Open Journal of Respiratory Diseases, 2013, 3, 68-72 Published Online May 2013 (
A Case of DIPNECH and Review of
the Current Literature
Patrick D. Mitchell*, Marcus P. Kennedy, Michael T. Henry
Cork University Hospital, Cork, The Republic of Ireland
Email: *
Received January 24, 2013; revised February 25, 2013; accepted March 3, 2013
Copyright © 2013 Patrick D. Mitchell et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Diffuse Idiopathic Neuroendocrine Cell Hyperplasia (DIPNECH) is a rare pulmonary disease. It was first described by
Aguayo et al. in 1992, and recognised by the World Health Organisation in 2004 as a precursor lesion to the develop-
ment of pulmonary carcinoid tumour. DIPNECH has been described in several isolated case reports and series. This
article describes a case of DIPNECH and summaries the recen t literature in an attempt to raise awareness of th is disease
and management options.
Keywords: Neuroendocrine; Carcinoid; DIPNECH
1. Case Review
This case report describes a 73-year-old female with
symptoms of intermittent cough, flushing and wheeze for
approximately 18 months. A chest x-ray revealed acir-
cumscribed 1.2 cm opacity in her left upper lobe. She
was an ex smoker with a ten year pack history. A con-
trast thoracic CT scan demonstrated a 1.4 cm nodule in
the left upper lobe biopsied by a CT guided procedure
(Figure 1(a)) and multiple other subcentimetre nodules
scattered through both lung (Figure 1(b)).
Histological analysis revealed neoplastic neuroendo-
crine cell proliferation consistent with a carcinoid tumour.
She had a PET/CT scan which was reported as normal
with no increased FDG uptake detected. She went on to
have an elective left upper lobectomy and mediastinal
The surgical specimen was examined and confirmed
the diagnosis of a carcinoid tumour but also that of sev-
eral discrete separate carcinoid tumourlets and the pres-
ence of Diffuse Idiopathic Neuroendocrine Cell Hyper-
plasia (DIPNECH) (Figure 2).
The lymph nodes sampled were benign. She was dis-
charged with regular three monthly follow up and imag-
ing. Unfortunately her symptoms of wheeze, cough and
episodic facial flushing failed to subside. A repeat CT
thorax demonstrated unchanged sub centimetre nodules
as previously described. A Somatostatin labelled scan did
not detect any abnormalities suggestive of carcinoid tu-
mour. Biochemical tests including serum Chromogranin
A, Chromogranin B and Urinary 5-Hydrxyindolacetic
Acid (5-HIAA) were all within normal physiological
ranges. She was commenced on a somatostatin analogue
Sandostatin® (Novatis, UK), 50 mg given once every
four weekssubcutaneously. Her symptoms of wheeze,
flushing and diaphoresis abated within weeks of com-
mencing treatment. CT thorax with contrast one year
later demonstrated no increase in the size of the lung
nodules. This case is a presentation of persistentpulmon-
ary carcinoid syndrome despite the excision of a carci-
noid tumour with DIPNECH concomitantly found and
treated with a Somatostatin analogue.
2. Introduction
Pulmonary neuroendocrine cells are found in very small
numbers in the adult lung. These cells produce many
physiologically active peptides such as Bombesin, Sero-
tonin, Substance P, Calcitonin and Gastrin. These pep-
tides have been shown to stimulate fibroblasts prolifera-
tion, cause bronchoconstriction and have other paracrine
effect (6). The World Health Organization (WHO) 2004
Pulmonary Neoplasm classification system formally
recognised diffuse idiopathic pulmonary neuroendocrine
cell hyperplasia (DIPNECH) as a precursor lesion to the
development of pulmonary carcinoid tumour and tu-
mourlets [1,2]. Aguayo et al. was the first to formally de-
*Corresponding a uthor.
opyright © 2013 SciRes. OJRD
Figure 1. Axial Contrast Ct thorax of a 73-year-old female
with symptoms of intermittent cough, flushing and wheeze
for approximately 18 months. (a) Demonstrates the 1.4 cm
left upper lobe nodule; (b) Demonstrates three smaller sub
centimetre nodules (red arrows).
scribe this lesion in 1992 in a case series of six patients.
