Characterisation of dysplastic liver nodules using low-pass DNA sequencing and detection of chromosome arm-level abnormalities in blood-derived cell-free DNA.

High-grade dysplasia carries significant risk of transformation to hepatocellular carcinoma (HCC). Despite this, at the current standard of care, all non-malignant hepatic nodules including high-grade dysplastic nodules are managed similarly. This is partly related to difficulties in distinguishing high-risk pathology in the liver. We aimed to identify chromosome arm-level somatic copy number alterations (SCNAs) that characterise the transition of liver nodules along the cirrhosis-dysplasia-carcinoma axis. We validated our findings on an independent cohort using blood-derived cell-free DNA. A repository of non-cancer DNA sequences obtained from patients with HCC (n = 389) was analysed to generate cut-off thresholds aiming to minimise false-positive SCNAs. Tissue samples representing stages from the multistep process of hepatocarcinogenesis (n = 184) were subjected to low-pass whole genome sequencing. Chromosome arm-level SCNAs were identified in liver cirrhosis, dysplastic nodules, and HCC to assess their discriminative capacity. Samples positive for 1q+ or 8q+ arm-level duplications were likely to be either HCC or high-grade dysplastic nodules as opposed to low-grade dysplastic nodules or cirrhotic tissue with an odds ratio (OR) of 35.5 (95% CI 11.5-110) and 16 (95% CI 6.4-40.2), respectively (p < 0.0001). In an independent cohort of patients recruited from Nottingham, UK, at least two out of four alterations (1q+, 4q-, 8p-, and 8q+) were detectable in blood-derived cell-free DNA of patients with HCC (n = 22) but none of the control patients with liver cirrhosis (n = 9). Arm-level SCNAs on 1q+ or 8q+ are associated with high-risk liver pathology. These can be detected using low-pass sequencing of cell-free DNA isolated from blood, which may be a future early cancer screening tool for patients with liver cirrhosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

The effects of terlipressin and direct portacaval shunting on liver hemodynamics following 80% hepatectomy in the pig.

Liver failure is the major cause of death following liver resection. Post-resection portal venous pressure (PVP) predicts liver failure, is implicated in its pathogenesis, and when PVP is reduced, rates of liver dysfunction decrease. The aim of the present study was to characterize the hemodynamic, biochemical, and histological changes induced by 80% hepatectomy in non-cirrhotic pigs and determine if terlipressin or direct portacaval shunting can modulate these effects. Pigs were randomized (n=8/group) to undergo 80% hepatectomy alone (control); terlipressin (2 mg bolus + 0.5-1 mg/h) + 80% hepatectomy; or portacaval shunt (PCS) + 80% hepatectomy, and were maintained under terminal anesthesia for 8 h. The primary outcome was changed in PVP. Secondary outcomes included portal venous flow (PVF), hepatic arterial flow (HAF), and biochemical and histological markers of liver injury. Hepatectomy increased PVP (9.3 ± 0.4 mmHg pre-hepatectomy compared with 13.0 ± 0.8 mmHg post-hepatectomy, P<0.0001) and PVF/g liver (1.2 ± 0.2 compared with 6.0 ± 0.6 ml/min/g, P<0.0001) and decreased HAF (70.8 ± 5.0 compared with 41.8 ± 5.7 ml/min, P=0.002). Terlipressin and PCS reduced PVP (terlipressin = 10.4 ± 0.8 mmHg, P=0.046 and PCS = 8.3 ± 1.2 mmHg, P=0.025) and PVF (control = 869.0 ± 36.1 ml/min compared with terlipressin = 565.6 ± 25.7 ml/min, P<0.0001 and PCS = 488.4 ± 106.4 ml/min, P=0.002) compared with control. Treatment with terlipressin increased HAF (73.2 ± 11.3 ml/min) compared with control (40.3 ± 6.3 ml/min, P=0.026). The results of the present study suggest that terlipressin and PCS may have a role in the prevention and treatment of post-resection liver failure.

Does a second resection provide a survival benefit in patients diagnosed with incidental T1b/T2 gallbladder cancer following cholecystectomy?

