Combined tubular adenocarcinoma and hepatoid adenocarcinoma arising in Barrett esophagus

Hepatoid adenocarcinoma arising in the esophagus is extremely rare. To date, there are only 3 cases in the world English literature. We report the fourth case here. A 76-year-old Japanese man was admitted to our hospital because of the deterioration of nephritic syndrome. He presented with chest burn, and the endoscopic examination of upper digestive tract disclosed the tumor in the lower esophagus. The subtotal esophagectomy was undertaken because of esophageal cancer. The postoperative histologic examination showed the finding of combined tubular adenocarcinoma and hepatoid adenocarcinoma arising in Barrett esophagus. Immunohistochemically, hepatoid adenocarcinoma cells were positive for a-fetoprotein, hepatocyte, a1-antitrypsin, a1-antichymotrypsin, and CDX2, but negative for MUC5AC and MUC6. Esophageal hepatoid adenocarcinoma seems to be closely associated with Barrett esophagus and show the intestinal phenotype rather than gastric phenotype.     

Cardiac rather than intestinal-type background in endoscopic resection specimens of minute Barrett adenocarcinoma

Many publications focusing on the background or original mucosa of Barrett adenocarcinoma have maintained that adenocarcinoma arises in intestinal-type mucosa with goblet cells in the columnar-lined esophagus, and this has become a central dogma. The mucosa on each side of a series of 141 minute esophageal adenocarcinomas (almost all of which were mucosal carcinomas) resected by endoscopic mucosal resection was recorded as the background mucosa. All 141 cases had endoscopic evidence of an esophageal origin, and for 113 of them, histologic evidence of an esophageal origin was also available. The mucosae were classified into 4 types--squamous, cardiac, fundic, and intestinal--based on routine histology and immunohistochemical staining. The present joint pathologic examination of the background mucosa of Barrett adenocarcinoma conducted by Japanese and German pathologists and gastroenterologists found that more than 70% of primary small adenocarcinomas (<2 cm) of the esophagus were adjacent to cardiac/fundic-type rather than intestinal-type mucosa. Moreover, intestinal metaplasia was not observed in any areas of the endoscopic mucosal resection specimens in 64 (56.6%) of the 113 cases. In other words, there was no evidence to support the previously held view that Barrett adenocarcinoma is nearly always accompanied and preceded by intestinal-type mucosa. Our study has demonstrated a close relationship between esophageal adenocarcinoma and cardiac-type mucosa. Therefore, it is not proven histogenetically that the background mucosa of esophageal adenocarcinoma is the intestinal type. Also, it seems better to define Barrett esophagus as metaplastic columnar-lined esophagus alone, without requiring the presence of goblet cells, in accordance with histogenetic and practical standpoints.     

Interinstitutional variability and effect of tissue fixative on the interpretation of a Barrett cytokeratin 7/20 immunoreactivity pattern in Barrett esophagus

A unique pattern of cytokeratin (CK) 7/20 immunostaining (diffuse staining with CK7 and surface and superficial crypt staining with CK20) has been reported to be useful in differentiating Barrett esophagus (BE) from intestinal metaplasia of the stomach. However, there are conflicting results regarding the prevalence of a BE CK7/20 staining pattern in BE between different studies. Therefore, this study was performed to determine the degree of variability in interpretation of a BE CK7/20 pattern and to determine the reasons for variability when present. Esophageal and gastric mucosal biopsies from 67 patients with BE and antral intestinal metaplasia at 2 institutions were immunostained for CK7/20. All cases were evaluated for the presence of a BE CK7/20 pattern by 2 gastrointestinal pathologists from each institution, and the degree of agreement between institutions was determined. To determine the effect of tissue fixation and staining methods on the pattern of CK7/20 staining, unstained slides were exchanged between institutions, stained separately by each institution, and reexamined by all pathologists. There was excellent agreement on the presence of a BE CK7/20 staining pattern between pathologists at the same institution but only moderate agreement between pathologists at different institutions (71% overall, kappa = 0.58). Among BE cases, a BE CK7/20 staining pattern was identified in 50 (96%) of 52 cases by Cleveland Clinic Foundation pathologists but only 35 (67%) of 52 cases by Brigham and Women's Hospital pathologists. The major source of disagreement related to the interpretation of weak or variable CK7 staining of deep intestinalized mucosa in BE biopsies that were fixed in Hollande, but not those that were fixed in formalin. After the creation of a new set of criteria for a positive BE CK7/20 staining pattern, which took into account the effects of Hollande's fixative, the degree of agreement between pathologists at each of the 2 institutions was excellent (100%, kappa value = 1.0). Therefore, the CK7/20 staining pattern is influenced by the type of fixative used. Only a moderate level of interobserver agreement among pathologists regarding a BE CK7/20 pattern can be achieved if one is not aware of these effects. Nevertheless, specific criteria for interpretation of CK7/20 staining can be successfully applied between institutions and need to be developed before use of this technique in clinical practice.     

