Clinical significance of wall invasion pattern of subserosa-invasive gallbladder carcinoma.

We have previously classified wall invasion patterns of gallbladder carcinoma (GBC) cases into two groups, i.e., the infiltrative growth type (IG type) and destructive growth type (DG type). The DG type was significantly associated with poor differentiation, aggressive infiltration and decreased postoperative survival in terms of its histological differentiation, lymphatic invasion, venous invasion, lymph node status, neural invasion and mode of subserosal infiltration. In the present study, we analyzed 42 surgically-resected subserosal invasive gallbladder adenocarcinomas, invading the perimuscular connective tissue (pT2). The cumulative 5-year survival rate in the series was 48.7%. Lymphatic invasion (p=0.021), venous invasion (p=0.020), mode of subserosal infiltration (p<0.001), histological differentiation (p=0.030) and biliary infiltration (p=0.007) were noted, respectively, at a significantly higher incidence in more aggressive infiltration or poor differentiation in the DG type. The cumulative 5-year survival rate of curative resection cases was lower in patients with the DG type than in those with the IG type (68.9 versus 20.2%, respectively, p=0.006, log-rank test). On Cox's proportional hazard regression modeling, the low degree of venous/perineural invasion and IG type of wall invasion pattern were associated with a significant improvement in overall survival. Our data suggest that the wall invasion pattern is an independent predictor of survival in subserosal invasive GBC. Regarding the clinical application of our concept, on the classification of patients with subserosal invasive GBC based on a combination of the wall invasion pattern and lymph node status, the overall survival rate in patients with the DG type and/or N2 metastasis (n=21) was lower than in patients with the IG type and N0, 1 metastasis (n=21) (p=0.0023, log-rank test). The wall invasion pattern could contribute to decision-making concerning curative resection for subserosal invasive GBC.

Good response chemotherapy for late-recurring gastric cancer in the gluteals, with peritoneal and retroperitoneal dissemination.

A 64-year-old woman presented with advanced gastric cancer (signet ring cell carcinoma) and underwent total gastrectomy in 1996. Postoperative recovery was good, and she was monitored regularly on an outpatient basis. Abdominal computed tomography in 1999 revealed a soft tissue shadow ventral to the origin of the celiac artery. Careful monitoring was continued on an outpatient basis. The patient began to experience gluteal swelling and pain in April 2008. Symptoms rapidly exacerbated and the patient was hospitalized for further examination. Gluteal muscle biopsy revealed signet ring cell carcinoma and bilateral hydronephrosis. Gluteal recurrence of the original gastric cancer was suggested, and systemic chemotherapy consisting of S-1 at 100 mg/day (3 weeks on, 1 week off) and CDDP (day 8) was started. Following the 6th cycle of chemotherapy, gluteal symptoms disappeared and the patient was judged to have achieved clinical complete response (CR). No adverse events or image findings suggesting new recurrence have since been identified. The patient received a total CDDP dose of 585 mg and clinical CR has been maintained as of 14 years after total gastrectomy and 18 months after recurrence.

Nonfunctioning pancreatic endocrine tumor with extension into the main pancreatic duct: report of a case.

Pancreatic endocrine tumors (PETs) rarely involve the main pancreatic duct. We report a case of malignant nonfunctioning pancreatic endocrine tumor (NFPET) with prevalent intraductal growth. A 47-year-old woman was referred to us after ultrasonography at a routine health check showed diffuse swelling of the pancreas. Preoperative imaging showed a solid mass in the tail of the pancreas and a bulging intraductal mass in the main pancreatic duct. We performed total pancreatectomy because the tumor occupied almost the entire lumen of the main pancreatic duct. Histological examination confirmed well-differentiated endocrine carcinoma. We review reported cases of the intraductal growth of NFPETs and discuss the pathogenesis of these unusual tumors.

The distance of tumor spread in the main pancreatic duct of an intraductal papillary-mucinous neoplasm: where to resect and how to predict it.

