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Background: Prediction of tissue origin of esophagogastric junction (EGJ) adenocarcinomas can be important for therapeutic decision, but no molecular marker is available. Here, we aimed to develop such a marker taking advantage of tissue-specific profiles of DNA methylation., Methods: DNA methylation profiles of gastric adenocarcinomas (GACs) were obtained by an Infinium HumanMethylation450 BeadChip array, and those of esophageal adenocarcinoma (EACs) were obtained from the TCGA database. DNA from formalin-fixed paraffin-embedded (FFPE) samples was analyzed by bisulfite pyrosequencing., Results: In the screening set, 51 of 145,841 CpG sites in CpG islands were methylated at significantly higher levels in 30 GACs compared to those in 30 EACs. Among them, SLC46A3 and cg09177106 were unmethylated in all the 30 EACs. Predictive powers of these two markers were successfully confirmed in an independent validation set (18 GACs and 18 EACs) (SLC46A3, sensitivity = 77.8%, specificity = 100%; cg09177106, sensitivity = 83.3%, specificity = 94.4%), and could be applied to FFPE samples (37 GACs and 18 EACs) (SLC46A3, P = 0.0001; cg09177106, P = 0.0028). On the other hand, EAC-specific markers informative in the FFPE samples could not be isolated. Using these GAC-specific markers, nine of 46 (19.6%) TCGA EGJ adenocarcinomas were predicted to be GACs., Conclusions: Two GAC-specific markers, SLC46A3 and cg09177106, had a high specificity for identifying the tissue origin of EGJ adenocarcinoma., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

We compared the therapeutic outcomes of mediastinoscopy-assisted transhiatal esophagectomy (MATHE) with transthoracic esophagectomy (TTE), and with video-assisted thoracoscopic esophagectomy (VATS-E) for the treatment of esophageal cancer. Twenty patients underwent MATHE in our institute from 2001 to 2005 were enrolled. We evaluated the therapeutic outcomes, including perioperative complications and long-term prognosis after surgery, and compared these with 15 patients who underwent TTE during the same time period and 15 who underwent VATS-E at a later date. MATHE was performed safely and the long-term prognosis were satisfactory compared with TTE. However, the number of dissected mediastinal lymph nodes, total blood loss, and sophistication of the procedure were inferior to VATS-E. MATHE represents a less invasive surgical procedure. However, in light of the risk of leaving lymph node metastasis around the tracheal bifurcation in patients with tumor invasion beyond the muscularis mucosa, MATHE should only be adopted in a minority of patients.

Apurinic/apyrimidinic endonuclease-1 (APE-1) is a key enzyme responsible for DNA base excision repair and is also a multifunctional protein such as redox effector for several transcriptional factors. Our study was designed to investigate APE-1 expression and to study its interaction with cyclooxygenase (COX)-2 expression and VEGF production in the esophageal cancer. The expression of APE-1, COX-2, monocyte chemoattractant protein (MCP)-1, CC-chemokine receptor (CCR)2, and VEGF were evaluated by immunohistochemistry in 65 human esophageal squamous cell carcinoma (ESCC) tissues. Real-time PCR and Western blotting were performed to detect mRNA and protein expression of APE-1 and p-signal transducer and activator of transcription 3 (STAT3) expression in MCP-1-stimulated ESCC cell lines (KYSE 220 and EC-GI-10). siRNA for APE-1 was treated to determine the role of APE-1 in the regulation of COX-2 expression, VEGF production, and antiapoptotic effect against cisplatin. In human ESCC tissues, nuclear localization of APE-1 was observed in 92.3% (60/65) of all tissues. There was a significant relationship (P = 0.029, R = 0.49) between nuclear APE-1 and cytoplasmic COX-2 expression levels in the esophageal cancer tissues. In KYSE 220 and EC-GI-10 cells, MCP-1 stimulation significantly increased mRNA and protein expression of APE-1. Treatment with siRNA for APE-1 significantly inhibited p-STAT3 expression levels in MCP-1-stimulated cells. Furthermore, treatment of siRNA for APE-1 significantly reduced COX-2 expression and VEGF production in MCP-1-stimulated esophageal cancer cell lines. Treatment with APE-1 siRNA significantly increased apoptotic levels in cisplatin-incubated KYSE 220 and EC-GI-10 cells. We concluded that APE-1 is overexpressed and associated with COX-2 expression and VEGF production in esophageal cancer tissues.

