Differentiated adenocarcinoma with a gastric phenotype in the stomach: difficulties in clinical and pathological diagnoses

Differentiated-type adenocarcinoma with gastric phenotype of the stomach is rare and is difficult to diagnose both clinically and pathologically. We report a case of differentiated-type adenocarcinoma with a gastric phenotype in the stomach. A 60-year-old Japanese female was referred to our hospital with gastric cancer. A barium meal examination and esophagogastroduodenoscopy revealed a granular elevated lesion in the lower body near the lesser curvature and a depressed lesion on the antrum. A biopsy specimen showed benign atrophic mucosa in a granulated lesion and moderately differentiated adenocarcinoma in the depressed lesion. The patient underwent laparoscopy-assisted distal gastrectomy with lymph node dissection. The postoperative course was uneventful. Histological examination of the resected tissue confirmed well-differentiated adenocarcinoma in the granulated lesion and moderately differentiated adenocarcinoma in the depressed lesion, without lymph node metastasis. Both lesions were confined to the mucosa. Since mucin immunohistochemistry revealed MUC5AC-positive staining in the granulated lesion, the final diagnosis was differentiated-type adenocarcinoma with gastric phenotype in the stomach. Despite the high malignant potential, the clinical and pathological diagnoses of gastric-type differentiated adenocarcinoma are often difficult. Mucin immunohistochemistry together with hematoxylin and eosin (HE) staining may be helpful in the pathological diagnosis of this rare disease.     

Cdx2和MUC2在反流性食管炎、Barrett食管和食管腺癌中的表达

目的研究Cdx2和MUC2在反流性食管炎、Barrett食管和食管腺癌中表达，探讨3种食管黏膜疾病的内在关系。方法选取反流性食管炎30例、Barrett食管18例及食管腺癌25例作为研究对象，以正常食管上皮黏膜25例作为对照，采用免疫组化方法检测Cdx2和MUC2的表达，对结果进行统计分析。结果Cdx2和MUC2在反流性食管炎、Barrett食管及食管腺癌中的蛋白阳性表达率均较正常对照组明显增高（P〈0．05）。Cdx2在正常食管黏膜上皮中无表达，在反流性食管炎、Barrett食管及食管腺癌中的阳性表达率分别为26．7％、66．7％和28．0％，在Barrett食管中表达明显高于反流性食管炎（P〈0．05），亦明显高于食管腺癌（P〈0．05）；MUC2在正常食管黏膜上皮和反流性食管炎组织无表达，在Barrett食管及食管腺癌中的阳性表达率分别为61．1％和24．0％，Barrett食管中表达率明显高于食管腺癌（P〈0．05）。两者表达情况相似。结论Cdx2是肠上皮化生的始动因素，MUC2的表达是肠上皮化生的晚发事件。Cdx2和MUC2在反流性食管炎、Barrett食管和食管腺癌组织中的表达情况支持这3种食管黏膜疾病间有密切的关系。     

Endoscopic mucosal resection for early adenocarcinoma arising in Barrett's esophagus

A 58‐year‐old man was diagnosed to have an esophageal adenocarcinoma arising in Barrett's esophagus by screening examination at the previous hospital. Endoscopically, a slightly reddish elevated lesion with a central depressed component was detected in the Barrett's epithelium. Endoscopic ultrasonography showed the thickness of the second layer of the esophagus and no enlarged lymph node. Histological examination of a biopsy specimen revealed well or moderately differentiated adenocarcinoma. From these findings, the lesion was diagnosed as a mucosal esophageal cancer, type IIa + IIc, arising in Barrett's esophagus. As he refused operation, the lesion was resected endoscopically with his informed consent. Histologically, the resected specimens showed moderately differentiated adenocarcinoma arising in Barrett's esophagus. The adenocarcinoma had invaded the superficial muscularis mucosa, but was limited to the deep one with no vessel invasion. Barrett's esophagus often has a double muscularis mucosa. Connective tissues containing vascular and lymphatic vessels exist between them. However, one consideration is whether the existence of vessels between the double muscularis mucosa and the presence of vessel invasion are risk factors for metastasis. In order for a definitive indication for endoscopic mucosal resection, the frequency of lymph node and distant metastasis in cases of early Barrett's cancer needs to be investigated.     

