A novel serum marker for biliary tract cancer: diagnostic and prognostic values of quantitative evaluation of serum mucin 5AC (MUC5AC).

BACKGROUND AND AIMS: Mucin 5AC (MUC5AC) is a glycoprotein found in different epithelial cancers, including biliary tract cancer (BTC). The aims of this study were to investigate the role of MUC5AC as serum marker for BTC and its prognostic value after operation with curative intent. PATIENTS AND METHOD: From January 2007 to July 2012, a quantitative assessment of serum MUC5AC was performed with enzyme-linked immunoassay in a total of 88 subjects. Clinical and biochemical data (including CEA and Ca 19-9) of 49 patients with BTC were compared with a control population that included 23 patients with benign biliary disease (BBD) and 16 healthy control subjects (HCS). RESULTS: Serum MUC5AC was greater in BTC patients (mean 17.93 ± 10.39 ng/mL) compared with BBD (mean 5.95 ± 5.39 ng/mL; P < .01) and HCS (mean 2.74 ± 1.35 ng/mL) (P < .01). Multivariate analysis showed that MUC5AC was related with the presence of BTC compared with Ca 19-9 and CEA: P < .01, P = .080, and P = .463, respectively. In the BTC group, serum MUC5AC ≥ 14 ng/mL was associated with lymph-node metastasis (P = .050) and American Joint Committee on Cancer and International Union for Cancer Control stage IVb disease (P = .047). Moreover, in patients who underwent operation with curative intent, serum MUC5AC ≥ 14 ng/mL was related to a worse prognosis compared with patients with lesser levels, with 3-year survival rates of 21.5% and 59.3%, respectively (P = .039). CONCLUSION: MUC5AC could be proposed as new serum marker for BTC. Moreover, the quantitative assessment of serum MUC5AC could be related to tumor stage and long-term survival in patients with BTC undergoing operation with curative intent.

Hepatocellular carcinoma in cirrhotic patients with portal hypertension: is liver resection always contraindicated?

AIM: To analyze the outcome of hepatocellular carcinoma (HCC) resection in cirrhosis patients, related to presence of portal hypertension (PH) and extent of hepatectomy. METHODS: A retrospective analysis of 135 patients with HCC on a background of cirrhosis was submitted to curative liver resection. RESULTS: PH was present in 44 (32.5%) patients. Overall mortality and morbidity were 2.2% and 33.7%, respectively. Median survival time in patients with or without PH was 31.6 and 65.1 mo, respectively (P = 0.047); in the subgroup with Child-Pugh class A cirrhosis, median survival was 65.1 mo and 60.5 mo, respectively (P = 0.257). Survival for patients submitted to limited liver resection was not significantly different in presence or absence of PH. Conversely, median survival for patients after resection of 2 or more segments with or without PH was 64.4 mo and 163.9 mo, respectively (P = 0.035). CONCLUSION: PH is not an absolute contraindication to liver resection in Child-Pugh class A cirrhotic patients, but resection of 2 or more segments should not be recommended in patients with PH.

Prognostic significance of lymph node ratio after resection of peri-hilar cholangiocarcinoma.

BACKGROUND: Lymph node (LN) metastases are a major negative prognostic factor for peri-hilar cholangiocarcinoma (PCC). Prognostic significance of the extent of LN dissection, number of metastatic LN and the lymph node ratio (LNR) are still under debate. AIMS: The aims of the present study were to evaluate the prognostic value of the LN status, the total number of LNs evaluated and LNR in PCC. METHODS: Between 1990 and 2008, 62 patients with PCC submitted to surgical resection with curative intent were retrospectively evaluated. Number and status of harvested LN were recorded. RESULTS: In 53 patients (85.4%) regional lymphadenectomy was performed. Median number of LNs examined was 7 (range 1-25). Median survival was 41.9 months in patients with N0 compared with 22.7 months in 21 patients (39.6%) with N+ (P= 0.03). Median survival was 3, 18.5 and 29 months for patients with 0, 1-3 and >3 LN retrieved, respectively (P < 0.01). Five-year survival for patients above and below the LNR cut-off value of 0.25 was 0% and 22.5%, respectively (P= 0.03). CONCLUSIONS: LN metastases are a major prognostic factor for survival after surgical resection of PCC. The number of LN harvested and LNR showed high prognostic value.

