Rare disease

Case report

Diffuse idiopathic neuroendocrine cell hyperplasia as

BMJ Case Rep: first published as 10.1136/bcr-2018-226203 on 28 November 2018. Downloaded from file:/ on 10 February 2019 by guest. Protected by copyright.
a rare cause of chronic cough
Paula Inês Pedro,1 Dolores Canário,1 Miguel Lopes,1 Ana Oliveira2

1
Pulmonology, Hospital Garcia Summary She was working in the recycling of electronic
de Orta EPE, Almada, Portugal A 39-year-old Caucasian woman, who has never smoked, material for the last 8 years.
2
Pathology, Hospital Garcia de presented a 16-year-duration chronic dry cough. She was Her family history was irrelevant in this context.
Orta EPE, Almada, Portugal
prescribed by her general physician with corticosteroid
and long-acting β-agonist inhalers assuming it was Investigations
Correspondence to
Dr Paula Inês Pedro, asthma, with mild symptomatic improvement. When A high-resolution CT (HRCT) of the chest was
​paulaines.​gpedro@g​ mail.​com cough got more persistent and associated with exertional performed, which showed multiple micronodular
dyspnoea and wheezing, a chest CT scan was performed, formations, bilateral and multilobar, uniform in
Accepted 31 October 2018 which showed multiple bilateral micronodular formations size, non-calcified and centrilobular. Additionally,
and diffuse mosaic lung pattern with air trapping. She there was diffuse mosaic lung pattern with air trap-
was sent to our Respiratory Department and performed ping (figure 1).
a bronchoalveolar lavage and cryobiopsy that were The paranasal sinus CT scan exhibited a mild
inconclusive. She underwent surgical lung biopsy with chronic sinusitis. The abdominal and pelvic CT scan
pathology revealing multiple foci of neuroendocrine cell showed no alterations.
hyperplasia and tumourlets associated with constrictive The lung function tests (LFTs) presented an
bronchiolitis, a histological pattern suggestive of diffuse isolated increase in RV (162% (2.35 L)), and the
idiopathic neuroendocrine cell hyperplasia (DIPNECH). blood gas analysis was normal.
DIPNECH is a rare and preinvasive disease. Presenting The patient was subjected to flexible bronchos-
symptoms can be cough and breathlessness. At the time copy with bronchoalveolar lavage which was unre-
of writing, the patient is on octreotide with symptomatic vealing, with no lymphocytosis or malignant cells.
improvement. Transbronchial lung biopsy was not performed due
to persistent cough during the procedure.
The patient did a second chest HRCT that
Background   revealed stability of the alterations already
Diffuse idiopathic pulmonary neuroendocrine described.
cell hyperplasia (DIPNECH) consists of a primary It was decided to perform rigid bronchoscopy
neuroendocrine cell proliferation often accompa- with cryobiopsy, which showed pulmonary paren-
nied by constrictive obliterative bronchiolitis. It is chyma with non-specific inflammatory infiltrate.
considered an extremely rare preneoplastic condi- Our patient underwent wedge resection of
tion in the spectrum of pulmonary neuroendocrine segment 6 of the right lung and middle lobe with
tumours.1 2 pathology revealing multiple foci of neuroendo-
The WHO definition is histological and the crine cell hyperplasia and tumourlets, adjacent to
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 attenua-
tion 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 Respi-
ratory 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
© BMJ Publishing Group
Limited 2018. No commercial persistent and associated with mild exertional
re-use. See rights and dyspnoea and occasional wheezing. For symptom-
permissions. Published by BMJ. atic relief, she had been prescribed with corticoste-
roid and long-acting β-agonist inhalers with mild
To cite: Pedro PI, Canário D,
Lopes M, et al. BMJ Case symptomatic improvement. She stopped working
Rep 2018;11:e226203. and maintained the symptoms. Figure 1  High-resolution CT of the chest showing
doi:10.1136/bcr-2018- She had never smoked and reported a medical multiple bilateral micronodules and mosaic attenuation
226203 history of non-allergic rhinitis. with air trapping.
Pedro PI, et al. BMJ Case Rep 2018;11:e226203. doi:10.1136/bcr-2018-226203 1
 Rare disease
Treatment
The patient was referred to Thoracic Oncology for ongoing
monitoring.

BMJ Case Rep: first published as 10.1136/bcr-2018-226203 on 28 November 2018. Downloaded from file:/ on 10 February 2019 by guest. Protected by copyright.
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 improve-
ment of the dry cough and exertional dyspnoea. The predniso-
lone 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.

