Mitsuo Kishimoto

The expression and role of Aquaporin 5 in esophageal squamous cell carcinoma

BackgroundAquaporins (AQPs) are water channel proteins that facilitate transcellular water movements. Recent studies have shown that AQP5 is expressed in various cancers, and plays a role in tumor progression. However, its expression and role in esophageal squamous cell carcinoma (ESCC) have not been investigated. We examined the pathophysiologic role of AQP5 in cell proliferation and survival, and also investigated its expression and effects on the prognosis of ESCC patients.MethodsAQP5 expression in human ESCC cell lines was analyzed by Western blot testing. Knockdown experiments with AQP5 siRNA were conducted, and the effects on cell proliferation, cell cycle progression, and cell survival were analyzed. The cells’ gene expression profiles were analyzed by microarray analysis. Immunohistochemistry of AQP5 for 68 primary tumor samples obtained from ESCC patients undergoing esophagectomy was performed.ResultsAQP5 expression was high in TE2 and TE5 cells. In these cells, the knockdown of AQP5 using siRNA inhibited cell proliferation and G1-S phase progression, and induced apoptosis. The AQP5 siRNA transfected TE5 cells showed significant increase in p21 and decrease in CCND1 mRNA expression, respectively. The expression pattern of AQP5 and p21 protein was sharply contrasted, but AQP5 and CCND1 protein expression showed a similar pattern in ESCC tissue. These findings agree with the microarray results. Immunohistochemical staining of 68 ESCC patients showed the AQP5 expression is associated with tumor size, histological type, and tumor recurrence.ConclusionThe AQP5 expression in ESCC cells may affect cell proliferation and survival, and impact on the prognosis of ESCC patients.

Oncocytic renal cell carcinoma having papillotubular growth: Rare morphological variant of papillary renal cell carcinoma

Herein is described a unique renal cell tumor with previously unreported morphological and immunohistochemical features. The patient was a 78‐year‐old Japanese man. A huge left renal tumor was found on ultrasound during evaluation of left abdominal distention. The tumor was macroscopically characterized by a non‐infiltrative border, pale yellow to grayish color, foci of hemorrhage and partial edematous change. Histologically the tumor had an extensive small tubular growth pattern often with papillary fronds mainly composed of oncocytic cells with deeply eosinophilic granular cytoplasm. Clear vacuolated cells were scattered among the oncocytic cells. The present case had an unusual immunohistochemical profile for all known types of renal cell tumors, but both the oncocytic cells and the clear vacuolated cells were strongly immunoreactive for α‐methylacyl‐coenzyme A racemase. It is concluded that the tumor may be a candidate for a rare variant of papillary renal cell carcinoma. Further cases having similar features are awaited for a definitive classification of this tumor as a previously undescribed tumor type.

Re: The decision criterion of histological mixed type in “T1/T2” gastric carcinoma‐comparison between TNM classification and Japanese classification of gastric cancer

This study was designed to evaluate the clinical significance of undifferentiated component in differentiated T1/T2 gastric adenocarcinoma.

xCT, component of cysteine/glutamate transporter, as an independent prognostic factor in human esophageal squamous cell carcinoma

BackgroundxCT is a component of the cysteine/glutamate transporter, which plays a key role in glutathione synthesis. The objectives of the present study were to investigate the role of xCT in the regulation of genes involved in cell cycle progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC).MethodsxCT expression in human ESCC cell lines was analyzed by Western blotting and immunofluorescent staining. Knockdown experiments were conducted with xCT siRNA, and the effect on cell cycle was analyzed. The cells’ gene expression profiles were analyzed by microarray analysis. An immunohistochemical analysis of 70 primary tumor samples obtained from ESCC patients that had undergone esophagectomy was performed.ResultsxCT was highly expressed in TE13 and KYSE170 cells. In these cells, the knockdown of xCT using siRNA inhibited G1-S phase progression. Microarray analysis identified 1652 genes whose expression levels in TE13 cells were altered by the knockdown of xCT. Pathway analysis showed that the top-ranked canonical pathway was the G1/S checkpoint regulation pathway, which involves TP53INP1, CDKN1A, CyclinD1/cdk4, and E2F5. Immunohistochemical staining showed that xCT is mainly found in the nuclei of carcinoma cells, and that its expression is an independent prognostic factor.ConclusionsThese observations suggest that the expression of xCT in ESCC cells might affect the G1/S checkpoint and impact on the prognosis of ESCC patients. As a result, we have a deeper understanding of the role played by xCT as a mediator and/or biomarker in ESCC.