In these six patients the authors described diffuse pul-
monary neuroendocrine cell hyperplasia in non-smokers
with no other lung disease.
3. Clinical Presentation
The demographic profile of DIPNECH is limited due to
its rarity. From the available case reviews it appears that
90% of those histologically confirmed have been diag-
nosed in females with a mean age of 62 (range 56 - 76)
[3]. About 67% of these patients were remote or life-long
non-smokers [4]. Of cases diagnosed in one case review
90% of patients were found to have pulmonary symp-
toms and the remainder was incidental findings found on
surgical biopsies. Symptoms reported included cough
(70%), dyspnoea (63%) and wheezing (25%) [3]. In an-
other case series Davis et al. identified 19 patients with
histologically confirmed DIPNECH. In this review 10
patients were asymptomatic (8 of these were under sur-
veillance for previously diagnosed cancer) whilst 9 pa-
Figure 2. (a) High power image of the CT guided biopsy
showing sparse Ki 67 staining suggestive of a low mitotic
turnover; (b) Stained extensively by CD 56 which is found
with neuroendocrine tumours.
tients had symptoms of dyspnoea (n = 6), cough (n = 4),
pleuritic chest pain (n = 2) and haemoptysis (n = 1) [5].
Interestingly there was a striking range from symptom
onset to diagnosis of 4 to 16 years (mean of 8.4 years).
This lag time suggests a relatively indolent course and
explains why it has often been misdiagnosed as asthma.
The patient reported in the initial case presentatio n is the
only case described where carcinoid syndrome persisted
after the surgical removal of a carcinoid tumour and
DIPNECH to our knowledge. Most patients with DIP-
NECH have indolent and non-progressive course, with
83% of patients with symptoms being alive at 5 years [5].
The majority of docu mented cases of DIPNECH occur in
non-smoking midd le aged females presen ting with cough
and obstructive spirometry. The general prognosis of pa-
tients with carcinoid tumourlets, probably an advanced
form of DIPNECH, has been shown be very good as
evidenced by one group reviewing 28 patients post sur-
gical resections which included one case of DIPNECH.
In this cohort of 28 patients 3 had died over a six year
surveillance period with two deaths following from lung
transplantation for progressive obstructive lung disease
and the other an unknown cause [6]. Pulmonary function
tests (PFTs) demonstrate obstructive d efects in ab ou t ha lf
Copyright © 2013 SciRes. OJRD
of cases (54%) but can be restrictive (13%) or demon-
strate a mixed obstructive and restrictive pattern (17%).
In the review by Davies et al. all symptomatic patients
had abnormal PFTs. Miller et al. looked at 25 consecu-
tive patients undergoing resection for peripheral carci-
noid tumours and found that only 8% had evidence of
airway obstruction associated with neuroendocrine cell
hyperpl a s i a [7 ].
4. Diagnosis
rkers of disease pulmonary neuroendo-
ronchoscopy in DIPNECH has been de-
oendocrine cell hyperplasia is
Biochemical ma
crine cells derive from the embryological foregut cells.
This differentiation is clinically relevant as foregut and
hindgut neuroendocrine cells usually lack the enzyme
DOPA decarboxylase and are therefore unable to convert
5-hydroxytryptophan (5-HT) to 5-hydroxyindoeacetic
acid (5-HIAA), a metabolite excreted in urine which can
be a useful marker of carcinoid activity. The usefulness
of serum biomarkers in both DIPNECH and pulmonary
carcinoid tumour seems to be limited with only isolated
case reports of elevated serum Chromogranin A and uri-
nary 5-HIAA levels [5,8]. Radiological imaging has an
essential role to play in the diagnosis of DIPNECH.