Barrett's adenocarcinoma of the esophagus with lymphoid stroma

We report a case of Barrett's adenocarcinoma of the esophagus with lymphoid stroma. We believe this is the first reported case of this entity, although six previous cases of esophageal lymphoepithelioma-like carcinoma have been reported. The esophageal tumor from a 58-year-old man was examined histologically. In situ hybridization to detect Epstein-Barr virus (EBV) was also performed. The tumor consisted of a poorly differentiated adenocarcinoma with dense lymphoid cell infiltration in the invasive portions and a well-differentiated adenocarcinoma without lymphoid stroma in the mucosa. Barrett's epithelium was observed adjacent to the carcinoma. No positive signals for EBV were detected in the tumor cells. Six previously reported patients with esophageal lymphoepithelioma-like carcinomas, and the current patient, all survived for longer than 24 months, a better outcome than that of patients with esophageal squamous cell carcinomas of usual type. The data suggest that this tumor arose as a mucosal, well-differentiated adenocarcinoma without lymphoid stroma and that EBV had no relation to either its pathogenesis or progression.     

Gastroesophageal reflux disease and Barrett��s esophagus

Gastroesophageal reflux disease is the most common gastrointestinal diagnosis recorded during visits to outpatient clinics. The spectrum of injury includes esophagitis, stricture, the development of columnar metaplasia in place of the normal squamous epithelium (Barrett’s esophagus), and adenocarcinoma. Barrett’s esophagus is a premalignant lesion detected in the majority of patients with esophageal and gastroesophageal adenocarcinoma. The incidence of these cancers has been increasing in the United States and they are associated with a low rate of survival (5-year survival rate, 15–20%). When symptoms of gastroesophageal reflux disease are typical and the patient responds to therapy, no diagnostic tests are necessary to verify the diagnosis. Endoscopy is the primary test in patients whose condition is resistant to empirical therapy but its yield in this setting is low because of the poor correlation between symptoms attributed to the condition and endoscopic features of the disease. Clinical experience suggests that lifestyle modifications may be beneficial for gastroesophageal reflux disease although trials of the clinical efficacy of dietary or behavioral changes are lacking. Abundant data from randomized trials show benefits of inhibiting gastric acid secretion and suggest that proton-pump inhibitors are superior to H2-blockers and that both are superior to placebo. In patients with Barrett’s esophagus, antireflux interventions are intended to control symptoms of reflux and promote healing of the esophageal mucosa. If a patient has symptoms refractory to proton-pump inhibitors or cannot tolerate such therapy, antireflux surgery, most commonly Nissen fundoplication, may be an alternative management approach. In patients with high-grade dysplasia, endoscopic therapies or surgical resection must be considered.     

The Role of Acid Suppression in Barrett's Esophagus

In recent years, proton pump inhibitors (PPIs) have come under great scrutiny due to possible adverse, long-term side effects. At the same time, Barrett's esophagus, a premalignant condition in the esophagus, continues to be a disease whose course is thought to be improved by the use of PPIs. We review the impact of proton pump therapy on the esophagus and on Barrett's mucosa. In analyzing changes on a cellular level, we explore the effect of mixed gastric refluxate and the complex cascade that ensues with esophageal exposure of these contents. Because the incidence of esophageal adenocarcinoma is on the rise, we explore other factors that may contribute to the progression of Barrett's from non-dysplastic mucosa to esophageal adenocarcinoma. By revisiting the need for adequate acid suppression in Barrett's and increasing our understanding of other possible factors that may have an effect of Barrett's progression, we hope to support our multifaceted approach to acid suppression in patients with Barrett's esophagus.     

