Low‐grade dysplasia component in early invasive squamous cell carcinoma of the esophagus

Background and Aims: It has not been determined whether low‐grade squamous dysplasia (LGD) of the esophagus is a precancerous lesion or not. If LGD progresses to squamous cell carcinoma, early carcinoma lesions that have such a natural history might contain a remaining LGD component. Methods: The lesions in the 68 patients with early invasive squamous cell carcinoma who underwent endoscopic mucosal resection were examined for the presence of an LGD component. If LGD components were observed, the degrees of architectural and cytological abnormalities of LGD components and those of tumor invasive fronts in the same lesions were studied. The degrees of abnormalities of 28 small LGD lesions were also studied. Results: Histological examination of resected specimens confirmed LGD components in 43% of the squamous cell carcinoma lesions. The lesions of lamina propria mucosae (m2) cancer contained a significantly broader area of LGD component than did the lesions of muscularis mucosae (m3) and submucosal layer (sm) cancer (P = 0.037). Mean score for the degrees of cytological abnormalities of LGD component was similar to that of tumor invasive front (P = 0.457) and significantly higher than that of small LGD lesions (P < 0.001). Conclusion: Our results indicate the possibility that the lesion was formed by a combination of small lesions that arose as a multicentric occurrence of squamous cell carcinoma and dysplasia. Our results also suggest that an LGD component would transform to carcinoma along with tumor progression. However, the concept of ‘basal cell layer type carcinoma in situ’ may be suitable for squamous cell lesions with a high degree of cytological abnormalities confined to the lower half of the epithelium.     

Squamous intraepithelial neoplasia of the esophagus: past, present, and future

With regard to the esophagus, the term “squamous dysplasia” has been used in European countries, the United States, and China, while its use is controversial in Japan. Recently, “low-grade intraepithelial neoplasia” and “high-grade intraepithelial neoplasia” have been used as inclusive terms for dysplasia and carcinoma in situ in the World Health Organization classification. Endoscopically, it is often difficult to identify squamous intraepithelial neoplasia by conventional endoscopy, but application of iodine is useful for the diagnosis of such a lesion. In addition, new types of endoscopic techniques, including magnifying endoscopy, narrow-band imaging (NBI), and endocytoscopy are helpful to detect squamous intraepithelial neoplasia. NBI is very useful for identifying the intrapapillary capillary loop pattern. Regarding the pathological criteria of squamous dysplasia and squamous cell carcinoma, the views of Japanese and Western pathologists have differed significantly. Before the term “intraepithelial neoplasia” was introduced, severe dysplasia as diagnosed by Western pathologists was in fact the same as squamous cell carcinoma in situ or noninvasive carcinoma as diagnosed by Japanese pathologists. This problem has been solved by the introduction of the Vienna classification; however, there are still some issues that need to be resolved. One of them is the presence of basal layer type squamous cell carcinoma in situ, which is often underdiagnosed as lowgrade intraepithelial neoplasia by Western pathologists. Endoscopic treatments such as endoscopic mucosal resection and endoscopic submucosal dissection have recently become possible choices for squamous intraepithelial neoplasia; however, these techniques are not in widespread use in the West. We believe that a consensus meeting between Japanese and Western pathologists as well as endoscopists should be held promptly to reach a common ground for the nomenclature.     

Intramucosal poorly differentiated and signet‐ring cell components in patients with ulcerative colitis‐associated high‐grade dysplasia

Despite the rarity of colorectal poorly differentiated adenocarcinoma (Por) and signet‐ring cell carcinoma (Sig), they are more frequent in patients with ulcerative colitis (UC). However, little is known about these components of early colitis‐associated cancer due to the difficulty of detection at an early stage. Here, we reviewed colitis‐associated high‐grade dysplasia/cancer with Por/Sig components within the submucosa among 103 lesions of 79 UC patients who presented between 1997 and 2017. In total, one Sig in situ, three intramucosal and two submucosal carcinomas (8.7%) were identified among 69 lesions within the submucosa. Depressed appearance, loss of crypt architecture and amorphous surface pattern suggested the presence of Por/Sig, rather than submucosal infiltration. All lesions were located in the rectosigmoid colon and included high‐grade dysplasia. While the surrounding noncancerous mucosa expressed E‐cadherin and MUC5AC, the expression of E‐cadherin was reduced and the expression of MUC5AC was negative in all of the carcinomas except for the Sig in situ. The gastric type metaplasia associated with altered MUC5AC profiles may be a sign of the stepwise accumulation of molecular alterations, including TP53 defects and a reduced expression level of E‐cadherin.     

