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ABSTRACT: BACKGROUND: The aim of the present study was to determine the optimal number of lymph nodes (LN) examined to stage pN0 tumors after surgery for ampulla of Vater carcinoma (AVC). METHODS: We reviewed retrospectively 127 patients with AVC who underwent pancreaticoduodenectomy (1990-2008). Univariate and multivariate analysis was performed. RESULTS: Fifty-nine patients (46.5 %) were pN0, whereas 68 patients (53.5 %) were pN1. The 5-year disease-specific survival (DSS) was worse for pN1 patients than for pN0 patients (46 vs. 77 %; P < 0.0001). In the pN0 cohort, the optimal cut-off number of LN analyzed was found to be 12. The 5-year DSS for patients with ≤12 LN was 50 %, compared with 89 % in those with >12 LN (P = 0.001). By multivariate analysis, a LN count >12 was the only independent predictor associated with improved survival (HR 0.16, P = 0.003) among pN0 patients. Among pN1 patients, a LN count >12 was associated with a significantly better 5-year DSS (59 vs. 22 %; P = 0.027). Patients with a lymph node ratio (LNR) >0.20 had a 5-year DSS of 24 %, compared with 58 % in those with 0 < LNR ≤ 0.20 (P = 0.038). CONCLUSIONS: Removal of more than 12 LN for examination is associated with improved survival rate after surgery for AVC in both pN0 and pN1 patients.
World Journal of Surgery 04/2013; · 2.36 Impact Factor
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ABSTRACT: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) constitute a heterogeneous group of neoplasms. In the last few decades, due to a substantial rise in incidence and prevalence, GEP-NETs have been included among the most common tumours of the gastrointestinal tract. Diagnosis could be challenging and a significant number of patients present with metastatic or unresectable disease. The development of appropriate tools for standardised prognostic stratification and the introduction of effective target therapies have opened new horizons for planning tailored surgical or medical management and follow-up programs for these complex neoplasms. An overview on the GEP-NETs' diagnostic and prognostic criteria proposed by the recently published WHO classification and ENETS and UICC TNM staging systems is presented, focussing on their impact on the clinical and therapeutical approaches.
Best practice & research. Clinical gastroenterology 12/2012; 26(6):705-17. · 2.48 Impact Factor
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ABSTRACT: Poorly differentiated, resectable pancreatic ductal adenocarcinoma is associated with early recurrence and may benefit from neoadjuvant treatment. The aim of this study was to evaluate clinicopathologic characteristics and survival of patients with resectable pancreatic ductal adenocarcinoma according to histologic grading.
A total of 502 patients who underwent resection for pancreatic ductal adenocarcinoma between 1990 and 2008 were analyzed via the use of different histologic grading.
Well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) pancreatic ductal adenocarcinomas were found in 23 (4.5%), 310 (62%), and 169 (33.5%) patients. Adjuvant therapy, N status, grading, and R status were independent predictors of disease-specific survival for the entire cohort, with 1- and 5-year disease-specific survival rates of 81% and 21%, respectively. Only the presence of symptoms was a significant clinical predictor of G3 status (P = .035). G3 neoplasms were characterized by a greater rate of lymph node metastases, microvascular/perineural invasion, and R2 resections. Median disease-specific survival was 77, 26, and 20 months for G1, G2, and G3 neoplasms (P < .0001). Median disease-free survival was 63, 14, and 9 months for G1, G2, and G3 pancreatic ductal adenocarcinoma (P < .0001). Adjuvant therapy improved disease-specific survival in G2 (P < .04) and G3 (P < .0001) pancreatic ductal adenocarcinoma, with a greater survival benefit for G3 neoplasms (hazard ratio: 1.334 vs 2.116).
G3 pancreatic ductal adenocarcinoma is associated with a lesser rate of disease-free survival after resection and with the presence of other poor prognostic factors. The benefit of adjuvant therapy is greater in G3 than in G1 and G2 neoplasms. On the basis of these findings, patients with resectable G3 PDAC can be considered as possible targets for neoadjuvant treatment.