A case of esophageal small cell carcinoma successfully treated with combination therapy consisting of preoperative chemotherapy, radiation therapy, and surgical resection. A 76-year-old man presented with a small cell carcinoma measuring 6 cm in diameter in the middle third of the thoracic esophagus. After preoperative therapy, the gross tumor was completely resected. The patient eventually died of metastatic disease 25 months after diagosis. We discuss the treatment of esophageal small cell carcinoma.

It is now evident that changes in microRNA are involved in cancer progression, but the mechanisms of transcriptional regulation of miRNAs remain unknown. Ski-related novel gene (SnoN/SKIL), a transcription co-factor, acts as a potential key regulator within a complex network of p53 transcriptional repressors. SnoN has pro- and anti-oncogenic functions in the regulation of cell proliferation, senescence, apoptosis, and differentiation. We characterized the roles of SnoN in miRNA transcriptional regulation and its effects on cell proliferation using esophageal squamous cell carcinoma (ESCC) cells. Silencing of SnoN altered a set of miRNA expression profiles in TE-1cells, and the expression levels of miR-720, miR-1274A, and miR-1274B were modulated by SnoN. The expression of these miRNAs resulted in changes to the target protein p63 and a disintegrin and metalloproteinase domain 9 (ADAM9). Furthermore, silencing of SnoN significantly upregulated cell proliferation in TE-1 cells, indicating a potential anti-oncogenic function. These results support our observation that cancer tissues have lower expression levels of SnoN, miR-720, and miR-1274A compared to adjacent normal tissues from ESCC patients. These data demonstrate a novel mechanism of miRNA regulation, leading to changes in cell proliferation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We report a case of esophageal squamous cell carcinoma (ESCC) directly invading the liver and causing a pyogenic liver abscess. The patient was a 66-year-old man who presented with dysphagia. Esophagography, endoscopic study, and computed tomography (CT) showed a mass lesion in the lower third of the esophagus. A high fever developed on hospital day 17 and another CT scan revealed a liver abscess, 50 × 45 mm, in the left lateral lobe of the liver. Although imaging demonstrated a liver abscess continuous with the tumor, we performed percutaneous transhepatic drainage, followed thereafter by distal esophagectomy and total gastrectomy with a left lateral segmental resection of the liver. The pathological findings confirmed a diagnosis of ESCC with direct invasion (T4N1M0, stage IVa in the TNM classification). The patient had an uneventful postoperative recovery. Microscopic examination of the resected specimen revealed the expansive growth of tumor cells into the hepatocellular tissues. To our knowledge, this is the first report of the direct invasion of esophageal cancer to the liver causing a pyogenic liver abscess; however, it should be borne in mind when a patient with esophageal cancer becomes febrile.

The Akt-Mdm2 pathway plays an important role in carcinogenesis in a variety of malignant tumors. However, the Akt-Mdm2 pathway in esophageal squamous cell carcinoma (ESCC) has not been fully studied. We investigated the proteins and mRNA expression of Akt and Mdm2 to elucidate the roles of these proteins in ESCC. We also examined the effect of Akt knockdown on Mdm2 expression in ESCC cells. ESCC tissue samples were obtained from 23 individuals who underwent surgical resection with no preoperative treatment. Akt1-3 and Mdm2 gene and protein expression were analyzed. The effect of siRNA-mediated Akt knockdown on Mdm2 expression was also studied, using ESCC cell lines. Akt1 and Mdm2 immunoreactivity was detected in 77.8 and 66.7% of tumor specimen from ESCC patients, respectively. Akt1 and Mdm2 mRNA expressions were correlated and significantly elevated in tumor tissue (p<0.0001 and p<0.05, respectively). The siRNA-targeted reduction of each Akt isoform reduced Mdm2 protein expression. The overexpression of Akt1 and Mdm2 may be related to esophageal carcinogenesis. Furthermore, Akt expression regulates Mdm2 expression, which may in turn regulate the function of wild-type p53. These results may provide the basis for future preventative or clinical therapies for esophageal cancer.