Prognostic significance of gamma‐glutamyltransferase in patients with resectable esophageal squamous cell carcinoma

Gamma‐glutamyltransferase (GGT) is a membrane‐bound enzyme involved in the glutathione metabolism. Studies suggested that GGT was a marker of apoptotic balance and modulated tumor progression, invasion and drug resistance. Recently, GGT was shown to be associated with the progression of high‐grade esophageal epithelial dysplasia to invasive carcinoma. This study was conducted to investigate the value of pre‐therapeutic serum GGT levels as prognostic parameter in esophageal squamous cell carcinoma. Six hundred thirty‐nine resectable esophageal squamous cell carcinoma patients were recruited in this study and were stratified into two GGT risk groups. The association of pre‐therapeutic serum GGT levels and clinical–pathological parameters was examined. Univariate and multivariate survival analyses were performed. GGT serum levels were associated with gender, smoking status, TNM stage and lymph node involvement. Higher pre‐therapeutic serum GGT was found in males, smoker, advanced TNM stage and lymph node positive patients. Patients assigned to the low‐risk group had higher 5‐year overall survival rate (53.1% vs. 33.0%, P < 0.01) and disease‐free survival rate (45.2% vs. 23.4%, P < 0.01) than the high‐risk group. Patients with high‐risk group of GGT had 1.568 (95% confidence interval [CI], 1.259 ∼ 1.952) times the risk of death and 1.582 (95% CI, 1.286 ∼ 1.946) times the risk of disease recurrence contrast with those with low‐risk group of GGT. The pre‐therapeutic serum GGT is a novel independent prognostic parameter for disease‐free survival and overall survival in resectable esophageal squamous cell carcinoma.     

Basal Layer Reactivity in Hyperplastic and Metaplastic Lesions of the Bronchi as Studied by Lectin Histochemistry

The relationship between squamous metaplasia and squamous cell carcinoma of the bronchi has been the subject of controversy. We investigated basal cell hyperplasia, stratification, squamous metaplasia, and squamous cell carcinoma by means of lectin histochemistry with peanut agglutinin (PNA), Ulex europeus agglutinin-I, soybean agglutinin, and Dolichos biflorus agglutinin for all normal basal cells that are reactive. A basal layer stained with PNA was observed in basal cell hyperplasia, stratification, and squamous metaplasia, but this layer was not exhibited by squamous cell carcinoma. In hyperplasia and metaplasia, PNA staining was biased toward the lowest (basal) layer, whereas staining for the other lectins was more uniformly distributed across the layers. A PNA-positive basal layer may be important for the morphologic reversibility of the bronchial mucosa in hyperplastic and metaplastic lesions, and destruction of this layer may be associated with a progression from metaplasia to squamous cell carcinoma. Accepted for publication: 7 January 2000     

Fhit,E‐cadherin,p53, and activation‐induced cytidine deaminase expression in endoscopically resected early stage esophageal squamous neoplasia

