Alain Sauvanet

Obesity and Fatty Pancreatic Infiltration Are Risk Factors for Pancreatic Precancerous Lesions (PanIN)

Purpose: The roles of intravisceral and subcutaneous fat are unknown, and the prevalence of precancerous lesions in obese patients was never evaluated. This study aims to assess the frequency and severity of pancreatic intraepithelial neoplasia (PanIN) and to correlate pathologic findings with metabolic abnormalities, type of fat, and fatty pancreatic infiltration. Experimental Design: Normal pancreatic tissue from surgical specimens was analyzed. Fatty infiltration and fibrosis in intra- and extralobular locations and PanIN lesions were assessed. General characteristics were collected: body mass index (BMI), diabetes, and tobacco intake. Liver steatosis and subcutaneous and intravisceral fat were assessed by CT scan (ImageJ software). Results: Of note, 110 patients were included [median age, 53.8 (17–85) years]. Arterial hypertension, diabetes, and tobacco intake were found in 19%, 9%, and 23%, respectively. Median BMI was 24 (16–37; BMI < 25: 45%, 25 ≤ 30: 24%, ≥30: 11%). Overall, PanIN lesions were found in 65% (type I, II, and III PanIN in 62%, 38%, and 1%, respectively). Fibrosis and fatty pancreas (intra- and extralobular locations) were found in 1% and 24% and in 30% and 51%, respectively. A correlation was observed between PanIN lesions and fatty pancreas [extralobular (0.01) and intralobular (<0.0001)], intralobular fibrosis (0.003), high BMI (P = 0.02), and subcutaneous (P = 0.02) and intravisceral fat (P = 0.02). The number of PanIN lesions was correlated with intravisceral fat (r = 0.22, P = 0.04), but not with subcutaneous fat (r = 0.14, P = 0.22). In multivariate analysis, PanIN lesions were associated with intralobular fibrosis [OR, 5.61; 95% confidence interval (CI), 1.18–42.99] and intralobular fat (OR, 17.86; 95% CI, 4.935–88.12). Conclusions: Obesity (especially android obesity) and pancreatic fatty infiltration are risk factors for pancreatic precancerous lesions. Clin Cancer Res; 21(15); 3522–8. ©2015 AACR. See related commentary by Wang et al., p. 3369

Reappraisal of Central Pancreatectomy A 12-Year Single-Center Experience

IMPORTANCE Central pancreatectomy, as an alternative to standard resection for benign and low-grade pancreatic neoplasms, has been described in mainly small retrospective series. OBJECTIVE To describe a large single-center experience with central pancreatectomy. DESIGN, SETTING, AND PARTICIPANTS A retrospective case series in a tertiary referral center included 100 consecutive patients undergoing central pancreatectomy with pancreaticogastrostomy from January 1, 2000, to March 1, 2012. MAIN OUTCOMES AND MEASURES Surgical indications, postoperative morbidity, mortality, and long-term outcomes regarding pancreatic function and recurrence. RESULTS Central pancreatectomies were performed mainly for neuroendocrine tumors (35%), intraductal papillary mucinous neoplasms (33%), solid pseudopapillary neoplasms(12%), and mucinous cystadenomas (6%). The postoperative mortality rate was 3% (due to pulmonary embolisms in 2 patients and hemorrhage after pancreatic fistula in 1 patient). Clavien-Dindo III or IV complications occurred in 15%of patients and were due mainly to pancreatic fistula, requiring 10 radiologic drainage procedures, 7 endoscopic procedures, and 6 reoperations overall. After a median follow-up of 36 months, the rates of new-onset exocrine and endocrine insufficiency were 6%and 2%, respectively. Overall, 7 lesions could be considered undertreated, including 3 node-negative R0 microinvasive intraductal papillary mucinous neoplasms (without recurrence at 27, 29, and 34 months) and 4 node-positive neuroendocrine tumors (with 1 hepatic recurrence at 66 months). Among the 25 patients with a doubtful preoperative diagnosis, 9 could be considered over treated (ie, operated on for benign non evolutive asymptomatic lesions). CONCLUSIONS AND RELEVANCE Central pancreatectomy is associated with an excellent pancreatic function at the expense of a significant morbidity and a non-nil mortality rate,underestimated by the published literature. The procedure is best indicated for benign or low-grade lesions in young and fit patients who can sustain a significant postoperative morbidity and could benefit from the excellent long-term results.

