Kanenori Endo

Protein expression of CD44 (standard and variant isoforms) in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, p53 expression, and patient survival

BACKGROUND/AIMS Members of the CD44 family are transmembrane glycoproteins which act mainly as receptors for hyaluronan. We have examined the expression of CD44s and several CD44v and the relationship between these and hepatocellular carcinoma (HCC) grade, clinicopathological parameters, p53 expression, and patient survival in HCC. METHODS Formalin-fixed, paraffin-embedded tissue sections from 107 surgically resected HCC were examined immunohistochemically using a semi-quantitative scoring system to detect the expression of different forms of CD44. RESULTS The number of CD44s-positive cases was 36 (34%), CD44v5 52 (49%), CD44v6 29 (27%), CD44v7-8 41 (38%), and CD44v10 26 (24%). Expression of these molecules correlated with high histological grade, being the highest in poorly-differentiated HCC. High CD44v6 expression significantly correlated with the presence of vascular invasion and p53 overexpression. Kaplan-Meier examination of patient survival revealed that HCC patients with positivity of each of these five molecules had a reduced survival rate, and that HCC patients positive for all the five CD44 molecules had worse survival than HCC patients positive for four or less of these CD44 molecules. In multivariate survival analysis, CD44s positivity was an independent factor. However, positivity for one or more CD44 isoforms was the most useful independent factor for overall survival. CONCLUSION These results suggest that up-regulation of CD44 isoforms is associated with poorly-differentiated HCC and shortened survival.

c-erbB-2 protein is expressed in hepatolithiasis and cholangiocarcinoma.

The c‐erbB‐2 proto‐oncogene encodes a transmembrane protein which is highly homologous to epidermal growth factor receptor. Overexpression of this c‐erbB‐2 protein has been reported in many human carcinomas, including breast carcinoma. However, there have been few studies of the expression of c‐erbB‐2 in cholangiocarcinoma and hepatolithiasis, a condition occasionally associated with cholangiocarcinoma.

Overexpression of p53 protein and MDM2 in papillary carcinomas of the thyroid: Correlations with clinicopathologic features

Expression of p53 protein and MDM2 was evaluated in paraffin‐embedded tissue from 78 patients with papillary carcinomas of the thyroid (PCT), in order to elucidate the relationship between them and their correlations with some clinicopathologic features implicated in tumor progression. These proteins were expressed in nuclei of tumor cells, but not in non‐tumor cells. Staining was defined as positive when 10% or more of tumor cells expressed these proteins. The number of cases positive for p53 protein was 21/78 (27%), and that positive for MDM2 was 26/78 (33%). Co‐overexpression of p53 protein and MDM2 was observed in 12/78 cases (15%). A significant positive relationship was found between them (P < 0.01); p53‐positive cases tended to be also positive for MDM2 and vice versa. Statistical analysis revealed that overexpression of p53 protein significantly correlated with large tumor size (P = 0.0271) and the presence of capsular invasion (P = 0.04). There were significant positive correlations between tumor size and intrathyroidal invasion and between tumor size and capsular invasion in PCT, suggesting that p53 protein overexpression is associated only with tumor progression (tumor size). However, we could not find any significant correlations between MDM2 expression and clinicopathologic features. Our findings suggest that overexpression of p53 protein and MDM2 in papillary carcinoma of the thyroid is associated with the progression of the tumors, and that p53 may be a marker of the progression of PCT.

Overexpression of MDM2 protein in intrahepatic cholangiocarcinoma: relationship with p53 overexpression, Ki-67 labeling, and clinicopathological features.

