A 54-year-old Caucasian woman was
referred for upper endoscopic examination because of early satiety and midepigastric pain. Endoscopic
examination revealed thickened gastric folds and multiple polypoid lesions in the gastric body and
fundus, which were biopsied. Serologic workup showed markedly elevated serum levels of chromogranin A
(1500 pg/mL; normal <14 pg/mL) and gastrin (1400 pg/mL; normal <75 pg/mL). Based on this
endoscopic appearance, laboratory work-up, and the biopsy results, she underwent subtotal gastrectomy
with antrectomy. Slides from the thickened folds and nodules in the gastric body are shown.
Case 3 - Figure 1 - Gross image of the subtotal gastrectomy specimen demonstrating thickened rugal folds and several polypoid nodules in the gastric body, ranging up to 1.3 cm in diameter.
Case 3 - Figure 2 - Low power photomicrograph of one of the polyps in the body mucosa, showing a carcinoid tumor, with invasion into the superficial submucosa.
Case 3 - Figure 3 - High power photomicrograph of the carcinoid tumor, here showing a pseudoacinar architecture and the uniform neoplastic cells characteristic of carcinoid tumors.
Case 3 - Figure 4 - Low power photomicrograph of the thickened body mucosa, which demonstrates marked hyperplasia and dilatation of the specialized oxyntic (fundic) glands. The overlying foveolar neck regions and surface epithelium are of normal thickness.
Case 3 - Figure 5 - In many areas of body mucosa, the parietal cells were cytologically abnormal, with vacuolated cytoplasm and cytoplasmic protrusions into dilated oxyntic glands.
Case 3 - Figure 6 - The carcinoid tumors arose in a background of nodular neuroendocrine (ECL cell) hyperplasia, which is evident here at the base of the gastric body mucosa.
Additional Complete History:
The multiple polypoid lesions in the
gastric body and fundus were diagnosed as carcinoid tumors on multiple biopsies. There was no endoscopic
evidence of gastric or duodenal ulcerations. pH probe monitoring on two occasions revealed achlorhydria.
Serologic workup also showed a normal anti-parietal cell antibody level. Radiologic workup included a
normal computerized tomography (CT) scan of the abdomen, normal endoscopic ultrasound of the duodenum and
pancreas, and an Octreotide scan which failed to reveal any discrete focus of uptake outside the stomach.
She had never received proton pump inhibitors or other acid suppression therapy. Clinically, the patient
was considered to have multiple carcinoid tumors in the setting of either autoimmune gastritis or
Zollinger-Ellison syndrome, despite the atypical clinical and laboratory findings for either of these
conditions. She underwent subtotal gastrectomy with antrectomy. Abdominal exploration performed at the
time of surgery, including careful palpation of the duodenum and pancreas, failed to reveal any evidence
for gastrinoma. Four months later, the patient underwent completion gastrectomy due to the presence of
carcinoid tumor at the initial proximal gastric margin and nodularity in the proximal fundus detected on
repeat upper endoscopic examination. Her postoperative course was unremarkable, with the exception of an
anastomotic stricture that responded to dilatation. Her post-antrectomy serum gastrin level returned to
The resected stomach contained multiple small
nodules measuring from 0.1 cm – 1.3 cm and distributed throughout the body and fundus, which also
demonstrated prominent rugae. The antrum was normal. No ulcers were present, either within the gastric
mucosa or in the small portion of adjoining proximal duodenal bulb. Twenty-one lymph nodes were also
submitted for histologic examination.
Four invasive carcinoid tumors infiltrated
into the superficial submucosa (largest 1.3 cm), and multiple (>10) intramucosal carcinoid tumors were
also present among the random sections submitted from the gastric body and fundus. Histologically, all
of the carcinoid tumors were typical low-grade carcinoids composed of uniform, round cells that contained
small centrally-placed and stippled nuclei. Architecturally, the neoplastic cells were arranged as nests
or trabeculae that were variably separated by delicate stroma. Immunohistochemistry for chromogranin A
was strongly positive in the carcinoids, whereas gastrin was negative. A micrometastasis (<1 mm) of
carcinoid tumor was present in one of 21 perigastric lymph nodes; immunohistochemistry also confirmed
this to be positive for chromogranin A positive and negative for gastrin.
The multiple carcinoid tumors in this patient arose in a background of marked ECL cell proliferation
in the body and fundus. All degrees of endocrine hyperplasia (linear and nodular)-dysplasia-neoplasia
were prominently displayed in the gastric body and fundus.