BACKGROUND: Incidental T1b/T2 gallbladder cancers are often managed with a second resection. However it is unclear whether the additional surgical risk is associated with any survival advantage. The aim of this study was to examine the outcomes of patients who underwent a second resection following a diagnosis of incidental T1b/T2 gallbladder cancer. METHODS: A retrospective analysis of patients undergoing surgical management following a diagnosis of incidental T1b/T2 gallbladder cancer between 1994 and 2014. Survival outcomes were analysed using the Kaplan-Meier method. RESULTS: Twenty two patients underwent completion surgery following diagnosis of T1b/T2 gallbladder cancer at initial cholecystectomy, 11 of which were found to have residual disease. The presence of residual disease at second surgery in T1b/T2 disease was associated with worse overall survival (residual disease: median survival 12 months, absence of residual disease: median survival not reached, p = 0.025). CONCLUSION: A significant percentage of patients with T1b/T2 disease have identifiable residual disease following second surgery. Residual disease is associated with poor survival. It is therefore important to inform patients that completion cholecystectomy is primarily performed to inform staging rather than to improve prognosis.

Pre-liver transplant biopsy in hepatocellular carcinoma: a potential criterion for exclusion from transplantation?

BACKGROUND: In cirrhotic patients with hepatocellular carcinoma (HCC), poor differentiation in pre-liver transplantation (LT) biopsy of the largest tumour is used as a criterion for exclusion from LT in some centres. The potential role of pre-LT biopsy at one centre was explored. METHODS: A prospective database of patients undergoing orthotopic LT for radiologically diagnosed HCC at St James's University Hospital, Leeds during 2006-2011 was analysed. RESULTS: A total of 60 predominantly male (85.0%) patients with viral hepatitis were identified. There were discrepancies between radiological and histopathological findings with respect to the number of tumours identified (in 27 patients, 45.0%) and their size (in 63 tumours, 64.3%). In four (6.7%) patients, the largest lesion, which would theoretically have been targeted for biopsy, was not the largest in the explant. Nine (31.0%) patients with multifocal HCC had tumours of differing grades. In two (6.9%) patients, the largest tumour was well differentiated, but smaller tumours in the explant were poorly differentiated. In one patient, the largest lesion was benign and smaller invasive tumours were confirmed histologically. CONCLUSIONS: The need to optimize selection for LT in HCC remains. In the present series, the largest tumour was not always representative of overall tumour burden or biological aggression and its potential use to exclude patients from LT is questionable.

Survey of liver pathologists to assess attitudes towards digital pathology and artificial intelligence.

AIMS: A survey of members of the UK Liver Pathology Group (UKLPG) was conducted, comprising consultant histopathologists from across the UK who report liver specimens and participate in the UK National Liver Pathology External Quality Assurance scheme. The aim of this study was to understand attitudes and priorities of liver pathologists towards digital pathology and artificial intelligence (AI). METHODS: The survey was distributed to all full consultant members of the UKLPG via email. This comprised 50 questions, with 48 multiple choice questions and 2 free-text questions at the end, covering a range of topics and concepts pertaining to the use of digital pathology and AI in liver disease. RESULTS: Forty-two consultant histopathologists completed the survey, representing 36% of fully registered members of the UKLPG (42/116). Questions examining digital pathology showed respondents agreed with the utility of digital pathology for primary diagnosis 83% (34/41), second opinions 90% (37/41), research 85% (35/41) and training and education 95% (39/41). Fatty liver diseases were an area of demand for AI tools with 80% in agreement (33/41), followed by neoplastic liver diseases with 59% in agreement (24/41). Participants were concerned about AI development without pathologist involvement 73% (30/41), however, 63% (26/41) disagreed when asked whether AI would replace pathologists. CONCLUSIONS: This study outlines current interest, priorities for research and concerns around digital pathology and AI for liver pathologists. The majority of UK liver pathologists are in favour of the application of digital pathology and AI in clinical practice, research and education.

Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity.

High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.

Liver transplant pathology - messages for the non-specialist.

This review, based on a presentation at the BDIAP meeting in London 2008, aims to guide histopathologists working outside transplant centres in the differential diagnosis of late post transplant liver biopsies. It focuses on the histological patterns of the late post transplant complications - autoimmune hepatitis, acute and chronic rejection, recurrent viral hepatitis, and biliary disease. Analysis of the character and distribution of inflammatory infiltrate, bile duct changes, and fibrosis by the histopathologist must then be set within the clinical context to arrive at the most appropriate diagnosis. For this reason, review of the biopsy at the transplant centre is recommended. In a broader context, the tabulation of diagnostic features in chronic inflammatory liver diseases produced by the Banff Working Group can, with the exception of rejection, usefully be applied outside the transplant setting.

