Validation of T Stage According to Depth of Invasion and N Stage Subclassification Based on Number of Metastatic Lymph Nodes for Distal Extrahepatic Bile Duct (EBD) Carcinoma.

According to the current AJCC staging system, the T stage of distal extrahepatic bile duct carcinoma (EBD) is classified according to the extent of the tumor within or beyond the bile duct wall. However many invasive carcinoma accompany stromal desmoplasia that obscure lower boundary of bile duct wall; it is frequently difficult to clearly define the extent of tumors using the current T classification system. In this study, we validated an alternative T classification system by depth of invasion (DoI; T1: < 5  mm, T2: 5 to 12  mm, and T3: ≥ 12  mm). Specifically, we evaluated DoI in 114 cases of distal EBD carcinoma using digital scan images to achieve more objective measurements of tumor DoI. In addition, we evaluated the effect of the number of metastatic lymph nodes (LNs) as well as the number of total examined LNs on the survival rate in the same patient group, and performed a comparative analysis of these data to assess patient survival. We also analyzed 114 cases of distal EBD carcinoma using the current T and N classification of the AJCC staging system (7th edition). The T stage of the current AJCC staging system was not associated with significant differences in patient survival, especially between T2 and T3. However, T staging by DoI was associated with statistically significant differences in patient survival (P < 0.001 in DoI-1, P = 0.002 in DoI-2). With respect to N stage, we divided patients into 3 tiers comprising class 1 (no nodal metastasis), class 2 (1-3 nodal metastases), and class 3 (4 or more nodal metastases). In 3-tier classification analysis, the median survival times for classes 1, 2, and 3 were 79.2, 28.8, and 10.9 months, respectively. The difference in survival among the 3 classes was statistically significant (P < 0.001). We found the cut-off value of 11 LNs (1 to 10 vs  ≥ 11) for N0 stage showed most significant difference (P = 0.007). We think at least 11 LNs should be examined for more accurate evaluation of N stage in distal EBD carcinoma. We propose an alternative T classification using DoI and 3-tier sub-classification of N stage for distal EBD carcinoma.

Clinicopathologic characteristics of 29 invasive carcinomas arising in 178 pancreatic mucinous cystic neoplasms with ovarian-type stroma: implications for management and prognosis.

Information on the clinicopathologic characteristics of invasive carcinomas arising from mucinous cystic neoplasms (MCNs) is limited, because in many early studies they were lumped and analyzed together with noninvasive MCNs. Even more importantly, many of the largest prior studies did not require ovarian-type stroma (OTS) for diagnosis. We analyzed 178 MCNs, all strictly defined by the presence of OTS, 98% of which occurred in perimenopausal women (mean age, 47 y) and arose in the distal pancreas. Twenty-nine (16%) patients had associated invasive carcinoma, and all were female with a mean age of 53. Invasion was far more common in tumors with grossly visible intracystic papillary nodule formation ≥1.0 cm (79.3% vs. 8.7%, P=0.000) as well as in larger tumors (mean cyst size: 9.4 vs. 5.4 cm, P=0.006); only 4/29 (14%) invasive carcinomas occurred in tumors that were <5 cm; however, none were <3 cm. Increased serum CA19-9 level (>37 U/L) was also more common in the invasive tumors (64% vs. 23%, P=0.011). Most invasive carcinomas (79%) were of tubular type, and the remainder (5 cases) were mostly undifferentiated carcinoma (2, with osteoclast-like giant cells), except for 1 with papillary features. Interestingly, there were no colloid carcinomas; 2 patients had nodal metastasis at the time of diagnosis, and both died of disease at 10 and 35 months, respectively. While noninvasive MCNs had an excellent prognosis (100% at 5 y), tumors with invasion often had an aggressive clinical course with 3- and 5-year survival rates of 44% and 26%, respectively (P=0.000). The pT2 (>2 cm) invasive tumors had a worse prognosis than pT1 (≤2 cm) tumors (P=0.000), albeit 3 patients with T1a (<0.5 cm) disease also died of disease. In conclusion, invasive carcinomas are seen in 16% of MCNs and are mostly of tubular (pancreatobiliary) type; colloid carcinoma is not seen in MCNs. Serum CA19-9 is often higher in invasive carcinomas, and invasion is typically seen in OTS-depleted areas with lower progesterone receptor expression. Invasion is not seen in small tumors (<3 cm) and those lacking intracystic papillary (mural) nodules of ≥1 cm, thus making the current branch-duct intraductal papillary mucinous neoplasm management protocols also applicable to MCNs.

Clinical significance of pathologic subtype in curatively resected ampulla of vater cancer.

