Diffuse large B-cell lymphoma of the gallbladder arised 8 years after malignant lymphoma of the right testis: A case report and literature review.

INTRODUCTION: Gallbladder involvement in lymphoma is extremely rare, and only 68 cases have been reported in the English literature so far. We experienced a case of diffuse large B-cell lymphoma (DLBCL) of the gallbladder arising 8 years after DLBCL of the right testis. PRESENTATION OF CASE: A 68-year-old man underwent orchiectomy for malignant lymphoma of the right testis pathologically diagnosed as DLBCL 8 years ago. Systemic surveillance incidentally revealed a gallbladder tumour, and elective resection of the gallbladder bed of the liver was performed under a preoperative diagnosis of gallbladder cancer. The histopathological examination revealed DLBCL. At re-evaluation 3 months after surgery, he was diagnosed as having DLBCL involving the stomach. There had been no recurrence for 39 months after chemotherapy and radiation, but he suffered from a poor general condition due to protein-losing enteropathy and died of infection. DISCUSSION: We compiled and analysed reported cases of malignant lymphomas involving the gallbladder in terms of background, symptoms, imaging findings, and prognosis. Compared to MALT lymphoma, DLBCL was significantly more involved in other organs simultaneously or heterochronously (p = 0.004). CONCLUSION: Gallbladder lymphoma should be added to the differential diagnosis of gallbladder tumours, especially when clinical findings are not consistent with the typical course of gallbladder carcinoma and cholecystitis.

Neutrophil-to-Lymphocyte Ratio and Intratumoral CD45RO-Positive T Cells as Predictive Factors for Longer Survival of Patients with Colorectal Liver Metastasis after Hepatectomy.

Colorectal cancer is the fourth most common malignancy across the world, and over 50% of patients had colorectal liver metastases (CLM). Activated neutrophils and tumor-infiltrating lymphocytes (TILs) are considered to interrupt progression of primary colorectal cancer; however, immunological host reactions to CLM have not been fully elucidated. We thus aimed to explore the prognostic implication of neutrophil-to-lymphocyte ratio (NLR) in peripheral blood and TILs in resected metastatic cancer tissues of 29 patients with CLM who underwent hepatectomy. To evaluate local immunological responses in CLM, we examined the infiltration of CD66b+ neutrophils and TILs, such as CD8+ T cells, CD45RO+ T cells, and forkhead box P3+ (FOXP3+) T cells. The presence of fewer than 4 tumors (p = 0.0005), the absence of distant metastasis (p = 0.018), adjuvant anti-cancer chemotherapy (p = 0.0013), and elevated NLR over 4.1 (p = 0.026) were found to be significant parameters related to longer survival after hepatectomy. Further, high numbers of infiltrated CD45RO+ T cells in CLM were significantly associated with longer patient survival (p = 0.020). The numbers of CD45RO+ T cells were correlated with those of CD8+ T cells (p = 0.008). The numbers of peripheral blood neutrophils were negatively correlated with those of CD45RO+ T cells (p = 0.038) and of CD66b+ neutrophils (p = 0.008) in CLM. The present data indicate that elevated peripheral blood NLR and high numbers of intratumoral CD45RO+ T cells are predictive of longer CLM patient survival after hepatectomy among current biomarkers.

Prognostic significance of hepatocyte growth factor activator inhibitor type 1 (HAI-1) immunoreactivity in pancreatic ductal adenocarcinoma.

OBJECTIVE: Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound serine protease inhibitor that is expressed on the surface of epithelial cells. Evidence has suggested that decreased cell surface HAI-1 in carcinoma cells results in enhanced invasiveness. However, little is known regarding the expression of HAI-1 in pancreatic ductal adenocarcinoma (PDAC). This study aimed to analyze HAI-1 expression in PDAC and its impact on patient prognosis. RESULTS: HAI-1 immunohistochemistry was performed on samples from 67 PDAC cases. HAI-1 expression was increased in intraepithelial neoplasia compared to the adjacent non-neoplastic ductal epithelium. Of the 67 samples tested, 58% (39/67) of PDAC cases showed diffuse (> 75%) immunoreactivity in PDAC cells. The remaining cases showed reduced HAI-1 immunoreactivity in a substantial number of cancer cells. Although there was no correlation between HAI-1 status and tumor size, histologic grade or lymph node metastasis, diffuse HAI-1 positive cases showed longer disease-free survival (DFS; p = 0.006, log-rank test). In conclusion, HAI-1 is upregulated in pancreatic intraepithelial neoplasia and broadly expressed in PDAC cells. However, PDAC cases having areas of reduced HAI-1 immunoreactivity may show shorter DFS.