内镜下氩离子凝固术联合雷贝拉唑治疗Barrett食管的疗效分析

目的探讨内镜下氩离子凝固术联合雷贝拉唑治疗Barrett食管疗效。方法选择经电子胃镜检查及病理组织学检查确诊为Barrett食管患者181例,随机分成3组,A组（56例）为单纯雷贝拉唑治疗组;B组（60例）为单纯内镜下氩离子凝固术治疗组;C组（65例）为内镜下氩离子凝固术联合雷贝拉唑治疗组。所有入选患者在首次治疗的3、6、12个月内随访复查内镜及病理组织学检查。结果 A、B、C三组在首次治疗的3、6、12个月内随访,A组总有效率分别为5.4%、4.9%、3.1%;B组总有效率分别为85.0%、82.4%、85.4%;C组总有效率分别为90.8%、92.5%、91.5%。以上两两组间比较均有统计学意义（P〈0.05）。结论内镜下氩离子凝固术联合雷贝拉唑治疗Barrett食管是安全有效的,值得临床推广与应用。     

食管癌旁组织核基质蛋白单克隆抗体的制备及初步鉴定

目的 制备抗食管癌旁组织核基质蛋白的特异性单抗。方法 ＳＤＳ－ＰＡＧＥ分析正常食管组织、食管癌旁组织及食管癌组织核基质蛋白间的差异。用食管癌旁组织核基质蛋白做免疫原免疫Ｂａｌｂ／ｃ小鼠,利用杂交瘤技术制备了５株能稳定分泌单克隆抗体的杂交瘤细胞株,并对９－１－２／Ｄ、９－１－７／Ｄ２株细胞作了初步鉴定。结果 免疫组化分析发现９－１－２／Ｄ单抗与食管癌及正常食管组织均有反应,而９－１－／７Ｄ单抗只与食     

伴有胃癌的多发性胃腺囊

在431例胃切除标本中,发现6例粘膜层和粘膜下层有多发性腺囊,占同期全部胃切除标本431例的1.39%,占其中胃癌163例的3.68%。粘膜下腺囊常和粘膜层腺体相连续,周围有平滑肌包绕和炎细胞浸润。6例均伴有胃癌,其中2例有2个癌灶。粘膜层常有糜烂、再生和不典型增生等改变,提示这些病变反复进行,可能引起胃腺囊形成和胃癌发生。     

Distinction between intestinal metaplasia in the cardia and in Barrett's esophagus: the role of histology and immunohistochemistry

