Alimentary Pharmacology and Therapeutics

Gastric carcinoid after long-term use of a proton pump inhibitor

C. S. Jianu*,, R. Fossmark*,, T. Viset, G. Qvigstad*,, . Srdal, R. Mrvik & H. L. Waldum*,

*Departments of Gastroenterology
and Hepatology, St. Olavs Hospital,
Trondheim, Norway.

Department of Cancer Research and

Molecular Medicine, Faculty of
Medicine, Norwegian University of
Science and Technology, Trondheim,
Norway.

Departments of Pathology and

Medical Genetics, St. Olavs Hospital,
Trondheim, Norway.

Departments of Surgery, St. Olavs

Hospital, Trondheim, Norway.

Correspondence to:
Dr C. S. Jianu, Department of
Gastroenterology and Hepatology, St.
Olavs Hospital, Prinsesse Kristinas gt.
5, 7030 Trondheim, Norway.
E-mail: constantin.jianu@ntnu.no

Publication data
Submitted 26 April 2012
First decision 18 May 2012
Resubmitted 18 July 2012
Accepted 18 July 2012

SUMMARY
Background
Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and give hypergastrinemia secondary to gastric hypoacidity. PPI treatment therefore induces enterochromafn-like (ECL) cell hyperplasia. Longterm hypergastrinemia in rodents and man also leads to ECL cell neoplasia.
Whether long-term PPI treatment will induce ECL cell neoplasia in man
has been disputed.
Aim
To describe gastric carcinoids in two patients with a history of long-term
PPI use.
Results
Two patients had been taking PPI for 1213 years due to gastro-oesophageal reux disease. At routine upper gastrointestinal endoscopy a solitary
tumour was found in the oxyntic mucosa of both patients. Histology from
the tumours showed in both cases a well-differentiated neuroendocrine
tumour. Biopsies from at oxyntic mucosa showed no signs of atrophic
gastritis and a normal presence of parietal cells in both cases, but hyperplasia of ECL cells. The tumour in patient 1 was resected endoscopically. After
cessation of PPI treatment the tumour regressed in patient 2 and the ECL
cell hyperplasia regressed in both patients. In patient 2 serum gastrin and
chromogranin A were elevated during PPI treatment, and normalised after
cessation of treatment. In patient 1, unfortunately, we had serum only after
treatment, and at that time both parameters were normal.
Conclusion
These cases show that hypergastrinemia secondary to proton pump inhibitors treatment, like other causes of hypergastrinemia, may induce enterochromafn-like cell carcinoids in man.
Aliment Pharmacol Ther

2012 Blackwell Publishing Ltd

doi:10.1111/apt.12012

C. S. Jianu et al.
INTRODUCTION
The ECL cell is the most predominant gastric neuroendocrine cell population and produces and releases histamine.1 The ECL cells have close connection to the acid
producing parietal cells.2 Gastrin stimulates the ECL cell
by interaction with a CCK2/ gastrin receptor. G cells
located in the antral mucosa play an important role in
regulating gastric acid secretion by releasing gastrin into
the bloodstream, thereby activating the release of
histamine from the ECL cells. Histamine subsequently
stimulates the parietal cells to produce hydrochloric acid.
The G cells have a direct contact with the gastric lumen
(open type) and gastrin release is inhibited or stimulated
by the presence or absence of gastric acid.
Gastric carcinoids are mainly ECL tumours. They are
classied in three groups3: (i) Gastric carcinoid type 1,
due to hypergastrinemia secondary to atrophic gastritis.
(ii) Gastric carcinoids type 2 due to hypergastrinemia
secondary to gastrinoma and (iii) gastric carcinoids type
3 in patients with normal serum gastrin. Gastric
carcinoids type 1 and 2 have a good overall prognosis
with a 96100% 5-year survival.4 However, metastatic
disease and highly malignant transformation have been
reported.5 The type 3 gastric carcinoids have a poorer
prognosis with 50% 5-year survival.4 PPIs are potent
inhibitors of gastric acid secretion. Patients treated with
PPI develop secondary hypergastrinemia and ECL cell
hyperplasia. However, in humans it has been disputed
whether PPI treatment will lead to ECL cell-derived
tumours. We here describe gastric carcinoids in two
patients with a history of long PPI use.
PATIENT 1
A 55-year-old man was referred to a upper gastrointestinal endoscopy (UGE) due to preoperative evaluation
before antireux surgery. An 18-mm tumour localised to
the upper gastric body was found and resected endoscopically. Histological examination revealed it to be a
well-differentiated neuroendocrine tumour (G1 neuroendocrine tumour). The patient had a previous medical
history of gastro-oesophageal reux disease (GERD) and
had been treated with PPI for the last 12 years, lansoprazole 30 mg daily for 10 years and esomeprazole 40 mg
daily for 2 years. He also had arterial hypertension and
was treated with lisinopril 40 mg daily; irbesartan 30 mg
daily; amlodipine 10 mg daily and acetylsalicylic acid
160 mg daily. Unfortunately serum gastrin and CgA
were not assessed during PPI treatment, but were normal
(5 pmol/L and 4 nmol/L, respectively) 20 months after
stopping PPI treatment.
2