Glypican-3 is a prognostic factor and an immunotherapeutic target in hepatocellular carcinoma.

Glypican-3 (GPC3) is a cell surface oncofetal proteoglycan that is anchored by glycosylphosphatidylinositol. Whereas GPC3 is abundant in fetal liver, its expression is hardly detectable in adult liver. Importantly, GPC3 is overexpressed in hepatocellular carcinoma (HCC), and several immunohistochemical studies reported that overexpression predicts a poorer prognosis for HCC patients. Therefore, GPC3 would serve as a useful molecular marker for HCC diagnosis and also as a target for therapeutic intervention in HCC. Indeed, some immunotherapy protocols targeting GPC3 are under investigations; those include humanized anti-GPC3 cytotoxic antibody, peptide vaccine and immunotoxin therapies. When considering the clinical requirements for GPC3-targeting therapy, companion diagnostics to select the appropriate HCC patients are critical, and both immunohistochemical analysis of tissue sections and measurement of serum GPC3 level have been suggested for this purpose. This review summarizes current knowledge regarding the clinical implication of GPC3 detection and targeting in the management of patients with HCC.

Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice.

Ghrelin is a 28-amino-acid peptide that stimulates the release of pituitary growth hormone. Because of its orexigenic effects, ghrelin is being developed as a therapeutic option for postoperative support and treatment of anorexia-cachexia syndrome of cancer patients. However, ghrelin has a multiplicity of physiological functions, and it also affects cell proliferation. Therefore, the effects of ghrelin administration on carcinogenesis and cancer progression in patients susceptible to cancer should be clarified. In this study, we examined the effects of ghrelin on cancer promotion in vivo using murine intestinal carcinogenesis models. Intestinal tumorigenesis was examined to determine the effects of either exogenous ghrelin administration or ghrelin deficiency following deletion of the Ghrl gene. Two murine intestinal tumorigenesis models were used. The first was the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced inflammation-associated colon carcinogenesis model and the second was the Apc(Min/+) genetic cancer susceptibility model. In AOM/DSS-treated mice, administration of ghrelin significantly suppressed tumor formation in the colon. In contrast, ghrelin administration did not affect the number of intestinal tumors formed in Apc(Min/+) mice. The absence of endogenous ghrelin did not affect the incidence of intestinal tumors in either AOM/DSS-treated mice or Apc(Min/+) mice, though tumor size tended to be larger in Ghrl(-/-) colons in the AOM/DSS model. No tumor-promoting effect was observed by ghrelin administration in either tumorigenesis model. In summary, this study provides in vivo experimental evidence for the usefulness of ghrelin administration in the chemoprevention of inflammation-associated colorectal carcinogenesis and may suggest its safety in patients under colitis-associated cancer susceptibility conditions.

High preoperative levels of serum glypican-3 containing N-terminal subunit are associated with poor prognosis in patients with hepatocellular carcinoma after partial hepatectomy.

Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored cell surface glycoprotein overexpressed in hepatocellular carcinoma (HCC) cells and may serve as a potential molecular target for therapeutic intervention. This study evaluated the prognostic significance of serum GPC3 in HCC patients receiving curative surgery. A novel sandwich enzyme-linked immunosorbent assay for the quantitative and sensitive determination of serum GPC3 N-terminal subunit antigen (sGPC3N) was developed and used to measure sGPC3N levels in 25 healthy volunteers and 115 HCC patients who underwent curative partial hepatectomy. The relationships between sGPC3N and clinicopathologic features were analyzed and the prognostic impact on overall survival (OS) or disease-free survival (DFS) was also investigated. Mean and median levels of sGPC3N in healthy controls were 110.12 and 115.95 pg mL(-1) , respectively, with 185.52 pg mL(-1) (mean + 2 SD) being set as the upper limit of the normal range. In HCC patients, sGPC3N levels were significantly increased (mean/median, 405.16/236.19 pg mL(-1) ) compared to healthy controls (p < 0.0001), and 60% of HCC cases (69/115) showed sGPC3N levels that were higher than the upper normal limit. High sGPC3N levels were significantly associated with serum AFP level, high Child-Pugh score and positive HCV. Kaplan-Meier analysis indicated that elevated pre-operative sGPC3N was associated with shorter OS and DFS after hepatectomy (p ≤ 0.01). Multivariate analysis revealed elevated sGPC3N as an independent poor prognostic marker for OS (p < 0.05) and DFS (p < 0.01). The pre-operative sGPC3N level serves as an independent prognostic biomarker in HCC patients.

