Pathogenesis of carcinoma of the papilla of Vater

Most adenomas and carcinomas of the small intestine and extrahepatic bile ducts arise in the region of the papilla of Vater. In familial adenomatous polyposis (FAP) it is the main location for carcinomas after proctocolectomy. In many cases symptoms due to stenosis lead to diagnosis at an early tumor stage. In about 80%, curative intended resection is possible. Operability is the most relevant prognostic factor. Most ampullary carcinomas resp. carcinomas of the papilla of Vater develop from adenomatous or flat dysplastic precursor lesions. They can be sited in the ampulloduodenal part of the papilla of Vater, which is lined by intestinal mucosa. They also can develop in deeper parts of the ampulla, which are lined by pancreaticobiliary duct mucosa. Intestinal-type adenocarcinoma and pancreaticobiliary-type adenocarcinoma represent the main histological types of ampullary carcinoma. Furthermore, there exist unusual types and undifferentiated carcinomas. Many carcinomas of intestinal type express the immunohistochemical marker profile of intestinal mucosa (keratin 7?, keratin 20+, MUC2+). Carcinomas of pancreaticobiliary type usually show the immunohistochemical profile of pancreaticobiliary duct mucosa (keratin 7+, keratin 20?, MUC2?). Even poorly differentiated carcinomas, as well as unusual histological types, may conserve the marker profile of the mucosa they developed from. These findings underline the concept of histogenetically different carcinomas of the papilla of Vater which develop either from intestinal- or from pancreaticobiliary-type mucosa of the papilla of Vater. Molecular alterations in ampullary carcinomas are similar to those of colorectal as well as pancreatic carcinomas, although they appear at different frequencies. In future studies, molecular alterations in ampullary carcinomas should be correlated closely with the different histologic tumor types. Consequently, the histologic classification should reflect the histogenesis of ampullary tumors from the two different types of papillary mucosa.     

Expression of hedgehog proteins in periampullary cancer]

BACKGROUND/AIMS: Hedgehog protein is an essential molecule for gastrointestinal tract development, and disruption of hedgehog signaling pathway is linked to some gastrointestinal tumorigenesis. Here, we performed hedgehog immunostaining in periampullary cancer to evaluate the differences according to the location type of cancer and the differentiation of adenocarcinoma. METHODS: We retrieved surgical specimens from 43 periampullary cancer patients (15 ampulla of Vater cancer, 12 distal common bile duct cancer, 13 pancreatic head cancer, and 3 combined ampulla of Vater/bile duct cancer). Immunohistochemical stain was performed in both normal and cancerous tissue portions of each case using Sonic hedgehog (H-160) rabbit polyclonal antibody. Immunohistochemical stain results were grouped into three groups according to the percentage of positive cytoplasmic stain in tumor volume (unstained: <5%, weakly stained: 5-50%, and strongly stained: >50%). RESULTS: All of the normal tissue revealed negative immunohistochemical stain while cancerous tissue revealed positivity in 95.3% (41/43 cases). Strongly stained cases were more frequently seen in ampulla of Vater cancers (13/15) and in combined ampulla of Vater/bile duct cancers (3/3) than in distal common bile duct cancers (4/12) and in pancreatic head cancers (3/13) (p=0.002). In addition, strongly stained cases were more frequently seen in well-differentiated adenocarcinoma than the others (p<0.001). CONCLUSIONS: Most of the periampullary cancers show hedgehog protein expression. In addition, hedgehog protein immunostainings shows stronger expression in ampulla of Vater cancers and in well-differentiated adenocarcinoma.     

A case of hepatectomy for liver metastasis after pancreatoduodenectomy for carcinoma of ampulla of Vater]

After curative resection of carcinoma of ampulla of Vater, 5-year survival rate has been reported ranging from 40% to 60%. Two major causes of the treatment failure are local recurrence and liver metastasis. Liver metastases are often multiple and are associated with poor prognosis. There have been few reports on long-term survivors after hepatectomy for metastatic liver tumors from carcinoma of ampulla of Vater. We report a 42 year-old female patient with solitary hepatic metastasis from carcinoma of ampulla of Vater, which was successfully treated by hepatectomy 69 months after curative Whipple's operation. Histologic examination of the resected specimen had revealed stage IB moderately-differentiated, intestinal type adenocarcinoma (T2N0M0). Since neither local recurrence or distant metastasis were detected, the patient underwent liver segmentectomy. Histologic study confirmed the presence of metastatic liver tumor from carcinoma of ampulla of Vater. She is doing well without evidence of recurrence at 20 months after hepatectomy.     