Helicobacter pylori (HP) was not detected in biopsies.

Computer tomography of the stomach and abdomen
showed an 18-mm gastric tumour localised to the
proximal part of the gastric body without evidences of
metastases. Octreotide scintigraphy was positive in the
gastric area.
Intragastric 24-h pH registration: After PPI cessation,
the intragastric pH was below 4.0 in 82% of the time,
demonstrating the presence of gastric acidity.
Histological examination of the tumour showed a typical
well-differentiated neuroendocrine pattern (Figure 1a) positive for CgA (Figure 1b) and VMAT-2 (Figure 1c). The
proliferation index (Ki-67) was lower than 2%. At the time
of diagnosis, biopsies from the oxyntic mucosa were normal without gastritis (Figure 2a). By immunohistochemistry using antibodies towards H+K+ATPase normal
presence of parietal cells was found (Figure 2b) whereas
antibodies against CgA disclosed linear ECL cell hyperplasia (Figure 2c) which was no longer present 20 months
after PPI discontinuation (Figure 2d).

PATIENT 2
A 68-year-old women was referred to our department
due to dyspeptic symptoms. At UGE one 15-mm
tumour localised to the proximal gastric body was
found. Histological examination showed a G1 neuroendocrine tumour. Hiatal hernia and GERD had been
diagnosed 13 years previously and she had received
treatment with lansoprazol 30 mg daily for 10 years
and pantoprazole 40 mg daily the last 3 years. The
patient had undergone several operations: total hysterectomy due to cervix cancer 47 years ago, cholecystectomy due to acute cholecystitis 25 years ago and
surgical spinal fusion L5-S1 due to spondylolisthesis
23 years ago. Her previous medical history included
type-2 diabetes, syringomyelia, gastric ulcer with HP
infection, chronic polyarthritis, arterial hypertension,
hypothyreosis and chronic obstructive pulmonary
disease due to cigarette smoking. The patient used
several drugs: metformin 500 mg daily, glibenclamid
1.75 mg daily, metoclopramide 1030 mg daily,
unitrazepam 1 mg daily, diazepam 5 mg daily, paracetamol 500 mg-1 g daily, amlodipine 10 mg daily and
levothyroxine 50 lg daily.
Fasting serum gastrin and CgA were both elevated
during PPI treatment (191 pmol/L and 19.7 nmol/L,
respectively) and normalised 3 months after PPI
termination (33 pmol/L and 4.5 nmol/L)
HP was found in biopsies from the gastric antrum
and eradication treatment was prescribed.
Aliment Pharmacol Ther
2012 Blackwell Publishing Ltd

Gastric carcinoid and proton pump inhibitors in man

(a)

(d)

(b)

(e)

(c)

(f)

Figure 1 | Tumour biopsies showing differentiated gastric carcinoid. Haematoxylin eosin safran staining and
immunhistochemistry using anti-CgA and anti-VMAT-2 antibodies. Patient 1: (a) HES 940; (b) CgA 940; (c) VMAT-2
940. Patient 2: (d) HES 940; (e) CgA 940; (f) VMAT-2 940.