Surgery 07/2012; 152(3 Suppl 1):S112-9. · 3.10 Impact Factor
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ABSTRACT: BackgroundThe value of splenic vessels invasion (which identified T3 tumors) in prognosis after resection for pancreatic ductal adenocarcinoma
(PDA) of the body and tail has not been extensively investigated. The goal of this study was to evaluate prognostic factors
in PDA of the body/tail, emphasizing the role of splenic vessels infiltration.
MethodsBetween 1990 and 2008, 87 patients who underwent distal pancreatectomy (DP) for histologically proven PDA of the body and
tail were analyzed. Clinicopathological prognostic factors for survival were evaluated. Univariate and multivariable analyses
were performed.
ResultsPostoperative morbidity was 31% with no mortality. The 1-, 3-, and 5-year overall survival rates were 77%, 48%, and 24.5%,
respectively. Invasion of the splenic artery (SA) was observed in 19 patients (22%). Patients with SA invasion had a significantly
poorer prognosis compared with those without SA invasion (median survival: 15 vs. 39months, P=0.014). On multivariable analysis, adjuvant therapy, poor differentiation (G3/G4), R2 resection, the presence of lymph
node metastases, and SA invasion were independent predictors of survival.
ConclusionsAlong with other well-known prognostic factors, invasion of SA is an independent predictor of poor survival in PDA of the
body/tail. In case of the presence of SA infiltration, neoadjuvant treatment should be considered. SA infiltration might be
reclassified from a T3 to T4 tumor.
Annals of Surgical Oncology 04/2012; 18(13):3608-3614. · 4.17 Impact Factor
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Hanno Matthaei,
Alexis L Norris,
Athanasios C Tsiatis,
Kelly Olino,
Seung-Mo Hong,
Marco dal Molin,
Michael G Goggins,
Marcia Canto,
Karen M Horton,
Keith D Jackson, [......],
Shigeru Ottomo,
Michiaki Unno,
Fuyuhiko Motoi,
Christopher L Wolfgang,
Barish H Edil,
John L Cameron,
James R Eshleman,
Richard D Schulick,
Anirban Maitra,
Ralph H Hruban
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ABSTRACT: To examine the clinicopathologic features and clonal relationship of multifocal intraductal papillary mucinous neoplasms (IPMNs) of the pancreas.
Intraductal papillary mucinous neoplasms are increasingly diagnosed cystic precursor lesions of pancreatic cancer. Intraductal papillary mucinous neoplasms can be multifocal and a potential cause of recurrence after partial pancreatectomy.
Thirty four patients with histologically documented multifocal IPMNs were collected and their clinicopathologic features catalogued. In addition, thirty multifocal IPMNs arising in 13 patients from 3 hospitals were subjected to laser microdissection followed by KRAS pyrosequencing and loss of heterozygosity (LOH) analysis on chromosomes 6q and 17p. Finally, we sought to assess the clonal relationships among multifocal IPMNs.
We identified 34 patients with histologically documented multifocal IPMNs. Synchronous IPMNs were present in 29 patients (85%), whereas 5 (15%) developed clinically significant metachronous IPMNs. Six patients (18%) had a history of familial pancreatic cancer. A majority of multifocal IPMNs (86% synchronous, 100% metachronous) were composed of branch duct lesions, and typically demonstrated a gastric-foveolar subtype epithelium with low or intermediate grades of dysplasia. Three synchronous IPMNs (10%) had an associated invasive cancer. Molecular analysis of multiple IPMNs from 13 patients demonstrated nonoverlapping KRAS gene mutations in 8 patients (62%) and discordant LOH profiles in 7 patients (54%); independent genetic alterations were established in 9 of the 13 patients (69%).
The majority of multifocal IPMNs arise independently and exhibit a gastric-foveolar subtype, with low to intermediate dysplasia. These findings underscore the importance of life-long follow-up after resection for an IPMN.
Annals of surgery 12/2011; 255(2):326-33. · 7.90 Impact Factor
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ABSTRACT: Malignant pancreatic neuroendocrine tumours (PNENs) are generally associated with a good prognosis after radical resection. In other pancreatic malignancies predictors of recurrence and the role of lymph node ratio (LNR) are well known, but both have been scarcely investigated for malignant PNETs.
