Clinicopathological and mutational analysis of esophageal basaloid squamous cell carcinoma.

Esophageal basaloid squamous cell carcinoma (EBSCC) is a poorly differentiated variant of esophageal squamous cell carcinoma (ESCC). We aimed to investigate the clinicopathological and molecular biological characteristics of EBSCC and enrolled 58 patients with EBSCCs. Clinicopathological factors including age, sex, tumor size and location, gross tumor type (superficial, protrusive, ulcerative, and unclassifiable), lymphovascular invasion, infiltrative growth, intramural invasion, TNM stage, and dominant histological type were examined. EBSCCs were classified into four types (solid, cribri, microcystic, and tubular) according to the dominant histology. Next-generation sequencing (NGS) of a cancer hotspot panel was performed in 19 cases. NGS identified TP53 as the most frequently mutated gene, and copy number variation analysis revealed the most frequent loss of heterozygosity (LOH) at the ataxia telangiectasia mutated (ATM) and retinoblastoma 1 (RB1) loci. Target sequencing for TP53 was performed for the remaining 39 cases. We also performed LOH analysis for TP53, ATM, and RB1 and immunohistochemical staining for p53, ATM, and Rb in all cases. The rates of TP53 mutations and LOH and p53 aberrant expression were high (79.3%, 63.2%, and 72.4%, respectively); however, the frequencies were similar to those reported for ESCC. LOH rates of the RB1 and ATM loci were also high (55.3% and 67.2%, respectively). Overall survival rate was 66.5%, and recurrence-free survival rate was 55.0%. Only conventional clinicopathological factors had a prognostic impact in EBSCC; the microcystic type had the poorest prognosis. Our findings could be useful in developing novel treatment strategies for EBSCC.

Outcomes of esophagectomy for patients with esophageal squamous cell carcinoma accompanied by recurrent laryngeal nerve palsy at diagnosis.

BACKGROUND: Hoarseness is one of the classical symptoms in patients with locally advanced thoracic esophageal squamous cell carcinoma (ESCC), and it results from recurrent laryngeal nerve palsy, which is caused by nodal metastasis along the recurrent laryngeal nerve or by main tumors. We reviewed the short-term and long-term results of esophagectomy for patients with locally advanced ESCC and hoarseness at diagnosis. PATIENTS: Patients who initially presented with hoarseness from recurrent laryngeal nerve palsy between 2009 and 2018 and underwent esophagectomy for thoracic ESCC were eligible for this study. Pharyngolaryngectomy or cervical ESCC were exclusionary. RESULTS: A total of 15 patients were eligible, and 14 underwent resection of the recurrent laryngeal nerves. The remaining patient had nerve-sparing surgery. Nine patients (60%) had post-operative complications ≥ Clavien-Dindo class II and, pulmonary complications were most common. Two patients (13%) died in the hospital. The 5-year overall survival rate for all patients was 16%. Age (≤ 65 years), cT1/T2 tumor, and remarkably good response to neoadjuvant treatment were likely related to longer survival; however, these relationships were not statistically significant. CONCLUSIONS: Esophagectomy for ESCC patients who are diagnosed with recurrent laryngeal nerve paralysis at initial presentation could be a treatment option if the patient is relatively young, has a cT1/T2 tumor, or shows a remarkably good response to neoadjuvant treatment. However, clinicians should be aware of the possibility of postoperative pulmonary complications, which were frequently observed with the procedure.

Carinal resection and double-barrel reconstruction following oesophagectomy for oesophageal carcinoma with broncho-oesophageal fistula.

A 54-year-old man presenting with dysphagia was diagnosed with locally advanced oesophageal carcinoma with a broncho-oesophageal fistula (c-T4bN2M0 stage IVa). Concurrent chemoradiotherapy (60 Gy) was planned; however, bleeding from the oesophageal lesions progressed during chemoradiotherapy (16 Gy). Oesophagectomy with carinal resection and double-barrelled reconstruction was performed. Despite the inevitable recurrent nerve palsy and a minor fistula at the tracheal anastomosis, he recovered with conservative treatment and was discharged 4 months after the salvage surgery. He is alive without recurrence 28 months after the surgery.