Does intrahepatic cholangiocarcinoma have better prognosis compared to perihilar cholangiocarcinoma?

BACKGROUND AND OBJECTIVES: Cholangiocarcinoma can be classified as intrahepatic (ICC) or perihilar (PCC). The objectives of this study is to evaluate the surgical outcomes of patients with PCC and ICC, identify the main prognostic factors related to survival and compare the outcome and the prognostic factors of PCC and ICC. METHODS: Ninety-five out of 152 patients observed between January 1990 and December 2007 at Surgical Division of University of Verona Medical School underwent the resection of ICC (33 patients) or PCC (62 patients). RESULTS: Overall median survival was 24 months with a 3- and 5-year survival rate of 45% and 23%, respectively. Prognostic factors for survival were macroscopic types of the tumor, the resection of extrahepatic bile duct, radical resection, lymph node metastases, and macro-vascular invasion. Survival was related with the macroscopic type of the tumors with a 5-year survival rate of 26% and 13% for ICC and PCC, respectively. Univariate analysis identified that negative clinico-pathological factors where significant more frequently found in PCC compared to ICC. CONCLUSION: We identified that ICC have longer survival rate compared to PCC. PCC showed a higher frequency of negative clinico-pathological factors such as non-radical (R+) resection, perineural infiltration and macro-vascular invasion.

Is liver resection justified in advanced hepatocellular carcinoma? Results of an observational study in 464 patients.

BACKGROUND AND OBJECTIVE: The role of liver resection in advanced hepatocellular carcinoma (multinodular or with macroscopic vascular involvement) is still controversial. The aim of this study is to evaluate the role of surgical resection compared to other therapeutic modalities in patients with advanced hepatocellular carcinoma (HCC). METHODS: Four hundred sixty four patients with HCC observed from 1991 to 2007 were included in the study. All the patients were evaluated for the treatment of HCC in relation to the severity of liver impairment and tumor stage. All the patients included in the study had no evidence of distant metastases. RESULTS: Median follow up time for surviving patients was 25 months (range 1-155). Two-hundred and eighty-three patients were in Child-Pugh class A, 161 in class B, and 20 in class C. Two-hundred and seventy-one patients had single HCC, 121 patients had two or three HCCs, and 72 more than three HCCs. One-hundred and thirty-six patients (29.3%) were submitted to liver resection (LR), 232 (50.0%) to local ablative therapies (LAT) (ethanol injection, radiofrequency ablation, chemoembolization), eight (1.7%) to liver transplantation (LT), and 88 (19%) to supportive therapy (ST). Median survival time for all patients was 36 months (95% CI 24-36). Median survival time was 57 months for LR, 30 months for LAT, and 8 months for ST, with a 5-year survival of 47%, 20%, and 2.5%, respectively (p = 0.001). Actuarial 5-year survival for patients submitted to LT was 75%. Overall survival was significantly shorter in patients with multiple HCCs compared to single HCC, with median survival times of 39, 16, and 11 months for patients with a single HCC, with two to three HCCs, and with more than three HCCs, respectively (p = 0.01). Survival for patients with single HCC was significantly longer in patients submitted to LR compared to LAT and ST with median survival times of 57, 37, and 14 months, respectively (p = 0.02). Also, in patients with multinodular HCCs (2-3 HCCs) LR showed the best results with a median survival time of 58 months compared to 22 and 8 months for LAT and ST (p = 0.01). In patients with more than three HCCs, LR did not show different results compared to LAT and ST. Seventy-three patients had evidence of macroscopic vascular involvement; median survival in this subgroup of patients was significantly shorter compared to patients without vascular involvement, 10 and 36 months, respectively. Survival for patients with macroscopic vascular involvement submitted to LR or LAT was significant longer compared to ST, with mean survivals of 27, 30, and 12 months, respectively (p = 0.01). CONCLUSIONS: The present study shows that the surgery can achieve good results in patients with single HCC and good liver function. Also, patients with multinodular HCCs (two to three nodules) could benefit from LR where survival is longer than after LAT or ST. In patients with more than three HCCs, LR have similar results of LAT. Macroscopic vascular invasion is a major prognostic factor, and the LR is justified in selected patients, where it can allow good long-term results compared to ST.