Figure 2  Carcinoid tumourlet is identified as nests of neuroendocrine Discussion

cells adjacent to the bronchiole which shows chronic lymphocytic DIPNECH is an extremely rare disease and was first described
inflammation and fibrosis consistent with constrictive obliterative by Aguayo et al in 1992.3 They reported on six patients,
bronchiolitis (H&E). 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
the bronchiolar wall, measuring 0.3 cm at maximum. No mitosis multiple carcinoid tumourlets, associated with signs of constric-
or necrosis was identified. The positive immunomarkers tested tive obliterative bronchiolitis.
were CKAE1AE3+, CK7+, TTF1+, CD56+ and Ki-67 <1%. Since then, there have been about 200 cases of DIPNECH
Moreover, the bronchiolar wall showed a moderate chronic described in the literature worldwide in the form of case reports
lymphocytic inflammation and fibrosis consistent with a pattern or case series.2
of constrictive obliterative bronchiolitis (figures 2 and 3). These In 2015, WHO defines DIPNECH as a preinvasive lesion char-
morphological findings were suggestive of DIPNECH.1 acterised by an idiopathic generalised proliferation of pulmo-
Our Thoracic Oncology multidisciplinary clinical team nary neuroendocrine cells that may stay confined to the mucosa
proposed to perform chromogranin A serum dosing, which was of the airways or invade locally to form tumourlets or carcinoid
normal, and a combined PET and CT (PET/CT) with 68Ga-DO- tumours (≤5 or >5 mm in diameter, respectively). Often, it can
TA-NOC that showed no clear evidence of tumour with soma- be accompanied by constrictive bronchiolitis due to chronic
tostatin receptors. lymphocytic inflammation and fibrosis of the involved airways.1
It is reported that patients with DIPNECH range from 36 to
Differential diagnosis 84 years of age and 93% of the patients are women.4
In this clinical context and due to the presence of mosaic perfu- DIPNECH can be presented without any clinical or radiolog-
sion and micronodules, the diagnoses considered most likely ical features of airway disease1 5 6; however, Rossi et al proposed
would be asthma (cough variant) and occupational lung disease. the term ‘DIPNECH syndrome’ to represent a different patient
Although it was unlikely, we could not exclude that it was not subgroup similar to the case of our patient, characterised by
pulmonary metastasis. After surgical biopsy results, the histolog- respiratory symptoms, airflow obstruction, mosaic attenuation
ical pattern was diagnostic of DIPNECH. 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-oesopha-
geal 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 diag-
nosis of DIPNECH1 2 5–7; nonetheless, some authors defend that
in the appropriate clinical and radiological setting, transbron-
chial 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
Figure 3  Positive staining for CD56 confirms the neuroendocrine inflammatory response induced by neuroendocrine cell–secreted
nature of the proliferation (CD56 immunohistochemistry). neuropeptides despite the lack of strong evidence of efficacy.
2 Pedro PI, et al. BMJ Case Rep 2018;11:e226203. doi:10.1136/bcr-2018-226203
 Rare disease
Patients can ultimately be referred for lung resection or lung Contributors  All the authors of this article have directly participated in the
transplantation evaluation in the presence of severe respiratory planning, execution and analysis of this case report. PIP was involved in patient’s
follow-up consult, bibliographic research and manuscript writing. DC and ML were
symptoms associated with progressive obliterative bronchiol- involved in patient’s follow-up consult and manuscript review. AO performed the

BMJ Case Rep: first published as 10.1136/bcr-2018-226203 on 28 November 2018. Downloaded from file:/ on 10 February 2019 by guest. Protected by copyright.
itis.1 2 6 11 histopathology analysis, contributed to the diagnosis of the disease and manuscript
In the case of our patient, due to persistent symptoms, it was review. All authors read and approved the final version submitted.
decided to start oral prednisolone. She showed mild symptom Funding  The authors have not declared a specific grant for this research from any
improvement, but as we tried to progressively reduce the dosage, funding agency in the public, commercial or not-for-profit sectors.
the symptoms grew worse. The patient was started on octreotide Competing interests  None declared.
and it was possible to progressively reduce the steroid dosage
Patient consent  Obtained.
and stop it, with symptomatic improvement. The lung function
and radiological changes remain stable to date. Provenance and peer review  Not commissioned; externally peer reviewed.
We cannot be certain that our patient has no carcinoid tumour,
but knowing that the disease is preinvasive, a major issue is the
References
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in the literature.1 2 6 In our case, we chose to initially do PET/ Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. eds. WHO classification of
CT with 68Ga-DOTA-NOC to help us exclude the presence of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press, 2015:78–9.
the active carcinoid tumour with somatostatin receptors, which 2 Rossi G, Cavazza A, Spagnolo P, et al. Diffuse idiopathic pulmonary neuroendocrine
cell hyperplasia syndrome. Eur Respir J 2016;47:1829–41.
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Learning points
5 Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine
cell hyperplasia: an under-recognised spectrum of disease. Thorax 2007;62:248–52.
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►► It affects mainly middle-aged women and usually presents neuroendocrine cell hyperplasia diagnosed by tranbronchoscopic cryoprobe biopsy
with complaints of chronic cough and wheezing. technique. Respirol Case Rep 2017;5:e0275–3.
►► At chest CT, the key features are mosaic perfusion and 9 Chauhan A, Ramirez RA. Diffuse Idiopathic Pulmonary Neuroendocrine Cell
Hyperplasia (DIPNECH) and the role of somatostatin analogs: a case series. Lung
multiple lung nodules, but can also be seen bronchiectasis, 2015;193:653–7.
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►► The main differential diagnoses based on the chest CT images neuroendocrine cell hyperplasia. Am J Respir Crit Care Med 2012;185:341.
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Pedro PI, et al. BMJ Case Rep 2018;11:e226203. doi:10.1136/bcr-2018-226203 3