The mucosa of the body and fundus showed variable thickening ranging from 0.5 cm to 1.5 cm. This
mucosal thickening was directly attributable to marked hyperplasia and hypertrophy of parietal cells.
Both the cytologic features of the individual parietal cells and their glandular formations were unusual.
The parietal cells were swollen, their cytoplasm ranged from deeply eosinophilic to vacuolated, and
projections of cytoplasm appeared to bud from the apical aspects of the cells into glandular lumens. The
oxyntic glands were frequently markedly dilated and the dilated glands were filled with inspissated
proteinaceous material. The oxyntic glands were lined predominantly by parietal cells, even at the base
of the mucosa, and parietal cells extended into the upper aspect of the foveolar neck region.
The hematoxylin-eosin appearance of the antral mucosa was unremarkable. Gastrin immunostaining,
however, revealed hyperplasia of the gastrin-producing antral G cells along the proliferative zone at the
junction of the foveolar neck region and the specialized antral glands.
Multiple gastric carcinoid tumors, arising in a background of
neuroendocrine hyperplasia and parietal cell hypertrophy associated with deficient gastric acid secretion
Gastric carcinoid tumors are well-differentiated
neuroendocrine neoplasms arising from one of the native non-peptide-secreting endocrine cell types of the
gastric mucosa, most commonly enterochromaffin-like (ECL) cells. They have been reported to account for
0.3% - 1.7% of stomach polyps [1-3]. Gastric carcinoid tumors have been described to occur in three
distinct settings, which differ in respect to their disease associations, clinicopathologic
characteristics, and prognosis [2,4-10].
Type 1 carcinoids, the most common type, arise in patients with chronic atrophic gastritis of
autoimmune type. These tumors eventually develop in 5-10% of patients with autoimmune gastritis [6,11]
and, mimicking the demographics of autoimmune gastritis itself, are found most commonly in women (71%)
with a mean age of 63 years . Type 1 carcinoids appear to develop at least in part as a consequence
of the hypergastrinemia that results from loss of parietal cell mass and gastric acid output in
autoimmune gastritis, and therefore are invariably found in a background of ECL cell hyperplasia confined
to the body/fundus regions of the stomach [2,8,12,13]. In 57% of cases, they are multifocal . Type 1
carcinoids are regarded as the most "benign" of the gastric carcinoids: they are <1.5 cm in diameter
in 97% of cases, limited to the mucosa and/or submucosa in 91% of cases, associated with distant (liver)
metastases in only 2-5% of cases, and almost never result in death [2,4].
Type 2 carcinoids arise in patients with Zollinger-Ellison syndrome (ZES); these almost invariably
represent patients with multiple endocrine neoplasia-1 (MEN-1)-associated ZES , although rare cases of
sporadic ZES-associated gastric carcinoids have been reported [14-16]. They do not show the sex
predilection of type 1 carcinoids, being distributed approximately equally between males and females,
with a mean age of 50 years . Like type 1 carcinoids, type 2 carcinoids develop in part as a
consequence of the hypergastrinemia that also produces a characteristic background of ECL cell
hyperplasia, and are therefore frequently multicentric lesions of the body and fundus .
Clinicopathologically, type 2 carcinoids are more likely than type 1 carcinoids to be >1.5 cm (23%),
have local lymph node metastases (30%), and have liver metastases (10%).2 However, death from type 2
gastric carcinoids themselves is rare and these patients are much more likely to die from the effects of
their gastrinomas .
In contrast to the gastrin-dependent type 1 and 2 carcinoids, type 3 gastric carcinoids are not
etiologically related to hypergastrinemia, are not associated with a background of ECL cell
hyperplasia-dysplasia, are almost always solitary tumors, and are not confined to the body and fundus
regions. They are most common in men (74%) with a mean age of 55 years.2 Most importantly, unlike
type 1 and 2 carcinoids, type 3 carcinoids have a significant potential for malignant behavior: 76% are
deeply invasive into the gastric subserosa and/or muscularis propria, and lymph node and distant
metastases are present in 71% and 22-75%, respectively [2,17].
Both type 1 and type 2 carcinoids arise in association with ECL cell hyperplasia. The pathophysiology
of normal ECL cell function and ECL cell proliferation/hyperfunction has been extensively investigated.