Aberrant expression of monocarboxylate transporter 4 in tumour cells predicts an unfavourable outcome in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: The tumour cell microenvironment, which includes local oxygen saturation, pericellular pH and stromal cells, can modulate tumour progression. This study determined the prognostic impact of infiltrating tumour-associated macrophages and the expression of monocarboxylate transporter 4 (MCT4) and glypican 3 (GPC3) in hepatocellular carcinoma (HCC) clinical specimens. METHODS: A total of 225 cases of resected HCC were subjected to immunohistochemical analyses of CD68, CD204, MCT4 and GPC3. Immunoreactivities and other common clinicopathological parameters were subjected to univariate prognostic analyses for overall survival (OS, n = 225) and disease-free survival (DFS, n = 222). All variables with prognostic impact were further analysed in multivariate analysis. RESULTS: Increased intratumoural infiltration of CD204-positive or MCT4-positive macrophages suggested shorter OS (P = 0.015 or P = 0.001 respectively), but DFS was not altered. The GPC3 score (with an emphasis on circumferential immunoreactivity) was correlated with shorter OS and DFS. Aberrant expression of MCT4 in HCC cells was observed in a subset of HCC cases (21%, 47/225). In those cases, significantly poorer OS (P < 0.0001) and DFS (P = 0.0003) were observed, and there was a positive correlation with the intratumoural infiltration of CD204- or MCT4-positive macrophages and the GPC3 score. Multivariate analysis showed that aberrant MCT4 expression in HCC cells was an independent prognostic factor for shorter OS (P = 0.018) and DFS (P = 0.006) after resection of HCC. CONCLUSION: Aberrant expression of MCT4 in carcinoma cells serves as a novel, independent prognostic factor for HCC, indicating a poorer patient outcome.

Loss of hepatocyte growth factor activator inhibitor type 1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model.

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound serine protease inhibitor that is expressed on the surface of epithelial and carcinoma cells. On the cell surface, HAI-1 regulates membrane-anchored serine proteases, with matriptase being the most critical target. Matriptase is involved in pericellular processing of biologically active molecules, including protease-activated receptor-2 (PAR-2). Previously we reported that S2-CP8 cells, a metastatic variant of the SUIT-2 human pancreatic adenocarcinoma cell line, showed markedly decreased HAI-1 expression. To assess the significance of HAI-1 loss in invasion and spontaneous metastasis of S2-CP8 cells, we established stable S2-CP8 sublines that expressed HAI-1 under the control of a tetracycline-regulated promoter. In vitro migration and invasion assays revealed inhibitory effects of HAI-1 on S2-CP8 cell migration and invasion. Matriptase activity was suppressed by the expression of HAI-1. As the enhanced invasiveness in the absence of HAI-1 was alleviated by knockdown of matriptase by 81% and of PAR-2 completely, and PAR-2 antagonist also suppressed the invasion, matriptase-mediated PAR-2 activation is involved in HAI-1 loss-induced invasion of S2-CP8 cells. We then analyzed the effect of HAI-1 expression on metastasis of S2-CP8 cells in vivo using a nude mouse orthotopic xenograft model. Although approximately 50% of the control mice developed distant metastasis, mice treated with doxycycline to induce HAI-1 expression did not develop metastasis. These data indicate that HAI-1 loss contributes to invasion and dissemination of a highly metastatic subline of SUIT-2, suggesting crucial roles for the balance of pericellular serine proteases/inhibitors in pancreatic cancer progression.

Hepatocyte growth factor activator inhibitor type 1 is a suppressor of intestinal tumorigenesis.