The prospective database from the surgical Department of Verona University was queried. Clinical and pathological data of all patients with resected malignant PNET between 1990 and 2008 were reviewed. Univariate and multivariate analysis were performed.
Fifty-seven patients (male/female ratio=1) with a median age of 58 years (33-78) entered in the study. Twenty-nine (51%) patients underwent pancreaticoduodenectomy and 28 (49%) distal pancreatectomy. Postoperative mortality was nil with a 37% morbidity rate. There were 36 (63%) patients with lymph node metastases (N1). Of these, 23 (64%) had a lymph node ratio (LNR) >0 and ≤0.20 and 13 (36%) had a LNR >0.20. The median overall survival and the median disease free survival (DFS) were 190 and 80 months, respectively. Recurrent disease was identified in 24 patients (42%) with a 2 and 5-year DFS rate of 82% and 49%, respectively. On multivariate analysis, LNR >0.20 (HR=2.75) and a value of Ki67 >5% (HR=3.39) were significant predictors of recurrence (P<0.02).
After resection for malignant PNETs, LNR and a Ki67 >5% are the most powerful predictors of recurrence. The presence of these factors should be considered for addressing patients to adjuvant treatment in future clinical trials.
European journal of cancer (Oxford, England: 1990) 11/2011; 48(11):1608-15. · 4.12 Impact Factor
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ABSTRACT: Pancreatic tumors in children and adolescents are uncommon. The aim of the present paper was to analyze short- and long-term outcomes after surgical treatment of primary pancreatic neoplasms in children and adolescents at a single high-volume center for pancreatic diseases.
Retrospective review of medical records and pathology reports of patients younger than 18 years who underwent surgery at Verona University Hospital from 1990 through 2010.
The study population consisted of 20 patients. Abdominal pain and palpable mass were the most common presenting symptoms. No patient had a locally advanced, unresectable or metastatic disease. Complete resection (R0) was achieved in 19 patients. There was no postoperative mortality, but postoperative complications occurred in 5 cases (25%). Histological examination showed 12 solid pseudopapillary tumors, 5 neuroendocrine tumors, 2 cystadenomas and 1 epithelial malignant tumor. At a median follow-up of 49.5 months (range: 7-234), there was no tumor recurrence. Postoperative diabetes was diagnosed in 1 patient and 4 other patients developed pancreatic exocrine insufficiency.
In the setting of a high-volume surgical center, radical resection of pancreatic tumors in children and adolescents is associated with acceptable postoperative morbidity and favorable long-term outcome.
Pancreatology 08/2011; 11(4):383-9. · 1.99 Impact Factor
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ABSTRACT: Neoadjuvant treatment frequently is performed in unresectable/borderline resectable pancreatic cancer. The aim of this study was to retrospectively compare postoperative outcomes and survival of patients who underwent pancreatectomy after neoadjuvant treatment for locally advanced/borderline resectable pancreatic cancer (neoadjuvant treatment group) with those of patients with resectable disease who underwent upfront surgery.
Between 2000 and 2008, there were 403 patients who underwent pancreatic cancer resection, 41 (10.1%) patients after neoadjuvant treatment for initially unresectable tumors and 362 (89.9%) patients had upfront surgery. Univariate and multivariable analyses were performed.
Mortality/morbidity rates were similar in the 2 groups. Nodal metastases were significantly lower in the neoadjuvant treatment group (31.7% vs 86.2%; P < .001). A complete pathologic response was observed in 13.6% after neoadjuvant treatment. Median disease-specific survival from resection was 35 and 27 months in the neoadjuvant treatment and upfront groups, respectively (P = .74). In the neoadjuvant treatment group survival rates were similar in N0/N1 patients.
Postoperative mortality and morbidity do not significantly increase after neoadjuvant treatment. Neoadjuvant treatment in locally advanced pancreatic cancer can lead to an objective pathologic response, but this does not significantly improve survival after resection.
American journal of surgery 08/2011; 203(2):132-9. · 2.36 Impact Factor
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ABSTRACT: Solid pseudopapillary tumors of the pancreas are rare exocrine pancreatic tumors. Through a review of pediatric cases in a single Institution, we present the clinical and surgical management of this neoplasm.
