Figure 2.163 Gastric hyperplasia pattern example, Ménétrier disease. A gastrectomy was performed in this patient with Ménétrier disease for intractable protein losing gastropathy and worsening anasarca. Grossly, the body and fundus had innumerable giant hyperplastic folds (not shown). Histologically, the folds consisted of prominent foveolar hyperplasia with oxyntic gland loss, in keeping with the clinicopathologic diagnosis of Ménétrier disease. CMV immunostain was negative.
Gastric hyperplasia can be difficult to appreciate in a mucosal biopsy specimen, but the findings can appear dramatic to the endoscopist (Fig. 2.163). Clinicians often use the following common red flags to describe this sometimes striking finding: “gastric hyperplasia,” “thickened gastric folds,” or “giant folds.” Accurate diagnosis is facilitated by first segregating the hyperplastic pattern according to the constituents of the hyperplasia: oxyntic gland hyperplasia versus foveolar hyperplasia.
CHECKLIST: Etiologic Considerations for the Gastric Hyperplasia Pattern
Oxyntic Gland Hyperplasia
Sporadic
Sporadic Fundic Gland Polyps (favor related to proton pump inhibitors)
Syndromic
Familial Adenomatous Polyposis Syndrome
Attenuated Familial Adenomatous Polyposis Syndrome
MutYH-Associated Polyposis
Sporadic Fundic Gland Polyposis Syndrome
Zollinger–Ellison syndrome, sporadic or familial
Foveolar Hyperplasia
Sporadic
Sporadic Gastric Hyperplastic Polyp
Gastric Juvenile Polyp
Gastric Peutz–Jeghers Polyp
Syndromic
Gastric Juvenile Polyp
Gastric Peutz–Jeghers Polyp
PTEN syndromes (Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Adult Lhermitte–Duclos disease)
Cronkhite–Canada Syndrome
Ménétrier Disease
OXYNTIC GLAND HYPERPLASIA
Oxyntic gland hyperplasia can result in either discreet gastric fundic polyps or giant gastric folds. Fundic gland polyps are the most common gastric polyp, comprising 77% of all gastric polyps in a study of over 120,000 patients.143They are seen in up to 5.9% of adults undergoing upper-tract endoscopy.144 In the sporadic setting, they are linked to proton pump inhibitor usage, and they regress with proton pump inhibitor cessation.145 Whether sporadic or syndromic, all fundic gland polyps consist of dilated cystic oxyntic glands with hypertrophic parietal cells whose luminal surface is often protuberant or “snout”-like (Figs. 2.164–2.173). Noted clinical associations include gastroesophageal reflux disease, gastric heterotopia, hyperplastic polyps (in men) and adenomas (in women) of the colon. They are inversely associated with Helicobacter infection, active gastritis, and neoplasia.144 In a study of over 100,000 patients in North America, there were no cases of high-grade dysplasia or carcinoma, suggesting the progression to carcinoma is uncommon in the sporadic setting.144 However, associations with high-grade dysplasia and carcinoma exist; these reports are predominantly in the syndromic setting.146,147 When the fundic gland polyps are innumerable or dysplastic, syndromic polyposis should be considered. Syndromic etiologies include familial adenomatous polyposis syndrome, attenuated familial adenomatous polyposis syndrome, MutYH-associated polyposis, and sporadic fundic gland polyposis syndrome.148 Sorting through these possibilities requires correlation with family history, physical examination, endoscopic appearance, and, in challenging cases, genetic studies: familial adenomatous polyposis syndrome and attenuated familial adenomatous polyposis syndrome are characterized by APCmutations; MutYH-associated polyposis is characterized by MutYH mutations; sporadic fundic gland polyposis syndrome is characterized by β-catenin mutations (Table 2.3).
Figure 2.164 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp. This fundic gland polyp was incidentally found in a 55 year-old man taking proton pump inhibitors for gastroesophageal reflux disease. Histologically, the polyp consists of dilated oxyntic glands.