Computer tomography of the stomach and abdomen

showed a 15-mm gastric tumour localised in the proximal
part of the gastric body without evidences of metastases.
Octreotide scintigraphy was without pathological ndings.
Intragastric 24-hours pH registration: After PPI cessation,
the intragastric pH was below 4.0 in 84% of the time, demonstrating the presence of normal gastric acidity.
Several UGEs were performed: at the diagnosis a
15-mm tumour localised to the gastric body was identied. That tumour was still present 2 months after PPI
discontinuation but had disappeared 3 months after PPI
discontinuation.
The microscopic examination of the tumour showed a
typical well-differentiated neuroendocrine pattern
(Figure 1d) positive for CgA (Figure 1e), and VMAT-2
(Figure 1f). The proliferation index (Ki-67) was lower
than 2%. Flat oxyntic mucosa at the time of the
carcinoid detection showed no signs of atrophic gastritis
(Figure 2e), abundant presence of parietal cells
(Figure 2f), and pronounced linear and micronodular
ECL cell hyperplasia (Figure 2g). Three months after
Aliment Pharmacol Ther
2012 Blackwell Publishing Ltd

stopping PPI treatment, the linear and micronodular

ECL cell hyperplasia had disappeared. However, a diffuse
increased ECL cell density was still present (Figure 2h).

DISCUSSION
The PPIs inhibit the nal step of gastric acid secretion by
irreversible binding to the parietal cell H+K+ATPase (the
proton pump). PPIs are efcient inhibitors of gastric acid
secretion making patients treated with PPI hypo/anacidic
most of the time resulting in secondary hypergastrinemia
in both man and rat.6 Gastrin not only stimulates ECL cell
function (production and release of histamine) but has
also a trophic effect on the oxyntic mucosa in general and
the ECL cell in particular.7 Hypergastrinemia is caused by
either hypo/anacidity such as seen in patients with atrophic gastritis or due to gastrinoma with increased gastric
acid secretion. The ECL cell hyperplasia and neoplasia has
been reported in patients with atrophic gastritis, in
patients with sporadic gastrinoma8 and patients with
gastrinoma as a part of MEN I.9 Long-term PPI treatment
is another condition with gastric hypo/anacidity and
3

C. S. Jianu et al.
(a)

(e)

(b)

(f)

(c)

(g)

(d)

(h)

Figure 2 | Biopsies from at oxyntic mucosa. Haematoxylin eosin safran staining and immunhistochemistry using antiH+K+ATPase and anti-CgA antibodies. Patient 1: (a) HES 9100 during PPI treatment; (b) H+K+ATPase 9200 during
PPI treatment; (c) CgA 9200 during PPI treatment showing linear ECL cell hyperplasia and (d) CgA 9100 2 years
after PPI discontinuation showing normal ECL cell density. Patient 2: (e) HES 9100 during PPI treatment; (f)
H+K+ATPase 9100 during PPI treatment; (g) CgA 9200 and 9400 during PPI treatment showing linear and
micronodular ECL cell hyperplasia and (h) CgA 9100 3 months after PPI discontinuation showing diffuse ECL cell
hyperplasia.

secondary hypergastrinemia.6 It has been known that

treatment/dosing with efcient inhibitors of acid secretion
causes ECL cell hyperplasia in both man and rodents.6, 7
In rodents, long-term dosing of PPI or so called insurmountable histamine 2 blocker (H-2-blocker) may also
induce ECL cell-derived tumours of variable malignancy.1012 In man there are three reports of gastric neuroendocrine tumours which developed after long-term H2-blocker/PPI treatment,1315 and in addition AstraZene4

ca reported some cases with ECL tumours that developed

during PPI treatment in patients with increased acid
secretion and disappearance of the tumours after discontinuation of PPI.16 These ndings are best explained by
hypergastrinemia causing ECL cell hyperplasia leading to
rebound acid hypersecretion as well as predisposing to
ECL cell neoplasia. Similarly to what was described by
Astra-Zeneca,16 the tumour in patient 2 disappeared after
stopping PPI treatment. In this context it should also be
Aliment Pharmacol Ther
2012 Blackwell Publishing Ltd