BACKGROUND: Ampullary cancer is considered to have a better prognosis than cancers of the distal bile duct and pancreas, and recent publications emphasize the prognostic importance of the histologic differentiation of the intestinal and pancreatobiliary types of ampullary cancer. The aims of this study were to identify those factors that affect recurrence after curative resection and to investigate differences between the clinicopathologic features of these two pathologic subtypes. PATIENTS AND METHODS: The medical records of patients that underwent pancreatoduodenectomy for ampullary carcinoma from February 1995 to March 2009 at our institute were retrospectively reviewed. One hundred and four patients that underwent curative resection for ampullary carcinoma were enrolled in this study. One pathologist reviewed all pathologic reports and histopathologic findings. Data on clinicopathologic factors and disease free and overall survival were analyzed. RESULTS: The 3- and 5-year disease free survival rates of the 104 study subjects were 62.2% and 57.7%, respectively, and overall survival rates were 69.4% and 60.1%, respectively. Multivariate analysis showed that an advanced T stage (P = 0.049), the presence of lymph node metastasis (P = 0.003), poor differentiation (P = 0.039), and the pancreatobiliary type (P = 0.022) significantly increased the risk of recurrence. Furthermore, the pancreatobiliary type was found to be more associated with an advanced T stage (P = 0.009), regional lymph node metastasis (P = 0.007), and perineural invasion (P = 0.026) than the intestinal type. In addition, pathologic subtype analysis showed that Carcinoembryonic antigen (CEA) level and lymph node metastasis were important predictors of recurrence in patients with the intestinal (P = 0.013) and pancreatobiliary types, respectively (P = 0.003). CONCLUSIONS: An advanced T stage, nodal metastasis, poor differentiation, and the pancreaticobiliary type were found to be independent predictors of recurrence after curative resection of ampullary carcinoma by multivariate analysis. In addition, the pancreatobiliary type tended to present in a more advanced T stage and more frequently with regional lymph node involvement and perineural invasion than the intestinal type. Furthermore, CEA level and lymph node metastasis were found to be independent predictors of recurrence for the intestinal and pancreatobiliary types, respectively.

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas.

AKT1 signaling pathway is important for the regulation of protein synthesis and cell survival with implications in carcinogenesis. In this study, we explored the prognostic significance of AKT1 pathway in intrahepatic cholangiocarcinomas. We investigated the status of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphorylated (p) AKT1 (p-AKT1), p-mammalian target of rapamycin (p-MTOR), p-p70 ribosomal protein S6 kinase (p-RPS6KB2) and p-eukaryotic initiation factor 4E-binding protein-1 (p-EIF4EBP1) in 101 intrahepatic cholangiocarcinomas by immunohistochemistry. Western blot analysis was performed to verify the expression levels of p-AKT1 and p-MTOR. The relationship of protein expression with clinicopathological data and the correlations of protein expression levels were explored. The overexpression of p-AKT1, p-MTOR, and PTEN was associated with a better survival in patients with intrahepatic cholangiocarcinoma (P=0.0137, 0.0194, and 0.0337, respectively). In a multivariate analysis, PTEN was an independent prognostic factor, and p-AKT1 showed tendency (P=0.032 and 0.051, respectively). The overexpression of p-MTOR was correlated with well-to-moderately differentiated tumors (P<0.001) and tumors without metastasis (P=0.046). Expression levels of the AKT1 signaling pathway proteins in this study showed positive correlations with each other, except for PTEN. Aberrant expressions of p-AKT1 and p-MTOR in intrahepatic cholangiocarcinoma were associated with a favorable prognosis, possibly in a PTEN-independent manner. Our results indicate that dysregulation of the AKT1 pathway may have an important role in the development of intrahepatic cholangiocarcinoma, but not necessarily in the progression of the disease.

Factors affecting long-term survival after surgical resection of pancreatic ductal adenocarcinoma.

PURPOSE: Some patients who undergo surgical resection of pancreatic cancer survive longer than other patients. The purpose of this study was to identify the factors that affect long-term survival after resection of histopathologically confirmed pancreatic ductal adenocarcinoma. METHODS: A single-center, retrospective study was conducted among 164 patients who underwent surgical resection of pancreatic cancer, between May 1995 and December 2004. The patient follow-up process was conducted via telephone survey and review of electronic medical records for at least 5 years or until death. RESULTS: We compared patients with long-term (≥60 months, n = 19) and short-term survival (<60 months, n = 145). Resection margin status, differentiation of the tumor, tumor stage, pre-operative serum level of albumin, total bilirubin and carbohydrate antigen (CA) 19-9 level are related with survival difference (all factors, P < 0.05). Multivariate analysis revealed that a pre-operative serum total bilirubin level <7 mg/dL and a pre-operative serum CA19-9 level <37 U/mL is a statistically significant prognostic factor for long-term survival. CONCLUSION: The preoperative serum total bilirubin and serum CA19-9 levels are associated with long-term survival after surgical resection of pancreatic cancer.

Clinicopathologic analysis of adenosquamous/squamous cell carcinoma of the gallbladder.