Figure 2.165 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp. There is no reliable histologic means to distinguish a sporadic fundic gland polyp from a fundic gland polyp due to familial adenomatous polyposis. The diagnostic distinction rests entirely on the associated clinical setting, gross findings, and, sometimes, genetic studies. In this case, the patient was taking proton pump inhibitors for Barrett esophagus, and an isolated gastric body polyp was seen consisting of dilated oxyntic glands. These clinical features are in keeping with a sporadic fundic gland polyp.
Figure 2.166 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp.
Figure 2.167 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp. Note the characteristic cystically dilated oxyntic glands of this sporadic fundic gland polyp.
Figure 2.168 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp.
Figure 2.169 Oxyntic gland hyperplasia pattern, fundic gland polyp, familial adenomatous polyposis. This case originated from a young man with innumerable stomach and colonic polyps. Subsequent APC mutational studies were positive, confirming a diagnosis of familial adenomatous polyposis.
Figure 2.170 Oxyntic gland hyperplasia pattern, fundic gland polyp, familial adenomatous polyposis. All of the sampled stomach polyps were fundic gland polyps.
Figure 2.171 Oxyntic gland hyperplasia pattern, fundic gland polyp, sporadic fundic gland polyposis syndrome. This patient had innumerable fundic gland polyps. Familial adenomatous polyposis was excluded based on an unremarkable endoscopic examination of the small and large bowel and normal APCgenetic studies. β-catenin mutations were identified, confirming a diagnosis of sporadic fundic gland polyposis syndrome.
Figure 2.172 Oxyntic gland hyperplasia pattern, fundic gland polyp, sporadic fundic gland polyposis syndrome. Under oil immersion, note the protuberant apical snouts pushing into the cyst lumen. These features can be seen in either the sporadic or syndromic setting.
Figure 2.173 Oxyntic gland hyperplasia pattern, sporadic fundic gland polyp with low-grade dysplasia. Low-grade dysplasia refers to the depicted nuclear enlargement, hyperchromasia, and pseudostratification. This focus looks distinct and has no associated inflammation to explain the cytologic atypia. Dysplastic fundic gland polyps occur both in either the sporadic or syndromic setting.
If massive oxyntic gland hyperplasia is seen, Zollinger–Ellison syndrome should be considered (Figs. 2.174 and 2.175). This syndrome describes the association of a gastrinoma of the small bowel (more common) or pancreas (less common), oxyntic gland hyperplasia, and gastric and small bowel ulcerations. This constellation of findings is due to tremendous tumor-mediated hypergastrinemia, which stimulates the oxyntic mucosa to release tremendous amounts of acid, resulting in gastric and duodenal ulcerations. The majority of patients with Zollinger–Ellison syndrome are sporadic, but up to 30% are owing to a genetic defect in the MEN1 tumor suppressor as part of multiple endocrine neoplasia type 1 (MEN1). Patients with MEN1 are important to identify because of the associations with other endocrinopathies (such as parathyroid and pituitary gland abnormalities) and neoplasia. MEN1 is often referred to as the “3P syndrome” based on its associations with neoplasms of the Parathyroid, Pituitary, and Pancreas (and small bowel) neuroendocrine tumors. It is inherited in an autosomal dominant inheritance pattern and imparts similar risks to the patient’s relatives. Determination of serum gastrin levels is theoretically helpful with gastrin levels at least ≥10 times normal suggestive of Zollinger–Ellison syndrome. Because approximately two-thirds of Zollinger–Ellison patients have nondiagnostic serum gastrin, other considerations include Helicobacter, renal failure, gastric outlet obstruction, and short bowel syndrome.149 In ambiguous cases, correlation with Helicobacter studies, gastric pH, careful imaging studies of the small bowel and pancreas, somatostatin receptor scintigraphy, and or MEN1 genetic sequencing studies are a consideration.