Gastric carcinoid and proton pump inhibitors in man

recalled that gastric carcinoids due to atrophic gastritis
may disappear when the functional hypergastrinemia is
removed by the treatment with the gastrin receptor
blocker YF47617 or antrectomy.18 However, at a certain
stage these ECL cell-derived carcinoids may become gastrin independent giving rise to highly malignant tumours
as seen in gastric carcinomas in patients with pernicious
anaemia5 and the highly malignant ECL cell-derived carcinoma after long-term PPI treatment that we described
recently.15 Concerns about the safety of long-term PPI use
in humans have previously been raised,19 and the present
report gives further evidence for risk of gastric neoplasia
after long-term acid inhibition. It may therefore be concluded that PPI-induced hypoacidity with secondary
hypergastrinemia will in long-term lead to ECL cell neoplasia as seen in every other condition with hypergastrinemia. However, what threat is this to our patients?
Recently, Brunner and co-workers described no ECL cell
tumours in a long-term (up to 15 years) follow-up study
of patients treated with PPIs due to severe peptic disease
or gastro-oesophageal reux disease.20 During this study
Helicobacter pylori infection was treated with antibiotics
resulting in a marked reduction of Helicobacter pylori
positive patients during the observation, which would be
expected to reduce the severity of the peptic ulcer disease.
No standard dose of PPI was used, but adjusted according
to symptoms. Thus, pantoprazole was given in doses from
20 to 160 mg daily. Taking into consideration the steep
concentration-response curve as well as the variation of
the bioavailability of PPIs21 it is reason to suspect that
some of the 36 patients followed for 15 years were not
treated with doses giving profound acid inhibition.20 The
great variation in serum gastrin20 also suggests that some
patients were markedly hypoacidic in their stomach
whereas others had normal gastric acidity. Nevertheless,
the study of Brunner et al.20 does suggest that most
patients will not develop any ECL-derived tumours at
least during the rst decade of PPI treatment. Thus, the
risk of inducing ECL cell neoplasia is small in people
starting PPI at old age.

On the other hand, it is worth reminding that

well-differentiated neuroendocrine tumours in general
are slow growing with patients surviving for years even
after liver metastases. Therefore, observations of 10 and
even 15 years (making up about 25% of expected life
span of a patient at 20 years of age) without the occurrence of ECL cell neoplasia should not be too reassuring
and should be compared with the appearance of such
tumours at the age of 1 year (50% of life span) in rats.
Moreover our two patients presented here as well as the
previously described highly malignant one15 were diagnosed after 1213 years of treatment. Although gastric
carcinoid incidence has been reported to increase,4 this
has not been attributed to PPI use but more to improved
diagnostic. It should also be recalled that parallel to the
increased use of PPIs, there has been a decline in the
rate of Helicobacter pylori infection. Since Helicobacter
pylori infection of the oxyntic mucosa is an important
cause of atrophic gastritis and thus hypergastrinemia22
predisposing to ECL cell carcinoids,23 epidemiological
studies may not detect an increase in ECL carcinoids
due to other causes. Therefore, it is important with initial case reports making clinicians aware of the problem.

CONCLUSIONS
Taking into consideration that every other condition with
long-term hypergastrinemia in animals and man causes
ECL neoplasia, it seems highly likely that PPI-induced
hypergastrinemia in man also should do so. Moreover, it
has for long been known that the initial steps in ECL cell
neoplasia (hyperplasia of different degrees) are seen in the
patients on PPI treatment. Theoretically, it may, nevertheless, be claimed that the ECL tumours in our patients on
long-term PPI treatment were coincidental. However,
since the tumour in case 2 disappeared after stopping PPI
treatment and normalisation of gastrin, such a coincidence
is highly unlikely.
ACKNOWLEDGEMENT
Declaration of personal and funding interests: None.

REFERENCES
1. Hakanson R, ed. Gastric endocrine cell
typing at the light microscopic level.
Amsterdam: Elsevier, 1991.
2. Gustafsson BI, Bakke I, Hauso O, et al.
Parietal cell activation by arborization
of ECL cell cytoplasmic projections is
likely the mechanism for histamine
Aliment Pharmacol Ther
2012 Blackwell Publishing Ltd

induced secretion of hydrochloric

acid. Scand J Gastroenterol 2011;
46: 5317.
3. Rindi G, Luinetti O, Cornaggia M,
Capella C, Solcia E. Three subtypes of
gastric argyrophil carcinoid and the
gastric neuroendocrine carcinoma: a

clinicopathologic study. Gastroenterology

1993; 104: 9941006.
4. Modlin IM, Lye KD, Kidd M. Carcinoid
tumors of the stomach. Surg Oncol
2003; 12: 15372.
5. Qvigstad G, Falkmer S, Westre B,
Waldum HL. Clinical and
5

C. S. Jianu et al.

6.

7.

8.

9.

10.