Comprehensive clinicopathological and molecular analysis of primary malignant melanoma of the oesophagus.

AIMS: This study was performed to elucidate the clinicopathological characteristics, genetic alterations and therapeutic targets of primary malignant melanoma of the oesophagus (PMME). METHODS AND RESULTS: The clinicopathology and molecular pathology of 13 PMME cases and 10 skin malignant melanoma (SKMM) cases were analysed with next-generation sequencing (NGS) and immunohistochemistry. The 3-year overall survival rate and the median survival time for PMME patients were 23.1% and 11.9 months, respectively. Three (23.1%) and eight (61.5%) PMME cases showed a papillary structure and lymph node metastasis, respectively. DNA and RNA hybridization capture-based NGS analysis revealed that NF1 was the most frequently mutated gene (30%) in 10 of the PMME cases. Other mutations detected in PMME included SF3B1 (20%), KRAS (10%), BRCA2 (10%), KIT (10%) and TP53 (10%) mutations. Commonly detected BRAF mutations in SKMM were not detected in PMME. Immunohistochemistry and mutation status were concordant between p53/c-Kit and TP53/KIT, respectively. Focal expression of programmed death-ligand 1 was observed in one PMME sample. The tumour mutation burden in PMME was significantly lower than that in SKMM (P = 0.030). No PMME case showed high microsatellite instability. RNA sequencing revealed a distinctive pattern with respect to RNA expression. T-cell co-stimulation differed between PMME and SKMM. CONCLUSIONS: The RAS-mitogen-activated protein kinase pathway is one of the main pathways involved in PMME. The genetic profile of PMME was similar to that of mucosal/acral melanoma, but differed from the SKMM profile. A subset of PMMEs may contain actionable mutations. Immunotherapy seemed to be less effective for most PMMEs in this series.

Clinical impact of baseline renal function on the safety of radiotherapy with concurrent docetaxel for esophageal cancer in elderly patients.

BACKGROUND: We aimed to compare the safety of radiotherapy with concurrent docetaxel (DOC-RT) for esophageal cancer (EC) in elderly patients who were divided into a creatinine clearance (Ccr) < 60 mL/min (Ccr-L) group and a Ccr ≥ 60 mL/min (Ccr-H) group. METHODS: Eligible patients included those aged ≥ 76 years who were diagnosed with esophageal squamous cell carcinoma. The patients received radiotherapy (60 Gy in 30 fractions) and concurrent docetaxel (10 mg/m2 weekly for six cycles), after which toxicity and treatment completion rates were retrospectively evaluated. RESULTS: The 73 elderly EC patients receiving DOC-RT were divided into two groups for evaluation: the Ccr-L group (49 patients) and the Ccr-H group (24 patients). The median survival time for patients in the Ccr-L and Ccr-H groups was 21 and 20 months, respectively (p = 0.2). The incidence of grade 1 acute kidney injury was 8% vs. 8% (p = 1) in the Ccr-L and Ccr-H groups, respectively. No other hematological or nonhematological toxicities differed between patients in the two groups. No grade 4 or 5 toxicities were observed in the two groups. No significant difference was observed in the treatment completion rates (88% vs. 92%, p = 1) between patients in the Ccr-L and Ccr-H groups. CONCLUSIONS: Regardless of baseline renal function, DOC-RT is a safe regimen for elderly patients with EC.

Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer.

