Natsumi Tomita

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.

CYSTIC LYMPHANGIOMAS OF THE COLON

Abstract: We report a patient with cystic lymphangiomas diagnosed by endoscopic ultrasonography and resected by partial polypectomy. A 42-year-old woman consulted a nearby physician because of a positive fecal occult blood test. Barium enema and colonoscopy revealed the presence of abnormalities. On March 11, 1997, she was admitted to our department for further evaluation and treatment. A barium enema examination revealed two protruding lesions in the transverse colon. Colonoscopy showed a teardrop-type mass in the left side of the transverse colon. The mass was cushion-sign positive, and its shape readily changed on respiration and with changes in body position. Another superficial smooth mass was found in the right side of the transverse colon. Ultrasonography of the colon confirmed the presence of a submucosal mass showing a cyst-like pattern. Cystic lymphangiomas were diagnosed and resected endoscopically. Histopathological examination revealed markedly dilated ducts consisting of a single layer of endothelial cells in the submucosa of the colon. The diagnosis was cystic lymphangioma.

Size analysis of lymph node metastasis in esophageal cancer: diameter distribution and assessment of accuracy of preoperative diagnosis

BackgroundIn esophageal cancer, lymphatic spread occurs more frequently and at an earlier stage than in other gastrointestinal cancers, and both preoperative and intraoperative diagnoses of lymph nodes metastases are sometimes incorrect. Our objective was to measure the sizes of lymphatic metastases and to examine the accuracy of clinical diagnosis of lymphatic spread in patients with squamous cell carcinoma of the esophagus.MethodsThe sizes of 320 metastatic lymph nodes of 9254 dissected nodes from 92 consecutive esophagectomy patients over 1 year were measured and compared with the sizes of the actual metastases within the nodes. These data allowed investigation of the correct rate of preoperative diagnosis of lymph node metastasis.ResultsThe mean diameter of the metastases was 4.8 mm, which was significantly smaller than that of the involved lymph nodes. Among the metastatic lymph nodes, 37.2% were less than 5 mm in diameter, and 63.1% of the metastases were less than 5 mm in diameter. The true-positive and true-negative diagnosis rate for all lymph node stations in three fields (neck, thorax, and abdomen) was only 23.2%, and the false-negative rate for diagnosis of lymph node metastasis was 53.7%.ConclusionsTwo-thirds of involved lymph nodes had very small metastases (<5 mm), suggesting that limited confidence should be placed in the preoperative diagnosis of lymphatic spread. Therefore, extensive lymph node dissection appears appropriate in esophageal cancer surgery, given the small sizes of many metastases and the difficulty with preoperative diagnosis.

Clinicopathological features of alpha-fetoprotein producing early gastric cancer with enteroblastic differentiation

AIM To investigate clinicopathological features of early stage gastric cancer with enteroblastic differentiation (GCED). METHODS We retrospectively investigated data on 6 cases of early stage GCED and 186 cases of early stage conventional gastric cancer (CGC: well or moderately differentiated adenocarcinoma) who underwent endoscopic submucosal dissection or endoscopic mucosal resection from September 2011 to February 2015 in our hospital. GCED was defined as a tumor having a primitive intestine-like structure composed of cuboidal or columnar cells with clear cytoplasm and immunohistochemical positivity for either alpha-fetoprotein, Glypican 3 or SALL4. The following were compared between GCED and CGC: age, gender, location and size of tumor, macroscopic type, ulceration, depth of invasion, lymphatic and venous invasion, positive horizontal and vertical margin, curative resection rate. RESULTS Six cases (5 males, 1 female; mean age 75.7 years; 6 lesions) of early gastric cancer with a GCED component and 186 cases (139 males, 47 females; mean age 72.7 years; 209 lesions) of early stage CGC were investigated. Mean tumor diameters were similar but rates of submucosal invasion, lymphatic invasion, venous invasion, and non-curative resection were higher in GCED than CGC (66.6% vs 11.4%, 33.3% vs 2.3%, 66.6% vs 0.4%, 83.3% vs 11% respectively, P < 0.01). Deep submucosal invasion was not revealed endoscopically or by preoperative biopsy. Histologically, in GCED the superficial mucosal layer was covered with a CGC component. The GCED component tended to exist in the deeper part of the mucosa to the submucosa by lymphatic and/or venous invasion, without severe stromal reaction. In addition, Glypican 3 was the most sensitive marker for GCED (positivity, 83.3%), immunohistochemically. CONCLUSION Even in the early stage GCED has high malignant potential, and preoperative diagnosis is considered difficult. Endoscopists and pathologists should know the clinicopathological features of this highly malignant type of cancer.

