Development of gallbladder cancer during follow-up of pancreaticobiliary maljunction: a report of two cases.

Pancreaticobiliary maljunction (PBM) is a congenital malformation. The reflux of pancreatic juice into the biliary tract caused by PBM plays a significant role in the development of biliary tract cancers (BTCs), such as gallbladder cancer and cholangiocarcinoma. Previous studies have demonstrated a high incidence of BTC in patients with PBM. However, there are only a few reports of patients who developed BTC after a diagnosis of PBM. We report the cases of two patients who developed gallbladder cancer after being diagnosed with PBM. They had refused treatment and were being managed with follow-up observation alone after the diagnosis of PBM and developed gallbladder cancer after several years of observation. Thus, surgical treatment should be recommended for all patients with PBM in order to prevent the development of BTC. Moreover, long-term, close, regular follow-up is necessary to facilitate the early diagnosis of subsequent BTC in patients with untreated PBM.

Intrahepatic cholangiocarcinoma with a tumor thrombus extending from the inferior vena cava to the right atrium: a case report.

BACKGROUND: Vascular invasion involving a tumor thrombus in the inferior vena cava and/or right atrium is an unfavorable prognostic factor after intrahepatic cholangiocarcinoma resection. We report an intrahepatic cholangiocarcinoma case with a tumor thrombus extending from the left hepatic vein via the inferior vena cava to the right atrium. CASE PRESENTATION: A 58-year-old man with epigastralgia was referred to our hospital after an emergent transcatheter arterial embolization was done following the radiological diagnosis of a ruptured hepatic tumor. The serum concentrations of carcinoembryonic antigen, carbohydrate 19-9, duke pancreatic monoclonal antigen type 2, and cytokeratin-19 fragments were elevated; meanwhile those of alfa-fetoprotein and des-γ-carboxy prothrombin were within normal ranges. A contrast-enhanced computed tomography scan showed a heterogeneously enhanced tumor, 13 cm in diameter, in the left lobe of the liver, enlarged lymph nodes along the lesser curvature of the stomach, and a tumor thrombus extending from the left hepatic vein via the inferior vena cava to the right atrium. We performed a left hemihepatectomy and tumor thrombectomy under total hepatic vascular exclusion to reduce the risk of sudden death. After dissection of the liver parenchyma along the left side of the middle hepatic vein, except for the left hepatic vein, the inferior vena cava just below the right atrium could be clamped by pulling down the left lobe of the liver toward the caudal side. The thrombus could be removed by incising the inferior vena cava under total hepatic vascular exclusion. Microscopic examination showed a tubular adenocarcinoma. Immunohistochemical staining was positive for cytokeratin-7, cytokeratin-19, and epithelial membrane antigen, but negative for arginase-1, glypican-3, and hepatocyte. The patient was pathologically diagnosed with an intrahepatic cholangiocarcinoma with a tumor thrombus in the inferior vena cava. Adjuvant chemotherapy with tegafur/gimeracil/oteracil was administered for 1 year. The patient remained in good health without cancer recurrence for over 4 years after the operation. CONCLUSION: An aggressive surgical approach may be indicated for intrahepatic cholangiocarcinoma with a tumor thrombus in the inferior vena cava and/or right atrium to avoid the risk of impending death.

Outcomes of Non-B Non-C Hepatocellular Carcinoma with Reference to Patients with Interferon-Induced Hepatitis C Virus Eradication.

