Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia

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. 

The diagnosis can be suggested when CT demonstrates characteristic findings including multiple bronchocentric nodules and mosaic attenuation.

Epidemiology

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.

Clinical presentation

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". Progressive functional impairment rarely causes respiratory failure.

Pathology

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.

Radiographic features

CT

Characteristic CT findings suggest the diagnosis, which is usually clinically occult. Multiple small bronchocentric solid circumscribed nodules typically affect all lobes, commonly lower zone and peripheral (small airways) predominant, or with a more diffuse distribution. Lobular or regional air-trapping (constrictive bronchiolitis) causes mosaic attenuation in the affected areas ¹³. Nodular bronchial wall thickening (cell clusters), mucus plugging, and bronchiectasis are common ¹³.

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

Treatment and prognosis

Treatment evaluation is difficult because of the rarity of the condition. Various strategies include somatostatin analogs, azithromycin, and lung transplantation for respiratory failure ¹⁰. Long-term surveillance is recommended; nodules tend to slowly increase in number and grow, and occasionally disseminated malignancy can occur ¹⁵. The optimum intervals have not been determined and depend on available histology. Annual low-dose CT with initial 3 or 6 monthly scans may suffice.

Complications

Severe disease can cause respiratory failure with no treatment option other than a lung transplant. The disease may progress to malignancy with lymph node spread and metastases to the bone, liver, adrenal gland, eye, etc.

History and etymology

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

Differential diagnosis

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

• pulmonary adenocarcinoma demonstrates greater interval growth and nodules may be irregular and sub-solid

• hematogenous metastases or infections cause random nodules

  • metastatic lung cancer commonly has a known primary and systemic disease

  • nodules are variable in size and have a predilection for the lower zones and the lung periphery

• follicular bronchiolitis is a bronchocentric lymphoproliferative disorder frequently related to Sjögren syndrome or rheumatoid disease which can cause air-trapping

• pulmonary hypertension, in particular CTEPH, could mimic DIPNECH

Practical points

This is almost a radiological Aunt Minnie but the delay in diagnosis can be 10 years or more. The astute radiologist may be the first to recognize this condition and initiate appropriate patient care and surveillance. 60% of 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 are typically well-demarcated, rounded and <10 mm. Nodules often number >10, and MIPs may reveal additional small nodules. Associated constrictive bronchiolitis causes regional air-trapping which may be obvious on MinIPs. Surgical biopsy is the only way to confirm the diagnosis.