BACKGROUNDS AND OBJECTIVES: Adenosquamous/squamous cell carcinoma (AS/SCC) of the gallbladder is rarely encountered and accounts for 1.4-10.6% of all gallbladder carcinomas (GBCs). This study was conducted to investigate the clinicopathologic features of AS/SCC of gallbladder. METHODS: The authors retrospectively reviewed 16 cases of pathologically proven AS/SCC of the gallbladder among 404 patients who underwent surgery for GBC from October 1994 to March 2009. Forty-eight conventional GBC patients were selected as controls after matching for age and gender. RESULTS: Mean patient age was 60.2 years and half were male. Tumor stages in the case group were significantly more advanced than the control group (P < 0.001). R0 resection rates in cases and controls were 50% and 81.2% (P = 0.022). Overall 1-year survival in the case group was significantly poorer than in the control group (18.8% vs. 87.3%, P < 0.001). However, no significant difference in disease-free survival rates was found between cases and controls after R0 resection (P = 0.072). CONCLUSIONS: AS/SCC of the gallbladder is often diagnosed at an advanced stage, which results in non-curative surgical resection and a poorer prognosis than conventional GBC. However, curative surgical resection of AS/SCC of the gallbladder might result in disease-free survival rates that are comparable with those of conventional GBC.

Intraductal papillary neoplasm of the bile duct associated with Clonorchis sinensis infection.

Intraductal papillary neoplasm of bile duct (IPNB) is one of the precursor lesions of cholangiocarcinoma. Although hepatolithiasis has been extensively studied in its association with IPNBs, there had been no comprehensive study of IPNBs with Clonorchis sinensis infection. Twelve IPNBs were selected from 20 surgically resected cholangiocarcinomas, positive for C. sinensis tests (60%) and compared with eight IPNBs, selected from 51 resected cholangiocarcinomas, negative for C. sinensis tests (16%), by histologic and immunohistochemical studies of mucin core proteins and cytokeratin panels. The predominant immuno-phenotype of IPNB cases with Clonorchiasis was pancreatobiliary type (MUC1+/MUC2-/CDX2-; 9/12 cases), while that of IPNB cases with negative for C. sinensis was intestinal type (MUC1-/MUC2+/CDX2+; 6/8; p = 0.04). The prevalence of IPNBs was higher when patients with cholangiocarcinoma had Clonorchiasis. IPNBs with Clonorchiasis tended to have a more pancreatobiliary phenotype, which suggests IPNBs with Clonorchiasis may have a different tumorigenesis pathway from IPNBs with other etiologies.

Intraductal tubular carcinoma of the pancreas: a case report with the imaging findings.

We describe here a case of intraductal tubular carcinoma of the main pancreatic duct. Gadolinium-enhanced pancreas magnetic resonance (MR) imaging showed an enhancing mass that was confined in the dilated main pancreatic duct of the pancreatic body, along with dilatation of the upstream main pancreatic duct and chronic pancreatitis that was due to obstruction. MR cholangiopancreatography and an endoscopic retrograde pancreatogram showed a filling defect that was due to an intraductal mass of the pancreatic body, along with dilatation of the upstream main pancreatic duct and no dilatation of the downstream main pancreatic duct. The pathological findings demonstrated an intraductal nodular appearance without papillary projection or mucin hypersecretion.

Immunohistochemical expression of Sonic hedgehog in intraductal papillary mucinous tumor of the pancreas.

Aberrant expression of Sonic hedgehog (Shh) has been reported in many human cancers including ductal carcinoma of the pancreas. The intraductal papillary mucinous tumor (IPMT) has been considered as one of the precursor lesions of invasive ductal carcinoma of the pancreas. Shh expression in pancreatic IPMT has not been reported. We investigated an immunohistochemical (IHC) expression of Shh in 55 cases of pancreatic IPMT. We analyzed the IHC expression of Shh in the following histologic grades of tumor: adenoma (AD), moderate dysplasia (MD), noninvasive carcinoma (NIC), and invasive carcinoma (IC), and with the following histologic subtype classification: intestinal, pancreatobiliary, null, and unclassifiable type. IHC Shh expression was noted in 6 (46.2%) of 13 AD, 5 (35.7%) of 14 MD, 12 (80%) of 15 NIC, and 11 (84.6%) of 13 IC. Shh expression was significantly increased in malignant IPMT (NIC+IC) compared with nonmalignant IPMT (AD+MD) (82.1% vs. 40.7%, P=0.0005). IHC Shh expression was found in 11 (68.8%) of 16 intestinal types, 13 (92.8%) of 14 pancreatobiliary types, 8 (38.1%) of 21 null types, and 2 (50%) of 4 unclassifiable types. Intestinal and pancreatobiliary subtypes showed a high expression of Shh compared with the null and unclassifiable type of IPMT. All 3 cases of node metastasis showed IHC Shh expression in tumor cells of metastatic lymph nodes. Therefore, Shh expression may have a critical role in the late stage of carcinogenesis of IPMT, and may impact metastatic progression to the lymph nodes in malignant IPMT.