Can pancreatic neuroendocrine tumour biopsy accurately determine pathological characteristics

BACKGROUND Assessment of the pathological characteristics of pancreatic neuroendocrine tumours is crucial for appropriate management. We compared preoperative pathological data with surgical specimens for accuracy. METHODS Surgical patients with pancreatic neuroendocrine tumours who underwent preoperative endoscopic ultrasound-guided fine needle aspiration of the primary tumour or biopsy of liver metastasis were retrospectively included. Tumour differentiation and the Ki67 proliferation index on biopsies were compared with pancreatic specimens. RESULTS Fifty-seven patients were included. A preoperative biopsy of the primary tumour or of a liver metastasis was obtained in 48 and 9 patients respectively. Tumour differentiation was high in 98%, and poor in 2% on biopsy and high in 100% of surgical specimens. Ki67 index values were 0 (0-19) and 2 (0-15) on biopsy and surgical specimens (p=0.01). Correlation between preoperative and surgical findings was stronger for liver (r=0.62, p=0.001) than for pancreas (r=0.23, p=0.11). Correlation for pancreas varied according to the tumour pattern: solid (r=0.24, p=0.16), mixed (r=0.91, p=0.0036) or cystic (r=0.04, p=0.89). Tumour grade was different between pancreatic biopsies and surgical specimens, for grade 1 (63% vs 37%) and grade 2 (28% vs 72%), p=0.0007. CONCLUSIONS Tumour grade assessment is accurate in biopsies of liver metastases of pancreatic neuroendocrine tumours, while pancreatic fine-needle aspiration biopsies are less accurate.

Lessons From McCune-Albright Syndrome-Associated Intraductal Papillary Mucinous Neoplasms GNAS-Activating Mutations in Pancreatic Carcinogenesis

GNAS-activating mutations are reported in intraductal papillary mucinous neoplasms (IPMNs) and in McCune-Albright syndrome, characterized by fibrous dysplasia, precocious puberty, and café au lait spots. Recently, IPMNs have been described as a McCune-Albright syndrome-associated tumor, present in about 15% of patients. The aim of the present work was to assess the prevalence of polyostotic fibrous dysplasia and McCune-Albright syndrome among patients operated on for presumptive sporadic IPMNs. All patients operated on for IPMNs between January 1, 2007, and December 31, 2012, with available imaging were retrospectively screened for polyostotic fibrous dysplasia based on their preoperative abdominal or thoracoabdominal spiral computed tomography images. Systematic screening of 272 patients operated on for IPMNs revealed 1 patient with axial and peripheral polyostotic fibrous dysplasia and café au lait spots on clinical examination suggestive of McCune-Albright syndrome. This patient had been operated on for an unusually large invasive colloid adenocarcinoma (pT3N0M0 R0) derived from an intestinal subtype GNAS-mutated IPMN. The patient underwent adjuvant chemotherapy with gemcitabine for 6 months and was alive without recurrence 6 years later. Besides providing additional evidence of a syndromic IPMN as a feature of McCune-Albright syndrome, this observation is further evidence of the functional oncogenic consequences of GNAS mutations in the pancreas.

Early biliary complications following pancreaticoduodenectomy: prevalence and risk factors

BACKGROUND Early biliary complications (EBC) following pancreaticoduodenectomy (PD) are poorly known. This study aimed to assess incidence, predictive factors, and treatment of EBC including bilio-enteric stricture, transient jaundice, biliary leak, and cholangitis. METHOD From 2007 to 2011, 352 patients underwent PD. Statistical analysis including logistic regression was performed to determine EBC predictive factors. RESULTS 49 patients (14%) developed 51 EBC, including 7(2%) bilio-enteric strictures, 15(4%) transient jaundices, 9(3%) biliary leaks, and 20(6%) cholangitis with no mortality and a 18% reoperation rate. In multivariate analysis, male gender, benign disease, malignancy with preoperative chemoradiation, and common bile duct (CBD) diameter ≤ 5 mm were predictive of EBC. Of the 7 strictures, all were associated with CBD ≤ 5 mm and 5(71%) required reoperation. Transient jaundice resolved spontaneously in all 15 cases. Among 8 patients with serum bilirubin level > 50 μmol/L (3 mg/dL) at POD3, 7(88%) developed bilio-enteric stricture. Biliary leak resolved spontaneously in 5(56%); otherwise, it required reoperation. Cholangitis recurred after antibiotics discontinuation in 5(25%). CONCLUSIONS EBC following PD do not increase mortality. EBC are more frequent with male gender, benign disease, malignancy with preoperative chemoradiation, and CBD ≤ 5 mm. Transient jaundice or cholangitis has a favorable outcome, whereas bilio-enteric stricture or biliary leak can require reintervention.