Ampullary carcinoma: prognostic significance of ploidy, cell-cycle analysis and proliferating cell nuclear antigen (PCNA).

BACKGROUND/AIMS: The aim of the present study is to assess the nuclear DNA ploidy patterns, the fraction of cells in the various phases of the cell cycle as determined by flow cytometry and to evaluate Proliferative cell-nuclear antigen (PCNA) expression in order to examine the relationships between phase-two molecular factors, clinicopathological aspects and outcome of patients with cancers of the ampulla of Vater. METHODOLOGY: Paraffin-embedded specimens from 18 cases of cancers of ampulla of Vater radically resected between 1985 and 1995 were analyzed by flow-cytometry and immunohistochemical staining with monoclonal antibody to the PCNA. The relationships between cell-proliferation kinetics, PCNA-positive cancer cells, clinicopathological findings and the clinical course were evaluated. RESULTS: Pathologist reports documented 17 papillary adenocarcinomas and one case of mucinous carcinoma. According to the TNM classification, 4 patients were in stage I, 7 in stage II and 7 in stage III. Locally advanced ampullary tumors (T3-T4) had a significantly worse prognosis (p = 0.01); survival at 3 and 5 years for stage I-II patients (11 cases) was 90% and 79% as compared to 42% and 42% for patients with stage III (8 cases), respectively (p = n.s.). Thirteen cancers (72%) were diploid and 5 (28%) aneuploid. Patients with aneuploid tumors were younger (mean age: 59 years) than patients with diploid tumors (mean age: 66 years; p = 0.04). No significant correlation was found between size of the tumor (T), lymphnodal status (N), grading (G) or aneuploidy. Difference in terms of survival between aneuploid and diploid patients was relevant (16 vs. 121 months) but, due to the small number of cases, was not statistically significant (p = n.s). The mean value of S-phase fraction (SPF) was 14.8%. PCNA positive rate significantly correlates with size of the tumor (T1-T2 vs. T3-T4; p = 0.03). Actuarial overall survival resulted in 70%, 63% and 31% at 1, 5 and 10 years, respectively. The high rate of diploidy (72%) supports the relative benign behavior of ampullary cancers. CONCLUSIONS: PCNA positive rate significantly correlates with size of the disease. Aneuploidy, although without significant prognostic value, correlates well with survival. Because of the wide range of all variables, more data are needed to establish the relationships between pathological factors, DNA ploidy and PCNA rate and their significance as molecular predictors of prognosis in ampulla of Vater cancers.     

Carcinoma of the ampulla of Vater: results of surgical treatment of a single center

BACKGROUND/AIMS: The aim of this study was to retrospectively evaluate our experience with ampulla of Vater tumors at the Creighton University and to establish the role of curative pancreaticoduodenectomy on the long-term survival rate of patients. METHODOLOGY: Between 1975 and 1997, 21 patients (15 M, 6 F) with ampulla of Vater tumors were identified using our tumor registry database. The mean age at diagnosis was 74 years (range 45-85). Family history of other types of cancers was positive in 11 patients. The two most common presenting symptoms were painless jaundice (75%) and abdominal pain (31%). RESULTS: Thirteen patients (62%) underwent curative pancreaticoduodenectomy and eight patients (38%) underwent palliative biliary bypass procedures. Pathological staging of thirteen pancreaticoduodenectomy patients included stage I, 5 patients; stage II, 1 patient; stage III, 2 patients and stage IV, 5 patients. There were nine patients with NO disease and 4 patients with N1 disease. The Kaplan-Meier analysis revealed significant survival benefit for pancreaticoduodenectomy patients (69.9 months) compared to the palliative procedure (4.8 months). Furthermore NO patients had a far better survival (69.9 months) compared to N1 patients (5.9 months) although this difference was not significant. There were no operative mortalities. CONCLUSIONS: Radical surgery such as pancreaticoduodenectomy seems to confirm long-term survival in patients with ampulla of Vater tumors especially when no nodal or distant metastases are present at the time of surgery. An aggressive approach, therefore, in such patients is justifiable.     