ECL cells are localized specifically to the gastric oxyntic mucosa, where they constitute approximately
30% of the endocrine cell population . Although specific histochemical or immunohistochemical stains
for ECL cells do not currently exist, for practical purposes endocrine hyperplasias and neoplastic
proliferations of the oxyntic mucosa that are revealed through the use of Gremelius stain for
argyrophilia or chromogranin A immunostain are representative of ECL cell growths . Through their
paracrine release of histamine, ECL cells are potent inducers of acid secretion by parietal cells.
Normally, stimulation of histamine production from ECL cells is accomplished via the action of gastrin
produced by G cells localized to the gastric antrum. Gastrin stimulates histamine by two mechanisms:
its immediate stimulation of histamine release from ECL cells (an acute effect) and its long-term
stimulation of histamine production via its trophic effect on ECL cells (a chronic effect) .
Proliferations of ECL cells (diffuse, linear, and/or micronodular hyperplasias, and their more advanced
lesions including ECL cell dysplasias and carcinoid tumors) are therefore a reflection of chronic
hypergastrinemia . However, hypergastrinemia itself does not usually lead to the full spectrum of
ECL hyperplasia-dysplasia-neoplasia . Previous studies of patients with hypergastrinemia related to
disorders such as Helicobacter pylori infection and chronic use of proton pump inhibitors have shown that
there is also a quantitative increase in numbers of ECL cells in the oxyntic mucosa, including examples
of diffuse hyperplasia, linear hyperplasia, and micronodular hyperplasia [19-22]. However, the
tumorigenic potential of this ECL hyperplasia per se is limited and carcinoid tumors in humans do not
occur in these settings [19-22].
The mechanism by which hypergastrinemia gives rise to neoplastic ECL cell proliferations is unclear.
Most studies indicate that hypergastrinemia and ECL cell hyperplasia themselves are not directly
preneoplastic, and that some additional factor is required for neoplastic progression. In the setting of
autoimmune gastritis, gastric mucosal atrophy appears to contribute to the background needed for full
expression of the ECL cell hyperplasia-dysplasia-neoplasia sequence. The carcinoids associated with ZES,
interestingly, are most commonly seen in patients with MEN-1-associated ZES , suggesting that
intrinsic endocrine cell abnormalities in these patients predispose to neoplastic progression. However,
there is some evidence that progression of ECL cell hyperplasia can occasionally occur outside of these
two predisposing factors of mucosal atrophy or MEN-1. Peghini et al recently demonstrated that nearly
all (99%) patients with sporadic ZES had ECL cell hyperplasia and that 7% had dysplastic ECL cell
growths, although none of the patients in that study had carcinoid tumors . However, several cases
of gastric carcinoids arising in apparently sporadic ZES have been reported [14-16], supporting that
hypergastrinemia-associated ECL cell neoplasia can occur without mucosal atrophy or MEN-1.
In 1995, Ooi et al reported an unusual patient who developed multiple gastric carcinoid tumors
(including a total of 19 intramucosal and invasive carcinoids) in the setting of marked hypergastrinemia
and ECL cell hyperplasia . This 47-year-old Japanese man did not suffer from either of the two
recognized causes of gastrin-dependent ECL cell carcinoids, autoimmune gastritis or ZES. The authors
described a distinctive appearance of the corpus mucosa, consisting of marked hypertrophy and hyperplasia
of the parietal cells, numerous dilated oxyntic glands, and accumulation of eosinophilic secretions
within the dilated oxyntic glands. Although overall this histologic appearance could have been confused
with that seen in ZES, this patient did not suffer from the peptic ulcerations characteristic of that
condition (and had not received acid suppression therapy). Moreover, the ultrastructural appearance of
the parietal cells was abnormal; numerous mitochondria were present, but the parietal cells lacked the
microvilli-lined intracytoplasmic canaliculi that would be expected during active acid secretion. The
authors therefore hypothesized that an intrinsic defect in acid secretion by parietal cells in this
patient accounted for this unique constellation of clinicopathologic features .
We believe that the patient presented here represents the second such case of multiple gastric
carcinoids and parietal cell hyperplasia in the setting of defective gastric acid secretion, and suggest
that this represents a rare, fourth type of gastric carcinoid tumor. It is possible that there are
other, clinically undetected patients with similar abnormalities, especially because hypergastrinemia and
achlorhydria themselves should have little to no associated clinical symptomatology. The etiology of
this acid secretory block in these cases remains unclear.
- Godwin JD 2nd. Carcinoid tumors. An analysis of 2,837 cases. Cancer
- Rindi G, Bordi C, Rappel S, et al. Gastric carcinoids and neuroendocrine carcinomas: pathogenesis,
pathology, and behavior. World J Surg 20:168-172;1996.