TABLE 2.3: Select Gastric Polyposis Summary
Sources: Adapted from Seshadri D, Karagiorgos N, Hyser MJ. A case of cronkhite-Canada syndrome and a review of gastrointestinal polyposis syndromes. Gastroenterol Hepatol (N Y). 2012;8:197–201; Lam-Himlin D, Arnold, CA, De Petris G. Gastric polyps and polyposis syndromes. Diagnostic Histopathology. 2013, http://dx.doi.org/10.1016/j.mpdhp.2013.12.002.
Figure 2.174 Oxyntic gland hyperplasia pattern, Zollinger–Ellison syndrome. This partial gastric resection originated from a patient with a widely metastatic gastrinoma and clinically significant GI bleeding. The patient was found to have Zollinger–Ellison syndrome, and a partial gastric resection and vagotomy were performed to reduce the gastric acid secretion. In Zollinger–Ellison syndrome, the tumor mediated hypergastrinemia results in overwhelming gastric acid production, extensive gastric and duodenal ulcerations, and sometimes, as in this case, clinically significant GI bleeding. The stomach resection had numerous, giant, hyperplastic folds in the body and fundus. At low power, note that this properly orientated section entirely fills the entire 2× field (!) and scattered dilated oxyntic glands are seen throughout. In the case of an unremarkable gastric resection, the oxyntic mucosa would take up a fraction of this width.
Figure 2.175 Oxyntic gland hyperplasia pattern, Zollinger–Ellison syndrome. At higher power, a number of dilated oxyntic glands are seen. The epithelial cells have apical snouts or rounded luminal surfaces (arrowheads).
KEY FEATURES of Oxyntic Gland Hyperplasia:
• Discreet gastric polyps
• Fundic gland polyps are the most common type of gastric polyp.
• They are most common in the sporadic setting (favored related to proton pump inhibitors).
• Syndromic settings include familial adenomatous polyposis syndrome, attenuated familial adenomatous MutYH-associated polyposis, and sporadic fundic gland polyposis syndrome.
• Dysplastic fundic gland polyps have a negligible rate of progression (rare case of progression exist, mainly in the syndromic setting).
• Giant gastric folds
• Zollinger–Ellison syndrome
• Triad of gastrinoma (small bowel >>> pancreas), oxyntic gland hyperplasia, and gastric and small bowel ulcerations.
• Secondary to tumor-mediated hypergastrinemia.
• Most are sporadic.
• Thirty percent are familial due to MEN1 tumor suppressor mutation.
Figure 2.176 Oxyntic gland hyperplasia pattern. This biopsy was of nonpolypoid mucosa and shows slight oxyntic gland dilatation with mild luminal snouting. This nonspecific pattern can be seen with any process that interferes with gastric acid production; it is not specific for proton pump inhibitor usage.
FAQ: If the biopsy is of flat mucosa and slight oxyntic gland dilatation is seen, is “proton-pump inhibitor change” appropriate (Fig. 2.176)?
Answer: Probably not.
In the sporadic setting, oxyntic gland hyperplasia is seen with any etiology characterized by low gastric acid production and, consequently, hypergastrinemia. Recall, gastric acid inhibits G-cell mediated production of gastrin and, conversely gastric acid depletion relieves this negative inhibition and results in enhanced G-cell mediated release of gastrin, in attempts to restore acid production (Fig. 2.80). High gastrin levels stimulate the oxyntic mucosa to produce acid and induce oxyntic gland hyperplasia, resulting in dilated oxyntic glands and hypertrophic oxyntic epithelium with protuberant luminal “snouts”. This nonspecific morphology is seen with any process that interferes with gastric acid production, such as proton pump inhibitors, autoimmune metaplastic atrophic gastritis, and late environmental metaplastic atrophic gastritis (Helicobacter, medications, reactive gastritis/gastropathy, etc.). To further emphasize this point, Helicobacter infections were recently found to produce identical histologic findings in oxyntic mucosa as those seen with PPIs.150 As a result, describing the histologic features of oxyntic hyperplasia without presuming the changes are linked to a particular medication is advised.