Background and Aim: Abnormal expression of Fragile Histidine Triad (Fhit), E‐cadherin and p53 is observed in esophageal squamous cell carcinoma. It has recently been reported that aberrant expression of activation‐induced cytidine deaminase (AID) in gastric epithelium leads to the accumulation of nucleotide alterations in the p53 gene. However, little is known about the association between these molecular events and the clinicopathological characteristics of early stage esophageal squamous neoplasia, especially in endoscopically resected tumors. Methods: Esophageal squamous neoplasias (n = 49) comprising nine cases of low‐grade intraepithelial neoplasia (LGIN), 22 of high‐grade intraepithelial neoplasia/carcinoma in situ (HGIN/CIS) and 18 of invasive cancers, were endoscopically resected. Their expression of the tumor‐related proteins: Fhit, E‐cadherin, p53 and AID was assessed using immunohistochemical methods, and the relationship between protein expression and clinicopathological data was examined. Results: Reduced or absent Fhit and E‐cadherin expression was detected in 22% and 0% of LGIN cases, 73% and 14% of HGIN/CIS cases, and 94% and 61% of invasive cancer cases, respectively, showing progressive increases during neoplastic progression (Fhit: P < 0.01, E‐cadherin: P < 0.01). Although p53 and AID were overexpressed in these samples, no change in their expression occurred during neoplastic progression. Moreover, p53 expression was not significantly associated with AID expression. Conclusions: These results indicate that a decrease in Fhit and E‐cadherin expression could be related to the development and progression of esophageal squamous neoplasia, and that the expression of p53 was independent of aberrant AID expression in the early stage of esophageal carcinogenesis.     

Randomized, placebo-controlled, esophageal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib

BACKGROUND & AIMS: Esophageal squamous cell carcinoma remains a leading cause of cancer death worldwide. Squamous dysplasia, the accepted histological precursor for esophageal squamous cell carcinoma, represents a potentially modifiable intermediate end point for chemoprevention trials in high-risk populations. METHODS: We conducted a randomized, controlled trial of selenomethionine 200 microg daily and/or celecoxib 200 mg twice daily (2 x 2 factorial design) among residents of Linxian, People's Republic of China. Subjects had histologically confirmed mild or moderate esophageal squamous dysplasia at baseline. Esophagogastroduodenoscopy was performed before and after a 10-month intervention. Per-subject change (regression, stable, or progression) in the worst dysplasia grade was defined as the primary end point. Results were compared by agent group (selenomethionine vs placebo; celecoxib vs placebo). RESULTS: Two hundred sixty-seven subjects fulfilled all eligibility criteria, and 238 (89%) completed the trial. Overall, selenomethionine resulted in a trend toward increased dysplasia regression (43% vs 32%) and decreased dysplasia progression (14% vs 19%) compared with no selenomethionine (P = .08). In unplanned stratified analyses, selenomethionine favorably affected a change in dysplasia grade among 115 subjects with mild esophageal squamous dysplasia at baseline (P = .02), but not among 123 subjects with moderate esophageal squamous dysplasia at baseline (P = 1.00). Celecoxib status did not influence changes in dysplasia grade overall (P = .78) or by baseline histology subgroup. CONCLUSIONS: After a 10-month intervention, neither selenomethionine nor celecoxib inhibited esophageal squamous carcinogenesis for all high-risk subjects. However, among subjects with mild esophageal squamous dysplasia at baseline, selenomethionine did have a protective effect. Although it is based on unplanned stratified analyses, this finding is the first report of a possible beneficial effect for any candidate esophageal squamous cell carcinoma chemopreventive agent in a randomized controlled trial.     

Squamous dysplasia and other precursor lesions related to esophageal squamous cell carcinoma

Squamous cell carcinoma is the most common tumor of the esophagus worldwide, and it is believed to develop through a sequence of dysplastic precursor lesions, which can be detected both endoscopically and microscopically. There are no published guidelines regarding treatment for dysplasia; however, most authorities recommend increased endoscopic surveillance, with biopsies, for patients with flat low-grade dysplasia and endoscopic mucosal resection, endoscopic submucosal dissection, or esophagectomy for patients with high-grade dysplasia. Future studies are needed to define appropriate endoscopic surveillance frequencies for patients with premalignant lesions of the esophagus. This article discusses squamous dysplasia in detail, which is the most important and well-described risk factor for squamous cell carcinoma of the esophagus.     

