airways are considered a “quiet area” of the lung; pulmonary function remains normal until the disease is advanced.

Characteristic findings suggest the diagnosis, which is usually clinically occult 13:

  • multiple small solid nodules in a peribronchovascular distribution, more numerous peripherally and with a lower zone predominance

  • mosaic attenuation due to a combination of air trapping and regional oligemia as a result of constrictive bronchiolitis

  • nodular bronchial wall thickening (cell clusters), mucus plugging, and bronchiectasis are common

MIP slabs aid in small nodule detection. MinIPs and expiratory CT highlight air-trapping.

Treatment evaluation is difficult because of the rarity of the condition. Various strategies include somatostatin analogs, azithromycin, and lung transplantation for respiratory failure 15.

Long-term surveillance is recommended; nodules tend to slowly increase in number and grow, and occasionally disseminated malignancy can occur 15. The optimum interval for surveillance has not been determined and depends on available histology; initial 3- or 6-month review followed by annual low-dose CT may suffice 10.

Severe disease can cause respiratory failure due to constrictive bronchiolitis with no treatment option other than a lung transplant 16.

Nodules may progress to malignancy with lymph node spread and metastases to the pleura, bone, liver and adrenal gland 15,17.

The first clinical series of six cases describing DIPNECH was published by Aguayo et al. in 1992 11.

The combination of multiple small-airway-centered solid nodules associated with air-trapping is characteristic of this diagnosis. Other considerations include:

  • many patients have a clinical diagnosis of asthma or COPD, most are women past middle age, have never smoked, and have no known cancer or immune disorder

  • scattered bronchocentric nodules (often >10) are typically well-demarcated, rounded and <10 mm; MIPs may reveal additional small nodules

  • associated constrictive bronchiolitis causes regional air trapping, which may be obvious on MinIPs or expiratory acquisition