Abstract Aberration of the p53 gene is thought to be the most frequent genetic alteration in human cancers. Tp53 protein may be inactivated by the binding of the MDM2 protein. MDM2, the product of the mdm2 gene, is an oncoprotein that binds to Tp53 and inhibits the p53- mediated transactivation. MDM2 overexpression has been reported in several human cancers, but not in intrahepatic cholangiocarcinoma (ICC). Therefore, we have evaluated the immunohistochemical overexpression of MDM2 and the relationship between its expression and histological grade, clinicopathological features, Tp53 overexpression, and Ki-67 labeling index in 47 cases of ICC. MDM2 and Tp53 were found to be overexpressed in 38% and 57% of the tumor, respectively. MDM2 and Tp53 were not expressed in non-tumorous liver tissue. There was no significant difference between the MDM2 overexpression and ICC tumor grade. However, MDM2 overexpression correlated with the presence of metastases (P<0.01) and advanced tumor stage (P<0.05). MDM2 overexpression also correlated with Tp53 overexpression (P<0.03) and Ki-67 labeling index (P<0.03). Our findings suggest that MDM2 overexpression may play a role in the late stage of human ICC.

Mixed ductal-endocrine carcinoma of the pancreas presenting as gastrinoma with Zollinger-Ellison syndrome: an autopsy case with a 24-year survival period

Abstract We report an autopsy case of mixed ductal-endocrine carcinoma of the pancreas presenting as gastrinoma with Zollinger-Ellison syndrome. A 38-year-old Japanese male was found to have Zollinger-Ellison syndrome and pancreatic gastrinoma, and gastrectomy and resection of the pancreatic tumor were performed. However, hypergastrinemia persisted, and the patient died of disseminated carcinomatosis at 62 years of age, 24 years after the onset of Zollinger-Ellison syndrome. At autopsy, the main tumor was present in the residual pancreas, and metastases were noted in many organs. In the pancreas and other organs, ductal and endocrine carcinoma areas were mixed and there was a gradual transition between the two. No acinar differentiation was noted. The ductal elements were positive for mucins and carcinoembryonic antigen but negative for neuroendocrine markers, while endocrine elements were positive for chromogranin A and synaptophysin and to a lesser extent for gastrin, but negative for mucins and carcinoembryonic antigen. The ductal elements comprised about 30% of the tumor cells, and endocrine elements 70%. According to the revised World Health Organization classification, our case was diagnosed as mixed ductal-endocrine carcinoma. Our case is rare because the tumor manifested as gastrinoma with Zollinger-Ellison syndrome and the patient survived for 24 years. To the best of our knowledge, no such case has been reported. Our case suggests that pancreatic endocrine tumors may evolve into mixed ductal-endocrine carcinomas.

Biological and clinical implications of retinoic acid-responsive genes in human hepatocellular carcinoma cells.

BACKGROUND & AIMS Accumulating data from epidemiological and experimental studies have suggested that retinoids, which are vitamin A derivatives, exert antitumor activity in various organs. We performed a gene screening based on in silico analysis of retinoic acid response elements (RAREs) to identify the genes facilitating the antitumor activity of retinoic acid (RA) and investigated their clinical significance in hepatocellular carcinoma (HCC). METHODS In silico analysis of RAREs was performed in the 5-kb upstream region of EST clusters. Chromatin immunoprecipitation analysis of the retinoic acid receptors and gene expression analysis were performed in HuH7, HepG2, and MCF7 cells treated with all-trans RA (ATRA). mRNA expression of RA-responsive genes was investigated using tumor and non-tumor tissues of clinical HCC samples from 171 patients. The association between gene expression and survival of patients was examined by Cox regression analysis. RESULTS We identified 201 candidate genes with promoter regions containing consensus RARE and finally selected 26 RA-responsive genes. Of these, downregulation of OTU domain-containing 7B (OTUD7B) gene, which was upregulated by ATRA, in tumor tissue was associated with a low cancer-specific survival of HCC patients. Functional analyses revealed that OTUD7B negatively regulates nuclear factor κB (NF-κB) signaling and decreases the survival of HCC cells. CONCLUSIONS We identified RA-responsive genes which are regulated by retinoid signal and found that low-OTUD7B mRNA expression is associated with a poor prognosis for HCC patients. OTUD7B-mediated inhibition of NF-κB signaling may be an effective target for antitumor therapy for HCC.

Epithelioid leiomyosarcoma with osteoclast-like giant cells in the rectum.