The role of mucin in GERD and its complications

Acid, pepsin and other noxious material reach the esophageal mucosa and interact with the luminal aspect of the squamous epithelium. The first protective barrier to these potentially injurious substances is the mucus buffer layer that covers the mucosa. In healthy people, the esophagus has a protective surface adherent mucus gel barrier. Levels of mucin glycoprotein are considerably increased in response to acid and pepsin. A wide spectrum of mucin genes are expressed in normal esophageal mucosa, squamous cell carcinoma of the esophagus, Barrett epithelium and esophageal adenocarcinoma. The mucins MUC5AC and MUC6 are expressed to a similar degree in Barrett metaplasia and gastric mucosa, as is MUC2 in Barrett intestinal metaplasia and small bowel mucosa. Increased expression of MUC1 is associated with progression from dysplasia to adenocarcinoma of the esophagus. Thus, mucins have an important role in the defense of esophageal mucosa against the acid, pepsin and bile that are present in the refluxate. Changes in the expression of mucins occur in patients with GERD, and might lead to the development of new drugs.     

Current status of ablative therapies in esophageal disorders

Endoscopic ablative therapies for esophageal diseases have been used for palliation of inoperable esophageal cancer, but their use in eradication of early esophageal cancer and Barrett’s esophagus (with and without dysplasia) has been reported in recent publications. Pharmacologic and surgical treatment of reflux symptoms in patients with Barrett’s esophagus has not consistently reversed the metaplastic epithelium. This has led investigators to try different modalities of local injury to the columnar mucosa in an acid-reduced environment. Endoscopic reversal of Barrett’s esophagus (visual replacement of columnar mucosa by squamous mucosa) is more readily achievable than complete histologic reversal. Preliminary data show that endoscopic reversal of Barrett’s esophagus can be achieved, but intestinal metaplasia underlying the new squamous mucosa is reported in almost all series. Incidence of adenocarcinoma in patients with Barrett’s without dysplasia is probably so low that endoscopic ablation as a therapy cannot be advocated outside of study protocols. Endoscopic therapy as a definitive treatment for patients with high-grade dysplasia (HGD) and/or early adenocarcinoma holds promise, especially in older patients with comorbid illnesses. Future long-term randomized studies are needed to determine whether ablative therapies can provide an alternative approach for patients with HGD and early cancer. Advanced cancers that are not resectable for cure can be effectively treated by endoscopic therapy for palliation of dysphagia.     

Multiple early esophageal cancers arising from Barrett's esophagus, and a review of cases of early adenocarcinoma in Barrett's esophagus in Japan

A case of early esophageal adenocarcinoma arising in Barrett's esophagus is reported. Many cases of Barrett's esophagus, which is considered a premalignant condition, have been reported in Western countries, but few cases have been reported in Japan. The patient, a 53-year-old man with nausea and vomiting, was a drinker (four glasses wine/day for about 30 years), but did not smoke. He had had a hiatal hernia of the esophagus. Since endoscopic biopsies demonstrated an early adenocarcinoma in Barrett's esophagus, subtotal esophagectomy was performed. In the resected esophageal material, Barrett's esophagus was seen to extend for 12 cm. In addition to the cancer detected preoperatively as a 0-IIc lesion (1.5 cm in diameter), a 0-IIb lesion (1.5 cm in diameter) was also detected in the post-operative survey. Both lesions were well differentiated adenocarcinoma that had invaded only into the lamina propria mucosa. The 23 cases of early adenocarcinoma in Barrett's esophagus that have been reported in Japan were reviewed, and it was learned that the present case is the second of multiple early cancer arising in Barrett's esophagus so far reported in Japan.     

Risk for cancer in Barrett’s esophagus: Medical versus surgical therapy

Esophageal adenocarcinoma associated with Barrett’s esophagus has been increasing in incidence over the past three decades. Our understanding of the risks for the development of esophageal adenocarcinoma in Barrett’s esophagus is evolving. Newer treatment options for Barrett’s esophagus are being developed in all areas, including endoscopic therapy, surgery, and chemoprevention trials.     