Superextended hepatectomy for resection of multiple giant hemangiomas: report of a case.

Most liver hemangiomas are small, asymptomatic, and require no treatment. Symptoms such as right upper quadrant abdominal pain and fullness are associated only with liver hemangiomas larger than 4 cm in diameter. Serious complications such as jaundice, Kasabach-Merritt syndrome, and rupture are rare. Surgical resection is the only effective treatment, but it is advocated only for patients with incapacitating symptoms or complications. We report a case of successful superextended hepatectomy with resection of segments III-VIII for multiple, bilobar hemangiomas. A 45-year-old woman, who had undergone transcatheter arterial embolization (TAE) for inoperable multiple giant liver hemangiomas 4 years earlier, was referred to our hospital for investigation of abdominal distension and consumption coagulopathy. Because of her severe and progressive symptoms despite treatment, the other hospital had considered her as a candidate for liver transplantation, which she had refused. After careful preoperative assessment of the future liver remnant volume and function, we considered that resection was possible. Based on our review of large surgical series in the literature from 1970, this is the first report of a superextended hepatectomy for a benign liver tumor.

A rare surgical case of multiple liver resections for recurrent liver metastases from pancreatic gastrinoma: liver and vena cava resection.

Pancreatic gastrinoma is a rare non-beta islet cell tumor. Approximately 60% of gastrinomas are malignant; despite the fact that they are usually slow growing, liver metastases have a major impact on prognosis. Most authors have advocated aggressive surgical management as being the only potentially curative therapy to improve survival as well as to provide outstanding relief from symptoms. We present a case of a 57-year-old man referred to our hospital with a diagnosis of liver metastases from pancreatic gastrinoma, with suspected involvement of the inferior vena cava (IVC). At the age of 37 years, he was diagnosed in his local hospital as having a pancreatic gastrinoma, with liver metastases, and he underwent distal pancreatectomy, splenectomy and enucleation of liver metastases. A liver tumor recurred twice, 7 and 9 years after the first surgery, for which double liver resections were performed: the first time he underwent enucleation of multiple liver metastases in segments II, III, IV, V, VI, VII and VIII, with resection of the right hepatic vein and partially resection of the diaphragm; the second time he underwent enucleation of multiple liver metastases in segments II, III, IV, and V. In our hospital, 8 years after the last surgery, the patient underwent right extended trisectionectomy, resection of segment I, combined resection of the IVC, and partial removal of the diaphragm. To the best of our knowledge, from a review of the literature, this is the first case to achieve successful long-term survival through aggressive surgical management of this type of metastatic endocrine tumor. The patient described here is still alive, free of disease and leading a normal life, 20 years after the initial diagnosis and 3 years after the last surgery.

Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor. The resectability rate is low because at the time of diagnosis this disease is frequently beyond the limits of surgical therapy. Curative resection (R0) is the most effective treatment and the only therapy associated with prolonged disease-free survival. Based on the gross appearance of the tumor the Liver Cancer Study Group of Japan (LCSGJ) defined three types: mass-forming type (MF), periductal infiltrating type (PI), intraductal growth (IG) type. The prognostic significance of gross type has been demonstrated in Eastern countries, but this issue has not been clarified in Western countries. The aim of this study was to identify the prognostic factors for survival in a group of patients submitted to surgical resection for ICC. METHODS: Between 1990 and 2007 a total of 81 consecutive patients with ICC were submitted to surgery. Patients with peritoneal carcinomatosis, extensive vascular involvement, or multiple intrahepatic metastases were excluded from surgical resection. Tumors were classified according to TMN stage (6th edition, 2002) and LCSGJ gross type classification. Tumor gross appearance on the cut surface was categorized into the following types according to the classification proposed by the Liver Cancer Study Group of Japan: MF, PI, or IG type. RESULTS: During the study period 52 patients were submitted to surgical resection with curative intent, whereas in 29 patients surgery was limited to explorative laparotomy. Curative resection (R0) was achieved in 43 patients (83%); and a major hepatic resection was performed in 63% (33/52) of the patients. Extrahepatic bile duct resection was carried out in 36% (19/52) of cases. According to the LCSGJ classification, the MF type was present in 34 patients (65%), the MF + PI type in 13 (25%), the PI type in 3 (6%), and the IG type in 2 (4%). Overall median survival time was 40 months, with a 1-, 3-, and 5-year actuarial survival rates of 83%, 50%, 20%, respectively. Survival was significantly related to the macroscopic gross type, with a median survival of 50 months for patients with the MF type, 19 months for the MF + PI type, 15 months for the PI type, and 17 months for the IG type. At univariate analysis, the macroscopic gross appearance of the tumor, the presence of lymph node metastasis, involvement of extrahepatic bile ducts, the presence of macroscopic vascular invasion, and positive resection margins were significant related to survival. At multivariate analysis, macroscopic vascular invasion and lymph nodes metastases were significant related to survival with hazard ratios of 4.11 and 2.79, respectively. Further statistical analyses were carried out to identify the relation between macroscopic gross type and prognosis. We identified that the MF + PI type tumors were significantly associated with negative prognostic factors, such as the involvement of extrahepatic bile ducts, the presence of lymph nodes metastases, the presence of macroscopic vascular invasion, the presence of perineural invasion, and higher T stage. CONCLUSIONS: Curative resection of ICC is the only therapy that can achieve long-term survival. The best results were observed in patients who underwent R0 resection for MF tumors without lymph node metastases or vascular invasion. Important predictive factors related to poor survival are MF + PI macroscopic tumor type, lymph node metastases, and vascular invasion. In these patients, other therapeutic approaches (i.e., adjuvant or neoadjuvant therapy) should be evaluated to improve results.

Undifferentiated embryonal sarcoma of the liver: case report and literature survey.

Undifferentiated embryonal sarcoma (UES) of the liver was first identified as an independent clinicopathologic type of sarcoma in 1978. It is an uncommon hepatic tumor, of mesenchymal origin, usually observed in children, and cases in adults are rare: to our best knowledge, reports of only 51 cases have been published in the past 50 years. We present a case of UES of the liver in a previously healthy 22 year-old woman, admitted to our hospital due to a palpable mass in the right upper abdomen. On admission, laboratory studies showed mildly elevated aspartate aminotransferase, alkaline phosphatase, and gamma-GPT. Hepatitis and tumor markers were negative. Ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) showed a large mass involving the right lobe and the medial segment of the liver, with compression of the bile duct. Right trisectionectomy with bile duct resection and reconstruction was performed. Microscopically, the tumor was composed of pleomorphic spindle cells in a myxoid stroma with focal staining of S-100 by immunohistochemistry. The histologic diagnosis was UES. Adjuvant therapy with vincristine, actinomycin-D, and cyclophosphamide was performed, and at 14 months of follow-up, the patient is alive without any evidence of recurrence. The clinical and histopathological features, as well as the therapeutic choices for adult UES, are described for this patient and in the literature of the past 50 years.

Radiofrequency ablation versus surgical resection for the treatment of hepatocellular carcinoma in cirrhosis.