Hepatocyte growth factor activator inhibitor type 1 (HAI-1/SPINT1) is a membrane-bound serine protease inhibitor expressed on the surface of epithelial cells. Although HAI-1/SPINT1 is abundantly expressed in the intestinal epithelium, its role in intestinal tumorigenesis is not known. In this study, we investigated the role of Hai-1/Spint1 in intestinal tumorigenesis using mouse models. The membranous Hai-1/Spint1 immunoreactivity was decreased in murine Apc(Min/+) tumors and also in carcinogen (azoxymethane treatment followed by dextran sodium sulfate administration)-induced colon tumors compared with the adjacent non-neoplastic epithelium. The decreased immunoreactivity appeared to be due to sheddase activity of membrane-type 1 matrix metalloprotease. Then, we examined the effect of intestine-specific deletion of Spint1 gene on Apc(Min/+) mice. The loss of Hai-1/Spint1 significantly accelerated tumor formation in Apc(Min/+) mice and shortened their survival periods. Activation of HGF was enhanced in Hai-1/Spint1-deficient Apc(Min/+) intestine. Gene expression profiling revealed upregulation of the Wnt/ß-catenin signaling circuit, claudin-2 expression, and angiogenesis not only in tumor tissue but also in the background mucosa without macroscopic tumors in Hai-1/Spint1-deficient Apc(Min/+) intestine. Intestinal deletion of Spint1 also enhanced the susceptibility to carcinogen-induced colon tumorigenicity of wild-type Apc mice. Our findings suggest that HAI-1/SPINT1 has a crucial role in suppressing intestinal tumorigenesis, which implies a novel link between epithelial cell surface serine protease inhibitors and protection from carcinogenic stimuli.

Role of the standardized uptake value of 18-fluorodeoxyglucose positron emission tomography-computed tomography in detecting the primary tumor and lymph node metastasis in colorectal cancers.

PURPOSE: To assess the role of positron emission tomography-computed tomography (PET-CT) and multidetector-row CT (MD-CT) in detecting the primary lesion and lymph node metastasis in patients with colorectal cancers. METHODS: A collective total of 80 lesions resected from 77 patients were examined pathologically. We analyzed the significance of the standardized uptake value (SUV) and its relationship with the clinicopathologic findings of primary lesions and lymph node metastasis. The detectability of primary lesions and lymph node metastases on PET-CT images was compared with that on MD-CT images. RESULTS: The detectability of primary lesions was better on PET-CT images than on MD-CT images (p = 0.0023). We observed no significant differences in the SUV with respect to staging, tumor grade, lymphatic or vessel invasion, and macroscopic type; however, primary tumor size analysis revealed that tumors larger than 3 cm had a higher SUV than those smaller than 3 cm. The sensitivity of PET-CT for detecting lymph node metastasis was lower than that of MD-CT, but the specificity of PET-CT was higher than that of MD-CT. CONCLUSIONS: The SUV of primary cancers tends to increase in proportion to tumor size. Although the value of PET-CT in detecting lymph node metastasis is limited, PET -positive lymph nodes can be considered metastatic.

Rectal endometriosis masquerading as dissemination in a patient with rectal cancer: report of a case.

A 57-year-old woman was diagnosed as having rectal cancer. A barium enema study showed the apple-core sign at the rectosigmoid colon, and colonoscopy revealed an encircled ulcerated tumor. A laparoscope-assisted resection of the rectum was planned; however, the rectal cancer directly invaded the uterus body. The operation was converted to open surgery. An elastic hard tumor suspected of being peritoneal dissemination at the peritoneal reflection was detected and excised together with the rectum below the peritoneal reflection. A histological examination of this tumor revealed that cystic glands lined by nonmucinous columnar epithelial cells were seen on the serosal side and were embedded in the proper muscle of the rectum. This tumorous lesion was diagnosed as endometriosis.

Asymptomatic extra-adrenal paraganglioma masquerading as retroperitoneal sarcoma.

A 41-year-old man without clinical symptoms was referred for treatment of an enlarging retroperitoneal tumor. Enhanced computed tomography showed a well-defined and heterogeneously enhanced tumor, 4 cm in size, in the dorsal portion of the pancreas. A low-density nodule was detected in the left adrenal gland, 10 mm in diameter. Retroperitoneal sarcoma and nonfunctional left adrenal tumor were suspected, and surgical treatment was performed. During excision of the retroperitoneal tumor, blood pressure was extremely elevated when the tumor was compressed. Blood pressure normalized after excision of the tumor; thus, a diagnosis of paraganglioma was favored over that of retroperitoneal sarcoma. The left adrenal gland was resected together with the adrenal tumor. Microscopically, the tumor cells of the retroperitoneum had round to oval nuclei, and abundant granular amphophilic cytoplasm proliferated in nest-like fashion. Extra-adrenal retroperitoneal paraganglioma was considered, and the adrenal tumor was diagnosed as cortical adenoma. In patients with retroperitoneal tumor, even in the absence of clinical symptoms, we should keep in mind the possibility of extra-adrenal paraganglioma.