Calogero Iacono

Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors

The clinicopathological features of 56 patients with mucinous cystic tumors (MCTs) of the pancreas were studied. Particular attention was paid to the prognosis of MCTs and the relationship to their ovarian, hepatic, and retroperitoneal counterparts. To distinguish MCTs from pancreatic intraductal papillary-mucinous tumors, MCTs were defined as tumors lacking communication with the duct system and containing mucin-producing epithelium, usually supported by ovarian-like stroma. All 56 tumors occurred in women (mean age 48.2 years) and were preferentially (93%) located in the body and tail of the pancreas. In accordance with the WHO classification, MCTs were divided into adenomas (n = 22), borderline tumors (n= 12), and noninvasive and invasive carcinomas (n = 22). Survival analysis revealed the extent of invasion to be the most significant prognostic factor (p<0.0001). Malignancy correlated with multilocularity and presence of papillary projections or mural nodules, loss of ovarian-like stroma, and p53 immunoreactivity. Stromal luteinization with expression of tyrosine hydroxylase, calretinin, or alpha inhibin was found in 66% of the cases. We conclude that the biologic behavior of MCTs is predictable on the basis of the extent of invasion. The similarities (i.e. gender, morphology, stromal luteinization) between pancreatic MCT and its ovarian, hepatobiliary, and retroperitoneal counterparts suggest a common pathway for their development.

Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: A comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables

Prediction for malignancy of pancreatic endocrine tumors (PET) is often a formidable challenge for the pathologist. The authors evaluated the role of the proliferative activity and progesterone receptor protein (PgRP) in predicting prognosis and survival of PET. Twenty-three functioning (FT) and 31 nonfunctioning tumors (NFT) were evaluated for mitotic activity and immunostaining for Ki-67 antigen, proliferating cell nuclear antigen (PCNA), and progesterone receptor protein (PgRP) on paraffin sections. The results were expressed as a percentage (index) of immunoreactive or mitosing cells. All 54 cases showed immunostaining for Ki-67 and PCNA, and valuable mitotic index, whereas only a fraction of tumors (25 of 54 cases) exhibited PgRP expression. Ki-67 and PCNA indexes correlated strongly between themselves and to mitotic index, whereas an inverse relationship was observed between cell proliferation and PgRP status in both FT and NFT. Although univariate analysis showed that Ki-67, PCNA, mitotic and PgRP indexes, stage, immunoreactivity for hormones other than insulin, diameter, and nonfunctioning type of tumor were statistically correlated to survival, Coxs regression method let only Ki-67 index emerge as an independent predictor of survival using a cutoff value of 5% in both FT and NFT.

How much remnant is enough in liver resection

Background: Liver resection represents the first choice of treatment for primary and secondary liver malignancies, offering the patient the best chance of long-term survival. The extensive use of major hepatectomy increases the risk of post-hepatectomy liver failure (PHLF), which is associated with a high frequency of postoperative complications, mortality and increased length of hospital stay. Aims: The aim of this review is to investigate the different risk factors related to the occurrence of PHLF and to identify the limits for a safe liver resection in patients with normal liver and injured liver (cirrhosis, cholestasis, steatosis and post-chemotherapy liver injury). Methods: A literature search was undertaken in PubMed and related search engines, looking for articles relating to hepatic failure following hepatectomy in normal liver or injured liver. Results: In spite of improvements in surgical and postoperative management, the parameters determining how much liver can be resected are still largely undefined. A number of preoperative, intraoperative and postoperative factors all contribute to the likelihood of liver failure after surgery. The safe limits for liver resection can be estimated from the data of the literature for patients with normal liver and for those with different types of liver injury. Conclusions: Preoperative assessment that includes evaluation of liver volume and function of the remnant liver is a mandatory prerequisite before major hepatectomy. The critical residual liver volume for patients able to predict PHLF is mainly related to the presence of pre-existing liver disease and liver function. Among patients with normal liver, the limit for safe resection ranges from 20 to 30% future remnant liver of total liver volume. In patients with injured liver (cirrhosis, cholestasis or steatosis), preoperative assessment of the risk of PHLF should include future remnant liver volumetry and accurate liver function evaluation, including different dynamic liver function tests.

Is there a place for central pancreatectomy in pancreatic surgery

Tumors located in the neck of the pancreas that are not small and superficial enough to be enucleated are usually resected with a pancreaticoduodenectomy or left splenopancreatectomy. Such operations may cause digestive disorders, glucose intolerance, and late postsplenectomy infection. Central pancreatectomy is a segmental resection whereby the cephalic stump is sutured and the distal stump anastomosed with a Roux-en-Y jejunal loop. The purpose of this study was to evaluate whether central pancreatectomy has a place in pancreatic surgery. Thirteen patients with the following tumors underwent central pancreatectomy: five endocrine tumors, one mucinous and six serous cystadenomas, and one solid cysticpapillary tumor. Mean operative time was 250 minutes. Operative mortality was zero. Complications occurred in three patients (23%). At mean follow-up of 68 months, no recurrences were found. Postoperative oral glucose tolerance, pancreolauryl, and fecal fat excretion tests were normal in all patients. We believe that central pancreatectomy does have a place in pancreatic surgery; it is a reliable technique for benign or low-grade malignant tumors and has a surgical risk similar to that of standard operations. Its principal advantage is that it preserves pancreatic parenchyma and the anatomy of the upper gastrointestinal and biliary tract and the spleen better than pancreaticoduodenectomy or distal pancreatic and splenic resection.

