Clinicopathological significance of laminin-5γ2 chain expression in superficial esophageal cancer.

The glycoprotein laminin 5γ2 chain (LN-5γ2) has recently become a focus of increased interest and investigation as a marker of invasion in gastrointestinal malignancies. We investigated the significance of LN-5γ2 expression as a prognostic factor in superficial esophageal cancer. The study population consisted of 87 patients who had undergone a transthoracic esophagectomy and three-field lymphadenectomy for the treatment of superficial esophageal cancer at Tokai University Hospital. Formalin-fixed, paraffin-embedded sections of the resected specimens were examined using immunohistochemical staining and hematoxylin and eosin staining to assess the correlations between the LN-5γ2 expression pattern and the clinicopathological factors (age, sex, T-factor, N-factor, ly-factor, v-factor, degree of differentiation, infiltrative growth pattern, tumor node metastasis classification of malignant tumors [TNM] stage, etc.) and the patient outcome. The expression pattern of LN-5γ2 was classified into an extracellular type (E type), characterized by the staining of extracellular matrix such as the basement membrane and the stroma (31 cases, 35.6%), and a cytoplasmic type (C type), characterized by the staining of the cytoplasm in the cancer cells (56 cases, 64.6%). The expression pattern was not correlated with any of the clinicopathological factors that were assessed. However, univariate analyses of the survival analysis data showed that the N-factor (P = 0.011), TNM stage (P = 0.011), and LN-5γ2 C type (P = 0.017) were prognostic factors. A multivariate analysis revealed that the N-factor (P = 0.049) and LN-5γ2 C type (P = 0.048) were prognostic factors. In the survival analysis, a univariate analysis of the 75 T1b cases also showed that the N-factor (P = 0.048), TNM stage (P = 0.048), and LN-5γ2 C type (P = 0.029) were prognostic factors, while a multivariate analysis showed that the LN-5γ2 C type (P = 0.035) was a prognostic factor. The C type expression of LN-5γ2, i.e. confined to the cytoplasm, was correlated with an unfavorable outcome among the patients with superficial esophageal cancer in the present series. Observation of the LN-5γ2 expression pattern may be useful for the diagnosis of highly malignant tumors.

Partial rescue of the Na+-Ca2+ exchanger (NCX1) knock-out mouse by transgenic expression of NCX1

The null mutation of cardiac Na+-Ca2+ exchanger (NCX1) gene in mice caused death of embryo in utero at embryonic day (ED) 9.0-9.5 and this embryonic lethality appears resulted from abnormal heart development. In the present study, we investigated whether transgenic re-expression of NCX1 in mutant cardiac myocytes could rescue these lethal defects. Transgenic mice expressing the canine NCX1 in a cardiac specific manner were bred into the NCX1 knock-out background but did not prevent the fetal lethality associated with the NCX1 null allele. However, the NCX1 knock-out embryos with an NCX1 transgene survived with heart beatings until ED 10.5 which was one day longer than the survival of the NCX1 knock-out embryos (ED 9.5). At ED 10.5, however, the partially rescued NCX1 embryos might have succumbed to the lack of an organized vasculature in the yolk sacs. The placental labyrinth layer was reduced in size and largely avascular. The transgenic re-expression of NCX1 rescued heart beatings and survived longer, but was still insufficient for the mice to be completely rescued. Importantly, NCX1 was observed to express in the yolk sac and the placenta of wild type mice. The results suggest that defects in extra-embryonic compartments are causal to the lethality, and that NCX1 may play an important role in establishing vascularization in extra-embryonic tissues.

Esophageal hernia in dementia: surgeon's role for mixed-type esophageal hernia in an elderly woman with dementia.

The mixed-type esophageal hernia is an indication for operation to prevent stomach volvulus and perforation. However, preventive operation is meaningful depending on the physical status. We encountered an 84-year-old, demented, bed-ridden woman of mixed-type esophageal hernia complicated with severe reflux esophagitis. First, the patient was conservatively treated by intravenous hyperalimentation and H2 blocker but, with onset of delirium, she removed the venous route twice. Subsequently, she was tightly restrained to the bed to avoid removing the line. Ethical deliberation for the patient tightly fixed to the bed and intravenous alimentation for her life prompted us to reconsider hernia operation after discussion with surrogate decision makers. The patient recovered uneventfully after operation, and movement without intravenous route or without any restraints was maintained by oral feeding assisted by gastrostomy feeding. In the coming decade, when senior patients are expected to increase, such operations can be forwarded to respect the patients' quality of life.