CD105 is a prognostic marker and valid endothelial target for microbubble platforms in cholangiocarcinoma.

PURPOSE: The current treatment outcomes in cholangiocarcinoma are poor with cure afforded only by surgical extirpation. The efficacy of targeting the tumoural endothelial marker CD105 in cholangiocarcinoma, as a basis for potential microbubble-based treatment, is unknown and was explored here. METHODS: Tissue expression of CD105 was quantified using immunohistochemistry in 54 perihilar cholangiocarcinoma samples from patients who underwent resection in a single centre over a ten-year period, and analysed against clinicopathological data. In vitro flow assays using microbubbles functionalised with CD105 antibody were conducted to ascertain specificity of binding to murine SVR endothelial cells. Finally, CD105-microbubbles were intravenously administered to 10 Balb/c nude mice bearing heterotopic subcutaneous human extrahepatic cholangiocarcinoma (TFK-1 and EGI-1) xenografts after which in vivo binding was assessed following contrast-enhanced destruction replenishment ultrasound application. RESULTS: Though not significantly associated with any examined clinicopathological variable, we found that higher CD105 expression was independently associated with poorer patient survival (median 12 vs 31 months; p = 0.002). In vitro studies revealed significant binding of CD105-microbubbles to SVR endothelial cells in comparison to isotype control (p = 0.01), as well as in vivo to TFK-1 (p = 0.02) and EGI-1 (p = 0.04) mouse xenograft vasculature. CONCLUSION: Our results indicate that CD105 is a biomarker eminently suitable for cholangiocarcinoma targeting using functionalised microbubbles.

Surgical technique and systemic inflammation influences long-term disease-free survival following hepatic resection for colorectal metastasis.

BACKGROUND: To date, there is limited data available on prognostic factors that influence long-term disease-free survival following hepatic resection for colorectal liver metastasis (CRLM). The aim of the study was to identify prognostic factors that were associated with long-term disease-free survival (>5 years) following resection for CRLM. METHODS: Patients undergoing resection for CRLM from January 1993 to March 2007 were identified from the hepatobiliary database. Data analyzed included demographics, laboratory results, operative findings and histopathological data. RESULTS: Seven hundred five curative primary hepatic resections were performed, of which 434 patients developed disease recurrence within 5 years and 67 patients were disease-free more than 5 years. There was a significant association between systemic inflammatory response (raised neutrophil to lymphocyte ratio and/or C-reactive protein), blood transfusion, >2 tumors, bilobar disease and resection margin involvement with developing recurrence during the follow-up period. On multivariate analysis, three independent predictors for recurrent disease within the 5-year follow-up were identified: pre-operative inflammatory response; blood transfusion requirement; and status of resection margin. CONCLUSION: Absence of a systemic inflammatory response and surgical technique to minimize transfusion requirements and obtain a R0 resection margin, are associated with long-term disease-free survival.

Neutrophil Gelatinase-associated Lipocalin as a Theragnostic Marker in Perihilar Cholangiocarcinoma.

BACKGROUND/AIM: Platforms using valid molecular targets can provide concurrent diagnostic and treatment (theragnostic) options in perihilar cholangiocarcinoma (PHC). Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker in the biliary secretome of PHC. Its potential as a theragnostic target and its prognostic significance in this cancer was, therefore, explored. MATERIALS AND METHODS: In-vitro studies were used to determine NGAL localization in several cholangiocarcinoma cell lines. Tissue expression of NGAL was quantified in PHC resection cases from 2000-2010 by immunohistochemistry. RESULTS: NGAL was expressed in the majority of tested cell lines and localized to their membranes. Tissues from 54 patients underwent NGAL immunohistochemistry. Median tumoral NGAL expression was significantly higher than that in matched liver controls (p<0.001). Higher NGAL tumor expression was associated with nodal metastasis (p=0.021), although no significant association with survival was observed. CONCLUSION: The expression and localization of NGAL in PHC make it a valid candidate biomarker for exploitation in theragnostic platforms.

Large hepatocellular carcinoma: time to stop preoperative biopsy.