Role of preoperative biliary drainage in jaundiced patients who are candidates for pancreatoduodenectomy or hepatic resection: highlights and drawbacks.

Introduction: In this review of the literature, we analyze the indications for preoperative drainage in jaundiced patients who are candidates for pancreaticoduodenectomy (PD) or major hepatectomy due to periampullary or proximal bile duct neoplasms. Objective: The aim of this study is to review the literature and to report on the current management of jaundiced patients with periampullary or proximal bile duct neoplasms who are candidates for PD or major liver resection. Background: Jaundiced patients represent a major challenge for surgeons. Alterations and functional impairment caused by jaundice increase the risk of surgery; therefore, preoperative biliary decompression has been suggested. Methods: A literature review was performed in the MEDLINE database to identify studies on the management of jaundice in patients undergoing PD or liver resection. Papers considering palliative drainage in jaundiced patients were excluded. Results: The first group of papers considered patients affected by middle-distal obstruction from periampullary neoplasms, in which preoperative drainage was applied selectively. The second group of papers evaluated patients with biliary obstructions from proximal biliary neoplasms. In these cases, Asian authors and a few European authors considered it mandatory to drain the future liver remnant (FLR) in all patients, while American and most European authors indicated preoperative drainage only in selected cases (in malnourished patients and in those with hypoalbuminemia, cholangitis or long-term jaundice; with an FLR < 30% or 40%) given the high risk of complications of drainage (choleperitoneum, cholangitis, bleeding, and seeding). The optimal type of biliary drainage is still a matter of debate; recent studies have indicated that endoscopy is preferable to percutaneous drainage. Although the type of endoscopic biliary drainage has not been clearly established, the choice is made between plastic stents and short, covered, metallic stents, while other authors suggest the use of nasobiliary drainage. Conclusions: A multidisciplinary evaluation (made by a surgeon, biliary endoscopist, gastroenterologist, and radiologist) of jaundiced neoplastic patients should be performed before deciding to perform biliary drainage. Middle-distal obstruction in patients who are candidates for PD does not usually require routine biliary drainage. Proximal obstruction in patients who are candidates for major hepatic resection in the majority of cases requires a drain; however, the type, site, number, and approach must be defined and tailored according to the planned hepatic resection. Recently, the use of preoperative biliary drainage limited to the FLR has been a suggested strategy. However, multicenter, randomized, controlled trials should be conducted to clarify this issue.

Comparison of seven staging systems in cirrhotic patients with hepatocellular carcinoma in a cohort of patients who underwent radiofrequency ablation with complete response.

BACKGROUND AND AIMS:Many staging systems for hepatocellular carcinoma (HCC) have been proposed but the best tool for staging of HCC remains controversial. The aim of the present study was to identify the best staging system evaluating the predictive ability for outcome for each of the seven different staging systems applied in a homogeneous group of patients who underwent percutaneous radiofrequency ablation (RFA).METHODS:We analyzed retrospectively 112 patients with HCC and cirrhosis treated with percutaneous RFA from January, 1998 to April, 2005. Response to treatment after 30 days and for long-term follow-up was evaluated with computed tomography (CT) or magnetic resonance imaging (MRI) and serum alpha-fetoprotein level (AFP). All of the 112 patients were grouped according to each one of the seven different staging systems: Okuda, TNM, BCLC, CLIP, GRETCH, CUPI, JIS.RESULTS:The mean follow-up time of the 112 patients submitted to RFA was 24 months (range 3–92 months) with survival rates at 1, 3, and 5 yr of 82%, 40%, and 18%, respectively. Univariate and multivariate analyses showed that factors related to survival were Child-Pugh score (P ≤ 0.01), serum AFP (P ≤ 0.01), and the response to treatment (P ≤ 0.01) with hazard ratios of 2.09 (95% CI 1.21–3.61), 2.79 (95% CI 1.59–4.90), and 2.76 (95% CI 1.25–6.09), respectively. The comparison of the results of the different staging systems in all of the 112 patients and in a subgroup of 96 patients with complete response to treatment showed that BCLC had the best discrimination ability, monotonicity of gradient (linear trend χ2 6.07, P = 0.01), and homogeneity ability (LR χ2 test 10.00, P = 0.008).CONCLUSIONS:The BCLC staging system shows a superior discriminatory power in our cohort of HCC patients who underwent RFA; moreover, it can give important prognostic information after complete response to treatment. Our study confirms the validity of the BCLC staging system in patients with HCC in cirrhosis.