OBJECTIVES: Considering that therapeutic strategies for older adult patients with esophageal cancer (EC) remain controversial, we aimed to assess the safety of radiotherapy with concurrent docetaxel (DOC-RT) among older adult patients with EC. MATERIALS AND METHODS: Eligible patients included those aged ≥76 years who were diagnosed with esophageal squamous cell carcinoma. Patients received radiotherapy (60 Gy in 30 fractions) and concurrent docetaxel (10 mg/m2 weekly for six cycles). Survival, toxicity, and treatment completion rates were retrospectively evaluated. RESULTS: Among 84 older adult patients receiving radical radiotherapy or chemoradiotherapy, 73 receiving DOC-RT were studied. Median follow-up duration was 14 months (range, 2-101 months). The 1-, 3-, and 5-year overall survival rates were 63%, 33%, and 13%, respectively, with a median survival time of 21 months. Grade 3 acute toxicities included esophagitis (7%), esophageal fistula (3%), pneumonitis (1%), leukopenia (10%), and anemia (8%). Grade 3 late toxicities included esophageal stenosis (4%), pleural effusion (3%), pericardial effusion (1%), and pneumonitis (1%). Grade 4 and 5 toxicities were not observed. DOC-RT was discontinued due to deterioration in the general condition (6%), esophageal fistula (3%), pneumonia (1%), and pain (1%), resulting in a DOC-RT completion rate of 89% (65/73 patients). The non-completion group comprised a higher proportion of older adults (age ≥ 80 years) and undernourished [geriatric nutritional risk index (GNRI <92)] patients than the completion group. CONCLUSION: DOC-RT can be a safe regimen for older adult patients with EC. Nonetheless, old age (≥80 years) and undernourishment (GNRI <92) should be considered prior to DOC-RT administration.

Molecular and clinicopathological analyses of esophageal carcinosarcoma with special reference to morphological change.

The molecular pathogenesis of esophageal carcinosarcoma (ECS) has not been fully investigated. This study includes 16 consequent cases of surgically resected ECS. Genetic alterations were independently examined for carcinoma in situ, carcinomatous, and sarcomatous areas. Six cases were analyzed by next-generation sequencing, and the remaining cases were analyzed by Sanger sequencing for TP53, PTEN, and INI1. Sarcomatous components in 3 cases showed histologically heterogenous feature of osteosarcoma. Lymph node metastasis was found in 12 out of 16 cases. Survival analysis revealed 5-year overall survival rate of 59.9%, and the median survival time was 5.37 years. TP53 was the most frequently mutated gene, being identified in 11 of 16 patients (68.8%), 7 of whom (63.6%) had the same mutations in both carcinomatous and sarcomatous areas. Almost complete concordance was found between p53 immunohistochemistry and TP53 missense mutations. Five-year overall survival tended to be worse for patients with p53 overexpression, although the data was not significant (p = 0.186). Nine of 16 patients (56.3%) showed loss of heterozygosity (LOH) at the INI1 locus, and this LOH status was consistent with both components. However, interestingly, INI1 expression was preserved in all cases. In addition, copy number variation analysis revealed gene amplification in several tyrosine kinase receptors. Accumulation of mutations in tumor suppressor genes such as TP53 and INI1 seemed to occur during ECS development.

Docetaxel, cisplatin and 5-fluorouracil adjuvant chemotherapy following three-field lymph node dissection for stage II/III N1, 2 esophageal cancer.

To determine the efficacy of postoperative adjuvant chemotherapy with docetaxel + cisplatin + 5-fluorouracil (DCF) in lymph node metastasis-positive esophageal cancer, we retrospectively analyzed 139 patients with stage II/III (non-T4) esophageal cancer with lymph node metastasis (1-6 nodes), who did not receive preoperative treatment and underwent three-field lymph node dissection in the Juntendo University Hospital between December, 2004 and December, 2009. The tumors were histologically diagnossed as squamous cell carcinoma. The patients were divided into two groups, a surgery alone group (S group, 88 patients) and a group that received postoperative DCF therapy (DCF group, 51 patients). The disease-free and overall survival were compared between the groups and a multivariate analysis of prognostic factors was performed. The same analysis was performed for cases classified as N1 and N2, according to the TNM classification. There were no significant differences between the S and DCF groups regarding clinicopathological factors other than intramural metastasis and main tumor location. The presence of intramural metastasis, blood vessel invasion and the number of lymph nodes were identified as prognostic factors. The 5-year disease-free and overall survival were 55.8 and 57.3%, respectively, in the S group and 52.8 and 63.0%, respectively, in the DCF group. These differences were not considered to be statistically significant (P=0.789 and 0.479 for disease-free and overall survival, respectively). Although there were no significant differences in disease-free and overall survival between the S and DCF groups in N1 cases, both disease-free and overall survival were found to be better in the DCF group (54.2 and 61.4%, respectively) compared to the S group (29.6 and 28.8%, respectively) in N2 cases (P=0.029 and 0.020 for disease-free and overall survival, respectively). Therefore, postoperative adjuvant chemotherapy with DCF was shown to improve disease-free and overall survival in moderate lymph node metastasis-positive cases (N2), suggesting that the DCF regimen may be effective as postoperative adjuvant chemotherapy for patients with lymph node metastasis from esophageal cancer.