We retrospectively reviewed the clinical charts of patients treated at our unit between 1995 and 2009 for SPT. Clinical and surgical management were analyzed and reported.
During the study period 11 patients underwent surgery for pseudopapillary tumor. Five patients were treated with duodenum-preserving pancreatic head resection and six patients with splenopancreasectomy with a Roux-en-Y pancreatic jejunostomy. Patients did not show recurrence and are currently disease free. Blood tests, Ultrasound, Computed tomography and Magnetic Resonance Imaging were not useful to preoperatively identify the nature of the pancreatic masses.
Solid pseudopapillary tumor is a rare condition that should be taken into account for the differential diagnosis of pancreatic masses in pediatric age. Due to its favourable prognosis, surgical removal should be planned and done following the intraoperative findings.
Pediatric Surgery International 07/2011; 27(12):1271-5. · 1.25 Impact Factor
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ABSTRACT: Tumor size is a criterion of staging in nonfunctioning pancreatic endocrine tumors as well as a predictor of outcome after curative resection. This study analyzes the correlation between tumor size and malignancy in patients with nonfunctioning pancreatic endocrine tumors.
All patients with nonfunctioning pancreatic endocrine tumors who underwent curative resection (R0) at our institution between 1990 and 2008 were considered. Their clinicopathologic characteristics were compared among 3 different groups according to tumor size. Univariate and multivariable analyses were performed.
Over the study period, 177 patients were identified. Overall, 90 patients (51%) had a tumor size ≤2 cm (group 1), 46 (26%) had tumor size between >2 cm and ≤4 cm (group 2), and 41 (23%) had tumor size >4 cm (group 3). Tumors ≤2 cm were more frequently incidentally discovered (group 1, 57% vs group 2, 51% vs group 3, 32%; P = .014) and benign (group 1, 81% vs group 2, 65% vs group 3, 5%; P < .0001). The presence of a nonfunctioning pancreatic endocrine tumor >2 cm and a nonincidental diagnosis of the tumor were independent predictors of malignancy at multivariable analysis. None of the 51 patients (29%) with a pancreatic endocrine tumor ≤2 cm that was incidentally diagnosed died of disease.
A strict correlation between tumor size and malignancy in nonfunctioning pancreatic endocrine tumors was demonstrated. A nonoperative management could be advocated for tumors ≤2 cm when discovered incidentally.
Surgery 07/2011; 150(1):75-82. · 3.10 Impact Factor
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ABSTRACT: The value of splenic vessels invasion (which identified T3 tumors) in prognosis after resection for pancreatic ductal adenocarcinoma (PDA) of the body and tail has not been extensively investigated. The goal of this study was to evaluate prognostic factors in PDA of the body/tail, emphasizing the role of splenic vessels infiltration.
Between 1990 and 2008, 87 patients who underwent distal pancreatectomy (DP) for histologically proven PDA of the body and tail were analyzed. Clinicopathological prognostic factors for survival were evaluated. Univariate and multivariable analyses were performed.
Postoperative morbidity was 31% with no mortality. The 1-, 3-, and 5-year overall survival rates were 77%, 48%, and 24.5%, respectively. Invasion of the splenic artery (SA) was observed in 19 patients (22%). Patients with SA invasion had a significantly poorer prognosis compared with those without SA invasion (median survival: 15 vs. 39 months, P = 0.014). On multivariable analysis, adjuvant therapy, poor differentiation (G3/G4), R2 resection, the presence of lymph node metastases, and SA invasion were independent predictors of survival.
Along with other well-known prognostic factors, invasion of SA is an independent predictor of poor survival in PDA of the body/tail. In case of the presence of SA infiltration, neoadjuvant treatment should be considered. SA infiltration might be reclassified from a T3 to T4 tumor.