Combined Irinotecan and Oxaliplatin in Patients with Advanced Pre-Treated Pancreatic Cancer

Objectives: This study evaluated the clinical activity and toxicity of combination chemotherapy with irinotecan and oxaliplatin in patients with advanced pancreatic cancer that had progressed despite ≧1 course of a gemcitabine-containing regimen. Methods: Thirty patients with metastatic pancreatic cancer and Karnofsky performance status ≧70 received oxaliplatin 60 mg/m2 on days 1 + 15 and irinotecan 60 mg/m2 on days 1 + 8 + 15 every 4 weeks. Patients were assessed on the basis of clinical benefit response, changes in serum tumour marker CA 19-9, objective tumour response, time to progressive disease (TTP), and survival. Results: Six patients (20%) had clinical benefit response (median duration of 7.2 months). CA 19-9 levels were reduced ≧50% from baseline in 8 patients (26%) and remained stable in 8 patients. CT scans revealed that 3 patients (10%) had a partial response and 7 (23%) had stable disease. Two patients (7%) were down-staged and underwent surgery. Median TTP was 4.1 months, median survival was 5.9 months and the 1-year survival rate was 23.3%. The most serious adverse events were grade 3–4 leukopenia in 2 patients (6%), grade 3 neuropathy in 2 (6%) and grade 3 diarrhoea in 1 (3%). Conclusion: Chemotherapy with irinotecan and oxaliplatin is an active and well-tolerated combination in patients with advanced pre-treated pancreatic cancer.

Expression of progesterone receptors in solid-cystic tumour of the pancreas : a clinicopathological and immunohistochemical study of ten cases

A role for sex hormones in the pathogenesis of solid-cystic tumour (SCT) of the pancreas is suggested by its predilection for young fertile women. Controversial data have been provided for the presence of progesterone receptors (PR) and/or oestrogen receptors (ER) in SCT. We report the immunohistochemical detection of PR in ten cases of SCT. Eight were from young women. The remaining two were from a post-menopausal woman and a young boy. All cases showed PR immunoreactivity in the large majority of neoplastic cells, whereas none exhibited ER positivity. In one tumour two types of cell populations were noted, the more anaplastic invasivetype being PR negative, whereas the more typical was PR positive. PR immunoreactivity in the absence of ER may simply reflect a lower sensitivity of ER antibody failing to reveal the biochemically detectable ER, or that the PR in cells of SCT are constitutively synthesized in an oestrogen-independent way, as in T47D breast carcinoma cell line, meningioma cells and some gastric cancer cells. Our findings support the hypothesis of a possible pathogenetic role of progesterone in SCT, independent of the patients sex and age.

Pancreatic endocrine tumours: Evidence for a tumour suppressor pathogenesis and for a tumour suppressor gene on chromosome 17p

Two molecular pathways leading to cancer are known. Common‐type cancers arise from the ‘tumour suppressor’ pathway, characterized by gross chromosomal changes and allelic losses (LOH) in an average of 25 per cent or more of randomly chosen chromosomal loci. The ‘mutator pathway’ has been recognized in a subset of cancers, characterized by widespread microsatellite DNA instability and rarity of chromosomal losses. The present study has investigated 20 pancreatic endocrine tumours (PETs) for loss of heterozygosity (LOH) at seven chromosomal loci (3p14, 7q31–32, 11q13, 13q14, 18q21, 17p13, and 17q21); microsatellite instability; and Ki‐ras, N‐ras, and p53 gene mutations. LOH was found in an average of 24 per cent of the chromosomal loci analysed. No tumour showed microsatellite instability. Ki‐ras and p53 mutations were each found in one case. The frequency of losses was higher in malignant (40 per cent) than in benign (17 per cent) tumours (p=0·009), and the specific chromosome 17p13 LOH was associated with extrapancreatic extension of disease (p=0·007), high proliferative activity (p=0·001), and absence of progesterone receptors (p=0·01). A common deleted region on chromosome 17p13 and the rarity of p53 gene mutations suggest the existence of a novel tumour suppressor gene involved in the pathogenesis of PETs in this chromosomal area.

Immunodetection of proliferating cell nuclear antigen assesses the growth fraction and predicts malignancy in endocrine tumors of the pancreas

Thirty-five endocrine tumors of the pancreas, 17 functioning and 18 nonfunctioning, were immunohistochemically studied for the expression of proliferating cell nuclear antigen (PCNA) using 19A2 and PC10 monoclonal antibodies. The proportion of PCNA-reactive cells (PCNA index) ranged from 0.2 to 27% in functioning tumors and from 0.1% to 55% in nonfunctioning tumors. PCNA index showed a statistically significant correlation with mitotic and Ki67 indexes. The median values of PCNA index identified three groups of patients: group A PCNA ≤ 2%), including 13 functioning and six nonfunctioning tumors; group B (PCNA between 2 and 5%), including three functioning and three nonfunctioning tumors; group C (PCNA > 5%), including one functioning and nine nonfunctioning tumors. All group A tumors were confined to the pancreas. In group B, the functioning tumors were limited to the pancreas, and the nonfunctioning tumors extended to extrapancreatic tissues. All group C patients had extrapancreatic extension of the disease. At follow-up, a PCNA index higher than 5% correlated to a decreased mean survival. Our data suggest that PCNA index is a reliable tool to assess the growth fraction, discern local from advanced diseases, and predict malignancy in pancreatic endocrine tumors.