Endocrine cells in extrahepatic bile duct carcinoma

Summary A total of 44 extrahepatic bile duct carcinomas comprising 13 well-differentiated adenocarcinomas, 25 moderately differentiated adenocarcinomas, and 6 poorly differentiated adenocarcinomas were examined histologically and immunohistochemically for somatostatin, gastrin, and glicentin. Argyrophil cells, argentaffin cells, and somatostatin- and gastrin-immunoreactive cells within the tumor were detected in 46.2%, 15.4%, 23.1%, and 15.4% of well-differentiated adenocarcinomas, and in 16.0%, 8.0%, 12.0%, and 4.0% of moderately differentiated adenocarcinomas, respectively. No tumor tissues of poorly differentiated adenocarcinomas contained endocrine cells. A statistically significant difference in the frequency of argyrophil cells was observed between well and poorly differentiated adenocarcinoma. The incidence of argyrophil cells and somatostatin-immunoreactive cells in nonneoplastic mucosa adjacent to well-differentiated adenocarcinoma was higher than in that adjacent to poorly differentiated adenocarcinoma. Glicentin-immunoreactive cells could not be demonstrated either in tumor tissue or in nonneoplastic mucosa of the extrahepatic bile duct. With reference to the histogenesis of extrahepatic bile duct carcinoma, it was assumed from these results that the development of well-differentiated adenocarcinoma might be closely related to the occurrence of endocrine cells and that poorly differentiated adenocarcinoma might develop from ordinary mucosa.     

Expression of sulfated carbohydrate chain and core peptides of mucin detected by monoclonal antibodies in Barrett's esophagus and esophageal adenocarcinoma

Columnar epithelium-lined esophagus (Barrett's esophagus) is an acquired disorder associated with a high incidence of adenocarcinoma of the lower esophagus. Columnar epithelium resembling intestinal metaplasia (IM) is especially important, since it is considered to be a premalignant condition. The aim of this study was to define the sulfated carbohydrate chain of mucin and its core peptide profile in Barrett's esophagus (BE) and to compare it with the profile in Barrett's adenocarcinoma and lower esophageal adenocarcinoma. The sulfated carbohydrate chain was not expressed in 16 specimens of normal esophageal epithelium, but in BE, it was expressed in 50% (8/16) of the specimens. This chain was detected in 100% (7/7) of esophageal adenocarcinoma specimens, including four cases of Barrett's adenocarcinoma. These data suggest that the sulfated carbohydrate chain may be associated with malignant phenotype of the esophagus. MUC1 core peptide was positive in 87% (13/15) of BE specimens and in 29% (2/7) of the esophageal adenocarcinoma specimens. MUC2 core peptide was present in 57% (8/14) and 43% (3/7) of these specimens, respectively. These data suggest that Barrett's epithelium, which is similar to IM, but not normal esophageal epithelium, expresses the sulfated sugar chain which is known to be present in gastric IM and colonic mucosa. However, there was no significant correlation between the expression of the sulfated sugar chain and the expression of either mucin core peptide MUC1 or MUC2. Thus, this carbohydrate chain may be expressed on as yet unidentified core proteins, other than MUC1 or MUC2 core peptide, in BE and esophageal adenocarcinoma. Identification of these proteins may be very important in helping to detect premalignant status in BE. (Received Jan. 26, 1998; accepted May 22, 1998)     

Adenocarcinoma arising in Barrett's esophagus after total gastrectomy

A 64-yr-old Japanese male who underwent a partial gastrectomy for a duodenal ulcer at the age of 21, a total resection of the remnant stomach for a stomal ulcer at age 25, and in whom Barrett's esophagus was diagnosed at age 47, was found to have a tumor at the distal esophagus and was operated on by thoracic esophagectomy. The tumor was a well to moderately differentiated adenocarcinoma invading down to the muscularis propria. The entire esophageal mucosa in the resected specimen was lined by columnar epithelium. This tumor was thought to derive from the Barrett's esophageal epithelium.     