Relational topographical anatomy between right bronchial artery and thoracic duct

Thoracic duct injury leads to “chylothorax”. We found a close relationship of topographical anatomy between right bronchial artery and thoracic duct from esophageal cancer operations. We retrospectively analyzed topographical anatomy of right bronchial artery and location of thoracic duct in 124 cases operated in 2012. Of 124 cases, we recognized 8 cases of anomalous right bronchial artery. In these cases, the right bronchial artery originated directly from descending aorta without connections with third intercostal artery. When the right bronchial artery has a connection with third intercostal artery, the thoracic duct was located within the loop of the right bronchial artery. However, in these 8 anomalous cases, thoracic duct was located dorsally outside the loop of the right bronchial artery without exceptions. We have to be very careful in exploring the thoracic duct when we notice the anomalous right bronchial artery during esophageal cancer operation.

Utility of weekly docetaxel combined with preoperative radiotherapy for locally advanced esophageal cancer from pathological analysis.

Esophageal squamous cell cancer (ESCC) is a high-grade carcinoma that is treated with multidisciplinary approaches, including chemoradiotherapy (CRT) followed by surgery. Despite some success with these therapies, overall survival remains poor. In order to investigate a newer CRT regimen, we designed a comparative study to evaluate preoperative CRT using docetaxel (DOC) or 5-Fluorouracil and cisplatin (FU+CDDP [FP] therapy) for treatment of resectable ESCC. In a retrospective review of patients with resectable, locally advanced ESCC, 95 patients received preoperative CRT between 2001 and 2007. CRT was administered using either FP (n = 40) or DOC (n = 55). Pathological response and clinical outcomes were compared between the two groups. Hazard ratios and time-to-event analyses were used to assess outcomes; the ratios were controlled by multivariate logistic regression analysis of potential prognostic factors, and survival was presented with Kaplan-Meier curves. In the FP group, a significant curative effect was observed on the basis of pathological examination of postoperative lesions. However, the DOC group presented a significantly better prognosis on the basis of cumulative survival rates. Logistic regression analysis revealed that the presence of five or more lymph node metastases was an independent predictor of reduced survival. Patients with lymph node metastasis exhibited a better prognosis in the DOC group than those in the FP group. Preoperative CRT for locally advanced esophageal cancer using DOC results in similar or better long-term outcomes compared with FP-based CRT. Therefore, CRT using DOC is a promising therapy option for esophageal cancer.

Transthoracic esophagectomy of adenocarcinoma in Barrett’s esophagus in Japanese patients: analysis of localization of lymph node metastases in 19 cases

BackgroundThe incidence of esophageal adenocarcinoma is only 1%–2% in Japan. For this reason, many aspects of this disease have not been clarified, such as its generation, progress, and the potential of malignancy. It is necessary to investigate the strategy for treating this disease.MethodsBetween 1998 and 2008, 19 cases were diagnosed as adenocarcinoma with Barrett’s esophagus and treated with esophagectomy at Juntendo University: 13 cases were early stage and 6 cases were advanced stage. Distribution of lymph node metastasis and prognosis were investigated.ResultsThe incidence of lymph node metastases of adenocarcinoma is statistically lower (15.4%) compared with that of squamous cell carcinoma (SCC) (44.0%) (P = 0.034) when the depth of the tumor is not beyond the submucosal layer. Even in the early stages of adenocarcinoma, positive nodes were found in the lower mediastinum and gastric cardia. In advanced cases, cancer had spread randomly to the upper mediastinum or celiac region. Mean survival time of superficial and advanced adenocarcinoma after esophagectomy was 3,517.5 ± 330.6 and 2,061.4 ± 451.3 days, respectively, whereas that of SCC was 2,794.7 ± 131.0 and 1,669.1 ± 101.5 days, respectively. Overall survival of superficial or advanced adenocarcinoma was better than that of SCC but was not statistically superior.ConclusionsEndoscopic mucosal resection is limitedly proposed for mucosal tumors. Esophagectomy with a mediastinal lymphadenectomy should be conducted for tumors invading the submucosa. An individualized strategy is required that could approach the upper mediastinum based on staging and location of lymph node metastases.