PURPOSE: This study aimed to evaluate survival outcomes in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC) with reference to patients with HCC achieving sustained virological response (SVR) by preoperative interferon (IFN) treatment for chronic hepatitis C. METHODS: We examined 781 patients who underwent hepatic resection for HCC. They were classified into NBNC-HCC, SVR-HCC, and non-SVR HCC groups. RESULTS: Multivariate analysis for recurrence-free survival (RFS) and overall survival (OS) revealed that the adjusted hazard ratios (HR) of NBNC-HCC and non-SVR HCC groups with reference to the SVR-HCC group were 1.46 (p = 0.10) and 2.10 (p < 0.001), respectively, for RFS, and 1.69 (p = 0.024) and 2.11 (p < 0.001), respectively, for OS. Worsening of Child-Pugh grade at recurrence was confirmed in 21 patients (17.1%) with NBNC-HCC but not in those with SVR-HCC (p = 0.017, SVR vs. NBNC). In the NBNC-HCC group, hepatic resection for intrahepatic recurrence was adopted in 17.4% of patients without worsening of Child-Pugh grade at recurrence, whereas hepatic resection was not adopted in those with grade worsening. Among patients with alcoholic hepatitis, Child-Pugh grade worsening at recurrence was more frequently observed in patients with sobriety than those without sobriety (14.3% vs. 46.2%, p = 0.049). CONCLUSIONS: NBNC-HCC patients had an increased risk for overall death as compared with those with SVR-HCC. Worsening of background liver function may reduce the chances of re-hepatic resection for recurrence and increase the risk for overall death in NBNC-HCC patients. For alcoholic hepatitis patients, sobriety may prevent deterioration of liver function after surgery.

Long-term outcomes after biliary diversion operation for pancreaticobiliary maljunction in adult patients.

AIM: Pancreaticobiliary maljunction (PBM) with or without congenital biliary dilatation (CBD) is a risk factor for biliary tract cancer. We investigated long-term outcomes after biliary diversion operation with special reference to types of CBD. METHODS: Subjects comprised 40 adult patients who underwent biliary diversion operation for PBM without biliary tract cancer. Group A comprised 20 patients with type Ia or Ic CBD, or non-dilated bile ducts, while group B comprised 20 patients with type IV-A CBD. The clinical findings and postoperative outcomes were compared between groups. RESULTS: Of 40 patients, nine patients suffered from repeated cholangitis and eight of these nine patients suffered from hepatolithiasis after biliary diversion operation. Biliary tract cancer or pancreatic cancer was detected in four patients at 3 years and 2 months to 24 years after the operation. In three of these four patients, the serum concentration of carbohydrate antigen 19-9 increased before detection of carcinoma. One patient died of hepatic failure due to repeated cholangitis. The proportions of patients with repeated cholangitis, hepatolithiasis, and re-operation, and patients who died of biliary tract cancer, pancreatic cancer, or hepatic failure, were significantly higher in group B than in group A. The survival rate was significantly worse in group B than in group A. CONCLUSIONS: Careful long-term follow-up with measurement of serum tumor markers is necessary after biliary diversion operation for PBM, especially in patients with type IV-A CBD or repeated cholangitis.

Pirfenidone suppresses polarization to M2 phenotype macrophages and the fibrogenic activity of rat lung fibroblasts.

Pirfenidone is a representative medication to treat interstitial pulmonary fibrosis. Researchers reported pirfenidone (>100 µg/ml) significantly suppressed fibroblast growth in vitro. However, clinically, the maximum concentration of pirfenidone in the blood is approximately 10 µg/ml. We hypothesized there might be an additional mechanism of pirfenidone to fibroblasts indirectly. Macrophages are known to control the activation of fibroblasts via the regulation of inflammatory M1 and suppressive M2 polarization. The aim of this study was to investigate the effects of pirfenidone on alveolar macrophage polarization. Rat alveolar macrophages (NR8383) were stimulated in vitro with lipopolysaccharide (LPS) + interferon (IFN)-γ, or interleukin (IL)-4 + IL-13. Expression of M1 and M2 markers and supernatant's levels of TGF-ß1 were assessed after pirfenidone treatment (0-100 µg/ml). Treatment with LPS + INF-γ or IL-4 + IL-13 significantly increased the expression of M1 and M2 markers, respectively. In macrophage polarization assays, pirfenidone significantly reduced the expression of M2 markers at concentrations greater than 10 µg/ml but had no effect on the expression of M1 markers. At these concentrations, pirfenidone significantly reduced TGF-ß1 levels in NR8383 culture supernatants. In rat lung fibroblasts treated with NR8383 culture supernatants, pirfenidone significantly suppressed proliferation, and the collagen mRNA and protein levels. In conclusion, our results demonstrated that pirfenidone suppressed polarization to M2 macrophages at clinically relevant concentrations and suppressed the rat lung fibroblasts fibrogenic activity.