Successful treatment for a patient with esophageal carcinoma that amalgamates with polymyositis: a case report

Polymyositis is known to amalgamate with malignant tumor. Here, we report a case of successfully resected esophageal carcinoma that amalgamated with polymyositis. Moreover, this is a rare case of squamous cell carcinoma combined with Barrett’s adenocarcinoma. A 47-year-old man was admitted to a hospital because of progressive dysphagia and difficulty in walking. Laboratory data showed creatine phosphokinase (CPK) was elevated, and he was diagnosed with polymyositis. He was treated with steroids, and the symptoms were improved with decreased CPK. Endoscopic and pathological examination showed a squamous cell carcinoma (0-Ipl, SM2-3) combined with Barrett’s adenocarcinoma (0-IIa, M2) of the esophagus. Although we were concerned about postoperative complications associated with polymyositis, the postoperative course was good, with decreased steroid, and he was discharged on the 21st postoperative day. At 1.5 years after surgery, he reports no recurrence of polymyositis or esophageal cancer.     

p53 and MIB-1 expression of esophageal carcinoma concominant with achalasia

Achalasia, insufficient relaxation of the lower esophageal sphincter (LES) causes the retention and stasis of food and secretions, chronic hyperplastic esophagitis and eventual malignant transformation. p53 alternation has been suggested to play an important role in the malignant transformation. A 53-year-old man was endoscopically followed up for esophageal achalasia for seven years, and endoscopy revealed an ulcerative region in the upper thoracic esophagus, and histopathologically the biopsy specimens showed moderately differentiated squamous cell carcinoma. In resected specimens, p53 staining was strong and diffuse in the tumor and MIB-1 immunoreactivity was strong and patchy in the tumor and the basal layer of squamous mucosa of the esophagus. No staining for either immunostains was noted in normal esophageal mucosa. It is necessary for patients with esophageal achalasia to be followed-up with endoscopy, and that p53 and MIB-1 immunostaining of biopsy specimens should be performed to detect pre-cancerous lesions.     

Low-grade dysplasia in an adenomatous polyp of the esophagus developing on pyloric-type heterotopic gastric mucosa treated with endoscopic mucosal resection: a case report

A 72-year-old woman with an unremarkable medical history underwent an upper gastrointestinal endoscopy in May 2002 because of dyspepsia. An examination showed a pedunculated polyp lesion in an inlet patch on the posterior wall of the esophagus, 20 cm distant from the incisors and measuring 1.5 cm. Forceps biopsies were obtained, and the pathological analysis showed a gastric-like mucosa with well-differentiated pyloric glands below an atrophic squamous epithelium; most of the glands were lined with atypical cells, compatible with low-grade dysplasia. Histological examination after endoscopic removal showed a low-grade dysplasia in an adenomatous polyp of the esophagus developing on pyloric-type heterotopic gastric mucosa (HGM). Three years later, the patient remains well with no evidence of esophageal disease. We review 25 reported cases of adenocarcinoma and 3 cases of high-grade dysplasia arising in HGM.     

The Effect of Retinoic Acid and Deoxycholic Acid on the Differentiation of Primary Human Esophageal Keratinocytes

The mechanism linking gastroduodenal reflux disease to intestinal metaplasia in the esophagus (Barrett’s esophagus) has not been determined. Active conjugate metabolites of retinoic acid, in addition to bile acids, undergo an enterohepatic circulation in bile. Retinoic acid and bile acids are candidate mediators of keratinocyte transdifferentiation in Barrett’s esophagus. We studied the effects of retinoic acid on the differentiation of primary human esophageal keratinocytes cultured in vitro. Retinoic acid induces expression of a marker of intestinal differentiation, MUC2, in these cells. However, retinoic acid, alone or in combination with the hydrophobic bile acid, deoxycholic acid, does not affect esophageal keratinocyte squamous differentiation as assessed by involucrin expression and cellular morphology. The ability of retinoic acid to induce MUC2 expression may be relevant to the pathogenesis of Barrett’s esophagus. However, this does not result in suppression of squamous differentiation.     