The genomic region containing PIK3CA was found to be amplified in esophageal squamous cell carcinoma (ESCC) tissue. PIK3CA at 3q26, which encodes the p110alpha catalytic subunit of phosphatidylinositol (PI) 3-kinase, is a unique intracellular signal transducer characterized by its lipid substrate specificity. In order to characterize PIK3CA in ESCC, we investigated hot-spot mutations in exons 1, 9 and 20, the copy number gain, the expression levels of mRNA and protein. Analysis in exon 9 of the PIK3CA gene revealed mutation in 7.7% (4 of 52) of ESCC samples. No mutation was detected in either exon 1 or exon 20. Copy number amplifications of PIK3CA were found in 12 of the 45 patients (26.7%). PIK3CA mRNAs were examined in 37 ESCC patients as determined by quantitative RT-PCR and the mean mRNA level of PIK3CA in ESCC tissues was 2.61-fold higher compared with that in corresponding non-tumorous esophageal epithelia (P<0.001). Immunohistochemically, positive immunoreaction for PIK3CA was detectable in 33 of 66 (50.0%) ESCC cases, while it was not detectable in the remaining 33 cases. Furthermore, comparing the cases with negative staining with those with positive staining for PIK3CA, the presence of node metastasis was significantly correlated with those with positive staining (P<0.05). This study is the first report providing comprehensive analysis of PIK3CA expression in ESCC. These results indicate that PIK3CA may play a crucial role in the development of ESCC and serve as an indicator for lymph node metastasis.

Basaloid squamous cell carcinoma is an uncommon malignancy of the esophagus. We present two cases of basaloid squamous carcinoma of the esophagus. Both tumors histologically consisted of solid cell nests and displayed focal immunoreactivity for type IV collagen. The nests comprised pseudoglandular structures containing myxoid matrix. Transthoracic esophagectomy with lymph node dissection was performed in both patients. The patients had uneventful postoperative courses. One patient showed no evidence of recurrence or metastasis in the 6-month postoperative period, and the other patient died of lung metastasis 28 months after the primary treatment.

Patients who undergo definitive chemoradiotherapy (CRT) face a risk of residual resistant disease or disease recurrence at the primary site; therefore, salvage treatment may be required. An optimum strategy to minimize these risks clearly needs to be established. Argon plasma coagulation (APC) is a safe and convenient procedure now applied widely for therapeutic endoscopy. In this report we describe the successful use of APC over 6 years for the treatment of recurrent esophageal cancer after CRT. A 61-year-old Japanese man underwent CRT for a thoracic esophageal cancer. Pathological examination before CRT revealed a well-differentiated squamous cell carcinoma. Locoregional failure was observed 2 years after CRT, and an initial APC treatment was performed. The patient has now undergone APC ablation 7 times with no postoperative complications. No metastasis to lymph nodes or to other organs has been detected during the last 6 years. The usefulness of APC as a salvage treatment for locoregional failure after definitive CRT has not been established. In our experience, salvage APC is the best treatment option for some patients.

Background: Earlier studies have identified the minimal overlapping region of amplification at 3q26 in esophageal squamous cell carcinoma (ESCC) by comparative genomic hybridization (CGH) analysis. These include PIK3CA which encodes the p110alpha catalytic subunit of phosphatidylinositol (PI) 3-kinase, a telomerase RNA component (TERC), a squamous cell carcinoma-related oncogene (SCCRO), ecotropic viral integration site-1 (EVI-1), and a Ski-related novel oncogene (SnoN). In the present study, we investigated the mRNA levels of four candidate genes (TERC, SCCRO, EVI-1, and SnoN) to determine whether genes other than PIK3CA are targets for amplification at 3q26 in ESCC. And also, we examined SnoN expression in ESCC samples., Methods: Fifty-nine representative cases with ESCC were selected from our archives. We performed quantitative RT-PCR of four candidate genes (TERC, SCCRO, EVI-1, and SnoN) and immunohistochemistry for SnoN. Finally, we correlated these findings with the clinicopathological characteristics to determine their interrelationship., Results: Among the four genes we tested, only SnoN mRNA was consistently overexpressed in primary ESCC, compared with those in corresponding nontumorous esophageal epithelia (P < 0.001). Immunoreactive SnoN was detectable in 31 of 59 (52.5%) esophageal squamous cell carcinoma specimens. The levels of SnoN expression were found to correlate with the depth of invasion and recurrence (P < 0.05). Furthermore, patients with positive staining for SnoN displayed more unfavorable outcomes than patients with negative staining (P < 0.05)., Conclusion: SnoN is likely to be the target of the amplification at 3q26 in ESCC and plays an important role in the development of ESCC, influencing disease-specific survival.