Pulmonary nodules may be identified on Chest X-ray but
it doesn’t possess the specificity to out rule subtle p aren-
chymal abnormalities found in DIPNECH.High resolu-
tion thoracic CT imaging may reveal small sub-centime-
tre nodules usually below 5mm in 60% of cases. A mo-
saic attenuation pattern is alsocommonly found and
probably represents the underlying histological features
of a constrictive bronchiolitis. Ground glass changes, air
trapping and in some case bronchiectasis are other de-
scribed radiological features. CT thorax identifies at least
one lung nodule in approximately 60% of patients,
ground-glass attenuation in 30% patients, bronchiectasis
in about 20% of patients and mosaic pattern in 17% in
another review [9]. None of these abnormalities are
pathognomic. This should prompt further appropriate in-
The role of b
ribed. Bronchoscopic inspection, bronchioalveolar lav-
age (BAL) and both endobronchial and transbronchial
biopsies are recommended to rule out other respiratory
conditions [10]. BAL results have been found to have a
lymphocytosis of around 30% in two confirmed cases of
DIPNECH. A BAL lymphocytosis of 30% has been de-
scribed in two cases of DIPNECH REF However the
paucity of published experience with bronchoscopy and
DIPNECH makes it largely conjecture to comment fur-
ther. Like wise endobronchial biopsies are felt to have a
limited diagnostic role in this condition. This is due to
the large biopsy sample needed to diagnose DIPNECH.
There are several cases reports of DIPNECH diagnosed
via transbronchial biopsy. Nasser et al. points out from a
literature review that the yield from transbronchial bi-
opsy is only about 12% in diagnosing DIPNECH. This is
due to the large amount of tissue necessary to pathologi-
cally characterize tumourlet and DIPNECH. The gold
standard for diagnosing DIPNECH is a surgical lung
biopsy [11]. Sampling error will occur if insufficient nu m-
bers of airways are included in a biopsy. Diagnosis also
relies heavily on histologic specimens being prepared
correctly in addition to an experienced lung histopa-
thologist. Nasser et al. reported that 88% of cases re-
quired a surgical biopsy to confirm the diagnosis [12].
The pathological diagnosis of DIPNECH is reserved only
for cases in which there is neuroendocrine cell hyperpla-
sia confined to airway epithelium. These proliferations
are superficial to the basement membrane and confined
to the bronchial and bronchiolar epithelium unlike carci-
noid tumourlets which invade the basement. There is
wide- spread proliferation of pulmonary neuroendocrine
cells which can manifest as increased numbers of indi-
vidual cells, small groups, or nodu lar aggregates or nests
in the bronchial or bronchiolar epitheliu m is the hallmark
of DIPNECH (Figure 3).
Reactive pulmonary neur
mmon but a separate entity to DIPNECH. One study
compared the morphology and antigenic profile of pul-
monary neuroendocrine cells (PNECs) proliferating as a
reaction to pulmonary injury with those proliferating in
diffuse idiopathic pulmonary neuroendocrine cell hyper-
plasia (DIPNECH) in which carcinoids develop. In this
study there were differences between the groups in ex-
pression of p53, p16 and Ki67. These are cell prolifera-
tion antigens. These antigens were seen more consis-
tently and earlier in DIPNECH than reactive pulmonary
neuroendocrine cell hyperplasia. CD56, chromogranin,
Figure 3. This a low power picture of a synaptophysinim-
munohistochemical stain which shows nicely a group of
positively staining neuroendoc rine cells (brown) confined to
bronchiolar epithelium not penetrating through the base-
ment membrane which is the classic appearance of DIP-
NECHmembrane (see Figure 3).
Copyright © 2013 SciRes. OJRD
synaptophysin are the immunohistochemical markers of
rted that 40% of cases of con-
5. Management
o consensus led guidelines for the
6. Conclusion
e clinical entity and its diagnosis re-
[1] W. D. Travis, er-Hermlink and C.