Development of Barrett's esophagus six months after total gastrectomy

Barrett's esophagus (BE) is an acquired disease of the esophagus, in which esophageal squamous epithelium is changed by injury from reflux to metaplastic intestinal type columnar epithelium. BE is the premalignant lesion of adenocarcinoma of the esophagus. It is widely accepted that the long-standing reflux of gastric acid is a catalyst for the development of BE. More recent work points toward the reflux of duodenal secretions as a catalyst in this disease process as well. Moreover, the time course for the development of BE once a patient has reflux is not known. Our case challenges the currently defined time course of "long-standing" reflux symptoms for the development of BE, and supports the role of duodenal secretions alone in the development of BE. A 68-yr-old Caucasian man was admitted with weight loss, left upper quadrant pain, a hemoglobin of 6.8, and heme-positive stool. Esophagogastroduodenoscopy (EGD) revealed normal esophageal mucosa and a mass in the gastric cardia. Biopsies showed moderately differentiated gastric adenocarcinoma. The patient underwent a total gastrectomy, distal esophagectomy, and a Roux-en-Y esophagojejunostomy. Pathology confirmed gastric adenocarcinoma (T1 N0 Mx). The distal esophagus and gastroesophageal junction in the resected specimen were grossly and microscopically normal. Six months later an EGD, prompted by new complaints of regurgitation and dyspepsia, revealed distal esophageal mucosa lined by red-colored columnar tissue. Biopsies showed intestinal type epithelium. Thus, our case report's contribution to the current literature is twofold. It provides evidence of development of BE solely from duodenal reflux, and it documents a relatively short time span to development of BE.     

Esophageal intramural spreading from an adenocarcinoma of the esophagogastric junction

Although intramural spreading from gastric carcinoma to the esophageal wall is occasionally reported, longitudinal intramural lesion of the esophagus is very rare. We herein report the case of a patient found to have a carcinoma of the gastric cardia with intramural spreading to the esophagus approximately 7.0 cm in length. A 65-year-old man was admitted to our department suffering from a persistent midthoracic pain and mild dysphagia during the previous 3 months. Upper gastrointestinal studies revealed an oval submucosal tumor of the lower esophagus and a flare irregular lesion on the esophagogastric junction. An endoscopic ultrasonography showed the main tumor was in the submucosal layer and invaded beyond the muscularis propria. Histopathological examination of the resected specimen confirmed a poorly differentiated adenocarcinoma, 7.0 cm in length, which penetrated through the gastric wall, and invaded the submucosal layer of the esophagus. When only a few scattered carcinoma cells infiltrate only the mucosa or submucosa, it is difficult to diagnose the extent of esophageal invasion. In treating patients with gastric cancer with esophageal invasion, it is important to determine the safety of the proximal margin for esophageal resection. Histological examination using frozen sections obtained during surgery is essential for deciding the operative safety margin.     

Mucoepidermoid carcinoma of the esophagus treated by endoscopic mucosal resection

Mucoepidermoid carcinoma is a mixed cell tumor with both adenocarcinomatous and squamous components. We report a rare case of superficial mucoepidermoid carcinoma of the esophagus with mucosal gastric cancer. Endoscopic mucosal resection was performed on a 67-year-old man with a slight but defined depressed lesion of the thoracic esophagus and two lesions of mucosal gastric cancer. Histological examination revealed that the lesion of the esophagus was a mucoepidermoid carcinoma and the two lesions of the stomach were well-differentiated adenocarcinoma. Since the mucoepidermoid carcinoma had only slightly invaded the submucosal layer, it was thought to arise from the ductal epithelium of the esophageal gland or the stratified squamous epithelium of the esophagus. Radiation therapy with a total dose of 60 Gy was performed and there has been no recurrence or metastasis to other organs during 36 months of follow-up.