Diffuse idiopathic neuroendocrine cell hyperplasia as a rare cause of chronic cough

Abstract

A 39-year-old Caucasian woman, who has never smoked, presented a 16-year-duration chronic dry cough. She was prescribed by her general physician with corticosteroid and long-acting β-agonist inhalers assuming it was asthma, with mild symptomatic improvement. When cough got more persistent and associated with exertional dyspnoea and wheezing, a chest CT scan was performed, which showed multiple bilateral micronodular formations and diffuse mosaic lung pattern with air trapping. She was sent to our Respiratory Department and performed a bronchoalveolar lavage and cryobiopsy that were inconclusive. She underwent surgical lung biopsy with pathology revealing multiple foci of neuroendocrine cell hyperplasia and tumourlets associated with constrictive bronchiolitis, a histological pattern suggestive of diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH). DIPNECH is a rare and preinvasive disease. Presenting symptoms can be cough and breathlessness. At the time of writing, the patient is on octreotide with symptomatic improvement.

Background

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) consists of a primary neuroendocrine cell proliferation often accompanied by constrictive obliterative bronchiolitis. It is considered an extremely rare preneoplastic condition in the spectrum of pulmonary neuroendocrine tumours.^{1 2}

The WHO definition is histological and the disease can be presented without any clinical or radiological features of airway disease.¹ However, there is a distinct patient subgroup who have chronic respiratory symptoms and mosaic attenuation with air trapping on chest imaging.^{2 3}

Case presentation

A 39-year-old Caucasian woman was sent by her general physician to an appointment in the Respiratory Department of our hospital in March 2016 because of an intermittent chronic dry cough with 16-year duration that in the last 6 months got more persistent and associated with mild exertional dyspnoea and occasional wheezing. For symptomatic relief, she had been prescribed with corticosteroid and long-acting β-agonist inhalers with mild symptomatic improvement. She stopped working and maintained the symptoms.

She had never smoked and reported a medical history of non-allergic rhinitis.

She was working in the recycling of electronic material for the last 8 years.

Her family history was irrelevant in this context.

Investigations

A high-resolution CT (HRCT) of the chest was performed, which showed multiple micronodular formations, bilateral and multilobar, uniform in size, non-calcified and centrilobular. Additionally, there was diffuse mosaic lung pattern with air trapping (figure 1).

Figure 1.

High-resolution CT of the chest showing multiple bilateral micronodules and mosaic attenuation with air trapping.

The paranasal sinus CT scan exhibited a mild chronic sinusitis. The abdominal and pelvic CT scan showed no alterations.

The lung function tests (LFTs) presented an isolated increase in RV (162% (2.35 L)), and the blood gas analysis was normal.

The patient was subjected to flexible bronchoscopy with bronchoalveolar lavage which was unrevealing, with no lymphocytosis or malignant cells. Transbronchial lung biopsy was not performed due to persistent cough during the procedure.

The patient did a second chest HRCT that revealed stability of the alterations already described.

It was decided to perform rigid bronchoscopy with cryobiopsy, which showed pulmonary parenchyma with non-specific inflammatory infiltrate.

Our patient underwent wedge resection of segment 6 of the right lung and middle lobe with pathology revealing multiple foci of neuroendocrine cell hyperplasia and tumourlets, adjacent to the bronchiolar wall, measuring 0.3 cm at maximum. No mitosis or necrosis was identified. The positive immunomarkers tested were CKAE1AE3⁺, CK7⁺, TTF1⁺, CD56⁺ and Ki-67 <1%. Moreover, the bronchiolar wall showed a moderate chronic lymphocytic inflammation and fibrosis consistent with a pattern of constrictive obliterative bronchiolitis (figures 2 and 3). These morphological findings were suggestive of DIPNECH.¹

Figure 2.

Carcinoid tumourlet is identified as nests of neuroendocrine cells adjacent to the bronchiole which shows chronic lymphocytic inflammation and fibrosis consistent with constrictive obliterative bronchiolitis (H&E).

Figure 3.

Positive staining for CD56 confirms the neuroendocrine nature of the proliferation (CD56 immunohistochemistry).

Our Thoracic Oncology multidisciplinary clinical team proposed to perform chromogranin A serum dosing, which was normal, and a combined PET and CT (PET/CT) with ⁶⁸Ga-DOTA-NOC that showed no clear evidence of tumour with somatostatin receptors.

Differential diagnosis

In this clinical context and due to the presence of mosaic perfusion and micronodules, the diagnoses considered most likely would be asthma (cough variant) and occupational lung disease. Although it was unlikely, we could not exclude that it was not pulmonary metastasis. After surgical biopsy results, the histological pattern was diagnostic of DIPNECH.