Pattern of postoperative recurrence and hepatic and/or pulmonary resection for liver and/or lung metastases from esophageal carcinoma.

BACKGROUND: We assessed the benefit of hepatic and pulmonary resections in patients with liver and lung recurrences, respectively, after resection of esophageal carcinoma. METHODS: The study population consisted of 138 consecutive patients with recurrent esophageal carcinoma after esophagectomy conducted between 2003 and 2005. The pattern, timing of appearance, and the prognosis of these recurrences were investigated, paying particular attention to those undergoing hepatic and pulmonary resections. RESULTS: In total, 55 and 92 patients developed locoregional and distant-organ metastases 13 and 6 months (median) after surgery, respectively, including 9 patients with both types of recurrence. The distant-organ metastases were found in the liver (n = 26), lung (n = 27), bone (n = 21), and other organs (n = 29). Patients with pulmonary recurrences had a better overall prognosis (median survival after recurrence detection 13 months) than those with hepatic metastases (5 months) or nonhepatic nonpulmonary metastases. (3 months) Hepatic and pulmonary resections were carried out in patients with oligonodular (n = ≤ 2) isolated liver and lung metastases (n = 5, respectively). Although the survivals of patients with lung metastases who were treated/not treated by pulmonary resection were different (median survival: 48 vs. 10 months, p < 0.01), the difference in the survivals between patients with hepatic metastases who were treated/not treated by hepatic resection reached only borderline statistical significance (13 vs. 5 months, p = 0.06). CONCLUSIONS: Resection of pulmonary metastases yields a survival benefit in properly selected patients. The benefit of resection for hepatic metastases remains controversial.

The importance of grouping of lymph node stations and rationale of three-field lymphoadenectomy for thoracic esophageal cancer.

BACKGROUND AND OBJECTIVES: Although the three-field lymphadenectomy has established as a standard operation for esophageal cancer in Japan, criticism remains due to the lack of randomized controlled trials with a high EBM level. This retrospective study aims to clarify the effectiveness of the three-field lymphadenectomy using the data obtained from 906 consecutive patients with esophageal cancer who underwent R0 esophagectomy with the three-field lymphadenectomy. METHOD: Efficacy Index (EI) was calculated for each lymph node station and grossly cervical, mediastinal, or abdominal dissection field. The values of EI were compared according to main tumor location. RESULTS: Cervical lymph node dissection had high EI in upper and middle thoracic esophageal cancer but it was very small in lower esophageal cancer. Abdominal lymphadenectomy for upper thoracic esophageal cancer had some but limited efficacy only in paracardiac and lesser curvature stations. Cervical lymphadenectomy for lower esophageal cancer showed some but limited efficacy only in cervical paraesophageal stations. CONCLUSION: Our investigation clearly shows the effectiveness and importance of wide range lymph node dissection defined as D3 according to the Japanese N-grouping system for thoracic esophageal cancer. The three-field lymphadenectomy is regarded as a standard procedure for upper and middle thoracic esophageal cancer.

Current status of primary malignant melanoma of the esophagus: clinical features, pathology, management and prognosis.