11.

histopathological tumour progression in

ECL cell carcinoids (ECLomas).
Apmis 1999; 107: 108592.
Larsson H, Carlsson E, Mattsson H,
et al. Plasma gastrin and gastric
enterochromafnlike cell activation and
proliferation. Studies with omeprazole
and ranitidine in intact and
antrectomized rats. Gastroenterology
1986; 90: 3919.
Bakke I, Qvigstad G, Brenna E, Sandvik
AK, Waldum HL. Gastrin has a specic
proliferative effect on the rat
enterochromafn-like cell, but not on
the parietal cell: a study by elutriation
centrifugation. Acta Physiol Scand 2000;
169: 2937.
Cadiot G, Lehy T, Mignon M. Gastric
endocrine cell proliferation and fundic
argyrophil carcinoid tumors in patients
with the Zollinger-Ellison syndrome.
Acta Oncol 1993; 32: 13540.
Solcia E, Capella C, Fiocca R, Rindi G,
Rosai J. Gastric argyrophil carcinoidosis
in patients with Zollinger-Ellison
syndrome due to type 1 multiple
endocrine neoplasia. A newly recognized
association. Am J Surg Pathol 1990; 14:
50313.
Havu N. Enterochromafn-like cell
carcinoids of gastric mucosa in rats
after life-long inhibition of gastric
secretion. Digestion. 1986; 35(Suppl. 1):
4255.
Poynter D, Pick CR, Harcourt RA,
et al. Association of long lasting
unsurmountable histamine H2 blockade

12.

13.

14.

15.

16.

17.

and gastric carcinoid tumours in the

rat. Gut 1985; 26: 128495.
Fossmark R, Martinsen TC, Bakkelund
KE, Kawase S, Waldum HL. ECL-cell
derived gastric cancer in male cotton
rats dosed with the H2-blocker
loxtidine. Cancer Res 2004; 64: 3687
93.
Dawson R, Manson JM. Omeprazole in
oesophageal reux disease. Lancet 2000;
356: 17701.
Haga Y, Nakatsura T, Shibata Y, et al.
Human gastric carcinoid detected
during long-term antiulcer therapy of
H2 receptor antagonist and proton
pump inhibitor. Dig Dis Sci 1998; 43:
2537.
Jianu CS, Lange OJ, Viset T, et al.
Gastric neuroendocrine carcinoma after
long-term use of proton pump
inhibitor. Scand J Gastroenterol 2012;
47: 647.
Food and Drug Administration. FDA
Background. Omeprazole Magensium
(Prilosec 1 TM) Astra Zeneca with
Proctor and Gamble. For the Joint
Meeting of the Nonprescription Drugs
Advisory Committee and the
Gastrointestinal Drugs Advisory
Committee On October 20, 2000.
Fossmark R, Srdal , Jianu C,
Qvigstad G, Boyce M, Waldum H.
YF476, a gastrin receptor antagonist,
causes regression of tumors and
normalizes serum chromogranin A in
patients with type 1 gastric carcinoids.
9th Annual ENETS Conferance for the

18.

19.

20.

21.

22.

23.

Diagnosis and Treatment of

Neuroendocrine Tumor Disease;
Copenhagen; Denmark 2012.
Hirschowitz BI, Grifth J, Pellegrin D,
Cummings OW. Rapid regression of
enterochromafnlike cell gastric
carcinoids in pernicious anemia after
antrectomy. Gastroenterology 1992; 102
(4 Pt 1): 140918.
Waldum HL, Brenna E, Sandvik AK.
Long-term safety of proton pump
inhibitors: risks of gastric neoplasia and
infections. Expert Opin Drug Saf 2002;
1: 2938.
Brunner G, Athmann C, Schneider A.
Long-term, open-label trial: safety and
efcacy of continuous maintenance
treatment with pantoprazole for up to
15 years in severe acid-peptic disease.
Aliment Pharmacol Ther 2012; 36:
347.
Pounder RE, Sharma BK, Walt RP.
Twenty-four hour intragastric acidity
during treatment with oral omeprazole.
Scand J Gastroenterol Suppl 1986; 118:
10817.
Oksanen A, Sipponen P, Karttunen R,
et al. Atrophic gastritis and
Helicobacter pylori infection in
outpatients referred for gastroscopy.
Gut 2000; 46: 4603.
Sato Y, Iwafuchi M, Ueki J, et al.
Gastric carcinoid tumors without
autoimmune gastritis in Japan: a
relationship with Helicobacter pylori
infection. Dig Dis Sci 2002; 47: 57985.

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2012 Blackwell Publishing Ltd