Carcinoma in situ of the gallbladder with superficial extension into the Rokitansky-Aschoff sinuses and mucous glands

Twenty-four cases of carcinoma in situ of the gallbladder encountered over the past 29 years were evaluated histopathologically. Macroscopic classification disclosed 12 protruding types and 12 superficial types (7 elevated types and 5 flat types). Histologically, 18 cases had papillary growth and 6 had tubular patterns. Epithelial dysplasia of varying degrees was observed around the carcinoma in situ in all except one case and was seen more extensively in superficial type cases, although it was often hard to distinguish dysplasia from carcinoma in situ in some cases. Metaplasia of the mucous glands was observed in 20/24 cases (83.3%). Superficial extension of carcinoma in situ into the Rokitansky-Aschoff sinuses (located below the muscle layer) was observed in 11 cases (45.8%), and extension into the mucous glands was seen in 8 cases (33.3%). These results indicate that it is very important to be able to differentiate invasive carcinoma from cases with superficial extension of dysplasia and/or carcinoma in situ deep into the mucous glands or Rokitansky-Aschoff sinuses. Histological assessment should also be conducted carefully while considering these factors.     

A combined hepatocellular/cholangiocellular carcinoma with sarcomatoid features

Abstract: A case of primary liver cancer showing combined hepatocellular and cholangiocellular features and an associated pseudosarcomatous (schwannomatous) component is presented. Histologically, compact microtrabecular and glandular patterns in a dense fibrous stroma were recognized. The latter showed transition towards spindle cell sarcomatous growth in several areas of both the primary and the lymph-node metastasis. Glandular areas expressed acidic mucins and AE1-reactive keratins; albumin mRNA was detected by in situ hybridization in both trabecular and glandular areas. Vimentin and S-100 protein were mostly expressed in the pseudosarcomatous areas. Both the morphological patterns and the phenotypic features indicate that divergent differentiation along both epithelial and mesenchymal lineages took place in this rare primary liver tumor.     

Expression of OCT4 in human esophageal squamous cell carcinoma is significantly associated with poorer prognosis

AIM: To explore the expression pattern of OCT4 in human esophageal squamous cell carcinoma and its significance in diagnosis and prognosis.METHODS: Using real-time polymerase chain reaction (PCR), Western blotting, immunocytochemistry and immunohistochemistry, the expression of OCT4 in three esophageal squamous cancer cell lines, KYSE70, KYSE140 and KYSE450, was characterized. OCT4 expression was investigated in a series of 153 esophageal squamous cell carcinoma samples using immunohistochemistry and explored its association with clinicopathological features.RESULTS: Immunohistochemically, OCT4 positive immunostaining was observed in cancer cell nuclei. OCT4 was variably expressed in three esophageal squamous cancer cell lines. Among 153 specimens, 105 (68.7%) were negative or weakly positive for OCT4 staining; 21 (13.7%) were moderately positive and 27 (17.6%) were strongly positive. Higher expression level of OCT4 was significantly associated with higher histological grade (P < 0.001) and poor clinic outcome (P < 0.001).CONCLUSION: The expression of OCT4 enables the tumor to have a higher degree of stemness, which in turn results in a poorer clinical outcome for patients with esophageal squamous cell carcinoma.     

Common single nucleotide polymorphism of hypoxia‐inducible factor‐1α and its impact on the clinicopathological features of esophageal squamous cell carcinoma

OBJECTIVE: Angiogenesis is one of the most important molecular events in solid tumor development and growth, in which hypoxia‐inducible factor (HIF)‐1α is a key regulator and plays an important role. Studies have shown that a single nucleotide polymorphism (C1772T) in the HIF‐1α gene exerts a large effect on the phenotype of human head and neck squamous cell carcinoma and renal cell carcinoma. But the impact of the C1772T polymorphism on the clinicopathological features of human esophageal squamous cell carcinoma (ESCC) remains unknown, and thus it is the main focus of our study. METHODS: The C1772T genotype of 95 ESCC patients and 104 healthy controls were studied by using the polymerase chain reaction and restriction fragment length polymorphism. Mutations were confirmed by direct DNA sequencing. The impact of C1772T on tumor size, invasive depth, lymph node metastasis, distant metastasis, histological grade and TNM stage was also studied. RESULTS: The genotype frequency observed in the patients and controls was 11.58% versus 10.58%, respectively, for genotype C/T (P > 0.05). Genotype T/T was not found in our study. Larger tumors and a higher rate of lymph node metastasis was found for the C/T group. CONCLUSIONS: Although there is no significant difference of genotype distribution between ESCC patients and healthy controls, genotype C/T is associated with larger tumor and higher rate of lymph node metastasis.     