BACKGROUND: In Western countries, hepatocellular carcinoma (HCC) often presents at a large size, which is seen as a contraindication to transplantation and often resection. Although diagnosis by imaging and alpha-fetoprotein is usually straightforward, nonspecialist units continue to use biopsy to prove the diagnosis before transfer for specialist surgical opinion. We have looked at the impact of this on our practice. STUDY DESIGN: We retrospectively analyzed all large HCCs resected in our unit during the last 12 years. Survival data were calculated according to size and univariate and multivariate analyses were carried out to determine impact of preoperative, operative, and histologic factors affecting outcomes. RESULTS: We identified 85 large HCCs (> 3 cm) and classified 42 as giant (> 10 cm). Overall survival at 1, 3, and 5 years was 76%, 54%, and 51%. Size did not influence survival, although more complex surgical techniques were required for giant tumors. Predictors of poorer disease-free survival were positive resection margin (p < 0.001), multiple tumors (p = 0.003), macroscopic vascular invasion (p = 0.015), and preoperative lesion biopsy (p = 0.027). CONCLUSIONS: Our data shows excellent outcomes after resection for large HCC. This supports the management of such patients in large-volume units that are fully equipped and experienced in the management of these patients. Preoperative biopsy should be avoided, as this unnecessary maneuver appears to have worsened our longterm results.

Diagnostic variation and outcome for high-grade gastric epithelial dysplasia.

HYPOTHESIS: High-grade dysplasia (HGD) of the gastric epithelium is associated with high prevalence of invasive carcinoma, and distinction by endoscopic biopsy is difficult. DESIGN: Cohort study, 1996 to 2003. SETTING: Tertiary care center. PATIENTS: Consecutive sample of 22 patients with initial diagnosis of gastric HGD by endoscopic biopsy. Biopsy specimens were separately reviewed by 3 experienced pathologists. Clinical management was individually decided. MAIN OUTCOME MEASURES: Strength of interpathologist agreement (kappa) and final pathological diagnosis. RESULTS: The diagnosis was revised to intramucosal carcinoma in 14% to 32% of patients or suspicious for invasive carcinoma in 23% to 41%. The strength of agreement between any 2 pathologists for distinguishing between dysplasia and invasive carcinoma was fair (kappa = 0.35-0.36). A diagnosis of intramucosal carcinoma or suspicious for invasive carcinoma by 2 pathologists correlated strongly with subsequent detection of invasive carcinoma. Three patients underwent gastrectomy for HGD, and invasive carcinoma was detected in all (2 patients, T1 N0; 1 patient, T2 N0). Six patients had invasive carcinoma on endoscopic surveillance at a median of 15 months (range, 3-34 months) after diagnosis of HGD and underwent endoscopic mucosal resection (2 patients, T1 NX), gastrectomy (2 patients, T1 N0), or no resection (2 patients). Another patient had metastatic gastric adenocarcinoma despite having a diagnosis of only HGD by endoscopy. Seven patients (32%) died of unrelated causes, without invasive carcinoma, at a median of 19 months (range, 1-38 months). Three patients were alive with persistent HGD at 26 to 61 months. Two patients had no dysplasia on follow-up. CONCLUSIONS: Experienced pathologists often disagreed in distinguishing invasive carcinoma from HGD in gastric biopsy specimens. One third of patients with gastric HGD died of causes unrelated to cancer. Invasive carcinoma was detected in 67% of the remainder.

Does the extent of lymphadenectomy, number of lymph nodes, positive lymph node ratio and neutrophil-lymphocyte ratio impact surgical outcome of perihilar cholangiocarcinoma?

BACKGROUND: Lymph node (LN) status is an important predictor of survival following resection of perihilar cholangiocarcinoma (PHCCA). Controversies still exist with regard to the prognostic value of optimum extent of lymphadenectomy, total number of nodes removed, LN ratio (LNR) and neutrophil-lymphocyte ratio (NLR) on overall survival (OS) and disease-free survival (DFS) following PHCCA resection. METHODS: From 1994 to 2010, 84 PHCCAs were resected; 78 are included in this analysis. Kaplan-Meier survival curves were studied using log-rank statistics to assess which variables affected OS and DFS. The variables that showed statistical significance (P<0.05) on Kaplan-Meier univariate analysis were subjected to multivariate analysis using Cox proportional hazards model. RESULTS: Five-year OS for node-positive status (n=45) was 10%, whereas node-negative (n=33) OS was 41% (P<0.001). Similarly, 5-year DFS was worse in the node-positive group (8%) than in the node-negative group (36%, P=0.001). There was no difference in 5-year OS (31 vs. 12%, P=0.135) and DFS (22 vs. 16%, P=0.518) between those with regional lymphadenectomy and those who underwent regional plus para-aortic lymphadenectomy, respectively. On univariate analysis, patients with 20 or more LNs removed had worse 5-year OS (0%) when compared with those with less than 20 LNs removed (29%, P=0.047). Moderate/poor tumour differentiation, distant metastasis and LN involvement were independent predictors of OS. Positive LNR had no effect on OS. Vascular invasion and an LNR of at least 0.37 were independent predictors of DFS. NLR had no effect on OS and DFS. CONCLUSION: Extended lymphadenectomy patients (≥20 LNs) had worse OS when compared with those with more limited (<20 LNs) resection. An LNR of at least 0.37 is an independent predictor of DFS.