FOVEOLAR HYPERPLASIA
Hyperplasia of the superficial gastric foveolar epithelium can result in either discreet gastric hyperplastic polyps or giant gastric folds. Because superficial gastric foveolar epithelium lines the entire stomach, this hyperplastic pattern can be seen in any stomach compartment. Gastric hyperplastic polyps are the second most common stomach polyp, comprising 17% of all stomach polyps.143 They are seen in any compartment of the stomach: antral (56%), oxyntic (60%), and transitional (60%).151 Earlier work found up to 85% were associated with background inflammatory injury, such as Helicobacter (25%), reactive gastritis/gastropathy (21%), autoimmune metaplastic atrophic gastritis (12%), and environmental metaplastic atrophic gastritis (8%), suggesting gastric hyperplastic polyps are a marker for nonspecific gastric mucosal injury, unlike their colonic counterparts.152 As a result, gastric hyperplastic polyps can be an important red flag for one to consider other specific etiologic agents of mucosal injury (Figs. 2.177 and 2.178). Histologically, gastric hyperplastic polyps are benign neoplasms defined by polypoid foveolar hyperplasia, cystic dilatation of antral and pyloric glands, and increased lamina propria acute and chronic inflammation. Ulcerations, erosions, increased lamina propria acute and chronic inflammation, and fibromuscular hyperplasia/prolapse change are common (Figs. 2.179–2.184).
Figure 2.177 Foveolar hyperplasia pattern, gastric hyperplastic polyp with iron deposition. Unlike colon hyperplastic polyps, gastric hyperplastic polyps are a result of mucosal injury. Careful inspection will occasionally uncover the potential injurious agent. In this case, iron deposition was found (arrowhead), a potential contributor to this injury pattern.
Figure 2.178 Foveolar hyperplasia pattern, gastric hyperplastic polyp with iron deposition. Higher power of previous figure.
Figure 2.179 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. This antral gastric hyperplastic polyp appears polypoid at scanning magnification. The characteristic histologic features include prominent foveolar hyperplasia and an inflammatory rich stroma. Focal intestinal metaplasia is also seen (arrowhead).
Figure 2.180 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. Higher power of previous case (Fig. 2.179) shows the focal intestinal metaplasia.
Lam-Himlin and colleagues found sporadic gastric hyperplastic polyps defied reliable distinction from syndromic gastric juvenile polyps (Figs. 2.185–2.189) and syndromic gastric Peutz–Jeghers polyps (Figs. 2.190 and 2.191), despite the latter two polyps’ more characteristic histology when seen in the small and large bowel.151 Similarly, nearly indistinguishable morphology is seen in polyps of Cronkhite–Canada syndrome (Figs. 2.192–2.194) and PTEN-associated hamartomatous polyps (Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Adult Lhermitte–Duclos disease) (Figs. 2.195 and 2.196). Although gastric polyps are themselves benign, if they are linked to a polyposis syndrome associated with an increased risk of neoplasia or mortality, then they become important red flags for close clinical follow-up. Since the histologic features of sporadic and syndromic gastric hyperplastic polyps are indistinguishable, awareness of these clinical syndromes and diagnostic criteria is important to assure appropriate clinical follow-up (Table 2.3).153,154 In challenging cases, correlation with endoscopic evaluation of the small and large bowel can be helpful to highlight the syndromic polyps’ more characteristic features, as is molecular correlation (syndromic juvenile polyposis is characterized by SMAD4, BMPR1 A mutations; syndromic Peutz–Jeghers is characterized by STK11/LKB1 germline mutations; Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Adult Lhermitte–Duclos disease have PTEN mutations).
Figure 2.181 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. In this polyp, foveolar hyperplasia and inflammatory stroma is seen. The foveolar epithelium is mucin depleted, a manifestation of focally reactive and regenerative change typical of this injury pattern.
Figure 2.182 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. Gastris hyperplastic polyps are often eroded and ulcerated with acute and chronically inflamed lamina propria, as in this case.
Figure 2.183 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. Higher power. The intact epithelium shows foveolar hyperplasia and cystic dilatation of the antral/pyloric glands.