食管鳞状细胞癌及不典型增生组织中 hMLH1基因蛋白表达的研究

目的 探讨在食管鳞状细胞癌及不典型增生组织中hMLH1基因的蛋白表达情况及其与食管鳞状细胞癌发生发展的关系。方法 40例食管鳞状细胞癌，相应40例正常组织及26例不典型增生组织，采用免疫组织化学方法，检测了hMLHI蛋白的表达情况。结果 在正常组织、小典跫增生组织、肿瘤组织中的阳性率分别为90％、57．6％和45％，不典型增生组织及肿瘤组织均低于正常组织（P〈0．05）。肿瘤组织中hMLH1蛋白表达阳性者年龄较阴性者大（P〈0．05）。结论 错配修复缺陷早期参与了食管鳞状细胞癌的发生过程；hMLH1蛋白可能抑制和延缓食管鳞状细胞癌的发生和浸润。     

Accelerated expression of a Myc target gene Mina53 in aggressive hepatocellular carcinoma

Aim: Expressions of the myc target genes Mina53 and mimitin are high in esophageal squamous cell carcinoma and colon cancer, and their relationship to cell proliferation and patient prognosis has been reported. Because c‐myc gene expression is closely related to hepatocellular carcinoma (HCC) growth or formation and/or maintenance, we examined the Mina53 and mimitin expressions in HCC. Methods: Surgically resected 53 HCC tissues were immunohistochemically examined for Mina53 and mimitin expressions and their relationship to clinicopathological factors. Results: Diffuse Mina53 expression was observed in the nuclei of cancer cells in the tumor nodule, but was often strong at the periphery of tumor nodules. Diffuse or scattered expression of mimitin was observed in the cytoplasm of HCC cells in tumor nodules. Mina53 expression was higher in poorly differentiated HCC than in well‐differentiated HCC, and significant relationship to histological grade was observed. The cases with a high Mina53 expression also had a high expression of a proliferation marker MIB‐1. This suggested the involvement of Mina53 in cell proliferation. Mina53 expression was high in the tumors of >2 cm of diameter than in ≤2 cm (P < 0.01). Mimitin expression tended to be high in tumors of >2 cm, but no significant relationship was observed either to histological grade, MIB‐1 expression, or the other clinicopathologic factors. Conclusions: Our findings suggested that Mina53 expression is accelerated in HCC with a lower histological grade, with cell proliferation capability, or with a larger diameter, and Mina53 is related to biological malignancy of HCC.     

Aberrant expression of epidermal growth factor receptor and its interaction with protein kinase C δ in inflammation associated neoplastic transformation of human esophageal epithelium in high risk populations

Background and Aim: Esophageal cancer is the second most common cancer among Indian males and is mostly associated with tobacco smoking and alcohol consumption. Epidermal growth factor receptor (EGFR) is a member of Type I tyrosine kinases. Its activation causes the docking of various proteins in its cytosolic tail. In the present study we have analyzed the expression pattern of EGFR, protein kinase C δ (PKCδ), tumor necrosis factor‐α (TNF‐α), nuclear factor κB (NFκB) and the interactions between EGFR and PKCδ in various pathological conditions. Methods: Human esophageal biopsies were obtained from 93 patients with a past history of smoking and alcohol consumption: 20 showed normal mucosa, 40 with dysplasia and 33 squamous cell carcinoma (SCC). These pathological conditions were analyzed immunohistochemically for the presence of EGFR expression and then subsequently analyzed using immunoblot and immunoprecipitation. Results: A statistically significant difference of EGFR overexpression was found between low‐ and high‐grade dysplasia and carcinoma (χ² = 3.3, χ² = 3.42: P = 0.07, 0.33). A statistical significance was observed between dysplasia and SCC and in all histopathological types (χ² = 4, χ² = 4.9; P < 0.05, P = 0.18 and χ² = 26.3, 26.6; P < 0.001). EGFR tyrosine phosphorylation and its association with PKCδ was significantly higher in all histopathological types with χ² = 7.965; P < 0.05 and 4.0830; P = 0.2530. Conclusion: Altogether, our findings reveal that the activation of EGFR and its subsequent interaction with PKCδ under inflammatory conditions might positively be attributed to the transformation of normal esophageal epithelia to SCC, which could explain ongoing inflammation in normal mucosa in a population prone to smoking and alcoholism.     