Accumulation of p53 in esophageal squamous cell carcinoma.

p53 is one of the most important tumor suppressor genes. Mutation of the p53 gene can be detected immunohistochemically as over-expression of its protein in the nucleus. The p53 gene product is known to regulate cell growth and proliferation. Genetic alterations related to the carcinogenesis or progression of esophageal cancer are poorly understood. We examined accumulation of p53 protein in esophageal squamous cell carcinomas including early-stage cancers, and its clinicopathological significance. p53 immunoreactivity in the cancer tissues was found in 61 (79.2%) of 77 esophageal squamous cell carcinomas. Over-expression of p53 protein (diffusely and focally positive staining) was seen in 70.1% (54/77). p53 over-expression was detected not only in the cases of in situ or intramucosal carcinomas, but also in invasive carcinomas. No significant correlations were found between p53 over-expression and clinicopathological features such as depth of tumor invasion, lymph node metastasis or venous/lymphatic invasion. These results suggested that p53 mutations may be closely associated with the early-stage of pre-invasive esophageal carcinoma, and p53 gene mutations may play an important role in the carcinogenesis of human esophageal cancer.

Pancreatic acinar cell carcinoma with endocrine differentiation: immunohistochemical and ultrastructural analyses.

The majority of pancreatic malignant tumors are adenocarcinomas of the ductal type (ductal cell carcinomas) and combined tumors consisting of different tumor components are very rare. We present here a rare case of acinar cell carcinoma with apparent foci of endocrine differentiation. A 46-year-old man underwent pylorus-preserving pancreatoduodenectomy under the diagnosis of pancreatic tumor. The pancreatic tumor was mainly composed of typical acinar cell carcinoma, but some tumor cells were positive for both acinar and endocrine cell markers such as pancreatic amylase, trypsin, lipase and chromogranin A. At the electron-microscopic level, the tumor cells were seen to have numerous electron-dense neuroendocrine, as well as a few zymogen-like, granules. The tumor part positive for both acinar and endocrine cell markers originated from a subclone (dis-differentiated tumor cells) of the typical acinar cell carcinoma tissue of the pancreas.

Immunohistochemical MUC1 (DF3 antigen) expression of human esophageal squamous cell carcinoma.

MUC1 (DF3 antigen) is a member of a family of high molecular weight glycoproteins. Recent studies have demonstrated that MUC1 is expressed in tumors of various human organs and may function as an anti-adhesion molecule that inhibits cell-to-cell adhesion, inducing tumor metastasis. However, expression patterns of MUC1 have not yet been established in human esophageal carcinomas. In this study, we examined MUC1 expression and its histopathological localization in human esophageal squamous cell carcinoma. MUC1 immunoreactivity was found in 17 (32.1%) out of 53 esophageal squamous cell carcinomas, regardless of the depth of tumor invasion, vascular invasion or lymph node status. MUC1 expression was detected in the intramucosal part in 28.3% (15 out of 53) and in the invasive part in 32.6% (14 out of 43) of the esophageal carcinomas (no significant difference). These observations suggested that expression of MUC1 is an early event in cancer progression, but that it is not significantly associated with metastasis of human esophageal carcinomas.

Idiopathic submucosal hematoma of esophagus complicated by dissecting aneurysm, followed-up endoscopically during conservative treatment.

Submucosal hematoma of the esophagus is encountered as a rare complication of endoscopic treatment for esophageal varices, but is seen more often with the increasing frequency of endoscopic applications. Idiopathic submucosal hematoma is a rarer event and in most cases sudden intense vomiting has been postulated as its cause. We report here the case of such a patient whose condition was complicated by a dissecting aneurysm. During conservative treatment, careful follow-up was required to differentiate the submucosal hematoma from an aorto-esophageal fistula.

Clinicopathological studies of esophageal carcinosarcoma: analyses of its morphological characteristics using endoscopic, histological, and immunohistochemical procedures.

BACKGROUND AND STUDY AIMS: Carcinosarcoma of the esophagus is a rare malignant neoplasm consisting of both carcinomatous and sarcomatous components, which characteristically forms polypoid tumors. PATIENTS AND METHODS: Seven carcinosarcomas were analyzed using endoscopic, histological, and immunohistochemical procedures. Endoscopically, six of the seven lesions were found to be of the protruding type, while the other one was an ulcerating tumor. RESULTS: In all seven cases, the carcinomatous component consisted of differentiated squamous cell carcinoma, and the sarcomatous component was spindle cell carcinoma. Histological analyses demonstrated that the majority of the protruding tumors consisted of the sarcomatous component, while the ulcerating tumor mainly consisted of squamous cell carcinoma. The Ki-67 (MIB-1) labeling index (LI) of the carcinomatous component (28.2%) did not differ significantly from that of the sarcomatous component (25.5%). The sarcomatous component showed abundant expression of type IV collagen and laminin. CONCLUSIONS: It is conceivable that the carcinomatous and sarcomatous components grow separately from the early stage of the tumors, and that the sarcomatous component forms a protruding tumor mass because it has abundant stroma positive for type IV collagen and laminin.