BACKGROUND AND AIMS: Percutaneous radiofrequency ablation (RFA) demonstrated good results for the treatment of hepatocellular carcinoma (HCC) in cirrhotic patients; it is still not clear whether the overall survival and disease-free survival after RFA are comparable with surgical resection. The aims of this study are to compare the overall survival and disease-free survival in two groups of cirrhotic patients with HCC submitted to surgery or RFA. METHODS: Two hundred cirrhotic patients with HCCs smaller than 6 cm were included in this retrospective study: 109 underwent RFA and 91 underwent surgical resection at a single Division of Surgery of University of Verona. RESULTS: Median follow-up time was 27 months. Overall survival was significantly longer in the resection group in comparison with the RFA group with a median survival of 57 and 28 months, respectively (P=0.01). In Child-Pugh class B patients and in patients with multiple HCC, survival was not significantly different between the two groups. In patients with HCC smaller than 3 cm, the overall survival and disease-free survival for RFA and resection were not significantly different in univariate and multivariate analysis. Whereas in patients with HCC greater than 3 cm, surgery showed improvement in outcome in both univariate and multivariate analysis. CONCLUSIONS: Surgical resection significantly improves the overall survival and disease-free survival in comparison with RFA. In a selected group of patients (Child-Pugh class B, multiple HCC, or in HCC

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

The Dagradi-Serio-Iacono operation central pancreatectomy.

Central pancreatectomy (CP) is a segmental pancreatic resection indicated to remove benign or low-grade malignant tumors of the isthmus and proximal part of the body of the pancreas. The main advantage of this operation compared with major resections is that it permits to spare normal pancreatic parenchyma; moreover, spleen and upper digestive and biliary tracts are saved. The description of the complete operation was reported for the first time by Dagradi and Serio in 1984 and subsequently spread worldwide by Iacono and Serio. In our opinion, it should be called the Dagradi-Serio-Iacono operation, by the names of the surgeons who first performed it (Dagradi and Serio), and by the names of the surgeons responsible for reporting it worldwide with precise indications (Iacono and Serio). Operation requires a midline or a bilateral subcostal incision; the lesser sac is entered through dissection of the transverse colon from the omentum or by transecting the gastrocolic ligament. The pancreatic segment harboring the lesion is then mobilized and its posterior surface carefully dissected from the splenic vein and artery. Subsequently, the pancreatic portion harboring the tumor is isolated at its superior margin from the splenic artery after the pancreas is transacted. The extent of the resection of the central segment is limited on the right by the gastroduodenal artery and on the left by the need to leave at least 5 cm of normal pancreatic remnant. The resected pancreatic specimen is sent to the pathologist for confirmation of diagnosis and to check if the resection margins are adequate. Hemostasis of the two raw surfaces is achieved with interrupted 5 or 4/0 nonabsorbable stitches. When it is not stapled, the Wirsung's duct of the cephalic stump is sutured selectively with a figure-of-eight nonabsorbable stitch. An end-to-end invaginated pancreaticojejunostomy is carried out with a single layer of interrupted stitches. The operation is concluded with the construction of an end-to-side jejuno-jejunostomy about 50 cm distal to the pancreatic anastomosis. Other techniques for reconstruction of the distal stump using jejunum or stomach have been described. One or two soft drains are brought out on the right side. The fluid collected from this drain is checked for amylase level on postoperative days 3, 5, and 7; if the level is low or absent, the drain is removed. Central pancreatectomy is a safe technique for benign or low malignant tumors of the pancreatic neck that allows curing the tumor with evident functional results without increasing the risk for the patient. We can say that CP has a clear role like pancreaticoduodenectomy and distal pancreatectomy and we think that a pancreatic surgeon has to include this procedure in his/her technical skills. In order to obtain excellent results, correct indications and experience in pancreatic surgery are recommended.

Radio frequency ablation for hepatocellular carcinoma in cirrhotic patients: prognostic factors for survival.