The carcinosarcoma of the esophagus is a rare malignant neoplasm consisting of both carcinomatous and sarcomatous components. A case of so-called carcinosarcoma of the esophagus is described herein. A 69-year-old man presented with dysphagia and was admitted to our hospital. Imaging studies revealed a localized ulcerative tumor in the middle intrathoracic esophagus without any invasion or metastasis. The patient was initially thought to have squamous cell carcinoma and underwent subtotal esophagectomy with lymphadenectomy. Final diagnosis of the tumor was so-called carcinosarcoma of the esophagus. The patient had an uneventful postoperative course and showed no evidence of recurrence or metastasis in the 4-year postoperative period.

Aims: Recently, endoscopic mucosal resection (EMR) has become the first choice of treatment for superficial esophageal cancer without metastasis. However, EMR is not safe for all patients. Argon plasma coagulation (APC) is a noncontact electrocoagulation technique that creates tissue damage. The risk of bleeding may be lower with APC than with EMR. Therefore, we selected APC for the treatment of patients with superficial esophageal cancer who could not undergo EMR. The aim of the present study was to describe these cases and analyze the results of this treatment., Patients and Methods: Ten patients with superficial esophageal cancer underwent APC at our institution from February 2001 through January 2002. None of the patients could undergo EMR because of complications. Ablation was performed using an APC probe (ERBE APC probe; ERBE Elektromedizin, Tübingen, Germany), a high-frequency electrosurgical generator (ERBE ICC200), and an argon delivery unit (ERBE APC 300). All patients had uneventful recoveries., Results: No incidents of bleeding from the ablated lesion or infection occurred. Oral intake was resumed on the day after treatment. The mean duration of the procedure was 20 minutes (range, 10 to 40 minutes). Disease recurred in two patients. Two patients died of laryngeal cancer and liver failure, respectively., Conclusion: APC is a safe and easy to perform procedure, but the effect of therapy is inferior to that of EMR in terms of the complete resection of the lesion. In conclusion, APC should be limited to cases of superficial esophageal cancer without metastasis in which EMR has been deemed difficult.

Cyclo-oxygenase (COX)-2 is not usually detectable in normal tissues but is induced in inflammation and carcinogenesis. The level of COX-2 is elevated in cancer tissues of the colon, bladder, and skin. In the esophagus, squamous cell carcinoma and adenocarcinoma are known to express COX-2. The purpose of this study was to clarify the association of COX-2 expression with clinicopathological factors of squamous cell carcinoma. The immunohistochemical expression of COX-2 was examined in 48 surgical specimens of esophageal squamous cell carcinoma. Although COX-2 over-expression was more frequently observed in tumors invading the submucosa (T1b, 76.4%), muscularis propria (T2, 57.1%), adventitia, or adjacent organs (T3 approximately 4, 83.3%), even 33.3% of mucosal cancers, such as T1a, showed COX-2 over-expression. COX-2 over-expression was present in 82.3% of lymph node-negative patients but in only 54.8% of lymph node positive patients. There was no difference in COX-2 over-expression between the earlier stages (0 and I, 60%) and more advanced stages (II approximately IV, 69.6%). COX-2 over-expression did not correlate with survival during 3 years of follow-up. These findings suggest that COX-2 is associated with the phenotype of the esophageal squamous cell carcinoma cells, including superficial cancer cells, and may be related to tumor growth in esophageal squamous cell carcinoma.

We report a case of double cancer of the liver and esophagus, an extremely rare condition that can be very difficult to treat. A tumorous lesion was pointed out in segment 6 of the liver of a 69-year-old man under treatment for liver cirrhosis. Abdominal computed tomography and angiography revealed a hepatocellular carcinoma. The patient underwent transcatheter arterial embolization and partial resection of segments 5 and 6. Fourteen months later, a small elevated lesion was detected in the esophagus during an endoscopic examination. The patient was treated by endoscopic mucosal resection and radiation therapy at a total dose of 50 Gy. Histological examination revealed a squamous cell carcinoma with cancer cells confined within the epithelium of the esophagus. Over the 6 years since the hepatectomy, there have been no signs of recurrence. We report a successful curative resection in an extremely rare form of double cancer with a poor prognosis.