Neoplastic diseases of the papilla of Vater

Although it is quite small, the papilla of Vater is an important part of the body. Carcinoma of the papilla may be one of the smallest cancers that can cause death. The 5-year survival rate after resection was 51%, which is not satisfactory. In this article, the topics discussed are (1) pathogenesis, (2) histological characteristics, and (3) the molecular biological characteristics of carcinoma of the papilla of Vater. From results obtained by the investigation of 576 autopsied and 51 resected cases, atypical epithelium was found most frequently in the common channel, where pancreatic juice and bile mix physiologically. Atypical epithelia may be a precursor of carcinoma of the papilla of Vater. Carcinoma of the papilla of Vater could be classified into two types histologically, an intestinal type and a pancreaticobiliary type. The prognosis of patients with the intestinal type was much better than that of patients with the pancreaticobiliary type. These two types of carcinoma should be treated by different operative procedures or adjuvant therapies. Regarding the molecular biological characteristics of carcinoma of the papilla of Vater; (1) K-ras mutation is mainly associated with the intestinal type, and carcinomas of the intestinal and pancreaticobiliary types may develop via different mechanisms; (2) p53 overexpression may play a role in tumor ulceration; and (3) p21/Waf1 overexpression was significantly correlated with a poor prognosis.     

Clinicopathological characteristics of biliary neuroendocrine neoplasms: a multicenter study

Objectives: This study assessed the clinicopathological features, therapeutic approaches, and prognosis of patients with biliary neuroendocrine neoplasm (NENs).

Materials and methods: Multicenter retrospective study of patients with biliary tract NENs in the gallbladder, the extrahepatic bile duct, or the ampulla of Vater between 2005 and 2014.

Results: Total of 43 patients were included in the study. The median age was 62 years (range: 29–84 years) and 58.1% of the patients were male. The tumors occurred in the gallbladder (n?=?11), the extrahepatic bile duct (n?=?5) or the ampulla of Vater (n?=?27). The liver was the most common metastatic site. Based on the 2010 World Health Organization classification, more patients with gallbladder NENs (11/11 (100%)) had neuroendocrine carcinoma G3 than those with NENs in the ampulla of Vater (10/27 (37.1%)). The median progression free survival time (39.3 vs 5.1 months, p?=?0.001) and median overall survival time (46.9 vs 7.9 months, p?<?0.001) were significantly longer in patients with ampulla of Vater NENs than gallbladder NENs. A 2010 World Health Organization classification of neuroendocrine carcinoma G3 was independently related to poor overall survival (hazard ratio (HR), 27.1; 95% confidence intervals (CI), 2.81-260.68; p?=?0.004).

Conclusion: The 2010 World Health Organization classification of neuroendocrine carcinoma G3 was the only factor related to poor prognosis in patients with biliary neuroendocrine neoplasms.     

Does ampullary carcinoma arise from distended glands in the papilla of Vater?

Background/Purpose

Glands near the surface of the papilla of Vater may become distended with mucus and become hyperplastic; that is, become distended. In this study, we tried to clarify carcinogenesis in these distended glands.

Methods

Twenty-nine pancreatoduodenectomized nontumorous duodenal papilla specimens from carcinoma of the pancreas and bile duct and 34 resected ampullary carcinoma specimens were studied histopathologically and immunohistochemically, using cytokeratins and mucin immunohistochemical features/phenotypes.

