Teaching Case

We present a case of a Caucasian 79-year-old-woman, non-smoker, with chronic dry cough for about 10 years and episodes of exertional dyspnoea and wheezing. Chronic obstructive pulmonary disease was diagnosed and medicated with corticosteroid and long-acting β-agonist inhalers.

Due to symptomatic worsening and weight loss, a chest computed tomography (CT) was obtained and multiple bilateral pulmonary nodules and a diffuse mosaic lung pattern with air trapping raised up (figure 1). Pulmonary function tests demonstrated mixed pattern, flexible bronchoscopy with bronchoalveolar lavage showed signs of chronic bronchitis with no malignant cells and PET-CT confirmed innumerable lung nodules with discrete FGD-F18 captation (SUV max: 1.3). Surgical lung biopsy was performed and neuroendocrine cells hyperplasia was diagnosed, with Ki-67 below 5%, absence of necrosis and with homogeneous cytoplasmic chromogranin marking, corresponding to DIPNECH (figure 3). The patient repeated the chest CT one year later and the changes already described maintained the same pattern (figure 2).

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) is a pulmonary disorder characterized by diffuse proliferation of bronchiolar and bronchial pulmonary neuroendocrine cells, initially described by Aguayo et al. in 1992 and recognized as a pre-invasive lesion for lung carcinoid tumours in 2015 by the World Health Organization.[1, 2]

DIPNECH typically occurs in non-smoking, middle-aged women with insidious onset, usually with non-productive cough, exertional dyspnoea and wheezing.[1, 3-5] Symptomatic patients are often misdiagnosed with asthma or chronic bronchitis and the definitive diagnosis is usually established several years after the onset of symptoms, frequently after the incidental discovery of lung nodules, as demonstrated in the case reported.[6]

Lung functional tests usually show an obstructive or mixed pattern. Chest CT typically reveals a mosaic attenuation with air trapping, better appreciated on expiratory CT scans, which is due to constrictive bronchiolitis and pulmonary nodules, usually multiple, small in size and ground glass or solid in attenuation, that correspond to either tumorlets (<5 mm) or carcinoid tumours (>5 mm).[4, 5, 7-9]

Although CT does not provide the diagnosis, in an appropriate clinical and demographic context the typical CT findings should raise a suspicion of DIPNECH.[5, 7, 10] The gold standard for the diagnosis remains surgical lung biopsy and recent study suggested that it can be established in the presence of 5 or more neuroendocrine cells, alone or in clusters, located within the basement membrane of the bronchiolar epithelium of at least 3 bronchioles, combined with 3 or more tumorlets.[11] The most common markers of these cells are chromogranin A, synaptophysin and CD56.[12]

There are no guidelines for the management of DIPNECH, however, the treatment options used include clinical observation, oral and inhaled steroids, chemotherapy, somatostatin analogues, surgical lung resection and even lung transplantation.[2-5, 13]

Most reports described an excellent long-term prognosis, although some patients with marked constrictive bronchiolitis may progress to severe airflow obstruction and respiratory failure with worse prognosis.[2-5] Currently there are no specific guidelines, however, a close follow-up of patients is essential.[9, 14]

Take-Home Message / Teaching Points

• The diagnosis of DIPNECH should be suspected when CT demonstrates diffuse mosaic perfusion and multiple lung nodules in middle-aged women with chronic cough.
• The gold standard for the diagnosis remains surgical lung biopsy for histopathological confirmation of neuroendocrine cell proliferation.
• There are no guidelines for the management of DIPNECH patients, although close follow-up is recommended.