BACKGROUND: The surgical decision regarding where to resect the pancreas is an important judgement that is directly linked to the surgical procedure. An appropriate surgical margin to resect intraductal papillary-mucinous neoplasm (IPMN) of the pancreas based on the distance of tumor spread (DTS) in the main pancreatic duct has not been adequately documented. We analyzed the appropriate surgical margin based on the DTS in the main pancreatic duct of IPMN and the positive rate at the pancreatic cut end margin. METHODS: Forty patients with main duct- or mixed-type IPMN diagnosed histopathologically who underwent surgery at Tokai University Hospital between 1991 and 2008 were retrospectively analyzed. The resection line was determined to achieve a 2-cm surgical margin in patients with main duct- or mixed-type IPMN and as limited a resection as possible to remove the dilated branch duct in patients with branch duct-type IPMN according to macroscopic type. The dysplastic state of the epithelium was judged as positive for carcinoma in situ (high-grade dysplasia) or adenoma (very low to moderate dysplasia) and judged as negative for hyperplasia or normal. RESULTS: The mean DTS in the main pancreatic duct was 41.6 +/- 30.0 mm, and that of the distance of tumor absence was 13.6 +/- 12.4 mm. The positive rate at the pancreatic cut end margin in frozen sections was 29.7%. The final positive rate at the pancreatic cut end margin was 26.2%. There has been no evidence of local recurrence in the remnant pancreas. DTS in the main pancreatic duct of IPMN was correlated with the maximum diameter of the duct (R = 0.678). CONCLUSION: Distance of tumor spread offered important insights about the appropriate site to resect the pancreas and the positive rate at the cut end margin in IPMN.

Gallbladder adenocarcinoma with human chorionic gonadotropin: a case report and review of literature.

BACKGROUND: The case of adenocarcinoma with human chorionic gonadtropin (HCG), primary in the male gallbladder, is extremely rare. A Medline search has shown only a few similar cases reported. METHODS: We herein describe a case of primary gallbladder adenocarcinoma associated by ectopic HCG positive tumor cells in a 79-year-old male. RESULTS: Pathological examination showed a mixture of moderately and poorly differentiated adenocarcinoma with ectopic HCG and placental alkaline phosphatase (PlAP) in tumor cells, though the increase of serum or urinary HCG secretion was not confirmed. The literatures were also reviewed. CONCLUSIONS: A case of gallbladder cancer with ectopic HCG production is quite rare in the literature, though many similar cases in other site, especially in GI tract, are reported. Embryological consideration suggests the increased frequency of similar cases more than being thought now.

Stromal thrombospondin-1 expression is a prognostic indicator and a new marker of invasiveness in intraductal papillary-mucinous neoplasm of the pancreas.

The invasion of intraductal papillary-mucinous neoplasm (IPMN) is sometimes difficult to diagnose using only ordinary hematoxylin-eosin sections. The aim of this study was to evaluate the invasion of IPMN more precisely using thrombospondin-1 (TSP1) immunohistochemistry as a useful adjunct to morphological examination. Eighty patients that underwent primary resection for pancreatic IPMNs were retrospectively analyzed. The 80 IPMNs were studied for the expression of TSP1, MUC1-CORE, MUC2, and MUC5AC. The cases were evaluated for dysplasia, the presence of invasion, hisological subtypes, and survival. The 80 IPMNs were classified into 29 intraductal papillary-mucinous adenomas (IPMAs), 10 borderline IPMNs, 18 noninvasive intraductal papillary-mucinous carcinomas (IPMCs), and 23 invasive IPMCs according to the WHO classification. Invasive IPMCs were further divided into 12 minimally invasive IPMCs (MI-IPMCs) and 11 invasive carcinomas originating from IPMCs (IC-IPMCs) according to the Japan Pancreatic Society classification. The rate of strongly positive cases with more than 30% of the cancer stroma area expressing TSP1 was significantly higher in MI-IPMC and IC-IPMC than in noninvasive IPMC (P = 0.035, 0.005). Furthermore, patients in the strongly positive group had a significantly poorer prognosis compared to patients in the negative-weakly positive group (P = 0.008, log-rank test). Of the 80 tumors, 22 were classified into gastric-, 45 into intestinal-, 7 into pancreatobiliary-, and 6 into oncocytic-type IPMNs according to criteria described previously. The cases with a strongly positive expression of TSP1 were frequently detected in the pancreatobiliary and oncocytic types (P = 0.001). In conclusion, stromal TSP1 expression is a prognostic indicator and a new marker of invasiveness in IPMN.

