Aberrant p16(INK4A) and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma.

BACKGROUND AND AIMS: Intraductal papillary mucinous tumours (IPMT) of the pancreas constitute a unique pathological entity with an overall incidence of associated invasive malignancy of 20%. The malignant potential of an individual IPMT cannot be accurately predicted. Preoperative estimation of the risk of associated invasive malignancy with IPMT would be of significant clinical benefit. As aberrations in cell cycle regulatory genes are associated with the progression of precursor pancreatic ductal lesions to invasive adenocarcinoma, we examined expression of key cell cycle regulatory genes in the cyclin D1/retinoblastoma pathway and the transforming growth factor beta/Smad4 signalling pathway in a cohort of patients with surgically resected IPMT. METHODS: Sections of formalin fixed paraffin embedded pancreatic tissue from a cohort of 18 patients with IPMT were examined using immunohistochemistry for protein expression of cell cycle regulatory genes p16(INK4A), p21(CIP1), p27(KIP1), cyclin D1, pRb, and p53, as well as the cell signalling molecule Smad4. A comparison of expression levels was made between adenoma/borderline IPMT (10 patients) and intraductal papillary mucinous carcinoma (IPMC) (eight patients, four of whom harboured invasive carcinoma). Statistical analysis was performed using the chi(2) and Fisher's exact tests. RESULTS: Aberrant expression of the proteins examined increased in frequency from adenoma/borderline IPMT to IPMC. Specifically, there was a significantly greater incidence of loss of p16(INK4A) expression in IPMC: 8/8 lesions (100%) compared with 1/10 (10%) adenoma/borderline IPMT (p<0.001). Similarly, loss of Smad4 expression was associated with IPMC: 3/8 (38%) versus adenoma/borderline IPMT 0/10 (p<0.03). Loss of Smad4 expression within the IPMT was the best marker for the presence of invasive carcinoma (p<0.001). CONCLUSIONS: These data indicate that loss of p16(INK4A) and Smad4 expression occur more frequently in IPMC alone, or with associated invasive carcinoma, compared with adenoma/borderline IPMT. Aberrant protein expression of these cell cycle regulatory genes in IPMT and pancreatic intraepithelial neoplasia in the current model of pancreatic cancer progression suggest similarities in their development and may also represent the subsequent risk of invasive carcinoma.

Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia.

Pancreatic cancer (PC) is thought to develop through a series of duct lesions termed pancreatic intraepithelial neoplasia (PanIN). Characterization of the molecular pathology of these lesions may lead to additional understanding of pancreatic ductal carcinogenesis. We examined the protein expression of four functionally related genes, p21(WAF1/CIP1) (CDKN1A), p53, cyclin D1 (CCND1), and DPC4/Smad4 (MADH4), aberrations of which are associated with PC, within 451 PanIN lesions present in the pancreata of 60 patients. p21(WAF1/CIP1) overexpression was present in the normal ducts of 9% of patients and increased progressively to 16% of patients with PanIN-1A lesions, to 32% of patients with PanIN-1B lesions, 56% of patients with PanIN-2 lesions, 80% of patients with PanIN-3 lesions, and 85% of patients with invasive carcinomas (P < 0.01). p53 and cyclin D1 overexpression occurred predominantly in PanIN-3 lesions (P < 0.01), and loss of DPC4/Smad4 expression occurred predominantly in PanIN-3 lesions and invasive carcinoma (P < 0.01). In addition, p21(WAF1/CIP1) overexpression occurred independently of p53 and DPC4/Smad4 expression within invasive carcinoma and PanIN-3 lesions. Cyclin D1 overexpression or loss of DPC4/Smad4 expression was apparent in 85% of invasive carcinomas but in only 14% of PanIN-2 lesions. These data demonstrate that overexpression of p21(WAF1/CIP1) occurs early in the development of PanIN, before aberrations in p53, cyclin D1, and DPC4/Smad4 expression. p21(WAF1/CIP1) overexpression, independent of p53 and/or DPC4/Smad4 expression, may reflect increased Ras activity, either directly through activating K-ras mutations or as a consequence of HER-2/neu (ERBB2) overexpression, both of which are common in PC and in early events in the development of PanIN. These data support further the current progression model for PC and demonstrate that aberrant expression of key cell cycle regulatory genes may be important in the early development and progression of PanIN.