- Stolte M, Sticht T, Eidt S, et al. Frequency, location, and age and sex distribution of various
types of gastric polyp. Endoscopy 26:659-665;1994.
- Granberg D, Wilander E, Stridsberg M, et al. Clinical symptoms, hormone profiles, treatment, and
prognosis in patients with gastric carcinoids. Gut 43:223-228;1998.
- Bordi C, D'Adda T, Azzoni C, et al. Pathogenesis of ECL cell tumors in humans. Yale J Biol Med 71:273-284;1998.
- Hirschowitz BI. Clinical aspects of ECL-cell abnormalities. Yale J Biol
- Solcia E, Rindi G, Silini E, et al. Enterochromaffin-like (ECL) cells and their growths:
relationships to gastrin, reduced acid secretion, and gastritis. Baillieres Clin
- Rindi G, Luinetti O, Cornaggia M, et al. Three subtypes of gastric argyrophil carcinoid and the
gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology
- Thomas RM, Baybick JH, Elsayed AM, et al. Gastric carcinoids. An immunohistochemical and
clinicopathologic study of 104 patients. Cancer 73:2053-2058;1994.
- Sculco D, Bilgrami S. Pernicious anemia and gastric carcinoid tumor: case report and review. Am J Gastroenterol 92:1378-1380;1997.
- Lahner E, Caruana P, D'Ambra G, et al. First endoscopic-histologic follow-up in patients with
body-predominant atrophic gastritis: when should it be done? Gastrointest
- Solcia E, Fiocca R, Villani L, et al. Morphology and pathogenesis of endocrine hyperplasias,
precarcinoid lesions, and carcinoids arising in chronic atrophic gastritis. Scand
J Gastroenterol Suppl 180:146-159;1991.
- Solcia E, Fiocca R, Villani L, et al. Hyperplastic, dysplastic, and neoplastic
enterochromaffin-like-cell proliferations of the gastric mucosa. Classification and histogenesis. Am J Surg Pathol 19 Suppl 1:S1-S7;1995.
- Cadiot G, Vissuzaine C, Potet F, et al. Fundic argyrophil carcinoid tumor in a patient with
sporadic-type Zollinger-Ellison syndrome. Dig Dis Sci 40:1275-1278;1995.
- Feurle GE. Argyrophil cell hyperplasia and a carcinoid tumour in the stomach of a patient with
sporadic Zollinger-Ellison syndrome. Gut 35:275-277;1994.
- Konturek S, Konturek P, Bielanski W, et al. Case presentation of gastrinoma combined with gastric
carcinoid with the longest survival record – Zollinger-Ellison syndrome: pathophysiology, diagnosis and
therapy. Med Sci Monit 8:CS43-CS59;2002.
- Rappel S, Rindi G, Bordi C, et al. Carcinoid tumors of the stomach in atrophic autoimmune gastritis:
classification, differential diagnosis and prognosis. Verh Dtsch Ges Pathol
- Bordi C, D'Adda T, Azzoni C, et al. Hypergastrinemia and gastric enterochromaffin-like cells. Am J Surg Pathol 19 Suppl 1:S8-S19;1995.
- Solcia E, Fiocca R, Havu N, et al. Gastric endocrine cells and gastritis in patients receiving
long-term omeprazole treatment. Digestion 51 Suppl 1:82-92;1992.
- Eissele R, Brunner G, Simon B, et al. Gastric mucosa during treatment with lansoprazole:
Helicobacter pylori is a risk factor for argyrophil cell hyperplasia. Gastroenterology 112:707-717;1997.
- Lamberts R, Brunner G, Solcia E. Effects of very long (up to 10 years) proton pump blockade on human
gastric mucosa. Digestion 64:205-213;2001.
- Sanduleanu S, Jonkers D, de Bruine A, et al. Changes in gastric mucosa and luminal environment
during acid-suppressive therapy: a review in depth. Dig Liver Dis
- Peghini PL, Annibale B, Azzoni C, et al. Effect of chronic hypergastrinemia on human
enterochromaffin-like cells: insights from patients with sporadic gastrinomas. Gastroenterology 123:68-85;2002.
- Ooi A, Ota M, Katsuda S, et al. An unusual case of multiple gastric carcinoids associated with
diffuse endocrine cell hyperplasia and parietal cell hypertrophy. Endocr