Wall-invasion pattern correlates with survival of patients with gallbladder adenocarcinoma.

Gallbladder carcinomas (GBC) frequently show vascular invasion and metastasis when the carcinoma cells invade the perimuscular connective tissue (pT2 according to the TNM classification) through the muscular layer. In this study, two intramural invasion patterns were defined as (i) infiltrative growth (IG) type, infiltrative growth in the muscle layer without destruction and (ii) destructive growth (DG) type, massive growth with destruction of the muscle layer. Sixty-six surgically resected gallbladder adenocarcinomas invading the perimuscular connective tissue (pT2) and beyond the gallbladder wall, including the visceral serosa, (pT3/pT4) were examined. The overall survival rate of the patients with the DG type was significantly lower than that of the patients with the IG type (p = 0.018). Lymphatic invasion (37.5% of IG and 62.5% of DG, p = 0.014), venous invasion (41.9%, 58.1%, p = 0.089), nodal status (30.4%, 69.6%, p = 0.015) and scirrhous growth (INFgamma) (31.0%, 69.0%, p = 0.0035) were more frequently detected in DG cases than in IG cases. In addition, median survival and survival rates were statistically analyzed. The patients with a high grade of lymphatic and venous invasion had lower survival rates (p < 0.0001 and p < 0.05, respectively). The patients with the DG type and scirrhous growth (INFgamma) also had lower survival rates (p < 0.05 and p < 0.0001, respectively) than did patients with the IG type and expansive/intermediate growth (INFalpha,beta). On multivariate analysis, neural invasion (odds ratio, 0.157; 95% confidence interval, 0.039-0.629) was an independent predictor of mortality. In conclusion, the DG invasion pattern is an indicator of high malignant potential and indirectly worsens the prognosis of patients with gallbladder adenocarcinoma.

Stromal laminin-5gamma2 chain expression is associated with the wall-invasion pattern of gallbladder adenocarcinoma.

Our previous study demonstrated that the pT2 and pT3-4 gallbladder carcinomas can be classified into two groups, i.e. infiltrative growth type (IG type) and destructive growth type (DG type) and that the DG type is associated with poor differentiation, aggressive infiltration, and decreased postoperative survival. The present study focused on the clinicopathologic significance of laminin-5gamma2 chain expression as an indicator of local aggressiveness and Ki-67 labeling index (Ki-67 LI) as an indicator of the cell proliferation activity of gallbladder carcinoma. Ki-67 LI was higher in the DG type (26.3%) than in the IG type (21.4%), and the rate of high-grade cell proliferation cases (Ki-67 LI > or = 30%) was high in the DG type (P = 0.012). Gallbladder carcinoma cases with high Ki-67 LI were significantly associated with poorly differentiation (P = 0.089) and distant lymph node metastasis (P = 0.079). Laminin-5gamma2 expression patterns of gallbladder carcinoma were divided into two distinct types, extracellular staining and cytoplasmic staining. The extracellular staining was subclassified into two groups, basement membrane staining and stromal staining. In the basement membrane staining, laminin-5gamma2 was present in the basement membranes surrounding neoplastic glandular structures. The basement membrane staining of laminin-5gamma2 was more frequent in the IG type (40%) than in the DG type (12.9%) (P = 0.025). The stromal staining was more frequent in the DG type. Furthermore, the stroma-positive group was more closely associated with decreased overall survival than the stroma-negative group (P = 0.028). The cytoplasmic staining was not significantly correlated with invasion pattern in gallbladder carcinoma (P = 0.545). Univariate analysis demonstrated that laminin-5gamma2 stromal staining is a predictor of lymphatic invasion, venous invasion, neural invasion, the mode of subserosal infiltration, and lymph nodal status. Multivariate analysis revealed the mode of subserosal infiltration is the strongest predictor of stromal invasion (P = 0.068). In conclusion, high-grade cell proliferation and stromal laminin-5gamma2 staining were significantly correlated with a wall-invasion pattern of aggressive gallbladder carcinoma indicating destructive growth (DG type).