Obesity and recurrence-free survival in patients with hepatocellular carcinoma after achieving sustained virological response to interferon therapy for chronic hepatitis C.

AIM: Some patients who achieve a sustained virological response (SVR) to interferon (IFN) treatment for chronic hepatitis C prior to hepatic resection for hepatocellular carcinoma (HCC) experience postoperative recurrence. This study investigated the relationship between obesity and postoperative HCC recurrence in SVR patients. METHODS: Fifty-nine patients who had achieved SVR before hepatic resection were evaluated. Patients had a solitary tumor ≤5 cm in diameter or ≤3 lesions each ≤3 cm in size with no macroscopic vascular invasion (Milan criteria). Patient characteristics potentially associated with recurrence risk were investigated. RESULTS: Three-, 5-, and 7-year recurrence-free survival after surgery were 65%, 44%, and 41%, respectively. Univariate analysis showed that obesity (P < .01), hypertension (P = .038), and non-anatomical resection (P = .022) were significantly associated with a lower recurrence-free survival rate. In a multivariate analysis, obesity (hazard ratio, 2.8; 95% confidence interval [CI] 1.3-6.1; P < .01) and non-anatomical resection (hazard ratio, 2.7; 95% CI 1.1-6.2; P = .025) were independently associated with postoperative recurrence. Three-, 5-, and 7-year overall survival rates after surgery were 100%, 80%, and 64% in obese patients and 100%, 92%, and 82% in non-obese patients, respectively (P = .014). However, other variables showed no significant difference in the overall survival rate. CONCLUSIONS: Obesity and non-anatomical resection were independent risk factors for HCC recurrence after hepatic resection and successful IFN therapy. Obesity is an important clinical problem to consider to improve postoperative outcomes in such patients.

The Clinical Significance of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography in Patients with Occupational Cholangiocarcinoma

Objective: The present study aimed to identify the clinical significance of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in patients with occupational cholangiocarcinoma. Methods: This study included 10 men with occupational cholangiocarcinoma who were former or current workers at a printing company in Osaka, Japan. Of the 10 patients, 2 had 2 main tumors and 1 had 3 main tumors. Twelve FDG-PET imaging findings in the 10 patients could be analyzed. We evaluated the relationships between FDG-PET imaging parameters and clinicopathological findings of occupational cholangiocarcinoma. Results: Abnormal FDG uptake was observed in 8 of the 14 main tumors, with maximum standardized uptake values ranging from 2.9 to 11.0, and the sensitivity was 57.1%. Four patients had lymph node metastases, and abnormal marrow uptake was detected in all these patients. Although precancerous lesions, such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB) without any invasion, were not detected, abnormal FDG uptake was demonstrated in 2 of 4 patients with IPNB having an associated invasive carcinoma.Conclusions: Although FDG-PET may be useful for assessing tumor progression factors, such as lymph node metastasis, it cannot accurately detect precancerous lesions, such as BilIN and IPNB without invasive carcinoma.

Occupational cholangiocarcinoma caused by exposure to 1,2-dichloropropane and/or dichloromethane.