Primary malignant melanoma of the esophagus (PMME) is a rare disease with an extremely poor prognosis. Up to 2011, approximately 300 cases had been reported worldwide. The average age of onset is 60.5 years old, with a prevalence of males (2:1). A typical finding of PMME is a lobular or polyploid, well-circumscribed and pigmented tumor, partly covered with normal mucosa. PMME represents various colors depending on its melanin quantity and commonly coexists with intramural metastases, melanocytosis or melanoma in situ. The tumor is located from the middle to lower thoracic esophagus. The accuracy of diagnosis from biopsy is approximately 80%, because many cases are misdiagnosed as a poorly differentiated carcinoma because of the absence of melanin granules. A definite diagnosis was made by immunohistochemical examination with positive results of S100 protein, HMB45 and neuron-specific enolase. PMME has a highly metastatic potential, and the incidence of distant metastasis at the initial diagnosis is around 40-80%. A metastatic tumor from cutaneous malignant melanoma is another pigmented esophageal tumor to be considered when making the differential diagnosis for PMME. Junctional activity with melanotic cells in the adjacent epithelium and the presence of in situ melanoma and/or a satellite tumor without a previous history of cutaneous melanoma are definitive. Most of the reported patients were treated with radical esophagectomy, which is believed to be an effective approach for localized PMME. Five-year survival rates have been achieved in 37% recently, while adjuvant therapy has not been proven to increase overall survival but plays a palliative role.

Effects of sivelestat on bronchial inflammatory responses after esophagectomy.

Post-operative pulmonary complications such as systemic inflammatory response syndrome (SIRS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are strongly associated with morbidity and mortality after esophagectomy. Post-operative administration of sivelestat sodium hydrate (sivelestat), a selective inhibitor of neutrophil elastase (NE), has been shown to improve the post-operative clinical course after esophagectomy. This study aimed to evaluate the effect of prophylactic administration of sivelestat on bronchial inflammatory responses. We randomized 24 patients into two groups. One group received 0.2 mg/kg/h sivelestat from the induction of anesthesia to post-operative day 1 (sivelestat group) and the other group received the same amount of physiological saline (control group). Bronchial alveolar epithelial lining fluid (ELF) samples were obtained from both groups at the induction of anesthesia and at the end of surgery. The serum and ELF levels of interleukin (IL)-6 and IL-8 were measured by enzyme-linked immunosorbent assay, and NE activity was spectrophotometrically determined using the same samples. Although IL-6 levels in the ELF significantly increased at the end of surgery compared with the pre-operative levels in both groups, the IL-8 levels and NE activity did not significantly increase at the end of the surgery compared to the corresponding pre-operative values in the sivelestat group. Moreover, IL-8 levels and NE activity in the ELF were significantly reduced at the end of surgery in the sivelestat group compared with corresponding values in the control group. The durations of ALI and ARDS were apparently shorter in the sivelestat group and the duration of SIRS was significantly shorter in the sivelestat group compared to the control group. We demonstrated that prophylactic use of sivelestat mitigated bronchial inflammation by suppressing NE activity and IL-8 levels in the ELF and shortened the duration of SIRS after transthoracic esophagectomy.

[Trans-thoracic esophagectomy with 3-field lymph nodes dissection].

Although open-chest surgery is the mainstay treatment for esophageal cancer, the understanding of the context of the surgery differs in Japan and the rest of the world. Three-field lymph node dissection has been unique to Japan, although some reports on its benefits are emerging elsewhere. In addition to three-field lymph node dissection, various efforts are made during surgical procedures to reduce complications at high-volume Japanese healthcare institutions.

Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles.

BACKGROUND: Oesophageal squamous cell carcinoma (OSCC) is considered a difficult cancer to cure. The detection of environmental and genetic factors is important for prevention on an individual basis. OBJECTIVE: To identify groups at high risk for OSCC by simultaneously analysing both genetic and environmental risk factors. Methods A multistage genome-wide association study of OSCC in Japanese individuals with a total of 1071 cases and 2762 controls was performed. RESULTS: Two associated single-nucleotide polymorphisms (SNPs), as well as smoking and alcohol consumption, were evaluated as genetic and environmental risk factors, respectively, and their interactions were also evaluated. Risk alleles of rs1229984 (ADH1B) and rs671 (ALDH2) were highly associated with OSCC (odds ratio (OR)=4.08, p=4.4×10(-40) and OR=4.13, p=8.4×10(-76), respectively). Also, smoking and alcohol consumption were identified as risk factors for OSCC development. By integrating both genetic and environmental risk factors, it was shown that the combination of rs1229984 and rs671 risk alleles with smoking and alcohol consumption was associated with OSCC. Compared with subjects with no more than one environmental or genetic risk factor, the OR reached 146.4 (95% CI 50.5 to 424.5) when both environmental and genetic risk factors were present. Without the genetic risks, alcohol consumption did not correlate with OSCC. In people with one or two genetic risk factors, the combination of alcohol consumption and smoking increased OSCC risk. CONCLUSIONS: Analysis of ADH1B and ALDH2 variants is valuable for secondary prevention of OSCC in high-risk patients who smoke and drink alcohol. In this study, SNP genotyping demonstrated that the ADH1B and/or ALDH2 risk alleles had an interaction with smoking and, especially, alcohol consumption. These findings, if replicated in other groups, could demonstrate new pathophysiological pathways for the development of OSCC.