End-to-end anastomosis after medial pancreatectomy for tumor.

Reconstruction by pancreaticoenterostomy has generally been employed after medial pancreatectomy for tumor. As a less invasive procedure, here we report three patients who successfully underwent pancreatic end-to-end anastomosis after medial pancreatectomy. The subjects consisted of 2 patients with serous cystadenomas and 1 patient with an intraductal papillary mucinous tumor. These tumors were detected in the pancreatic neck or body, and the maximal tumor diameters ranged from 10 to 33mm. The pancreatic duct diameters were 2 mm in 2 patients and 4 mm in 1 patient. The procedure was carried out by ductal anastomosis and parenchymal anastomosis with interrupted sutures. A pancreatic tube was inserted for decompression at the anastomotic site in all patients. The mean operative time was 3 hours and 31 minutes, and the intraoperative blood loss was 428 mL. Although pancreatic fistula was observed in 2 patients with the normal pancreas, conservative therapy relieved this complication. Neither tumor relapse nor stenosis of the pancreatic duct at the anastomotic site was detected in any patient, with a follow-up of 4 to 27 months. Our experience confirmed that in selected cases, this reconstructive procedure was feasible and safe for physiological reconstruction without involvement of the digestive tract.

A liver-derived immunosuppressive factor is an arginase: identification and mechanism of immunosuppression.

We found a substance in culture medium of neonatal pig liver fragments, which suppresses an immune response monitored by (3)H-thymidine incorporation using phytohemagglutinin (PHA)-stimulated lymphocytes. We named it as an immunosuppressive factor (ISF). To purify ISF, ammonium sulfate fractionation, DE52, SP-Sephadex, hydroxyapatite, blue Sepharose, heparin Sepharose and Superdex gel filtration columns were used. Using these purification procedures, ISF was purified 1,254-fold, with 9.2% recovery, from the culture medium of neonatal pig liver fragments, and was identified as arginase by its biochemical characteristics including molecular size, amino acid sequences of digested peptides and expression of arginase activity. The addition of ISF caused to decrease in arginine concentration in culture medium and at the same time DNA synthesis was suppressed dose-dependently, both of which were recovered by the addition of NOHA (N(G)-hydroxy-L-arginine), an arginase inhibitor. In addition, the depletion of arginine in culture medium also led to the inhibition of DNA synthesis. These results led us to the conclusion that immunosuppressive effect of ISF was due to arginase activity that decreased arginine concentration in culture medium, not to another function of ISF.

Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer.

The calcium-binding protein, S100A4, with an inverse association of E-cadherin, is known to correlate with prognosis in various cancers. In this study, we investigated the expression of the S100A4 and E-cadherin status in relation to the clinicopathological parameters of pancreatic cancer. The expression status of these two proteins was examined in 72 specimens of primary pancreatic carcinoma with immunohistochemistry. Fifty-six of 72 (78%) surgical specimens of primary pancreatic cancer were positive for S100A4 according to immunohistochemistry. Thirty-one (43%) specimens of pancreatic cancer showed positive expression of E-cadherin. The inverse association of S100A4 and E-cadherin expression was significant in the cancers (p < 0.0001). The S100A4 expression correlated significantly with the pathological T stage and poorer prognosis (p = 0.024). The 41 E-cadherin-negative cases showed poorer prognoses and a higher incidence of liver metastasis (p = 0.0344, p = 0.027). The 10 cases with S100A4-negative/E-cadherin-positive cancers showed a significantly better prognosis than the others (p < 0.05). The histological grade (p = 0.004), nodal status (p < 0.0001) and S100A4-positive status (p = 0.048) were highly significant independent prognostic predictors (p < 0.05). These results suggest that S100A4 overexpression combined with reduced E-cadherin expression play important roles in tumor progression and metastasis in pancreatic cancer. The combined examination of these two molecules is useful in evaluating the outcome of pancreatic cancer patient.