Detection of colorectal metastases in patients being treated with chemotherapy utilising SPIO-MRI: a radiological-pathological study.

OBJECTIVE: Chemotherapy commonly causes liver injury through sinusoidal obstructive syndrome and steatosis. Chemotherapy-induced liver injury may make it more difficult to detect metastases secondary to reduced contrast between the injured liver and metastases. The aim of this study was to determine the sensitivity of superparamagnetic iron oxide (SPIO) contrast-enhanced imaging in patients who have undergone chemotherapy prior to liver surgery. METHODS: Local ethics committee approval was obtained. Thirty-one patients with hepatic metastases completing preoperative chemotherapy were prospectively recruited. Images were reviewed independently by two blinded observers who identified and localized lesions with a four-point confidence scale. The alternative free-response receiver operator characteristic method was used to analyze the results. RESULTS: The sensitivity in detecting colorectal metastases following chemotherapy was 78% and 76%, respectively, for observers 1 and 2 (95% confidence interval: 71%-85% and 68%-82%). The areas under the alternative free-response receiver operator curves were 0.73 and 0.80 for observers 1 and 2, respectively. CONCLUSION: Compared to previously published work on chemotherapy-naïve patients, it is clear that the sensitivity of SPIO-enhanced magnetic resonance imaging (MRI) in detecting colorectal metastases following chemotherapy is reduced. It is therefore critical that all imaging--pre-, during and postchemotherapy--is reviewed when reporting liver MRI prior to surgery.

Histologic oddities at the porta hepatis in biliary atresia.

PURPOSE: Highly unusual histologic findings at the porta hepatis in 3 infants who underwent Kasai portoenterostomy for biliary atresia are reported. METHODS: Portoenterostomy was performed using a standard operative technique. Serial transverse sections of the excised portal plate were examined by light microscopy along with sections from the distal extrahepatic biliary remnants, gallbladder, and liver biopsy. RESULTS: Of 61 consecutive infants who underwent Kasai portoenterostomy for biliary atresia, 3 were found to have highly unusual histologic features at the porta hepatis. All had type 3 biliary atresia. Two had hilar biliary ductules lined in part by squamous epithelium, and the third had a focus of mature hyaline cartilage surrounded by perichondrium adjacent to biliary ductules. In each case, these unusual histologic features were localized to the porta hepatis in the region of the transected portal plate. CONCLUSIONS: The presence of hyaline cartilage at the portal plate is likely to be an expression of defective morphogenesis, thus supporting the concept of disordered embryogenesis in the etiology of biliary atresia. Squamous epithelium within biliary ductules might also reflect a similar mechanism but could alternatively be an unusual metaplastic response to inflammation at this site.

Sinusoidal obstructive syndrome diagnosed with superparamagnetic iron oxide-enhanced magnetic resonance imaging in patients with chemotherapy-treated colorectal liver metastases.

PURPOSE: To assess the predictive value of superparamagnetic iron oxide (SPIO) -enhanced T2-weighted gradient echo (GRE) imaging to determine the presence and severity of sinusoidal obstructive syndrome (SOS). PATIENTS AND METHODS: Sixty hepatic resection patients with colorectal metastases treated with chemotherapy underwent unenhanced magnetic resonance imaging (MRI) followed by T2-weighted GRE sequences obtained after SPIO. The images were reviewed in consensus by two experienced observers who determined the presence and severity of linear and reticular hyperintensities, indicating SOS-type liver injury, using a 4-point ordinal scale. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with 95% CIs for the detection of SOS were calculated. RESULTS: Twenty-four of 60 patients had moderate to severe SOS on MRI. MRI achieved a sensitivity of 87% (95% CI, 66% to 97%), specificity of 89% (95% CI, 75% to 97%), PPV of 83% (95% CI, 63% to 95%), and NPV of 92% (95% CI, 77% to 98%). SOS was never found at surgery or histology in patients whose background liver parenchyma was normal on SPIO-enhanced MRI. CONCLUSION: SOS is present in a significant proportion of patients with treated colorectal metastases and is effectively detected on SPIO-enhanced T2-weighted GRE images.