Intestinal metaplasia in Barrett's esophagus (BIM) is a precancerous condition, whereas the carcinogenic potential of intestinal metaplasia of the cardia (CIM) is uncertain. Although clinically important, histological distinction between both conditions by endoscopic biopsies is considered problematic. In the present study, 4-mm samples of BIM (n=31) and CIM (n=9) were selected from esophagectomy specimens that had been resected for esophageal cancer. Slides were coded and stained with hematoxylin and eosin (H&E), Alcian blue-periodic acid-Schiff (PAS), cytokeratins (CK) 7 and 20, and CD10, which labels the intestinal brush border. The predictive value of these stains for the recognition of BIM and CIM was evaluated independently by two senior pathologists. With the use of H&E-stained slides exclusively, BIM samples were categorized correctly in 93.5% and 83.9% of cases (pathologists 1 and 2, respectively), and CIM samples, in 100% and 88.9% of cases. Alcian blue-PAS-positive goblet cells were identified by both investigators in all BIM and CIM samples. BIM-typical CK 7 and 20 immunostaining pattern was identified in 90.3%/83.9% of BIM but only in 11.1%/11.1% of CIM. CD10-positive brush border was present in 32.3%/25.8% of BIM and in 88.9%/88.9% of CIM. When HE-stained slides and immunohistologically stained slides were used together for tissue recognition, BIM were categorized correctly in 90.3%/80.6% of cases, and CIM, in 88.9%/88.9% of cases. In conclusion, BIM and CIM can be usually distinguished on the basis of HE sections. CK 7 and CK 20 expression pattern analysis discriminates correctly between BIM and CIM in the majority of cases. CD10-positive intestinal brush border is present in the majority of CIM but only in a minority of BIM. However, immunohistochemical investigations could not improve the diagnostic accuracy of HE histology alone.     

A monoclonal surface immunoglobulin (IgM/D-L) with specificity for surface antigen of ox red blood cells in a patient with leukemic lymphosarcoma

A patient with B-cell leukemic lymphosarcoma, whose lymphocytes had a monoclonal (IgM/D-L) surface immunoglobulin (SmIg) and formed rosettes with ox red blood cells (ORBC), is described. The leukemic cells were documented to have a monoclonal SmIg and cytoplasmic Ig (CIg) and secreted a monoclonal immunoglobulin (MIg) whose antibody activity was directed to the surface antigen of ORBC. (i) Pretreatment of the leukemic cells with anti-, anti-, or anti- inhibited E(ox) rosette formation specifically. (ii) Pretreatment of the leukemic cells with pronase removed the SmIg and abolished E(ox) rosette formation simultaneously, and regeneration of the SmIg was parallel with recovery of the rosette formation. (iii) A small amount of serum MIg could be detected by agarose gel electrophoresis and antiidiotypic antibody against the 19 S component of the serum revealed that the monoclonal SmIg, CIg, and serum MIg shared the same idiotope. This case suggests that lymphocytes of some B-cell malignancies may bind to ORBC through SmIg.     

Effects of acetylsalicylic acid and celecoxib on the N-nitrosodiethylamine induced carcinogenesis in rat liver and esophagus

The effects of nonsteroid antiinflammatory drugs (acetylsalicylic acid and celecoxib) on N-nitrosodiethylamine-induced carcinogenesis in the liver and esophagus were studied in rats. The inhibitory effect of celecoxib on carcinogenesis was more pronounced (in comparison with acetylsalicylic acid), which manifested in a significantly decreased incidence of neoplastic changes in the liver tissue (from 91.7 to 65.2%), number of tumors in the esophagus (from 4.13 to 2.61 tumor/rat), and in delayed malignization in the liver and esophagus. The incidence of erosions and ulcers of the gastric mucosa was significantly lower after celecoxib treatment. These data indicate that celecoxib inhibits N-nitrosodiethylamine-induced carcinogenesis in the liver and esophagus. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 1, pp. 93–96, January, 2007     

不同胃黏膜病变患者的血清胃蛋白酶原变化

目的：探讨胃溃疡、十二指肠球部溃疡、非萎缩性胃炎、萎缩性胃炎、胃癌患者胃蛋白酶原(pepsinogen,PG)Ⅰ、PGⅡ水平和PGⅠ/PGⅡ比值变化。方法：选择2015年1月至2015年10月因消化道症状行胃镜检查的门诊及住院患者共133例,根据胃镜检查及组织病理学结果,将受检者分为5组。非萎缩性胃炎组42例、萎缩性胃炎组33例、胃溃疡组20例、十二指肠球部溃疡组23例、胃癌组15例、比较各组血清PGⅠ、PGⅡ水平。结果：与非萎缩性胃炎组相比,胃溃疡、十二指肠球部溃疡患者PGI明显升高(P<0.05),胃溃疡PGII明显升高(P<0.05),萎缩性胃炎组、胃癌组血清PGⅠ及PGⅠ/PGⅡ水平降低(P<0.05)。结论：血清PGⅠ、PGⅡ水平以及PGⅠ/PGⅡ比值对提高消化性溃疡、胃癌前病变及胃癌的诊断有重要的临床价值。     