Hepatocellular carcinoma metastatic to the orbit: a case report.

Hepatocellular carcinoma rarely metastasizes to the orbit. We report on a 72-year-old man with a past history of resection for hepatocellular carcinoma and recurrent HCC, who presented with diplopia and left painful proptosis. Head scans revealed a large and irregular mass in the left orbit that caused destruction of the orbital bone superiorly and posterolaterally. A biopsy specimens of the orbital tumor showed features of metastatic foci of hepatocellular carcinoma. The tumor was surgically excised and histological findings revealed moderately differentiated hepatocellular carcinoma, resembling hepatocytes with a tendency to form trabeculae. Immunohistochemically, the tumor cells showed positive reaction against low-molecular-weight keratin and α-fetoprotein. There have been only 12 previous cases of hepatocellular carcinoma metastatic to the orbit cited in the literature. We presented here a rare case of hepatocellular carcinoma metastatic to the orbit.

Hepatocellular carcinoma with metastasis to the pharynx: report of a case.

Hepatocellular carcinoma (HCC) is rarely metastasized to the pharyngeal region. We report the case of a 59-year-old man admitted to our hospital with a complaint of hematemesis. An endoscopic examination revealed a tumor located in the left piriform sinus. Histological examination showed metastasis from HCC. Subsequent abdominal examinations demonstrated mild liver cirrhosis due to chronic HCV infection and primary nodules in the lateral segment of the liver. The pharyngeal tumor was completely removed by endoscopic polypectomy after radical hepatectomy for HCC. The patient died of recurrence of HCC 8 months after the first admission. With the presentation of this case, we review the literature reported so far.

Treatment of infantile hepatoblastoma and related complications.

Hepatorblastoma is an uncommon childhood malignant tumor of hepatic origin and recent progress of treatment strategy resulted in improved prognosis of patients with hepatoblastoma. Although patients within one year of age were considered to have better prognosis than those over that age, the treatment related deaths have been reported to be the only cause of the treatment failure of the infantile hepatoblastoma. We have successfully treated 4 infants including one with spontaneous rupture and the other with recurrence. Treatment protocol was preoperative chemotherapy using cisplatin and THP-ADR, doses of which were modified according to the age, with optional radiological interventions followed by resection of the primary tumor. This report would describe their clinical courses and experienced side effects of the treatment in order to demonstrate its risk. Trans-arterial embolizations were beneficial to stop bleeding due to rupture and to reduce intraoperative blood loss. In spite of dose modifications high hematological side effects were inevitable and cisplatn-induced hearing loss persisted in one case. In conclusion, for small infants with hepatoblastoma, controlling the inevitable side effects and active but strategic surgical and radiological interventions are essential for successful treatment.

Effect of pouched reconstruction after total gastrectomy on ERCP and ENBD--report of two cases.

Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic nasobiliary drainage (ENBD) are well known to be useful but these procedures are rarely indicated in patients after total gastrectomy, because the endoscopic approach is more difficult in the patients with standard reconstructions such as Roux-en-y esophagojejunostomy after total gastrectomy. Gastric replacement with various enteric reservoirs after gastrectomy has been used to improve the postprandial symptoms and nutrition of patients after total gastrectomy. We have been performing jejunal pouch double tract reconstruction (JPD) after gastrectomy and the patients' postoperative course has been satisfactory. In this report, we describe two cases of biliary tract disorders after total gastrectomy. One was choledocholithiasis and the other was bile leakage after cholecystectomy. In each case, we performed ERCP, and treated with ENBD tube placement, and we obtained satisfactory results. We emphasize that ERCP and ENBD are also useful and easy procedures for biliary tract disease in postgastrectomy patients with JPD reconstruction as well as in patients who have not undergone intestinal reconstruction. The advantages of JPD reconstruction are not only improving the postprandial symptoms and the nutrition of patients after total gastrectomy, but that it provides an easy endoscopic approach to the papilla of Vater.

Clinicopathological significance of sialyl Lex expression in human gallbladder carcinoma.