Annals of Surgical Oncology 05/2011; 18(13):3608-14. · 4.17 Impact Factor
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ABSTRACT: Mucinous cystic neoplasm of the liver has been a controversial entity, in particular, regarding differentiation from intraductal papillary neoplasm of the bile duct. In this study, we compared the characteristics of hepatic mucinous cystic neoplasms with ovarian-like stroma (n=29) to those of cyst-forming intraductal papillary neoplasms of the bile duct (n=12). Radiological or macroscopic appearance, histological grade of malignancy, and postoperative clinical course were recorded. Immunohistochemistry for biliary or gastrointestinal markers was performed to characterize cell phenotypes. The patients with hepatic mucinous cystic neoplasm were all female and ranged in age from 21 to 67 years, which was significantly younger than that in the patients with biliary intraductal papillary neoplasm. Eighteen mucinous cystic neoplasms (76%) were located in the left lobe, with 13 (54%) in segment IV. Mucinous cystic neoplasms were significantly larger than intraductal papillary neoplasms (median diameter: 110 vs 50 mm, P=0.008). In contrast to intraductal papillary neoplasms that were all histologically malignant, 26 mucinous cystic neoplasms (90%) were adenomas, 2 (7%) were borderline malignant, and 1 (3%) was a carcinoma in situ. Benign mucinous cystadenomas had the pure biliary immunophenotype, whereas gastrointestinal markers including cytokeratin 20 and mucin core proteins 2, 5AC, and 6 were more frequently expressed in borderline or malignant mucinous cystic neoplasms and biliary intraductal papillary neoplasms. There was no mortality in the patients with mucinous cystic neoplasm, whereas one patient with intraductal papillary neoplasm died of cancer. In conclusion, hepatic mucinous cystic neoplasms and biliary intraductal papillary neoplasms have different clinicopathological characteristics as evidenced by differences in the age and gender of patients, macroscopic appearance, immunophenotypes, and grades of malignancy.Keywords: cyst; cholangiocarcinoma; dysplasia; intestinal metaplasia; liver
Modern Pathology 04/2011; 24(8):1079-1089. · 4.79 Impact Factor
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ABSTRACT: To assess presentation and outcome of pancreaticoduodenal endocrine tumors (PDETs) in a single center series of multiple endocrine neoplasia type 1 (MEN1) patients. Methods: Retrospective analysis of prospectively collected data of MEN1 patients observed at the University of Verona.
Thirty-one MEN1 patients had PDETs, including 16 nonfunctioning (NF), 6 insulinomas and 9 Zollinger-Ellison syndrome (ZES). In 16 of these patients (52%), PDET was the manifestation which led to the diagnosis of MEN1; among this group, 15 patients (94%) previously had unidentified primary hyperparathyroidism (PHPT), which was asymptomatic in 9 cases (60%). Of the 31 patients, 19 (61%) underwent curativesurgery and 13 (68%, 7 NF-PDETs, 4 insulinomas and 2 ZES) were disease-free after a median follow-up of 3 years (range: 0.5-15). One patient had debulking surgery with stable disease after 2 years of follow-up. Eight patients with NF-PDETs ≤20 mm and 2 with ZES, treated with a conservative approach, showed stable disease. One patient with insulinoma was lost to follow-up.
PDET may be the manifestation that leads to MEN1 diagnosis since the almost constant presence of PHPT is very often unrecognized or considered sporadic. Conversely, the presence of PDETs should be looked for in all patients presenting PHPT, even if asymptomatic, particularly before age 50. Surgery may be curative in the majority of insulinomas and can prolong disease-free survival in NF-PDET, but is not proven to be effective in ZES. A conservative approach can be safely reserved for patients with NF-PDETs ≤20 mm.
Neuroendocrinology 04/2011; 94(1):58-65. · 2.38 Impact Factor
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ABSTRACT: The Italian Group of Gastrointestinal Pathologists has named a committee to develop recommendations concerning the surgical pathology report for pancreatic cancer. The committee, formed by individuals with special expertise, wrote the recommendations, which were reviewed and approved by council of the Group. The recommendations are divided into several areas including an informative gross description, gross specimen handling, histopathologic diagnosis, immunohistochemistry, molecular findings, and a checklist. The purpose of these recommendations is to provide a fully informative report for the clinician.
Digestive and Liver Disease 03/2011; 43 Suppl 4:S282-92. · 3.05 Impact Factor
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ABSTRACT: PDAC is an aggressive disease and early infiltrates peripancreatic tissues and adjacent organs, and gives distant metastasis
and peritoneal involvement, making often surgical resection impossible. About 80% of PDACs are inoperable at the time of diagnosis.