Results

Distended glands were found in 11 of the 29 pancreatoduodenectomized specimens. These glands were immunopositive for cytokeratin (CK) 7 and MUC-5AC Glycoprotein (MUC5AC), but not for CK20, while the intrapapillary portion was CK7-positive and CK20-negative, but mostly negative for MUC5AC. Immunopositivity for CK7, CK20, and MUC5AC was found in 25, 21, and 18 of the 34 specimens of ampullary carcinoma, respectively. In 23 of the 34 specimens, immunoreactivity for MUC5AC and that for CK7 was coincident, that is, when the former was immunopositive, so was the latter, and vice versa, while in 25 of the 34 specimens, immunoreactivity for MUC5AC was opposite to that for CK20. Among the 23 cases in which immunoreactivity for MUC5AC and CK7 was coincident, 10 were MUC5AC+, CK7+, CK20? and 7 were MUC5AC?, CK7?, CK20+, suggestive of disease arising from the pancreaticobiliary mucosa or the distended glands in the former and disease arising from the duodenal mucosa in the latter. In MUC5AC+ cases, other than the 10 cases of MUC5AC+, CK7+, CK20?, 6 were double-positive and 1 was double-negative for CK7 and CK20, and 1 was CK20-positive, and at least 1 case showing double-negativity for CK7 and CK20 was suggestive of disease arising from the distended glands.

Conclusions

Although most ampullary carcinomas arise from the duodenal mucosa or intra-ampullary mucosa, both CK7-positive and MUC5AC-positive or only MUC5ACpositive ampullary carcinomas may arise from the distended glands.

     

Small-cell neuroendocrine carcinoma of the ampulla of Vater

We report a patient (an 80-year-old woman) with anemia and fecal occult blood, who had an emergency operation for carcinoma of the cecum (well-differentiated adenocarcinoma without local lymph node metastasis). Postoperative magnetic resonance cholangiopancreatography, cholangiography, and upper gastroduodenal endoscopy showed a tumor of the ampulla of Vater, and pylorus-preserving pancreatoduodenectomy was performed. Histology of the resected tumor was that of small-cell carcinoma, and immunohistochemistry showed positive staining for neuron-specific enolase, chromogranin A, and synaptophysin, confirming the neuroendocrine nature of the tumor. As the histology of the tumor was distinct from cecal carcinoma, and no tumors were found in other organs, the tumor was diagnosed as primary small-cell neuroendocrine carcinoma of the ampulla of Vater. The patient died due to multiple liver metastases of the carcinoma of the ampulla of Vater 7 months after the pancreatoduodenectomy. The clinical and morphological features of this disease have been reported in nine individuals previously.     

Primary acinar cell carcinoma of the ampulla of Vater

Acinar cell carcinoma of the pancreatobiliary system is a relatively rare malignant neoplasm arising usually in the pancreatic parenchyma. We experienced a 68-year-old woman who presented with obstructive jaundice due to an ampullary mass 1.0 cm in diameter, detected by abdominal computed tomography and endoscopic examination. The patient underwent a curative surgical operation, and histopathological examination revealed that the tumor was confined to the ampulla of Vater with no continuity to the pancreatic parenchyma. The tumor cells showed acinar or tubular arrangement with eosinophilic to basophilic granular cytoplasm, findings identical to those of acinar cell carcinoma of the pancreas. Immunohistochemically, the tumor cells were positive for lipase. From these findings, we concluded that the tumor was primary acinar cell carcinoma arising in the ampulla of Vater, probably originating from heterotopic pancreatic tissue. This is the first reported case of primary acinar cell carcinoma in the ampulla of Vater.     

Immunohistochemical study of mucin expression in periampullary adenomyoma

Background/purpose

Benign tumors and tumor-like conditions in the ampullary area are uncommon, and there are extremely rare cases of adenomyoma (AM) and adenomyomatous hyperplasia (AMH). Surgical treatment is necessary if these lesions cause biliary obstruction. In addition, the differential diagnosis of AM and AMH from carcinoma is often difficult by standard endoscopic biopsy and cytopathological analysis that may show differential findings, resulting in unnecessary surgeries sometimes being performed.

Methods

Immunohistochemical (IHC) analysis of periampullary AM and AMH was performed.

Results

For both types of lesions, epithelial glandular cells (EGCs) showed diffuse expression of MUC6 and focal expression of HIK1083, mainly in the inner region, and focal expression of MUC5AC, mainly at the surface. The EGCs showed no expression of MUC1 or MUC4, both of which were identified as malignant tumor markers in our previous series of mucin expression studies in pancreatobiliary tumors. The expression of CK7, which was diffusely positive in normal periampullary mucosa, was decreased in the EGCs of AM and AMH.