Sialyl Lex antigen, a member of a family of high molecular weight glycoproteins, is a ligand for E-selectin and may play an important role in tumor metastasis. However, expression patterns of sialyl Lex have not yet been established in human gallbladder carcinomas. In this study, we analyzed the clinicopathological significance of sialyl Lex expression and patients' prognosis in cases of human gallbladder adenocarcinoma. Sialyl Lex immunoreactivity was detected not only in cancer cells (cytoplasmic type; 51.9%, 28/54) but also in cancer stroma (stromal type; 38.9%, 21/54). Stromal sialyl Lex expression was detected in 50.0% (20/40) and 7.1% (1/14) of T2-4 and T1 cancers, respectively (p<0.05). Stromal sialyl Lex-positive gallbladder cancers frequently showed lymphatic invasion, venous invasion and lymph node metastasis (54.3, 50.0 and 60.0%, respectively) (p<0.05), and the expression was associated with a poor outcome. Sialyl Lex expression plays important roles in the vascular invasion and metastasis of human gallbladder adenocarcinoma.

Epidermal growth factor receptor expression in human pancreatic cancer: Significance for liver metastasis.

Pancreatic cancer is a malignant tumor with an extremely poor prognosis. The mechanisms of the aggressive growth and metastasis are not yet extensively understood. Over-expression of epidermal growth factor receptor (EGFR) was suggested to be associated with malignant transformation of pancreatic cancer. We examined EGFR expression in 77 cases of invasive ductal adenocarcinoma of the pancreas, and analyzed the relation between the EGFR expression pattern and clinicopathological factors. EGFR immunoreactivity was detected in 41.6% (32/77) of human pancreatic cancers; i.e. diffuse expression in 32.5% (25/77) and focal expression in 9.1% (7/77). The EGFR expression was associated with gender (p<0.05), histological differentiation (p<0.05) and metastatic status of TNM classification (p<0.01). The observations suggested that EGFR expression plays important roles in metastasis, especially liver metastasis and recurrence of human pancreatic cancer.

Undifferentiated spindle and giant cell carcinoma of the common bile duct.

Undifferentiated spindle and giant cell carcinoma of the common bile duct has not been reported previously. We present here a case of 71-year-old man with the undifferentiated spindle and giant cell carcinoma of the common bile duct, including immunohistochemical findings. A nodular infiltrating tumor was located at the lower portion of the extrahepatic bile duct, and measured 1.2 x 0.6 cm in size. Histologically, the tumor was composed of proliferated sarcomatoid spindle tumor cells. Numerous multinucleated giant cells were intermingled with the sarcomatoid spindle tumor cells. Immunohistochemically, the tumor cells were positive for both cytokeratin and vimentin. We speculated that the tumor originated from epithelial cells, and showed sarcomatoid neplastic changes.

Thrombospondin-1 expression as a prognostic predictor of pancreatic ductal carcinoma.

Pancreatic cancer is a malignant tumor with an extremely poor prognosis. Thrombospondin-1 (TSP-1) was suggested to be a potential regulator of tumor growth and metastasis. We examined TSP-1 expression in 77 cases of invasive ductal adenocarcinoma of the pancreas, and analyzed the correlation between the TSP-1 expression pattern and clinicopathological features in pancreatic cancer. TSP-1 immunoreactivity was detected in the cancer stroma. The diffusely positive and focally positive patterns of TSP-1 were found in 33 (42.9%) and 40 (51.9%) of 77 cases, respectively. The TSP-1 diffuse expression was significantly correlated with lymph node metastasis (p<0.01), neural invasion (p<0.05) and TNM stage (p<0.01). The prognostic significance of clinicopathological parameters were analyzed by univariate and multivariate analysis using the log-rank test and the Cox proportional hazards model. Based on the univariate analysis, histological differentiation (p<0.01), lymphatic invasion (p<0.01), venous invasion (p<0.05), neural invasion (p<0.01), TNM stage (p<0.01) and TSP-1 expression (p<0.01) were significant parameters. These observations suggested that TSP-1 plays important roles in cancer cell growth and metastasis of human pancreatic cancer, and that stromal TSP-1 immunoreactivity is a good prognostic predictor of patients with pancreatic cancer.