High levels of fatty acid synthase expression in esophageal cancers represent a potential target for therapy.

Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. To investigate the expression of this candidate target in esophageal cancer, we evaluated expression of FAS protein in 22 cases of esophageal squamous cancer, 79 cases of esophageal adenocarcinoma and 16 cases of Barrett's esophagus with high-grade dysplasia--a lesion thought to represent a pre-invasive precursor to esophageal cancer. Using immunohistochemistry, we found significantly higher levels of FAS expression in 77% of the squamous cancers, 96% of the adenocarcinomas and 94% of the Barrett's lesions with high-grade dysplasia, when compared to levels in normal esophageal epithelium and non-dysplastic Barrett mucosa. To evaluate the potential for inhibiting this enzyme as a treatment of esophageal cancer, we treated mice bearing xenografts of the Colo680N esophageal squamous cell carcinoma cell line using C93, a rationally designed molecule that inhibits FAS activity. In these experiments, C93 significantly inhibited the growth of orthotopic xenograft tumors without causing anorexia and weight loss in the treated animals. We conclude that, similar to several other common types of human cancer, FAS is expressed at very high levels in esophageal cancer and growth of these cancers can be inhibited by pharmacological agents that target this enzyme. Moreover, this high expression of FAS is also seen in high-risk, pre-invasive lesions of the esophagus, leading us to propose considering FAS-inhibitors for purposes of esophageal cancer chemoprevention.

Study of abnormal chromosome regions in esophageal squamous cell carcinoma by comparative genomic hybridization: relationship of lymph node metastasis and distant metastasis to selected abnormal regions.

Squamous cell carcinoma of the esophagus (ESCC) has a poor prognosis among digestive tract cancers. Lymph node metastasis and distant metastasis are the major factors determining its prognosis. We used comparative genomic hybridization (CGH) to evaluate primary tumor lymph nodes and metastatic areas from ESCC patients in order to determine the relationship between abnormal chromosome regions and outcome. Tumor tissues and lymph nodes were collected from 51 patients with ESCC, and abnormal chromosome regions were detected by CGH. We searched for regions that were significantly more common in patients with lymph nodes metastases (n>/= 6) or distant metastases, and correlated those chromosomal changes with survival. Regions showing amplification in more than 65% of esophageal squamous cell cancers were as follows: 17q12 (90.2%), 17q21 (86.3%), 3q29 (82.4%), 3q28 (78.4%), 8q24.2 (76.5%), 22q12 (76.5%), 3q27 (74.5%), 8q24.3 (74.5%), 1q22 (70.6%), 5p15.3 (70.6%), 22q13 (70.6%), 3q26.3, 8q23, 8q24.1, 9q34, 11q13, 17p12, 17q25, 20q12, 20q13.1 (68.6%), 1q32, 1q42, and 20q13.2 (66.7%). Regions showing deletion in more than 50% of the tumors were as follows: Yp11.3 (62.7%), 3p26 (56.9%), Yq12 (54.9%), 13q21 (52.9%), 4q32 (51.0%), and 13q22 (51.0%). When Fisher's test was used to assess associations of these regions with metastases to lymph nodes, amplification at 2q12-14 (P= 0.012), 3q24-26 (P= 0.005), and 7q21-31 (P= 0.026) were significant. Survival was worse for patients with amplification at all 3 regions. In patients with distant organ metastases, amplification at 7p13-21 was significant (P= 0.008), and survival was worse. Chromosomal amplifications in ESCC at 2q12-14, 3q24-26, and 7q21-31 were associated with lymph node metastasis, while amplification at 7p13-21 was related to distant metastasis. Amplification at these regions correlated with worse survival. Genes involved in the phenotype of ESCC may exist in these regions. Identification of these genes is a theme for future investigation.