Treatment

The patient was referred to Thoracic Oncology for ongoing monitoring.

She was started on a trial of oral prednisolone (40 mg per day) and maintained the inhaled therapy. Initially, there was a mild clinical improvement, but she could not tolerate a dosage reduction without worsening of symptoms. So a long-acting release formulation of octreotide was initiated, with improvement of the dry cough and exertional dyspnoea. The prednisolone dosage was progressively reduced and then stopped.

Outcome and follow-up

Currently, the patient is on octreotide. She shows symptomatic improvement, and her lung function and radiological changes remain stable.

Discussion

DIPNECH is an extremely rare disease and was first described by Aguayo et al in 1992.³ They reported on six patients, non-smoking and mainly women, with cough and exertional dyspnoea that on histological examination of the lung had diffuse hyperplasia of pulmonary neuroendocrine cells with multiple carcinoid tumourlets, associated with signs of constrictive obliterative bronchiolitis.

Since then, there have been about 200 cases of DIPNECH described in the literature worldwide in the form of case reports or case series.²

In 2015, WHO defines DIPNECH as a preinvasive lesion characterised by an idiopathic generalised proliferation of pulmonary neuroendocrine cells that may stay confined to the mucosa of the airways or invade locally to form tumourlets or carcinoid tumours (≤5 or >5 mm in diameter, respectively). Often, it can be accompanied by constrictive bronchiolitis due to chronic lymphocytic inflammation and fibrosis of the involved airways.¹

It is reported that patients with DIPNECH range from 36 to 84 years of age and 93% of the patients are women.⁴

DIPNECH can be presented without any clinical or radiological features of airway disease^{1 5 6}; however, Rossi et al proposed the term ‘DIPNECH syndrome’ to represent a different patient subgroup similar to the case of our patient, characterised by respiratory symptoms, airflow obstruction, mosaic attenuation with air trapping, and nodular proliferation of neuroendocrine cells with constrictive obliterative bronchiolitis on histology.²

Our patient has a very long history of chronic dry cough and, as usually happens in this disease, the diagnosis is often delayed and confused with obstructive lung disease or gastro-oesophageal reflux.^{2 5} Despite that, we would like to highlight that our patient does not show an important airflow obstruction in LFT as we could expect in this disease.^{2 5 6}

Surgical lung biopsy remains the ‘gold standard’ in the diagnosis of DIPNECH1 2 5–7; nonetheless, some authors defend that in the appropriate clinical and radiological setting, transbronchial lung biopsy may provide the diagnosis.^{7 8}

For DIPNECH, there are still no evidence-based management guidelines. There are multiple management options that have been suggested such as oral and inhaled steroids, somatostatin analogues, inhibitors of the mechanistic target of rapamycin, surgical lung resection and lung transplantation.2 3 6 9 10 Clinical observation alone for mild and stable cases is a possibility, but the majority of symptomatic patients are treated with steroid-based therapy. It is thought that corticosteroids may reduce the inflammatory response induced by neuroendocrine cell–secreted neuropeptides despite the lack of strong evidence of efficacy. Patients can ultimately be referred for lung resection or lung transplantation evaluation in the presence of severe respiratory symptoms associated with progressive obliterative bronchiolitis.1 2 6 11

In the case of our patient, due to persistent symptoms, it was decided to start oral prednisolone. She showed mild symptom improvement, but as we tried to progressively reduce the dosage, the symptoms grew worse. The patient was started on octreotide and it was possible to progressively reduce the steroid dosage and stop it, with symptomatic improvement. The lung function and radiological changes remain stable to date.

We cannot be certain that our patient has no carcinoid tumour, but knowing that the disease is preinvasive, a major issue is the follow-up of these patients taking into account the limited data in the literature.^{1 2 6} In our case, we chose to initially do PET/CT with ⁶⁸Ga-DOTA-NOC to help us exclude the presence of the active carcinoid tumour with somatostatin receptors, which was negative. Then we decided to do interval screening with chest HRCT, LFT and serum dosing of chromogranin A, and our patient has remained stable until now.

Learning points.

• The definition of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is histological and surgical biopsy remains the gold standard for diagnosis.

• It is a rare condition but potentially progressive, and there are no management guidelines.

• It affects mainly middle-aged women and usually presents with complaints of chronic cough and wheezing.

• At chest CT, the key features are mosaic perfusion and multiple lung nodules, but can also be seen bronchiectasis, bronchial wall thickening and mucoid impactions.

• The main differential diagnoses based on the chest CT images are the small airway diseases, chronic thromboembolism and lung metastisation.