Neuroendocrine Cells. A Ki-67 index is used as a marker
of cell proliferation [13].
Nasser et al. again repo
med DIPNECH there was a concomitant carcinoid
tumour and 70% of cases had concomitant carcinoid tu-
mourlets [12]. Pulmonary neuroendocrine cells commonly
produce bombesin and gastrin-releasing peptides [14].
These amine peptides stimulate fibroblasts and broncho-
constriction of airway cells which may lead to peribron-
chiolar and interstitial fibrosis accounting for symptoms
and spirometric abnormalities [14]. DIPNECH stains
nearly universally for EGFR (cells exhibited a maximum
EGFR expression score of 3 in 100% of cells) and in
contrast 90% of large cell neuroendocrine and small cell
neuroendocrine carcinomas were negative for EGFR.
This may have certain clinical ramifications as well as a
potential pathophysiological role [15]. In another case
report DIPNECH found in association with an invasive
lung adenocarcinoma DIPNECH has been described in
association with an invasive lung adenocarcinoma but
this case appears isolated [16].
Currently there are n
management of DIPNECH. Essentially the evidence for
treatment is based upon case reports and small case series
and the follow up of these patients. Swigris et al. pre-
sented 4 patients and found an excellent long-term prog-
nosis over 14 years [4]. Reviewing of the literature sug-
gests that current therapeutic options have remained fo-
cused on steroid-based therapies or Somatostatin ana-
logues in symptomatic patients [14,17-19]. The possible
explanationfor the effectiveness of steroids would be the
blunting of the inflammatory response stimulated by the
neuropeptide secretions from neuroendocrine cell groups
[14]. If DIPNECH is histologically confirmed options
may include observational “watch and wait” policy or
trial of inhaled or systemic corticosteroid therapy with
bronchodilator therapy particularly in patients who dem-
onstrate reversible airflow obstruction [12,20,21]. Patients
with severe refractory respiratory diseasemay ultimately
are referred need to be referred for lung transplant ev alu a-
tion [4]. Chemotherapy in one small case review of two
patients did not have favourable results with one patient
ultimately died from progressive respiratory failure while
on treatment with fluorouracil [22]. In patients in who
are symptomatic with carcinoid symptoms, somatostatin
analogues and interferon α have been proposed as tu-
mourostatic agents [17,18,23,24]. The patient described
in the introductory case study to this review was treated
with a lung resection and with a Somatostatin analogue
and responded to this therapy with a significant decrease
in wheeze, flushing and diarrhoea and stability in the
appearance of sub centimetre pulmonary nodules on fol-
low up chest imaging. Gorschtein et al. retrospectively
reported on 11 patients, all female, with both carcinoid
lung tumour and DIPNECH who were treated with lung
resection and a somatostatin analogue. All patients were
alive at follow up of a mean of 4.5 years [10,24].. There
are also reports of clinical endocrinopathies in patients
with DIPNECH and include acromegaly and pituitary
adenoma, MEN1 syndrome and parathyroid gland hy-
perplasia with lung tissue immunohistochemical staining
positive for GHRH and ACTH [19]. This may relate to
its neuroendocrine origins.
DIPNECH is a rar
quires a high level of suspicion with the available corre-
lating clinical and radiological findings. Several diagno-
sis of DIPNECH have made inadvertently through surgi-
cal biopsy. Again, to make the diagnosis a surgical lung
biopsy is regarded as the gold standard. The management
of patients with DIPNECH remains controversial but
several treatments including surgery, steroids and soma-
tostatin analogues are frequently successful. Further stud-
ies with somatostatin analogue and steroid therapies in
patients with DIPNECH who have evidence of hormonal
syndromes or obstructive spirometry are certainly war-
ranted. Given its rarity a multi-centred registry should be
established to further guide clinicians and patients.
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