Frequent expression of sialyl Le(a) in human esophageal squamous cell carcinoma.

Sialyl Le(a) antigen (CA19-9), a member of a family of high molecular weight glycoproteins, was originally described as a gastrointestinal- and pancreatic-specific tumor marker. Recent studies have demonstrated that sialyl Le(a) is a ligand for E-selectin and may play an important role in tumor metastasis. However, expression patterns of sialyl Le(a) have not yet been established in human esophageal carcinomas. In this study, we examined sialyl Le(a) expression and its histopathological localization in human esophageal squamous cell carcinoma. Sialyl Le(a) immunoreactivity was detected in 28 (51.9%) of the 54 esophageal squamous cell carcinomas, regardless of the depth of tumor invasion, vascular invasion or lymph nodal status. In 13 cases (29.5%), significant sialyl Le(a) expression was detected not only in the intramucosal carcinoma components, but also in the invasive carcinoma components. These observation suggested that sialyl Le(a) expression is associated with early-stage cancer progression.

Stromal CEA immunoreactivity is correlated with lymphatic invasion of human esophageal carcinoma.

Carcinoembryonic antigen (CEA) is a good marker of colorectal cancer. Recent studies have demonstrated that CEA may function as a metastatic potentiator by different pathways; i.e. modulation of immune responses, facilitation of intercellular adhesion and cellular migration. However, expression patterns of CEA have not yet been established in human esophageal carcinomas. In this study, we examined CEA expression in human esophageal squamous cell carcinoma and its clinicopathological significance. CEA immunoreactivity was frequently detected in the cancer cells (cytoplasmic type; 81.1%, 43/53) as well as in the cancer stroma (stromal type; 32.1%, 17/53), regardless of the depth of tumor invasion. Lymphatic invasion of cancer cells was frequently found in the stromal CEA-positive esophageal cancer (44.4%, 16/36), compared to stromal CEA-negative cancer (5.9%, 1/17) (p<0.05). These observations suggested that stromal CEA expression plays important roles in lymphatic invasion of human esophageal squamous cell carcinoma.

Simultaneous treatment of multiple primary cancers of the oral cavity and other sites.

Multiple primary cancers are not uncommon in the head and neck region. Since the time for treatment will be prolonged if each lesion is treated separately, simultaneous treatment of the cancers is preferred to ensure complete remission of lesions and increased survival of patients. In this paper, the efficacy of combined treatment was evaluated in 9 patients with oral cancers and concurrent cancers in other sites. The mean age of the patients was 54 years (range 44 to 66). The tongue (8) and mandible (1) were the sites of involvement. Concurrent cancers were found most often in the esophagus, followed by stomach and lung. Histologically, 7 lesions were diagnosed as squamous cell carcinomas. All oral cancers were treated by surgery. Neck dissection and simultaneous reconstruction were performed in 5 patients. In addition, concurrent cancers were treated simultaneously by endoscopic mucosal resection in 2 patients and radical resection followed by immediate reconstruction in 6 other patients. However, simultaneous surgical treatment of all lesions could not be performed in an individual with 3 cancers. The time of surgery ranged from 23 minutes to 17 hours and 30 minutes. With the exception of 2 patients who died of postoperative complications and had needed treatment for dysphasia, all patients were discharged after 1 to 2 months. Four of the patients are still alive 2 years and 6 months after surgery. These results indicate that simultaneous treatment is effective in selected cases of multiple cancers.

Clinicopathological studies of esophageal carcinoma in achalasia: analyses of carcinogenesis using histological and immunohistochemical procedures.

Achalasia of the esophagus is a benign disease caused by dyskinesia of the lower esophagus and cardia and is presumed to be a premalignant lesion leading to an increased risk of squamous cell carcinoma. We analyzed six surgically or endoscopically resected carcinomas among 54 cases of esophageal achalasia using histological and immunohistochemical procedures. The mean interval between the diagnosis of achalasia and carcinoma was 21.5 years. Four of the six cases were superficial early-stage cancers whilst the other two were advanced cancers invading the adventitia. Histological mapping of the resected esophageal specimens demonstrated marked hyperplastic changes of stratified squamous epithelium and multiple foci of dysplastic changes. The squamous cell carcinomas showed well-differentiated type with low-grade atypia, closely associated with dysplastic foci. Immunohistochemical staining for p53, p21, p16 and epidermal growth factor receptor suggested that the dysplastic epithelium was a borderline lesion between hyperplasia and in situ carcinoma. Our observations suggested that esophageal food stasis induces chronic hyperplastic esophagitis and eventually malignant transformation of esophageal epithelial cells, associated with dysplasia-carcinoma sequence.