Basaloid squamous carcinoma of the esophagus developed from achalasia: report of a case

A 57-year-old man, who had been diagnosed as having flask type, grade II achalasia of the esophagus at the age of 26, underwent Heller’s esophagomyectomy in a nearby hospital in 1971. A type 0-Is lesion measuring 2 cm in size was found on the middle thoracic esophagus in September 2002. A protruding tumor with a central depression, not stained with iodine, was detected by endoscopic examination. Standard subtotal esophagectomy with three-field lymph node dissection was performed. By histopathological examination, the esophageal lesion was classified as basaloid squamous carcinoma, extending to the middle part of the submucosa (T1b; sm2), without lymph node metastasis. The majority of the invasive carcinoma was composed of basaloid carcinoma, while a part showed as squamous cell carcinoma at the mucosal site. Achalasia of the esophagus is considered as a risk factor for squamous cell carcinoma by persistent mucosal inflammation caused by chronic stasis and food retention. Most of the reported carcinomas developing from esophageal achalasia are squamous cell carcinoma histologically. An extremely rare case of superficial basaloid squamous carcinoma with achalasia is presented.     

Localization of human epidermal growth factor receptor in cervical intraepithelial neoplasias

Summary Immunohistochemical staining of epidermal growth factor receptor (EGF-R) with a monoclonal antibody was performed in 43 biopsies of cervical tissue. The distribution of the receptors in normal cervical tissue differs from that of cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma of the cervix. Whereas the staining reaction in normal squamous epithelium was confined to the basal and deep parabasal cell layer, in all cervical intraepithelial neoplasias, with or without human papilloma virus association, a homogeneous EGF-R staining reaction could be observed throughout the entire lesion. This means that the dysplasia cells of a CIN I-III, like the tumor cells of a squamous cell carcinoma, have a raised EGF-R content, which in the normal squamous epithelium is usually only found in the basal and deep parabasal cells that are capable of dividing. No EGF-R staining reaction could be detected in the higher, differentiated cell layers of the normal squamous epithelium of the cervix.Abbreviations EGF-R epidermal growth factor receptor - CIN cervical intraepithelial neoplasia     

Immunoexpression of C4 Binding Protein in Oral Leukoplakia and Oral Squamous Cell Carcinoma

Background: The immune evasion of dysplastic cells plays an important role in suppressing the immune response and progression of malignancy. The role of the complement inhibitors in the development of oral epithelial dysplastic lesions and squamous cell carcinoma (SCC) is still unclear. Objective: This study aimed to assess the expression of C4 binding protein (C4BP) as a complement inhibitor in oral squamous cell carcinoma and leukoplakia. Methods: In this study, 94 samples were classified into four groups: leukoplakia with mild to moderate dysplasia, leukoplakia with severe dysplasia or carcinoma in situ, early invasive SCC, and invasive SCC. The expression of C4BP marker was evaluated by immunohistochemistry (IHC) and real-time PCR. The results were analyzed by the Kruskal-Wallis, Bonferroni adjusted Dunn’s multiple comparison, and one-way ANOVA tests. Results: The results of IHC revealed the expression patterns of C4BP in oral dysplasia and SCC, and indicated that the C4BP expression was not significantly different between different histopathological grades in epithelial cells and vessels (P=0.157 and P=0.123, respectively) but, it was significantly different in fibroblasts and lymphocytes (P=0.017 and P=0.043, respectively). The real-time PCR showed a significant correlation between the dysplasia grade and expression of C4BP (p <0.05). Conclusion: According to the results, C4BP is expressed in the cancerous tissue by the tumor cells and their surrounding stroma. In addition, upregulation of the C4BP gene as an inhibitor of the complement system is a possible strategy adopted by the tumor cells to evade the immune system.