We report a rare case of rectal epithelioid leiomyosarcoma with osteoclast-like giant cells. A 71-year-old Japanese man was admitted to a hospital with melena. Results of a colonoscopy test revealed a polypoid tumor in the rectum, and a biopsy specimen from the lesion showed a sarcoma; the patient underwent rectosigmoidectomy. At gross inspection, the tumor measured 8 x 7 x 4 cm and was polypoid with ulcerations. Necrotic and hemorrhagic foci were scattered. Microscopically, the tumor consisted of 2 cell types: malignant tumor cells with epithelioid features and benign-appearing osteoclast-like giant cells. The tumor cells were polygonal and epithelioid in shape and had eosinophilic or clear cytoplasms, with scattered giant tumor cells. Immunohistochemical examination revealed that the tumor cells were positive for vimentin, muscle actin, alpha-smooth muscle actin, and desmin, whereas the osteoclast-like giant cells were positive for CD68, leukocyte common antigen, and lysozymes. We diagnosed this case as epithelioid leiomyosarcoma with osteoclast-like giant cells. To the best of our knowledge, this is the first case of rectal epithelioid leiomyosarcoma with osteoclast-like giant cells.

Isolated port-site metastasis of hepatocellular carcinoma after laparoscopic liver resection

Port‐site metastasis of hepatocellular carcinoma (HCC) is extremely rare, and only one case has been reported in the English‐language literature. Contamination with malignant cells along the needle tract during percutaneous biopsy or radiofrequency ablation is a well‐recognized cause of HCC recurrence. Here, we describe a case of port‐site metastasis after laparoscopic liver resection of HCC. The patient, who had undergone laparoscopic partial resection of the left lateral segment of the liver 18 months earlier, was diagnosed with HCC. CT showed a nodule in the abdominal wall where the laparoscopic port had been inserted during resection. Local excision was performed, and histological examination revealed HCC consistent with recurrence after laparoscopic resection. The experience described in this report highlights the risk of port‐site metastasis of HCC. Imaging for oncologic surveillance after laparoscopic resection must include all port sites.

Median arcuate ligament syndrome and aneurysm in the pancreaticoduodenal artery detected by retroperitoneal hemorrhage: A case report

Here, we report a case with successful treatment of inferior pancreaticoduodenal artery aneurysm rupture due to celiac artery trunk compression caused by the median arcuate ligament. When clinicians see visceral aneurysms, the possibility of arcuate midline ligament compression syndrome (MALS) and ligamentectomy for MALS should be considered.

C-Reactive Protein/Albumin Ratio and Prognostic Nutritional Index Are Strong Prognostic Indicators of Survival in Resected Pancreatic Ductal Adenocarcinoma

Abstract Purpose: We evaluated the clinical importance, such as the occurrence of postoperative pancreatic fistula (POPF) or prognosis, of preoperative serum markers of chronic inflammation, nutrition, and immunity, as well as that of serum tumor markers after curative resection of pancreatic ductal adenocarcinomas (PDACs). Methods: Between 2006 and 2015, 43 patients with PDACs underwent curative resection at Tottori Prefectural Central Hospital. We analyzed which preoperative indicators (i.e., C-reactive protein/albumin ratio [CAR], neutrophil/lymphocyte ratio [NLR], prognostic nutritional index [PNI], carcinoembryonic antigen [CEA], and carbohydrate antigen 19-9 [CA 19-9]) were the most relevant risk factors for occurrence of POPF and poor patient survival. Results: POPF was detected in 8/43 (18.6%) patients. One patient died of pancreatic fistula at 2 months postoperatively. Among nine candidate factors (operative procedure, operation time, tumor stage, preoperative serum amylase, preoperative CAR, NLR, PNI, CEA, and CA 19-9), we did not identify any significant risk factor for the occurrence of POPF. The 5-year overall survival (OS) rate of the 43 patients was 22.4%, and the overall median survival time was 21 months. The multivariate OS analysis demonstrated that high CAR and low PNI were strong preoperative markers of poor prognosis independently of tumor stage. Conclusions: Preoperative CAR and PNI are useful prognostic markers for patients with operable PDACs.