Hypoxia inducible factor (HIF)-1alpha is a transcription factor that regulates the transcription of genes associated with cell proliferation and vascular development. In various cancer tissues, HIF-1alpha is associated with clinicopathological factors, such as the tumor size, histological grade, and lymph node status. Although HIF-1alpha plays a critical role in tumor growth by inducing vascular endothelial growth factor (VEGF), it is unclarified whether HIF-1alpha affects lymphatic metastasis. The purpose of this study is to clarify the correlation of HIF-1alpha protein expression with lymph node metastasis in esophageal squamous cell carcinoma (ESCC). The expressions of HIF-1alpha and VEGF-C, which is one of the main lymphangiogenic factors, were examined in five ESCC cell lines and 48 surgical specimens of ESCC. HIF-1alpha and VEGF-C mRNAs were expressed in all the five ESCC cell lines as determined by RT-PCR analysis. Immunohistochemically, 34 of the 48 patients (70.8%) were positive for HIF-1alpha and 29 patients (60.4%) were positive for VEGF-C. Clinicopathologically, HIF-1alpha expression correlated with lymphatic invasion and VEGF-C expression (P = 0.003 and P = 0.01, respectively). Furthermore, HIF-1alpha expression tended to correlate with lymph node metastasis (P = 0.09). These findings suggest that HIF-1alpha plays a role in lymphatic invasion and lymph node metastasis through the induction of VEGF-C in ESCC.

Mucoepidermoid carcinoma of the esophagus (MEC) is uncommon and has not been fully investigated. The biological behavior and clinical aspects of MEC were studied. The clinical features of eight patients with MEC were compared with 51 cases of squamous cell carcinoma of the esophagus (SCC). Proliferating cell nuclear antigen (PCNA), p53, and carcinoembryonic antigen (CEA) were stained in the resected specimens by immunohistochemistry. Seven out of 8 cases (87.5%) had stage III by TNM classification. Four cases died of widespread metastases and 2 cases died of local recurrence within 2 years after the surgery. Neither chemotherapy and radiotherapy were effective against MEC. Overall median survival periods were 10.8 months for MEC and 32.1 months for SCC (P<0.05). When patients in stage III alone were compared, MEC tended to have a worse prognosis than SCC (P=0.058). Immunohistochemical studies revealed that the positive rates of PCNA and CEA were significantly higher in MEC than in SCC (P<0.05), while there was no significant difference in p53 positive rate. Esophageal MEC had an aggressive biological nature and was resistant to adjuvant therapies. The poor prognosis of esophageal MEC may be caused by high proliferative and metastatic potential.

Background/aims: The presence of lymph node metastasis is the most important prognostic factor in esophageal squamous cell carcinoma. Molecular biology techniques have improved the ability to recognize micrometastasis in lymph nodes, bone marrow, and peripheral blood. Previous studies have demonstrated that cytokeratin 19 reverse transcriptasepolymerase chain reaction can detect tumor cells even when lymph nodes appear normal histologically. However, the presence of pseudogenes for cytokeratin 19 have reduced the specificity of reverse transcriptase-polymerase chain reaction, thereby reducing its clinical worth as a sensitive diagnostic technique., Methodology: We examined the expression of mRNA for cytokeratin 19 using a newly designed set of primers, and compared the results with data from histologic examinations. Samples were obtained from tumors, intact tissues, resected lymph nodes and in 10 patients who underwent esophagectomy via right thoracotomy with lymph node dissection in the neck, mediastinum and abdomen., Results: All tumors, non-cancerous tissues were positive for cytokeratin 19 by reverse transcriptasepolymerase chain reaction. However, 2 of the 6 lymph nodes that appeared normal on histologic examination were positive for cytokeratin 19; sensitivity and specificity were 100% and 67%, respectively., Conclusions: Reverse transcriptase-polymerase chain reaction using new primers for cytokeratin 19 detected micrometastasis in specimens of lymph nodes from patients with squamous cell carcinoma. This method may increase the accuracy of tumor staging and provide clinicians with valuable information that will help individualize treatment options.

A 51-year-old male was assessed as having esophageal squamous cell carcinoma with trachea invasion and cervical lymph node metastasis. After one course of chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU) and Leucovorin (LV), the patient had progressive disease (PD) of the primary lesion and metastatic lymph nodes, and a side effect of severe nausea. One course of nedaplatin, 5-FU and LV combined with radiation was performed alternatively. The effect was evaluated as a partial response (PR) of the primary lesion and metastatic lymph nodes. There were no adverse side effects such as nausea or renal dysfunction except for pancytopenia of grade 2. Increased serum levels of vascular endothelial growth factor (s-VEGF) decreased after the chemoradiotherapy and increased again during continued radiotherapy alone. More information is needed as to whether changes in s-VEGF relate to the clinical effects of the treatment.