A cluster of cholangiocarcinoma among printing company workers who were exposed to 1,2-dichloropropane and/or dichloromethane was classified by the Ministry of Health, Labour and Welfare of Japan on 1 October 2013 as "occupational cholangiocarcinoma". At the time of the diagnosis of cholangiocarcinoma, levels of γ-glutamyl transferase, and aspartate and alanine aminotransferases were elevated, and had been elevated in some patients several years prior to the diagnosis. Regional dilatation of intrahepatic bile ducts without tumor-induced obstruction was characteristic in diagnostic imaging. Pathological examination found chronic bile duct injury with DNA damage, precancerous/preinvasive lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct in various sites of the large bile ducts, and invasive cholangiocarcinoma such as mass-forming type and intraductal growth-type intrahepatic cholangiocarcinoma and mainly papillary-type extrahepatic cholangiocarcinoma. Whole-exome analysis of the cancerous tissues showed hypermutation, substantial strand bias, and unique trinucleotide mutational changes. Patients seemed to suffer high incidence of postoperative complications including intra-abdominal, which might be related to chronic bile duct injury. Postoperative recurrence from multicentric origins occurred in some patients, as DNA-injured bile ducts have high carcinogenic potential. Aggressive treatment, including second resections for such multicentric recurrences, appeared to be effective. In 2014, the International Agency for Research on Cancer classified 1,2-dichloropropane as Group 1 (carcinogenic to humans) and dichloromethane as Group 2A (probably carcinogenic to humans) carcinogens.

Ruptured focal nodular hyperplasia observed during follow-up: a case report.

BACKGROUND: Focal nodular hyperplasia (FNH) is the second most common benign hepatic tumor and is very rarely complicated by hemorrhage or rupture. Although thought to be extremely rare, there have been several reports of hemorrhage caused by ruptured FNH. Herein, we report the case of a patient with ruptured FNH, who subsequently developed hemorrhage during follow-up. CASE PRESENTATION: A 32-year-old man was admitted to our department for an asymptomatic hepatic tumor in segments 4 and 5 (S4/5), which measured 8 cm in diameter and observed to project from the liver. Imaging and pathologic examination of a biopsy specimen confirmed the diagnosis of FNH. Three years after the diagnosis, the patient was readmitted to our hospital because of sudden onset of upper abdominal pain. Dynamic abdominal computed tomography revealed ascites around the tumor with high-density areas that were considered to represent hematoma caused by ruptured FNH. Transcatheter arterial embolization (TAE) was performed to stop the hemorrhage. One month after TAE, S4/5 of the liver was resected; macroscopic findings revealed that a large part of the tumor was composed of necrotic tissue and hematoma. Pathological examination using hematoxylin-eosin staining and immunohistochemical examination indicated a final diagnosis of FNH rupture and hemorrhage. CONCLUSION: Although a well-established diagnosis of FNH usually requires no treatment or surveillance, careful examination remains necessary when the FNH is large and projects from the liver because of the possibility of rupture and hemorrhage.

Outcomes after resection of occupational cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma caused by exposure to 1,2-dichloropropane and/or dichloromethane is recognized as occupational cholangiocarcinoma. The aim of this study was to investigate the outcomes after resection of occupational cholangiocarcinoma to establish a treatment strategy for this disease. METHODS: Clinicopathological findings and outcomes after surgical intervention in 20 patients with occupational cholangiocarcinoma were investigated. RESULTS: Of 20 the patients, curative resection was performed in 16 patients. Three patients underwent radiation at the stump of the bile ducts. Adjuvant chemotherapy was performed in 12 patients. Biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, and/or chronic bile duct injury was detected in most subjects. Intraabdominal infection developed after surgery in nine patients. Cholangiocarcinoma recurred in 12 of the 20 patients. The recurrent tumors in five patients developed at a different part of the bile duct from the primary tumor and a second resection was performed in four of these five patients. CONCLUSIONS: The incidence of postoperative complications including intraabdominal infection was high in patients with occupational cholangiocarcinoma. Multicentric recurrence occurred not infrequently after surgery because the bile ducts had a high potential for the development of carcinoma. The aggressive treatment including second resection for the multicentric recurrence appeared to be effective.