Hypoxia pathways and cellular stress activate pancreatic stellate cells: development of an organotypic culture model of thick slices of normal human pancreas.

Pancreatic stellate cells (PSC) are involved in fibrogenesis and oncogenesis by modulating the extracellular matrix. Aim To evaluate the effect of cellular stress on PSC activation using a model of normal human pancreatic tissue slices culture preserving the microenvironment. Methods Thin sections (300μm) of normal human pancreas were cultured under hyperoxia (90% O2) during 72 hours. Viability and morphological analysis were performed at baseline, H24, H48 and H72. Cell differentiation (insulin, trypsin, CA9 and CK7), hypoxia (HIF1-α), apoptosis (caspase-3), proliferation (Ki67), TGF-β expression and PSC activation (smooth muscle actin (SMA), nestin) were assessed using immunostaining, longitudinally. Control experiments were performed under normoxic conditions (21% O2). Results Thirty sections per specimen (n=10) were cultured. Hypoxia pathways were activated by the higher expression of HIF1-α at H48 and H72. Apoptosis was limited with only rare acinar cells expressing of the caspase-3 at 48 and H72 (NS). Morphological analysis showed gradual appearance of acinoductal metaplasia, proven by CK7 expression and ductal phenotype of dedifferentiated acini. Transdifferentiation of PSC was shown by de novo SMA immunochemistry at H24 and H48. Expression of Ki67 index identified significant proliferation of activated PSC (double immunostaining Ki67-SMA) at H48 and H72 (p=0.02). In vitro culture of normal human pancreas thin sections is feasible with optimized cell viability at 72 hours. This model of culture in hyperoxic conditions provides evidences that cellular stress may rapidly induce transactivation of PSC with ducto-acinar metaplasia.

Familial intraductal papillary mucinous neoplasms of the pancreas

UNLABELLED The prevalence of intraductal papillary mucinous neoplasms in patients with a high risk of pancreatic adenocarcinoma was estimated to be 15%. However, a familial form of intraductal papillary mucinous neoplasms was never described. METHODS Three families (8 patients) with intraductal papillary mucinous neoplasms familial forms were described. Diagnosis was made according to radiological criteria and was confirmed by pathological data. Genetic predisposing factors of pancreatic cancer were searched for. RESULTS Symptoms related to intraductal papillary mucinous neoplasms were recurrent acute pancreatitis (n=3) or fortuitous discovery (n=5). Number of cystic lesions was ≤3 (n=4) or >3 (n=4). Intraductal papillary mucinous neoplasms involved branch ducts (n=7) or both main pancreatic duct and branch duct (n=1). Severe and moderate dysplasia was found on surgical specimens. No genetic alteration was found (BRCA2, p16 or CDKN2A genes). CONCLUSION A familial form of intraductal papillary mucinous neoplasms was found in three families. No pancreatic cancer was found in relatives but an attentive survey has to be proposed.

EGFR expression in pancreatic adenocarcinoma. Relationship to tumour morphology and cell adhesion proteins