Conclusions

A combined evaluation of IHC findings may be effective in the detection of AM and AMH, and also in distinguishing benign periampullary lesions, such as AM and AMH, from ampulla of Vater adenocarcinoma, thus avoiding excessive surgery.     

Diagnostic utility of GLUT1 in the differential diagnosis of liver carcinomas

BACKGROUND/AIMS: Malignant cells require high energy via glycolytic generation of ATP for cell proliferation and survival. This process is thought to be mediated by glucose transporters (GLUTs). GLUT1 appears to be expressed aberrantly in many cancers. The liver is the main organ closely related to glycogen metabolism and it is thought that GLUT expression might be altered in the tumors arising in the liver. METHODOLOGY: We studied GLUT1 expression in 22 hepatocellular carcinomas (HCC) and 16 cholangiocarcinomas (CC) and compared it to the expression of hepatocyte specific antigen (HSA) and cytokeratin 19 (CK19) by immunohistochemical studies. RESULTS: In HCC, GLUT1 was expressed in 4.5% (1/22), HSA in 77.3% (17/22) and CK19 in none (0/22). In CC, GLUT1 was expressed in 81.3% (13/16), HSA in none (0/16) and CK19 in 100% (16/16). Interestingly, GLUT1 was not expressed in normal hepatocytes and bile duct epithelium around the tumor, whereas CK19 was expressed in normal bile ducts and tumor cells. CONCLUSIONS: These results indicate that GLUT1 might be related to development of bile duct carcinoma and its expression was a more reliable marker for detection of bile duct carcinoma than CK19. Additionally, GLUT1 might potentially be useful as a means of distinguishing CC from HCC.     

Signet-ring cell carcinoma of ampulla of Vater： Contrast-enhanced ultrasound findings

Signet-ring cell carcinoma （SRCC） of ampulla of Vater is extremely uncommon, and less than 15 cases have been reported so far in literature. It mainly occurs in elderly people （median age 57 years）. We report a rare case of SRCC of the ampulla of Vater in a 38-year-old woman who presented with a small tumor at the Vater, discovered by the contrast-enhanced ultrasound （CEUS）. Histopathological examination showed prominent signet-ring features. We also describe the imaging features of SRCC of ampulla of Vater in CEUS.     

Histamine-producing neuroendocrine tumor of the ampulla of Vater

Neuroendocrine tumors of the ampulla of Vater are rare (less than 100 cases reported). We report here a new case characterized by histamine secretion, a hitherto unreported feature. Clinical presentation is similar to that of other tumors of the ampulla of Vater. In our observation, the patient had noticed urticaria on the right forearm for several months. Tumor of the ampulla was confirmed by endoscopic ultrasonography, while neuroendocrine characterization was assessed on biopsies after endoscopic sphincterotomy. Histamine concentration in blood was the only elevated neuroendocrine marker and returned to normal after surgical resection. Histology showed a neuroendocrine tumor with extension to lymph nodes. On immunohistochemical analysis, production of histamine was confirmed, and the diagnosis of mastocytoma was eliminated. In view of the literature, neuroendocrine tumors of the ampulla of Vater are associated with a good prognosis (5 year-survival rate: 90%) despite early lymph node involvement.     

Carcinoid of the ampulla of Vater

Endocrine neoplasms only rarely occur at the ampulla of Vater, comprising mostly carcinoids and malignant carcinoids, as well as few cases of poorly differentiated endocrine carcinomas (small cell carcinomas). Only 105 cases are reported in the literature, most as single case reports. For many years, the neoplasms of the disseminated neuroendocrine cell system of the gastrointestinal tract have been subsumed as 'carcinoids'. Instead, in the latest World Health Organization (WHO) classification published in 2000, it is recommended to distinguish between (i) well-differentiated endocrine tumors (carcinoids); (ii) well-differentiated endocrine carcinomas (malignant carcinoids); and (iii) poorly differentiated endocrine carcinomas (small cell carcinomas). Patients with carcinoid tumors of the ampulla of Vater are very often free of clinical and laboratory findings that belong to the carcinoid syndrome. Approximately 26% of all patients with carcinoid tumor reported in the literature had neurofibromatosis. Besides endoscopic retrograde cholangiopancreatography, endosonography, computed tomography or magnetic resonance imaging may complete the staging approach of this tumor. The Kausch-Whipple procedure or pylorus-preserving pancreaticoduodenectomy is considered the treatment of choice for ampullary, well-differentiated carcinoids >2.0 cm and for ampullary neuroendocrine carcinomas. However, it should be considered that long-term survival of patients with ampullary carcinoids is also reported after local tumor excision (5-year survival rate of 90%). The dilemma is that the differentiation of neuroendocrine tumors cannot be assessed intraoperatively in most cases. Therefore, considering that the 5-year survival rate in patients with neuroendocrine carcinomas of the ampulla of Vater is very low without radical resection, neuroendocrine tumors of the ampulla of Vater without definite histological differentiation should undergo extended surgery.     