Figure 2.184 Foveolar hyperplasia pattern, sporadic gastric hyperplastic polyp. Note the prominent foveolar hyperplasia and cystic dilatation of the antral/pyloric glands.
Figure 2.185 Foveolar hyperplasia pattern, juvenile polyposis syndrome, gastric resection. This partial gastric resection was for gastric obstruction secondary to innumerable gastric polyps in a patient with established juvenile polyposis syndrome.
Figure 2.186 Foveolar hyperplasia pattern, juvenile polyposis syndrome, gastric resection. Juvenile polyposis syndrome is characterized by SMAD4 and BMPR1 A mutations.
Figure 2.187 Foveolar hyperplasia pattern, juvenile polyposis syndrome. Corresponding histologic sections of the polyps show indistinguishable morphology from sporadic gastric hyperplastic polyps: foveolar hyperplasia, cystic dilatation of the antral/pyloric glands, and an inflamed lamina propria.
Figure 2.188 Foveolar hyperplasia pattern, juvenile polyposis syndrome. Alternate field.
Figure 2.189 Foveolar hyperplasia pattern, juvenile polyposis syndrome. Higher power. Foveolar hyperplasia, cystic dilatation of the antral/pyloric glands, and an inflamed lamina propria is seen. This gastric juvenile polyp is indistinguishable from a sporadic gastric hyperplastic polyp.
Figure 2.190 Foveolar hyperplasia pattern, Peutz–Jeghers polyp. This gastric polyp features foveolar hyperplasia, cystic dilatation of the antral/pyloric glands, and an inflamed lamina propria. Scattered smooth bundles are seen (arrowheads), a feature which can be seen as a manifestation of prolapse injury in large polyps of any sort, and also in gastric Peutz–Jeghers polyps. In the small bowel and colon, these lesions are more easily recognized based on the prominent arborizing smooth muscle fibers enveloping large groups of unremarkable mucosa. Analogous findings in the stomach are minimal and nonspecific.
Figure 2.191 Foveolar hyperplasia pattern, Peutz–Jeghers polyp. Higher power of previous case (Fig. 2.190). Patients with syndromic Peutz– Jeghers have germline STK11/LKB1 mutations and a 93% lifetime risk for malignancy, including carcinomas of the gastrointestinal tract, breast, ovary, and testis. Sporadic Peutz–Jeghers polyps have a similar lifetime risk of malignancy, and require similarly close surveillance.
Figure 2.192 Foveolar hyperplasia pattern, Cronkhite–Canada syndrome. In Cronkhite–Canada syndrome, both the polyp and intervening nonpolypoid mucosa show similar features to a sporadic gastric hyperplastic polyp, as seen here. Note the foveolar hyperplasia, cystic dilatation of the antral/pyloric glands, and the inflamed lamina propria.
Figure 2.193 Foveolar hyperplasia pattern, Cronkhite–Canada syndrome. Cronkhite-Canada is a noninherited clinical condition characterized by gastrointestinal hamartomatous polyposis, diarrhea, and dermatologic abnormalities (alopecia, onychodystrophy, and hyperpigmentation).
Figure 2.194 Foveolar hyperplasia pattern, Cronkhite-Canada syndrome. Despite this bland appearance, only 55% of patients are alive at 5 years after diagnosis; accurate, timely diagnosis is critical to ensure appropriate supportive therapy. In isolation, these features are indistinguishable from a gastris hyperplastic polyp.
Figure 2.195 Foveolar hyperplasia pattern, Cowden syndrome. Gastric polyps of PTEN syndromes are indistinguishable from those of sporadic gastric hyperplastic polyps. PTEN syndromes of interest include Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, and adult Lhermitte–Duclos disease.
Figure 2.196 Foveolar hyperplasia pattern, Cowden syndrome. Higher power. The PTEN pathway negatively regulates the phosphatidylinositol 3-kinase-AKT and mammalian target of rapamycin (mTOR) signaling pathways, thereby, leading to tumorigenesis through interfering with cell proliferation, cell cycle progression, and apoptosis.