Aims We aimed to study epidermal growth factor receptor (EGFR) expression in surgically resected pancreatic ductal adenocarcinomas (PDACs) by immunohistochemistry and their relationship to clinicopathological features, cell proliferation and cell adhesion protein expression. Methods A total of 99 PDACs were analysed on tissue microarrays for EGFR, E-cadherin and β-catenin expression patterns in tumour cells. The percentage of cells expressing the three proteins (membrane, cytoplasm or nuclear pattern) and of Ki67-positive tumour cells was assessed. Tumour protein expression was studied with regard to clinicomorphological features, Ki67 index and for postsurgical survival. Results Membrane tumour EGFR correlated with histological poor differentiation (dedifferentiation), increased number of mitoses and severe tumour cell atypia (pleiomorphism) as well as with aberrant adhesion protein expression such as nuclear β-catenin and cytoplasmic E-cadherin. Cytoplasmic tumour E-cadherin correlated with an increased Ki67-positive tumour cell component, whereas nuclear E-cadherin correlated with a shorter postsurgical overall survival, as well as with tumour necrosis and an abundant clear cell component. Conclusions In conclusion, the results of our study suggest a complex role for EGFR in PDAC carcinogenesis, tumour expression of this protein being associated with tumour dedifferentiation, mitotic activity or pleiomorphism, as well as with aberrant tumour cell adhesion protein expression.

Surgery for pancreatic neoplasms: How accurate are our surgical indications?

Background. Accurate preoperative diagnosis is critical for the determination of appropriate surgical indications. The aim of this study was to assess the accuracy of preoperative diagnosis and indications for operative therapy for presumed pancreatic neoplasms. Methods. From 2005 to 2013, 851 patients underwent pancreatectomies for presumed pancreatic neoplasms. A formal preoperative diagnosis was established during a multidisciplinary tumor board and compared to the final pathologic examination. The preoperative diagnosis and its accuracy were assessed according to demographics, symptoms, and diagnostic workup. Results. Tumors were benign in 8% of patients (n = 67), premalignant in 43% (n = 370), and malignant in 49% (n = 414). The mean number of preoperative examinations was 3.2; 27% (n = 144) of patients had computed tomography, magnetic resonance imaging, endoscopic ultrasonography, and fine needle examination all performed together. Preoperative diagnosis was confirmed in 89% of patients (n = 754). The morbidity and mortality rates were 65% and 1%, respectively. Of the 97 patients (11%) with a misdiagnosis, operative resection was ultimately relevant (premalignant, malignant tumor, or symptomatic benign tumor) in 51 (6%) but inappropriate in 46 (5%). The rate of misdiagnosis was increased for cystic lesions and in patients under 50 years of age. For lesions <2 cm, diagnostic accuracy was increased when computed tomography, magnetic resonance imaging, endoscopic ultrasonography, and fine needle examination were all performed together. Conclusion. Misdiagnosis can lead to an inappropriate resection in 5% of patients with presumed pancreatic neoplasms. For lesions difficult to characterize, such as small and cystic lesions, association of several modalities of preoperative workup could help to decrease the rate of inappropriate operative care.

Predicting the efficacy of surgery for pain relief in patients with alcoholic chronic pancreatitis

Background Recurrent pain is the most disabling complication in patients with chronic pancreatitis. Pancreatic surgery is currently considered as last‐resort therapeutic option. The aims of this study were to assess pancreatic surgery performance for chronic pain in patients with alcoholic chronic pancreatitis and to determine factors predictive of therapeutic response. Methods All patients with chronic pancreatitis who underwent pancreatic surgery for chronic pain were included and divided into 2 groups according to the cause of chronic pancreatitis: alcoholic and any other chronic pancreatitis causes as the control group. Alcohol, tobacco, and painkiller intake, quality of life data 6 months and 1 year after surgery, and morphological and pathological features were analyzed. Results Fifty patients were included in the alcoholic chronic pancreatitis group and 16 patients in the control group. Smoking cessation before pancreatic surgery was achieved in 40% of the alcoholic chronic pancreatitis group compared with 73% of the control group (P = .005). Histological analysis revealed a higher prevalence of hypertrophic nerves and perineural inflammation in the alcoholic chronic pancreatitis group than in the control group (P = .03 and P = .04 respectively). In multivariate analysis, in the alcoholic chronic pancreatitis group, factors predictive of 6‐month narcotic use cessation were surgery performed within a maximum of 2 years after chronic pancreatitis diagnosis (odds ratio = 4.228 [1.04–17.17]) and postoperative smoking cessation (odds ratio = 3.561 [1.021–12.41]); at 1 year, only smoking cessation was predictive of narcotic use cessation (odds ratio = 11.33 [2.677–47.98]). Conclusion In patients with alcoholic chronic pancreatitis undergoing surgery for chronic pain, narcotic use cessation and improved quality of life depend on early surgery and complete smoking cessation.