However, even if radiologically resectable, some PDAC microscopically involves the resection margins (pancreatic, retroperitoneal,
or biliary, the retroperitoneal being the most important because it cannot be evaluated intraoperatorially) resulting in a
nonradical excision. Local aggressiveness consists in the invasion of contiguous structures and organs (spleen, stomach, left
adrenal gland, colon, and peritoneum), whereas distant metastases can occur in liver, lungs, adrenals, kidneys, bones, brain,
and skin.
Most PDACs arise in the head of the pancreas often involving and occluding the intrapancreatic biliary duct and the main pancreatic
duct, typically resulting in their upstream dilation associated with jaundice and cholangitis when the former is involved,
and cystic formation with a variable degree of scleroatrophy of the surrounding parenchyma when the latter is involved. PDAC
can spread through the papilla of Vater and duodenal wall with or without ulceration, raising the problem of differential
diagnosis with primary duodenal and ampulla of Vater carcinomas infiltrating the pancreatic parenchyma. Less frequently, PDACs
occur in the tail, where they are usually larger at diagnosis, determining weaker symptoms mainly due to loco-regional invasiveness.
01/2011: pages 11-18;
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ABSTRACT: Autoimmune pancreatitis (AIP) is a type of pancreatitis whose immunopathogenesis is still unknown. It has been reported that renal biopsy specimens from patients diagnosed with both AIP and tubulointerstitial nephritis reveal deposits containing complement C3, immunoglobulin (Ig)G and IgG4 at the tubular basement membranes (BMs). The aim was to investigate the deposition of complement and immunoglobulins in pancreatic tissue from AIP patients compared to non-AIP patients.
Double immunofluorescence microscopy for C3c, IgG4 and IgG together with CK7, trypsin, collagen IV, CD31 and CD79a, as well as immunofluorescence microscopy for C1q, IgA and IgM, were performed on frozen pancreatic tissue from AIP and alcoholic chronic pancreatitis (ACP) patients.
In AIP patients, complement C3c, IgG4 and IgG were deposited at the collagen IV-positive BMs of pancreatic and bile ducts and of acini. In a minority of the ACP patients, weak C3c-positive BM deposits were detected, but no IgG4- or IgG-positive BM deposits were present.
The deposition of C3c, IgG4 and IgG at the BM of small- and medium-sized ducts and acini of the pancreas is characteristic of AIP. This suggests that immune complex-mediated destruction of ducts and acini play a role in the pathogenesis of AIP.
Histopathology 12/2010; 57(6):825-35. · 3.08 Impact Factor
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ABSTRACT: Pancreatic endocrine tumors (PET) are rare neoplasms classified as functioning (F-PET) or non-functioning (NF-PET) according to the presence of a clinical syndrome due to hormonal hypersecretion. PETs show variable degrees of clinical aggressiveness and loss of chromosome 3p has been suggested to be associated with an advanced stage of disease. We assessed chromosome 3p copy number in 113 primary PETs and 32 metastases by fluorescence in situ hybridization (FISH) using tissue microarrays. The series included 56 well-differentiated endocrine tumors (WDET), 62 well-differentiated endocrine carcinomas (WDEC), and 6 poorly differentiated endocrine carcinomas (PDEC). Chromosome 3p alterations were found in 23/113 (20%) primary tumors, with losses being predominant over gains (14% vs. 6%). Loss of 3p was found in 5/55 (9%) WDET, 11/52 (21%) WDEC, and never in PDEC. Gains of 3p were detected in 4/55 (7%) WDET, no WDEC, but notably in 3/6 (50%) PDEC (OR 23.6; P = 0.003). Metastases were more frequently monosomic for 3p compared to primary tumors (OR 3.6; P = 0.005). Monosomy was significantly associated with larger tumor size, more advanced tumor stage, and metastasis. No association was found with survival. Chromosome 3p copy number alterations are frequent events in advanced stage PET, with gains prevailing in PDEC while losses are more frequent in WDEC, supporting the view that a specific pattern of alterations are involved in these diverse disease subtypes.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 10/2010; 458(1):39-45. · 2.49 Impact Factor
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Vincenzo Corbo,
Irene Dalai,
Maria Scardoni,
