Rare disease
Case report
1
Pulmonology, Hospital Garcia
de Orta EPE, Almada, Portugal
2
Pathology, Hospital Garcia de
Orta EPE, Almada, Portugal
Correspondence to
Dr Paula Inês Pedro,
​paulaines.​gpedro@g​ mail.​com
Accepted 31 October 2018
© BMJ Publishing Group
Limited 2018. No commercial
re-use. See rights and
permissions. Published by BMJ.
To cite: Pedro PI, Canário D,
Lopes M, et al. BMJ Case
Rep 2018;11:e226203.
doi:10.1136/bcr-2018-
226203
Diffuse idiopathic neuroendocrine cell hyperplasia as
a rare cause of chronic cough
Paula Inês Pedro,1 Dolores Canário,1 Miguel Lopes,1 Ana Oliveira2
Summary
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   revealed stability of the alterations already
Diffuse idiopathic pulmonary neuroendocrine
cell hyperplasia (DIPNECH) consists of a primary
neuroendocrine cell proliferation often accompa-
nied by constrictive obliterative bronchiolitis. It is
considered an extremely rare preneoplastic condi-
tion 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 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
persistent and associated with mild exertional
dyspnoea and occasional wheezing. For symptom-
atic relief, she had been prescribed with corticoste-
roid 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.
Pedro PI, et al. BMJ Case Rep 2018;11:e226203. doi:10.1136/bcr-2018-226203
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 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 trap-
ping (figure 1).
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 bronchos-
copy with bronchoalveolar lavage which was unre-
vealing, 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
described.
It was decided to perform rigid bronchoscopy
with cryobiopsy, which showed pulmonary paren-
chyma 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 neuroendo-
crine cell hyperplasia and tumourlets, adjacent to
Figure 1  High-resolution CT of the chest showing
multiple bilateral micronodules and mosaic attenuation
with air trapping.
1
 Rare disease
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).
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
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-DO-
TA-NOC that showed no clear evidence of tumour with soma-
tostatin receptors.
Differential diagnosis
In this clinical context and due to the presence of mosaic perfu-
sion 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 histolog-
ical pattern was diagnostic of DIPNECH.
Figure 3  Positive staining for CD56 confirms the neuroendocrine
nature of the proliferation (CD56 immunohistochemistry).
2 Pedro PI, et al. BMJ Case Rep 2018;11:e226203. doi:10.1136/bcr-2018-226203
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.
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 constric-
tive 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 char-
acterised by an idiopathic generalised proliferation of pulmo-
nary 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 radiolog-
ical features of airway disease1 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-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
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 bronchiol-
itis.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.
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Pedro PI, et al. BMJ Case Rep 2018;11:e226203. doi:10.1136/bcr-2018-226203
Rare disease
Contributors  All the authors of this article have directly participated in the
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
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.
histopathology analysis, contributed to the diagnosis of the disease and manuscript
review. All authors read and approved the final version submitted.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-for-profit sectors.
Competing interests  None declared.
Patient consent  Obtained.
Provenance and peer review  Not commissioned; externally peer reviewed.
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