Tumorigenesis and phenotypic characteristics of mucin-producing bile duct tumors: an immunohistochemical approach

Intraductal papillary neoplasm of the bile duct (IPNB) is characterized by exophytic proliferation of neoplastic epithelial cells with fibrovascular stalks in bile duct lumen, mucin hypersecretion, and considerable dilatation or multilocular changes of the affected bile ducts. A mucin-producing bile duct tumor is an IPNB with excessive mucin production and clinical symptoms. Herein, the phenotypes as well as the tumorigenesis and progression of IPNB are reviewed with immunohistochemical assistance. The tumors are subdivided into three phenotypes: pancreatobiliary, intestinal, and gastric. About half of IPNB cases are of the pancreatobiliary type, and the remaining half are of the intestinal type. Aberrant expression of CDX2 with MUC2 and CK20 is related to the development of intestinal metaplasia. Inactivation of P16INK4a and nuclear expression of β-catenin are related to the development of IPNB. Decreased expression of membranous β-catenin and E-cadherin and aberrant expression of MMP-7 and -9 and of MUC1 are related to invasion of IPNB with tubular adenocarcinoma, whereas MUC2 is involved in the invasion of IPNB with mucinous carcinoma. IPNB can be regarded as a counterpart of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, particularly the main duct type. More comparative studies between IPNB and pancreatic IPMN are recommended for further analysis of these papillary neoplasms.     

Characterization of intrahepatic cholangiocarcinoma of the intraductal growth-type and its precursor lesions

A cohort of patients with intraductal growth-type intrahepatic cholangiocarcinoma (IG-ICC) and its precursor lesions, collectively termed intraductal papillary neoplasm of the liver (IPNL), was characterized with respect to demographics, clinical manifestations, perioperative management, long-term survival, and molecular features associated with carcinogenesis. A total of 122 patients with IPNL types 1 through 4, 108 patients with non-IG-ICC and 210 patients with hepatolithiasis alone were studied. Expression of CDX2, TFF1, MUC1, MUC2, MUC5AC, EGFR, and p53 was determined by using immunohistochemistry. Females predominated in those with hepatolithiasis alone and IPNL. The mean age of patients with hepatolithiasis alone was 6 to 8 years younger than that of those with IPNL. The association with hepatolithiasis in patients with IPNL types 1 and 2, IPNL types 3 and 4, and non-IG-ICC was 100%, 79%, and 64%, respectively. Mucobilia, anemia, and elevated serum carcinoembryonic antigen levels were helpful in distinguishing IG-ICC and its precursor lesions. The mean survival of patients with IPNL type 3, IPNL type 4, and non-IG-ICC was 55.5 months, 36.9 months, and 15.8 months, respectively. The incidence of expression of CDX2 and TFF1 was maximal in IPNL type 3. Expression and cellular distribution of MUC2 and CDX2 were similar. MUC5AC was strongly expressed in all patients with IPNL; EGFR and p53 were rarely expressed in patients with IPNL. In conclusion, hepatolithiasis appears to be a precipitating factor in the development of IPNL. Signs of mucobilia were specific for the diagnosis of IPNL. Expression of CDX2 and MUC2 are helpful in differentiating IPNL and non-IG-ICC. Significant differences in survival associated with the various lesions studied warrants a more aggressive surgical strategy in their management.     

p53 and p21/Waf1 protein expression and K-ras codon 12 mutation in carcinoma of the papilla of Vater