Endoscopic mucosal resection for early gastric cancer.

Progress in the detection of early gastric cancer has made endoscopic mucosal resection (EMR) possible for the treatment of gastric cancer instead of only conventional surgical resection. The most commonly employed modalities include strip biopsy, double snare polypectomy, and resection with combined use of highly concentrated saline and epinephrine, and resection using a cap. The indications should be strictly limited to the differentiated IIa type (the slightly elevated type) that is smaller than 2 cm, or the differentiated IIc type (slightly depressed type) without ulcer formation and smaller than 1 cm. Both of these entities are thought to have a negligible risk of lymph node metastasis. Prognosis after this treatment is comparable that of surgical resection for early gastric cancer in completely resected cases. EMR also permits local resection in elderly patients with various complications who would be at risk for conventional surgical operations. EMR should be encouraged for treatment of gastric cancer if the indications are strictly chosen.

Frequent expression of inducible nitric oxide synthase in esophageal squamous cell carcinomas.

Nitric oxide (NO) plays important biological roles in cardiovascular, nervous and immune systems, and is synthesized by nitric oxide synthase (NOS). Intracellular NO is known to cause DNA damage as a mutagen. We examined the expression of cytokine-inducible NOS (iNOS) in human esophageal squamous cell carcinomas. Weak iNOS immunoreactivity was seen in the basal and parabasal layers of non-neoplastic esophageal stratified squamous epithelium. iNOS expression was detected in 50 (87.7%) of the 57 esophageal squamous cell carcinomas, regardless of the depth of tumor invasion, histological differentiation and lymph node status. Early-stage cancers, i.e. mucosal squamous cell carcinomas, also showed significant iNOS expression. We speculate that increased iNOS expression is associated with the carcinogenesis of human esophageal cancer.

Stromal thrombospondin-1 expression is correlated with progression of esophageal squamous cell carcinomas.

Thrombospondin-1 (TSP1) is an extracellular matrix glycoproteins that affecting cell adhesion, motility and growth. Based on its effects on tumors, TSP1 is thought to be a potential regulator of tumor growth and metastasis. In this study, we clarified TSP1 immunoreactivity in human esophageal squamous cell carcinoma and its clinicopathological significance. TSP1 immunoreactivity was detected mainly in the cancer stroma and was observed infrequently in cancer cells. According to the TNM classification, 70.6% (12/17) of the T3 esophageal cancers were TSP1-positive, while only 26.9% (7/26) of the Tis and T1 cancers showed TSP1 expression. Lymph node metastasis and venous involvement was frequently found in the TSP1-positive cases (71.4% and 80.0%, respectively) of esophageal squamous cell carcinoma (p < 0.001). This observation suggested that TSP1 expression plays an important role in cancer cell growth and metastasis of human esophageal squamous cell carcinomas, and that stromal TSP1 immunoreactivity is a good predictor of venous involvement and lymph node metastasis.

Assessment of the proliferative activity of superficial esophageal carcinoma using MIB-1 immunostaining for the Ki-67 antigen.

BACKGROUND AND OBJECTIVES: Lymph node metastasis or vascular invasion may occur in superficial esophageal squamous cell carcinoma when it invades to or into the muscularis mucosae. Therefore, the correlation between histopathological characteristics and the proliferative activity of superficial esophageal carcinoma was investigated. METHODS: Thirty-eight cases of esophageal squamous cell carcinoma, including 14 cases of mucosal carcinoma and 24 cases of submucosal carcinoma, who underwent surgical resection without preoperative treatment, were studied using monoclonal antibody MIB-1 for the Ki-67 antigen immunohistochemically. The labeling index (LI) was calculated with a computed image analyzer. RESULTS: The LI of MIB-1 at the invasive tip of m3 carcinoma was significantly higher than that of m1 or m2 carcinoma (P < 0.01). The LI at the invasive tip was significantly higher than that at the core of sm2 (P < 0.05) and submucosal carcinoma overall (P < 0.01). The LI values at both the invasive tip and core of poorly differentiated carcinoma in submucosal carcinoma were higher than that of well or moderately differentiated carcinoma with a significant difference (P < 0.05). The LI at the invasive tip of submucosal carcinoma with lymph node metastasis or lymphatic invasion was significantly higher than that without them (P < 0.05). CONCLUSION: Proliferative activities of cancer cells in superficial esophageal squamous cell carcinoma, immunostaining with the MIB-1, were related to the depth of invasion, differentiation, lymph node metastasis, and lymphatic invasion with a significant difference.