Stefano Barbi,
Stefania Beghelli,
Samantha Bersani,
Luca Albarello,
Claudio Doglioni,
Christina Schott, Paola Capelli,
Marco Chilosi,
Letizia Boninsegna,
Karl-Friedrich Becker,
Massimo Falconi,
Aldo Scarpa
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ABSTRACT: Pancreatic endocrine tumors (PETs) may be part of hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. While MEN1 gene mutation is the only ascertained genetic anomaly described in PETs, no data exist on the cellular localization of MEN1-encoded protein, menin, in normal pancreas and PETs. A total of 169 PETs were used to assess the i) MEN1 gene mutational status in 100 clinically sporadic PETs by direct DNA sequencing, ii) immunohistochemical expression of menin in normal pancreas and 140 PETs, including 71 cases screened for gene mutations, and iii) correlation of these findings with clinical-pathological parameters. Twenty-seven PETs showed mutations that were somatic in 25 patients and revealed to be germline in 2 patients. Menin immunostaining showed strong nuclear and very faint cytoplasmic signal in normal islet cells, whereas it displayed abnormal location and expression levels in 80% of tumors. PETs harboring MEN1 truncating mutations lacked nuclear protein, and most PETs with MEN1 missense mutations showed a strong cytoplasmic positivity for menin. Menin was also misplaced in a significant number of cases lacking MEN1 mutations. In conclusion, the vast majority of PETs showed qualitative and/or quantitative alterations in menin localization. In 30% of cases, this was associated with MEN1 mutations affecting sequences involved in nuclear localization or protein-protein interaction. In cases lacking MEN1 mutations, the alteration of one of the menin interactors may have prevented its proper localization, as suggested by recent data showing that menin protein shuttles between the nucleus and cytoplasm and also affects the subcellular localization of its interactors.
Endocrine Related Cancer 09/2010; 17(3):771-83. · 4.36 Impact Factor
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Pancreas 08/2010; 39(6):939-40. · 2.39 Impact Factor
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ABSTRACT: Pancreatic endocrine tumors are rare diseases and devising a clinically effective prognostic stratification of patients is a major clinical challenge. This study aimed at assessing whether the tumor-node-metastasis (TNM)-based staging and proliferative activity-based grading recently proposed by the European NeuroEndocrine Tumors Society (ENETS) have clinical value. TNM was applied to 274 patients with histologically diagnosed pancreatic endocrine tumors operated from 1991 to 2005, with last follow-up at December 2007. According to World Health Organization (WHO) classification, 246 were well-differentiated neoplasms (51 benign, 56 uncertain behavior, 139 carcinomas) and 28 poorly differentiated carcinomas. Grading was based on Ki67 immunohistochemistry. Survival analysis not only ascertained the prognostic value of the TNM system but also highlighted that in the absence of nodal and distant metastasis, infiltration and tumor dimensions over 4 cm had prognostic significance. T parameters were then appropriately modified to reflect this weakness. The 5-year survival for modified TNM stages I, II, III and IV were 100, 93, 65 and 35%, respectively. Multivariate analysis identified TNM stages as independent predictors of death, in which stages II, III and IV showed a risk of death of 7, 29 and 58 times higher than stage I tumors (P<0.0001). Ki67-based grading resulted an independent predictor of survival with cut-offs at 5 and 20%. In conclusion, WHO classification assigns clinically significant diagnostic categories to pancreatic endocrine tumors that need prognostic stratification by applying a staging system. The ENETS-TNM provides the best option, but it requires some modifications to be fully functional. The modified TNM described in this study ameliorates the clinical applicability and prediction of outcome of the ENETS-TNM; it (i) assigns a risk of death proportional to the stage at the time of diagnosis, and (ii) allows a clinically based staging of patients, as the T parameters as modified permit their clinical-radiological recognition. Ki67-based grading discerns prognosis of patients with same stage diseases.
Modern Pathology 03/2010; 23(6):824-33. · 4.79 Impact Factor