Histological mixed-type as an independent prognostic factor in stage I gastric carcinoma

AIM To evaluate the clinicopathological features of mixed-type gastric cancer and their influence on prognosis of mixed-type stage I gastric cancer. METHODS We analyzed 446 patients who underwent curative gastrectomy for stage I gastric cancer between 1999 and 2009. The patients were divided into two groups: those with differentiated or undifferentiated cancer (non-mixed-type, n = 333) and those with a mixture of differentiated and undifferentiated cancers (mixed-type, n = 113). RESULTS The overall prevalence of mixed-type gastric cancer was 25.3% (113/446). Compared with patients with non-mixed-type gastric cancer, those with mixed-type gastric cancer tended to be older at onset (P = 0.1252) and have a higher incidence of lymph node metastasis (P = 0.1476). They also had significantly larger tumors (P < 0.0001), more aggressive lymphatic invasion (P = 0.0011), and deeper tumor invasion (P < 0.0001). In addition, they exhibited significantly worse overall survival rates than did patients with non-mixed-type gastric cancer (P = 0.0026). Furthermore, mixed-type gastric cancer was independently associated with a worse outcome in multivariate analysis [P = 0.0300, hazard ratio = 11.4 (1.265-102.7)]. CONCLUSION Histological mixed-type of gastric cancer contributes to malignant outcomes and highlight its usefulness as a prognostic indicator in stage I gastric cancer.

Prognostic significance of RB1-inducible coiled-coil 1 in salivary gland cancers

No generally agreed‐upon method is available for predicting the prognosis of salivary gland cancers. RB1‐inducible coiled‐coil 1 (RB1CC1) is a positive regulator for the retinoblastoma tumor suppressor (RB1) pathway, and is a suitable marker for evaluating the clinical course of breast cancer. We investigated whether RB1CC1 predicts the prognosis of salivary gland cancers.

Gastric leiomyosarcoma manifesting peculiar findings: Radiological–pathological correlation

Reported herein is a gastric leiomyosarcoma, which, nowadays, is extremely rare. Attention was focused not only on pathological findings but also on the histological basis of magnetic resonance imaging (MRI) findings. The patient was a 29‐year‐old Japanese woman. Preoperative T2‐weighted MRI showed a large high‐intensity gastric tumor with isointense streaks. The tumor was a broad‐based large polypoid lesion and histologically consisted of fascicles of spindled cells having eosinophilic cytoplasm and cigar‐shaped nuclei. Immunoreactivity for several smooth muscle markers including desmin on tumor cells, low amplification of both c‐kit and PDGFRA cDNA on polymerase chain reaction, and absence of c‐kit gene mutation in exons 9 and 11 strongly suggested that the tumor was not a gastrointestinal stromal tumor but a true leiomyosarcoma. In vitro MRI of the fresh tumor was obtained to explain the radiological findings on a morphological basis. In vitro MRI clearly depicted the very high‐intensity areas separated by radially extended isointense lines. This radiological finding corresponded best to the most characteristic histological feature, that is, linearly extended fascicles of the tumor cells often with myxedematous change separated by radially elongated thin fibrovascular stroma: in other words, spouting appearance.

Extraarticular paravertebral diffuse-type giant cell tumor.

A diffuse-type giant cell tumor (DGCT) of the paravertebral region is a rare condition characterized by an ill-demarcated mass with facet joint involvement. We describe a case of extra-articular DGCT of the paravertebral cervical region without association to the facet joint. A 51-year-old male presented with a headache. Diagnostic imaging showed a dumbbell-shaped mass with enlargement of the right intervertebral foramen between C6 and C7. The tumor was completely resected in multiple fragments with the suspicion that it was a schwannoma. Histologically the tumor consisted chiefly of mononuclear histiocytoid cells, foamy macrophages and multinucleated giant cells, which led to a diagnosis of DGCT. The case alerts one to be aware that DGCT may originate from a paravertebral location as a soft-tissue mass without facet joint involvement.

Pigmented squamous cell carcinoma of the uterine cervix.

A 57-year-old female presented with an abnormal Pap smear. Colposcopic examination of the cervix revealed white mucosa with erosion and several areas of black pigmentation. After a colposcopically directed biopsy and loop conization, radical hysterectomy and bilateral salpingo-oophorectomy with pelvic and paraaortic lymphadenectomy were performed. Pathological examination disclosed an invasive squamous cell carcinoma admixed with many dendritic melanocytes. Melanin granules were present within the melanocytes and tumor cells. Although similar tumors have been reported in other sites, this is the first report to our knowledge of a pigmented squamous cell carcinoma of the uterine cervix.

The K–Cl Cotransporter KCC3 as an Independent Prognostic Factor in Human Esophageal Squamous Cell Carcinoma

The objectives of the present study were to investigate the role of K–Cl cotransporter 3 (KCC3) in the regulation of cellular invasion and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC). Immunohistochemical analysis performed on 70 primary tumor samples obtained from ESCC patients showed that KCC3 was primarily found in the cytoplasm of carcinoma cells. Although the expression of KCC3 in the main tumor (MT) was related to several clinicopathological features, such as the pT and pN categories, it had no prognostic impact. KCC3 expression scores were compared between the MT and cancer nest (CN), and the survival rate of patients with a CN > MT score was lower than that of patients with a CN ≤ MT score. In addition, the survival rate of patients in whom KCC3 was expressed in the invasive front of tumor was lower than that of the patients without it. Furthermore, multivariate analysis demonstrated that the expression of KCC3 in the invasive front was one of the most important independent prognostic factors. The depletion of KCC3 using siRNAs inhibited cell migration and invasion in human ESCC cell lines. These results suggest that the expression of KCC3 in ESCC may affect cellular invasion and be related to a worse prognosis in patients with ESCC.