If diffuse changes are seen involving both the polypoid and nonpolypoid mucosa, Cronkhite–Canada should be considered. It is an exceptionally rare, nonfamilial syndrome characterized by the triad of alopecia, onychodystrophy, and hyperpigmentation.155,156 Patients present with altered taste, diarrhea, nutritional deficiency, and generalized edema. Histologic sections of both the polyp, and, importantly, the nonpolypoid mucosa show features indistinguishable from gastric hyperplastic polyps with foveolar hyperplasia, cystic dilatation of antral and pyloric glands, increased lamina propria acute and chronic inflammation, and fibromuscular hyperplasia/prolapse change (Figs. 2.192–2.194). The 5-year mortality rate is 55%, underscoring the importance of recognizing this pattern so that appropriate supportive measures can be taken with electrolyte stabilization and immunosuppression.
Figure 2.197 Foveolar hyperplasia pattern, Ménétrier disease. Note the prominent foveolar hyperplasia and cystic dilatation of the superficial glands. The oxyntic glands are relatively attenuated (bracket). Superficial biopsy of this lesion would be indistinguishable from a sporadic gastric hyperplastic polyp.
Another consideration for massive foveolar hyperplasia is Ménétrier disease. It is another rare syndrome (so an extremely popular subject for examinations!) seen in the foveolar hyperplasia pattern. In biopsy material, it is indistinguishable from sporadic gastric hyperplastic polyps, but clinically it is characterized by gigantic gastric folds that histologically consist of dramatic foveolar hyperplasia and oxyntic gland loss (Fig. 2.197). Clinically, patients have protein losing enteropathy, peripheral edema, and hypochlorhydria (increased pH) secondary to the massive mucus secretion that impairs normal absorption and alters the local microenvironment.157 In adults, the disease is chronic, progressive, and associated with TGFα overexpression.158 Transgenic mice with TGFα overexpression show Ménétrier disease–like findings, suggesting this molecule may be play a central role in Ménétrier disease, at least in the adult setting.159 In children, Ménétrier disease is associated with CMV infection and can spontaneously regress.160 Treatment is generally supportive with a high-protein diet, although some patients ultimately require gastrectomies for intractable symptoms. Newer studies show promising success with EGF receptor inhibitors, which competitively inhibit TGFα binding and activation of the EGF receptor.161–163
KEY FEATURES of the Foveolar Hyperplasia Pattern:
• Discrete gastric polyps
• Sporadic gastric hyperplastic polyps indicate background mucosal injury.
• They can be seen in any gastric compartment.
• Sporadic gastric hyperplastic polyps are histologically indistinguishable from the syndromic counterparts (Gastric Juvenile Polyp, Gastric Peutz–Jeghers Polyp, Cronkhite–Canada Syndrome, PTENsyndromes (Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Adult Lhermitte–Duclos disease), and Ménétrier disease.
• Awareness of the syndromic associations is critical because of the increased risk of neoplasia and mortality
• Giant gastric folds
• Cronkhite–Canada is characterized by the triad of alopecia, onychodystrophy, and hyperpigmentation.
• Patients present with altered taste, diarrhea, nutritional deficiency, and generalized edema.
• Histologic sections of both the polyp and nonpolypoid mucosa show features indistinguishable from gastric hyperplastic polyps.
• The 5-year mortality rate is 55%.
• Treatment is supportive.
• Ménétrier disease is characterized by protein losing enteropathy, peripheral edema, and hypochlorhydria (increased pH).
• Biopsy is indistinguishable from gastric hyperplastic polyp but the clinical presentation consists of dramatic, giant gastric folds.
• Associated with TGFα overexpression in adults, and CMV in children.
PEARLS & PITFALLS
Patients with syndromic Peutz–Jeghers have germline STK11/LKB1 mutations and a 93% lifetime risk for malignancy, including carcinomas of the gastrointestinal tract, breast, ovary, and testis. SporadicPeutz–Jeghers polyps have a similar lifetime risk of malignancy, and require similarly close surveillance.164