Significance and Outlook of Preoperative Serum Interleukin-1β and Interleukin-6 as Prognostic Factors in Esophageal Cancer

Objective: We evaluated various cytokines in patients with esophageal cancers to elucidate the relationship between the Th1/Th2 balance and the patients’ prognosis. Materials and Methods: Various serum cytokines of preoperative 98 patients, who subsequently underwent radical esophagectomy between September 2005 and December 2006, were quantitatively measured by Cytometric Bead Array (CBA) system. The cytokines include Th1/Th2 balance related 14 cytokines-IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, INFγ and IgE. Multivariable analysis was performed using the Cox proportional hazard model. The survival rates based on CRP values were analyzed by the Kaplan-Meier method. Eight clinical pathological factors of the tumors, which are regarded as relevant prognostic factors: diameter, histological type, invasion type, vascular invasion, venous invasion, depth of the invation (T factor), regional lymph nodal status (N factor) and intramural metastasis (IM) and the 14 cytokines were evaluated by the multivariable analysis. Results: The multivariable analysis showed that T factors (p=0.001), N factors (p=0.002), IL-1β (p=0.003) and IL-6 (p=0.021) were significantly related to the worse prognosis. The two cytokines are known as inflammatory cytokines and they theoretically induce the production of acute inflammatory proteins, including C-reactive protein (CRP). We hereby evaluated the preoperative serum CRP values of the same patients. By means of ROC analysis (Youden index), the cut off value of the serum CRP was determined as 0.25 mg/dl and the survival rates were analyzed by the Kaplan-Meier method. The high CRP group (CRP ≥ 0.25 mg/dl) showed significantly poorer prognosis than low CRP group (<0.25 mg/dl) (p=0.027; Log-rank test). Conclusion: Out study showed that the inflammatory cytokines, IL-1β and IL-6, are significant prognostic factors of the patients with esophageal cancers and the Th1/Th2 balance in the patients of poorer prognosis may be shifted toward Th2-dominant side.

Utility of weekly docetaxel combined with preoperative radiotherapy for locally advanced esophageal cancer from pathological analysis: Chemoradiotherapy for esophageal cancer

Esophageal squamous cell cancer (ESCC) is a high-grade carcinoma that is treated with multidisciplinary approaches, including chemoradiotherapy (CRT) followed by surgery. Despite some success with these therapies, overall survival remains poor. In order to investigate a newer CRT regimen, we designed a comparative study to evaluate preoperative CRT using docetaxel (DOC) or 5-Fluorouracil and cisplatin (FU+CDDP [FP] therapy) for treatment of resectable ESCC. In a retrospective review of patients with resectable, locally advanced ESCC, 95 patients received preoperative CRT between 2001 and 2007. CRT was administered using either FP (n = 40) or DOC (n = 55). Pathological response and clinical outcomes were compared between the two groups. Hazard ratios and time-to-event analyses were used to assess outcomes; the ratios were controlled by multivariate logistic regression analysis of potential prognostic factors, and survival was presented with Kaplan-Meier curves. In the FP group, a significant curative effect was observed on the basis of pathological examination of postoperative lesions. However, the DOC group presented a significantly better prognosis on the basis of cumulative survival rates. Logistic regression analysis revealed that the presence of five or more lymph node metastases was an independent predictor of reduced survival. Patients with lymph node metastasis exhibited a better prognosis in the DOC group than those in the FP group. Preoperative CRT for locally advanced esophageal cancer using DOC results in similar or better long-term outcomes compared with FP-based CRT. Therefore, CRT using DOC is a promising therapy option for esophageal cancer.

Setting of the candidate exposure conditions in an individualized tumor response testing (ITRT) toward an individual chemotherapy for esophageal cancer

BackgroundTo apply the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) technique to individualized tumor response testing (ITRT) in esophageal cancer, optimal exposure conditions that would permit us to predict the clinical response to the low-dose cisplatin (CDDP)/5-fluorouracil (5-FU) regimen and docetaxel (DOC) regimen were determined.MethodsCD-DST was performed on 35 surgical specimens and 27 endoscopic biopsy samples from patients with esophageal squamous cell cancer. The reported blood AUC values were reproduced, or an in vitro concentration-response curve was constructed, for each regimen to determine exposure conditions using surgical specimens. For endoscopic samples, we estimated the evaluation rate (of CD-DST) and compared in vitro sensitivity with clinical response in measurable lesions to validate the exposure conditions determined.ResultsOverall, data were evaluated in 75.8% of the cases (94.3% in surgical specimens and 51.9% in endoscopic biopsy samples). Modeled exposure conditions were 5-FU 2.0 μg/ml/120 h with a cutoff inhibition rate (IR) of 50% for the low-dose CDDP/5-FU regimen and DOC 0.04 μg/ml/120 h with a cutoff IR of 50% for the DOC regimen.ConclusionsAlthough the study failed to compare in vitro results with clinical outcomes in measurable lesions, and the practical usefulness and applicability of the technique remain to be demonstrated, CD-DST might be a useful tool in selecting optimal chemotherapeutic agents.