OBJECTIVE: There have been few studies on the molecular biological characteristics of carcinoma of the papilla of Vater. In this study, p53 and p21/Waf1 expression and K-ras codon 12 mutation in carcinoma of the papilla of Vater were investigated. METHODS: Thirty-seven cases of carcinoma of the papilla of Vater were studied. Macroscopically, the carcinoma was ulcerative in 15 cases and nonulcerative in 22 cases. Histologically, nine were intestinal type, 27 were pancreaticobiliary type, and one was undifferentiated. Formalin-fixed, paraffin-embedded sections were immunohistochemically stained for p53 and p21. K-ras codon 12 mutation was detected with the two-step polymerase chain reaction-restriction fragment length polymorphism method, followed by direct sequencing. RESULTS: p53 overexpression was found in 17 of 37 cases (46%) and was more frequent in the ulcerative type than in the nonulcerative type (67% vs 32%, p < 0.05). p21/Waf1 protein expression was found in 15 of 37 cases (41%), and was not correlated with that of p53. K-ras codon 12 mutation was found in 14 of 37 cases (38%), and was more frequently detected in the intestinal type than in the pancreaticobiliary type (66% vs 30%, p < 0.05). On direct sequencing, the mutations were mainly GGT to GAT (9/14) and GGT to GTT (4/14). The type of mutation did not correlate with the histological type. CONCLUSIONS: In carcinoma of the papilla of Vater, p53 overexpression may play a role in tumor ulceration. p21/Waf1 expression is induced via a p53-independent pathway. Carcinomas of the intestinal and pancreaticobiliary types may develop via different mechanisms, and K-ras mutation is mainly associated with the intestinal type.     

KL-6 mucin expression in carcinoma of the ampulla of Vater： Association with cancer progression

AIM: To assess histochemical expression of KL-6 and its clinicopathological significance in carcinoma of the ampulla of Vater. METHODS: Ampullary carcinoma tissues were collected from 38 patients who underwent pancreatoduodenectomy or local resection. Tissues were subjected to immunohistochemical analysis using KL-6 antibody. RESULTS: Positive staining of ampullary carcinoma cells was observed in 26 (68.4%) cases. Staining was not found in the surrounding non-cancer regions of the ampullary tissues. Remarkable KL-6 expression was observed in invasive carcinoma cells in pancreatic and duodenal tissues and in metastatic carcinoma cells in lymph nodes. Positive KL-6 expression was related to lymph node metastasis (P=0.020), pancreatic invasion (P=0.016), duodenal invasion (P= 0.034), and advanced stage of TNM clinical classification (P=0.010). Survival analysis showed that positive expression of KL-6 was related to a poorer prognosis (P=0.029). CONCLUSION: The aberrant expression of KL-6 mucin is significantly related to unfavorable behaviors of carcinoma of the ampulla of Vater.     

Proposed indications for limited resection of early ampulla of Vater carcinoma: clinico-histopathological criteria to confirm cure

Background

Limited resection is reserved for patients with high operative risk or benign adenomas. We aimed to define indications for limited resection of early ampulla of Vater carcinoma with curative intent through detailed preoperative examinations and histopathological evaluations.

Methods

We performed a retrospective cohort study of all consecutive Japanese patients who underwent resection for ampulla of Vater neoplasms at our hospital from 1986 to 2010.

Results

A total of 75 patients were identified. Moderately/poorly differentiated histology, lympho-vascular/perineural invasion, and duodenal/pancreatic invasion were significant risk factors for lymph node metastases. Macroscopically, non-exposed protruded- or ulcerative-type disease did not correlate directly with lymph node metastases; however, these tumor types were associated with other invasive features. In a subset of early carcinomas fulfilling the conditions of exposed protruded adenoma or papillary/well-differentiated adenocarcinoma determined by endoscopic biopsy, negative duodenal invasion determined by endoscopic ultrasonography, no tumor infiltration into the pancreatic duct determined by intraductal ultrasound, and diameter of the pancreatic duct ≤3?mm determined by endoscopic retrograde cholangiopancreatography (N?=?11), the incidence of lymph node metastasis and tumor infiltration into the pancreatic duct was 0%.

Conclusion

Strictly selected patients with early ampulla of Vater carcinomas may benefit from limited resection if the resected specimen is evaluated to confirm all histopathological criteria.