BACKGROUND: Radio frequency ablation (RFA) of hepatocellular carcinoma has proved to be useful in local control of tumor. A few data on survival after treatment are available in literature. The aim of the study was to evaluate factors related to survival and to identify different classes of risk after radio frequency ablation. METHODS: Ninety-eight cirrhotic patients with 145 hepatocellular carcinomas were treated with radio frequency ablation from January 1998 to May 2004. In 55 patients, cirrhosis was in Child-Pugh class A, and in 43, in class B. Tumor was single in 60 and multiple in 38; mean tumor number was 1.5 (range 1-3). Tumor size ranged from 1.5 to 6.0 cm, mean 3.8 cm. Mean follow up period was 24.9 months. Radio frequency ablation was performed with expandable type needle with percutaneous approach under real-time ultrasound guidance. For statistical analysis, univariate and multivariate analysis were performed. RESULTS: Complete ablation of the tumor was achieved in 85.5% of lesions. Survival, 1 and 3 years, was 76.7 and 36.6%, respectively. Univariate analysis showed that Cancer of the Liver Italian Program (CLIP) score, tumor growth pattern, alpha-fetoprotein level, and complete tumor necrosis, were factors significantly related to poor survival. Multivariate analysis identified that factors related to poor survival were alpha-fetoprotein level >100 ng/ml, Child-Pugh class B, and incomplete tumor necrosis with a hazard ratio of 4.0, 2.7, and 3.8, respectively. After complete ablation, median survival was 38 months in patients with Child-Pugh class A cirrhosis and alpha-fetoprotein level < or =100 ng/ml, 22 months for patient with Child-Pugh class B cirrhosis and alpha-fetoprotein < or =100 ng/ml, and 9 months for patient with Child-Pugh class A cirrhosis and alpha-fetoprotein >100 ng/ml (P < 0.01). CONCLUSIONS: Complete necrosis and absence of residual tumor positively affect survival after RFA. In patients with Child-Pugh A cirrhosis and alpha-fetoprotein level < or =100 radio frequency, ablation have results, 55% after 3 years, that are comparable to those of surgical resection. Patients with Child-Pugh B cirrhosis and/or alpha-fetoprotein >100 ng/ml showed less satisfactory results, and in these patients, multimodality treatment or other treatments should be considered.

Rapid progression of hepatocellular carcinoma after Radiofrequency Ablation.

AIM: To report the results of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) in cirrhotic patients and to describe the treatment related complications (mainly the rapid intrahepatic neoplastic progression). METHODS: Eighty-seven consecutive cirrhotic patients with 104 HCC (mean diameter 3.9 cm, 1.3 SD) were submitted to RFA between January 1998 and June 2003. In all cases RFA was performed with percutaneous approach under ultrasound guidance using expandable electrode needles. Treatment efficacy (necrosis and recurrence) was estimated with dual phase computed tomography (CT) and alpha-fetoprotein (AFP) level. RESULTS: Complete necrosis rate after single or multiple treatment was 100%, 87.7% and 57.1% in HCC smaller than 3 cm, between 3 and 5 cm and larger than 5 cm respectively (P=0.02). Seventeen lesions of 88(19.3%) developed local recurrence after complete necrosis during a mean follow up of 19.2 mo. There were no treatment-related deaths in 130 procedures and major complications occurred in 8 patients (6.1 %). In 4 patients, although complete local necrosis was achieved, we observed rapid intrahepatic neoplastic progression after treatment. Risk factors for rapid neoplastic progression were high preoperative AFP values and location of the tumor near segmental portal branches. CONCLUSION: RFA is an effective treatment for hepatocellular carcinoma smaller than 5 cm with complete necrosis in more than 80% of lesions. Patients with elevated AFP levels and tumors located near the main portal branch are at risk for rapid neoplastic progression after RFA. Further studies are necessary to evaluate the incidence and pathogenesis of this underestimated complication.