Lymphatic invasion according to D2-40 immunostaining is a strong predictor of nodal metastasis in superficial squamous cell carcinoma of the esophagus: algorithm for risk of nodal metastasis based on lymphatic invasion.

In squamous cell carcinoma (SCC) of the esophagus, D2-40 immunostaining has recently been used to detect lymphatic invasion, but invasion detected using D2-40 immunostaining for a predictor of nodal metastasis was controversial. Therefore, the usefulness of detecting lymphatic invasion by D2-40 immunostaining as a predictor of nodal metastasis was examined in superficial (mucosal and submucosal) SCC of the esophagus. A total of 115 superficial SCC of the esophagus were examined on immunohistochemistry using D2-40. It was found that lymphatic invasion demonstrated on D2-40 immunostaining was mainly detected in the lamina propria mucosa. Lymphatic invasion was found in 37 cases and the invasion detected in the entire tumor tissue was statistically correlated with nodal metastasis. Based on the lymphatic invasion according to D2-40 immunostaining, an algorithm was devised for the risk (low, intermediate and high) of nodal metastases in superficial SCC in the esophagus. In conclusion, the detection of lymphatic invasion on D2-40 immunostaining in tumor tissue is a strong predictor for nodal metastasis in superficial SCC of the esophagus. Lymphatic invasion was found mainly in the lamia propria mucosa, thus the devised algorithm is useful for determining the optimal treatment strategy after endoscopic mucosal resection for esophageal SCC.

Subepithelial extension of squamous cell carcinoma in the esophagus: histopathological study using D2-40 immunostaining for 108 superficial carcinomas.

Squamous cell carcinoma (SCC) of the esophagus occasionally produces subepithelial extension (SEE) in the stroma below the non-cancerous epithelium. Little information on SEE has been obtained, therefore the purpose of the present study was to carry out a clinicopathological study using D2-40 immunostaining in 108 cases of superficial (mucosal and submucosal) SCC of the esophagus. SEE occurred in 24 cases (22.2%). The SEE was present in both mucosa and submucosa in 19 cases, but in five cases SEE was located in the mucosa. Lymphatic invasion of tumor cells was well determined on D2-40 immunostaining. In the SEE group lymphatic invasion was found in 15 cases, and in two cases there was lymphatic invasion in the lamina propria mucosa of the edge of SEE. In the SEE group 23 (95.8%) had infiltrative growth of tumor cells. Lymphatic invasion and growth pattern of tumor cells were statistically correlated with SEE. Lymph node metastases were found in 48 cases, but SEE was not correlated with nodal metastases statistically. In conclusion, esophageal SCC produces SEE from the early stage by infiltrative growth and lymphatic invasion of tumor cells. The detection of lymphatic invasion on D2-40 immunostaining in the mucosal edge of SEE is useful for evaluation of endoscopic mucosal resection tissue.

[Value of postoperative surveillance of tumor recurrence after curative esophageactomy].

A study of 256 patients whose dates and patterns of first mode of recurrence after curative esophagectomy from 1984 to 2004 revealed the recent improvement in survival after the detection of tumor recurrence. This tendency was evident in lymphatic recurrence, particularly in the cervical area. Lung metastasis was another mode of recurrence that has shown recent improvement. In this series, 20 patients with lymph node metastases underwent reoperation for local or regional tumor control. The addition of systemic chemotherapy or chemoradiotherapy was our general rule. The 5-year survival rate after the detection of tumor recurrence in these 20 patients was 47.4%. Six with lung metastases in the group of patients whose esophagectomies were performed in the last 7 years underwent video-assisted pulmonary tumor resection. Five patients in this group are alive without signs of further recurrence for 92 to 1,437 days. The early detection of recurrent tumor, vigorous attempts to achieve locoregional control, and the addition of systemic chemotherapy are all important in achieving better results. We routinely perform conventional cervical and abdominal ultrasonography and computed tomography every 6 months until 6 years after surgery is performed.