Mucin core polypeptide expression in the progression of neoplasia in Barrett's esophagus

We have previously demonstrated a specific pattern of mucin (MUC) core polypeptide expression in Barrett's esophagus (BE) characterized by MUC1 and MUC6 positivity in goblet cells in a proportion of cases. The aim of this study was to determine the pattern of MUC expression associated with the development and progression of dysplasia in BE. Endoscopic mucosal biopsies from 35 patients with BE (10 with no dysplasia, 6 with indefinite for dysplasia, 12 with low-grade dysplasia [LGD], and 7 biopsies with high-grade dysplasia [HGD]) were immunostained (ABC method) with antibodies against MUC1, MUC2, MUC3, MUC5AC, and MUC6. The extent and pattern of staining for each marker was evaluated in intestinalized Barrett's epithelium and in the various grades of dysplasia. For cases with dysplasia, staining was evaluated separately in nondysplastic epithelium adjacent to (<1 cm) and distant from (>2 cm) areas of dysplasia. In nondysplastic BE, MUC1, MUC2, MUC3, MUC5AC, and MUC6 stained 40%, 100%, 100%, 100%, and 90% of cases, respectively, in goblet or nongoblet columnar epithelium. With the progression of dysplasia (from metaplasia to indefinite, LGD and HGD), there was a significant decrease in expression of MUC1, MUC2, and MUC3, and alterations in the staining patterns of MUC5 and MUC6. In fact, MUC1 and MUC3 were entirely absent from all cases of HGD. Interestingly, BE-associated adenocarcinomas showed an MUC phenotype distinct from that of HGD, with expression of MUC1 and MUC3 in 47% and 67% of cases, and expression of MUC1 in a membranous pattern. There was no significant difference in MUC staining in nondysplastic BE between patients with and without dysplasia. Alterations in MUC expression occur in the progression of dysplasia in BE. However, none of these markers helps identify a subgroup of patients at increased risk for neoplasia.     

The origin and future of oxidative stress pathology: From the recognition of carcinogenesis as an iron addiction with ferroptosis‐resistance to non‐thermal plasma therapy

Helmut Sies established the concept of oxidative stress in 1985. However, it took some time to introduce this concept into pathology, where investigators count on formalin‐fixed paraffin‐embedded tissue sections. I sought out antigens for this purpose based on an oxidative stress‐induced rat renal carcinogenesis model, which revealed that 8‐hydroxy‐2′‐deoxyguanosine and 4‐hydroxy‐2‐nonenal‐modified proteins are ideal. These two monoclonal antibodies successfully revealed the involvement of oxidative stress in numerous human diseases, including carcinogenesis and atherosclerosis. Shigeru Okada established the aforementioned ferric nitrilotriacetate (Fe‐NTA)‐induced rat renal carcinogenesis model, which thus far has answered many questions regarding the presence of target genes in oxidative stress‐induced carcinogenesis and the sites that are susceptible to oxidative stress in the genome. Particularly, the similarity of genomic alterations between Fe‐NTA‐induced renal cancer and human cancers suggests that excess iron plays a role also in human carcinogenesis. Furthermore, excess iron is a major pathology in asbestos‐induced mesothelioma, including chrysotile. Despite an analogy to asbestos, multi‐wall carbon nanotubes were distinct in that diameter is another responsible factor for mesothelial carcinogenesis. Recently, non‐thermal plasma emerged as a candidate for medical intervention for wounds and cancers via manipulating oxidative stress. Counteracting excess iron is a promising preventive strategy for major diseases.     

Expression of pepsinogen II with androgen and estrogen receptors in human prostate carcinoma

The expression of pepsinogen II (PG II), an aspartyl proteinase usually involved in the digestion of proteins in the stomach, was immunohistochemically investigated in conjunction with androgen (AR) and estrogen receptor (ER) status in prostate adenocarcinomas. Of a total of 38 samples obtained from radical prostatectomies, 23 tumors (60.5%) were positive for PG II and there was a significant positive correlation to the expression of AR but not to ER. Cells positive for PG II were localized mainly to the peripheral zones of tumorous glands which, in normal prostate, are negative, and in areas also expressing AR. In addition, a significant correlation between AR and ER was detected in the prostate carcinomas examined, which suggests a hormone-dependent status. On the basis of these results, PG II expression might be closely related to hormonal alterations associated with the development of prostate tumors.     