Laparoscopic intraperitoneal foreign body from adhesive drapes.

The present paper reports three cases where portions of adhesive drape were drawn into the peritoneal cavity during cannula insertion. If adhesive drapes are used it is recommended that generous skin incisions be made to avoid this complication.

Incidence of deep vein thrombosis after laparoscopic vs minilaparotomy cholecystectomy.

OBJECTIVES: To determine the frequency of deep vein thrombosis (DVT) associated with minimally invasive cholecystectomy and to determine, using minilaparotomy cholecystectomy as a control operation, the influence of the laparoscopic pneumoperitoneum on DVT formation. DESIGN: Prospective nonrandomized control trial. SETTING: Tertiary care university hospital. PATIENTS: One hundred consecutive patients intended to undergo either laparoscopic cholecystectomy (59 patients) or minilaparotomy cholecystectomy (41 patients) with either of 2 surgeons were prospectively enrolled between April 1996 and April 1997. The minilaparotomy cholecystectomy group served as controls to isolate the effect of the pneumoperitoneum. Patient details, operative details, and any thromboembolic or bleeding complications were recorded. The same thromboprophylaxis regimen was prescribed for each group; namely, preoperative and postoperative subcutaneous low-molecular-weight heparin (LMWH), graduated compression stockings, and intraoperative intermittent calf compression. INTERVENTION: Minimally invasive cholecystectomy. MAIN OUTCOME MEASURE: Frequency of DVT. Bilateral lower limb venous color duplex scanning was used to detect DVT. Scans were performed on 3 occasions: (1) preoperatively on admission to hospital, (2) on the first postoperative day, and (3) between 2 and 4 weeks postoperatively. RESULTS: Three patients in the laparoscopic group and 2 patients in the minilaparotomy group underwent conversion to conventional open cholecystectomy. There were no significant differences between patients in the 2 groups for age, sex, body mass index, preoperative white blood cell count, platelet count, prothrombin time, or activated partial thromboplastin time. There were no significant differences between the 2 groups for elective vs emergency operations, public hospital vs private hospital admissions, or consultant vs resident surgeon. Macroscopic gallbladder pathology grades for both groups were not significantly different, and there was no significant difference in the duration of postoperative hospital stay. Operative cholangiography was performed in a significantly larger proportion of laparoscopic cases (86% vs 66% in the minilaparotomy group; chi(2) test, P=.002), and the duration of anesthesia was significantly longer for the laparoscopic operation (118 minutes vs 98 minutes; t test, P=.05). Ninety-seven patients received preoperative LMWH and all patients received graduated compression stockings, intraoperative intermittent calf compression, and postoperative LMWH. Two of the 100 patients had postoperative DVT, 1 after laparoscopic cholecystectomy and 1 after minilaparotomy cholecystectomy. Both DVTs were detected by duplex examination on the first postoperative day. The DVT found after laparoscopic cholecystectomy was in 1 of the 3 patients who did not receive preoperative LMWH. There were no DVTs in any of the 40 patients who had an additional duplex scan between 2 and 4 weeks after operation. CONCLUSIONS: Despite the theoretical risk of thromboembolic disease due to use of the laparoscopic pneumoperitoneum, the frequency of DVT after either laparoscopic cholecystectomy or minilaparotomy cholecystectomy is low if adequate thromboprophylaxis is provided.

Inflammatory pseudotumour of the spleen.

Inflammatory pseudotumours are benign tumour-like masses of unknown aetiology that show microscopically a range of inflammatory and reactive responses and are of importance because they may be mistakenly identified as neoplasms. This case report describes a 15 year old girl with a cystic inflammatory pseudotumour of the spleen in whom a partial splenectomy was performed with a satisfactory outcome.