—  SPECIALTY CONFERENCE  —

Gastrointestinal Pathology

Case 3 - Multiple Gastric Carcinoid Tumors and Parietal Cell Hyperplasia in Secretion

Susan Abraham
Mayo Clinic
Rochester, Minnesota


Click on each slide thumbnail image for an enlarged view
Clinical History:
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 normal.

Macroscopic Examination:
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.

Microscopic 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.

Diagnosis:
Multiple gastric carcinoid tumors, arising in a background of neuroendocrine hyperplasia and parietal cell hypertrophy associated with deficient gastric acid secretion

Discussion:
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 [2]. 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 [2]. 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 [2], 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 [2]. 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 [2]. 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 [2].

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 [18]. 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 [18]. 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) [18]. 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 [13]. However, hypergastrinemia itself does not usually lead to the full spectrum of ECL hyperplasia-dysplasia-neoplasia [13]. 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 [2], 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 [23]. 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 [24]. 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 [24].

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.

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