Characterization of antigenic structures in autoimmune atrophic gastritis with pernicious anaemia. The parietal cell H,K-ATPase and the chief cell pepsinogen are the two major antigens

Using isolated cells and subcellular fractions from pig gastric mucosa, antigenic structures with specific binding of IgG from sera of patients with auto-immune atrophic gastritis were characterized by means of immunoblotting and enzyme-linked immunosorbent assay. In immunoblotting experiments using mucosal cells as the antigen source, two dominating bands of 94 and 41 kDa were found. The two major antigens were identified as the H,K-ATPase (94 kDa), which constitutes the parietal cell acid pump, and pepsinogen (41 kDa) located in the chief cells. There was also a small but significant binding of antibodies to a preparation of Na,K-ATPase, an enzyme which is about 60% homologous to H,K-ATPase. Commercial preparations of hog gastric pepsinogen and pepsin bound pernicious anaemia IgG with equal efficacy. When sera from seven patients with the diagnosis pernicious anaemia were tested, all were found to contain auto-antibodies against H,K-ATPase as well as pepsinogen. In intact, isolated H,K-ATPase-containing vesicles the cytosolic part of the ATPase molecule is facing the outside of the vesicles. Both intact and trypsinized vesicles were incubated with patient sera and with a monoclonal antibody against H,K-ATPase. Pernicious anaemia IgG was found to bind to a cytosolic, trypsin-resistant structure, but the binding of the monoclonal antibody was lost upon trypsinization. The present results indicate that intracellular structures of the gastric mucosa, due to cell damage, may be exposed to immune-competent cells, which do not recognize these structures as ‘self’.     

Ski/SnoN expression in the sequence metaplasia-dysplasia-adenocarcinoma of Barrett's esophagus

Barrett's esophagus (BE) is a precancerous condition. However, the mechanisms underlying the transformation from metaplastic to dysplastic to adenocarcinomatous epithelium are still poorly understood. As loss of transforming growth factor-beta growth inhibition is considered a hallmark of several human neoplasms, we evaluated the expression of Ski and SnoN (proteins that antagonize transforming growth factor-beta signaling through physical interaction with Smad complex and by recruiting histone deacetylases), as markers of the transforming growth factor-beta signaling pathway, in BE with and without dysplasia. Biopsy samples from 37 patients (26 men, aged 60 +/- 8 years) with histologically proven BE were evaluated; 10 patients had concomitant low-grade dysplasia, 7 high-grade dysplasia (HGD), and 6 HGD associated with adenocarcinoma. Ski and SnoN expression was assessed immunohistochemically. Neither Ski nor SnoN was expressed in normal esophageal epithelium, but both were strongly expressed in BE tissue, with intense cytoplasmic positivity. Expression of these proteins decreased markedly in dysplastic areas in patients with low-grade dysplasia and was absent in those with HGD or HGD/adenocarcinoma. Ski and SnoN proteins are overexpressed in BE and may be involved in abnormal signaling elicited by transforming growth factor-beta in this epithelium, enhancing the tumorigenesis process. These observations might help to elucidate the molecular mechanisms involved in the BE tumorigenesis process.     

Investigation of the Esophageal Rho-kinase Expression in Patients with Barrett’s Esophagus

Abstract

The mechanisms responsible for the malignant transformation in Barrett’s esophagus (BE) are still poorly understood. The authors have evaluated the role of Rho-kinase (ROCK1 and ROCK2) expressions in patients with BE. All patients underwent upper gastrointestinal system endoscopy, which was confirmed histologically. Real-time PCR revealed no marked change in gene expressions of ROCK1 and ROCK2 at mRNA levels in BE when compared to controls. Immunohistochemical and western blot analyses showed no change in ROCK1 and ROCK2 protein expressions in BE. This study demonstrates that Rho-kinase gene and protein expressions are not modified in BE.     

Malignant lymphoma of the esophagus associated with macroglobulinemia: Report of a case

A case of non-Hodgkin's lymphoma of the esophagus in a 74 year old man is presented. Grossly, the surgically removed esophagus had a fuslform submucosal mass covered with smooth surfaced mucosa. Microscopic examination revealed that the mass consisted of a dense infiltrate of small to medium-sized lymphoid cells with plasmacytoid differentiation, leading to a diagnosis of diffuse small cell lymphoma with lymphoplasmacytic subtype. Laboratory data as well as immunohistochemical studies proved that the lymphoma produced monoclonal immunoglobulin M, giving rise to macroglobulinemia.     

Production and characterization of human monoclonal lymphocytotoxic autoantibodies from a renal dialysis patient

Abstract: We have produced human monoclonal lymphocytotoxic autoantibodies from a renal dialysis patient by the generation of a mouse/human heterohybridoma. The antibodies are of the IgM class and react with the patient's autologous cells, the B-Iymphoblastoid cell line producing the antibody, normal T and B lymphocytes, B cells from chronic lymphatic leukemia patients (CLL cells), and the autoantibody-sensitive cell line K562. Screening of the monoclonal antibodies (mAb) against panels of normal T and B cells and CLL cells demonstrated that different reactivity profiles could be generated at different dilutions of the mAb. These profiles were identical to those seen with autoantibodies from different renal patients and this suggests that these profiles do not imply different antibody specificities but differing target cell sensitivity. Reactivity profiles seen in the fluorescence binding assays suggest that the target cell sensitivity is dictated not by antigen density alone but also by antibody/ antigen affinity. The results from studies of enzyme treatment of target cells and lectin inhibition of the molecular specificity suggest that the autoantibodies are polyreactive, capable of binding sialic acid-dependent epitopes and other negatively-charged cell surface molecules.     

Heterotopic sebaceous glands in the esophagus: Histopathological and immunohistochemical study of a resected esophagus

A resected esophagus with numerous heterotopic sebaceous glands was examined in an attempt to determine whether esophageal heterotopic sebaceous glands are the result of a metaplastic process or a congenital anomaly. The present case concerns a 79-year-old Japanese man with numerous esophageal heterotopic sebaceous glands accompanied by superficial esophageal cancer. The resected esophagus possessed numerous heterotopic sebaceous glands, which could be seen clearly as slightly elevated, yellowish lesions. Histological examination of these glands, all of which were located in the lamina propria, revealed lobules of cells that showed characteristic sebaceous differentiation. Bulbous nests of proliferating basal cells showing sebaceous differentiation were occasionally observed in the esophageal epithelium. Of the antibodies against six different keratins used, only anti-keratin 14 labeled both the heterotopic sebaceous glands and the bulbous nests. Acquired metaplastic change of the esophageal epithelium is probably the pathogenetic mechanism involved in these unusual lesions.     

Cyclooxygenase-2 expression and cell proliferation are increased in MUC2-positive area of columnar-lined esophagus

Columnar-lined esophagus is composed of intestinal type and gastric type epithelium. Only the specialized or intestinal type columnar epithelium is susceptible to the development of esophageal adenocarcinoma. The aim of the present paper was to evaluate the expression of cyclooxygenase (COX) and microsomal prostaglandin E synthase (mPGES) in gastric-type and intestinal-type metaplasia in columnar-lined esophagus and compare these with cell proliferation. Biopsy specimens of 30 columnar-lined esophagus patients were collected, and immunohistochemistry was performed for secretory mucins (MUC2, MUC5AC), COX, mPGES and cell proliferation (Ki-67). The MUC2-positive area had higher COX-2 expression and cell proliferation than the MUC5AC-positive area. There was a close correlation between COX-2 expression and cell proliferation. In contrast, the expression of COX-1, mPGES-1 and -2 was similar between intestinal metaplasia and gastric metaplasia. In conclusion, intestinal-type columnar-lined esophagus possesses COX-2 expression and a higher proliferation potential, suggesting that esophageal adenocarcinoma may arise from specialized columnar-lined esophagus.