Solitary liver cysts in children: not always so simple.

AIM: Liver cysts in children are uncommon. Many are simple and solitary and do not require intervention. However, this series demonstrates a broad range of potential pathologies, some of which are life-threatening. METHODS: All children referred to our unit during an 8-year period (1998-2005) and found to have a solitary liver cyst were prospectively recorded. Clinical, radiologic, and pathologic features were analyzed. Children with an isolated extrahepatic choledochal cyst and polycystic disease were excluded. RESULTS: Twenty-one children with a liver cyst were identified. Two had undergone unsuccessful surgical intervention before referral. There were 11 prenatally detected cysts. Median gestational age at detection was 22 weeks (19-35 weeks); only 1 was specifically characterized as a liver cyst prenatally. Six of these required surgery: 2 large simple cysts, 2 intrahepatic choledochal cysts, 1 giant complex biliary cyst causing respiratory distress, and 1 ciliated hepatic foregut cyst. Of the 5 cysts remaining under ultrasound surveillance, 4 decreased in size or resolved. In 10 children presenting between birth and 15.8 years, a liver cyst was diagnosed postnatally: 3 huge cystic mesenchymal hamartomas, 1 type V choledochal cyst, 1 hydatid cyst, and 5 simple cysts. Four of these required surgical resection. Simple cysts tended to be small and could be distinguished from other pathologies using a combination of imaging techniques (ultrasound, magnetic resonance imaging/magnetic resonance cholangiopancreatography [MRCP], radionuclide scan). Only 2 of 12 children with "simple" cysts required surgery for symptoms. However, a wide range of other cyst pathologies were found in 9 children, and although none was malignant, some were life-threatening and 7 required resection. CONCLUSIONS: Simple solitary nonparasitic liver cysts rarely cause symptoms or require surgery, but the pediatric surgeon should be aware of the wide range of other types of liver cyst in children to ensure appropriate treatment.

Gallbladder mucin production and calcium carbonate gallstones in children.

In contrast to adults, calcium carbonate gallstones are relatively common in children. Their pathogenesis is poorly understood. Cystic duct obstruction promotes calcium carbonate formation in bile and increases gallbladder mucin production. We tested the hypothesis that mucin producing epithelial cells would be increased in gallbladders of children with calcium carbonate gallstones. Archival gallbladder specimens from 20 consecutive children who had undergone elective cholecystectomy for cholelithiasis were examined. In each case, gallstone composition was determined by Fourier transform infrared microspectroscopy. Gallbladder specimens from six children who had undergone cholecystectomy for conditions other than cholelithiasis during the same period were used as controls. Multiple sections were examined in a blinded fashion and scored semiquantitatively for mucin production using two stains (alcian blue and periodic acid-Schiff). Increased mucin staining was observed in 50% or more epithelial cells in five gallbladder specimens from seven children with calcium carbonate stones, compared to 5 of 13 with other stone types (P = 0.17) and none of the control gallbladders (P = 0.02). Gallbladders containing calcium carbonate stones were significantly more likely than those containing other stone types or controls to contain epithelial cells with the greatest mucin content (P = 0.03). Gallbladders containing calcium carbonate stones were also more likely to show the ulcer-associated cell lineage. These results demonstrate an increase in mucin producing epithelial cells in gallbladders from children containing calcium carbonate stones. This supports the hypothesis that cystic duct obstruction leading to increased gallbladder mucin production may play a role in the development of calcium carbonate gallstones in children.

Ciliated hepatic foregut cyst.

A male infant was found to have a large congenital hepatic cyst, first noted in late gestation by prenatal ultrasound scan. The cyst communicated with the biliary tree and was eventually removed completely by an extended right hepatectomy. Histopathologic examination showed a thick-walled, unilocular cyst lined predominantly by ciliated, stratified squamous epithelium with an outer wall composed of smooth muscle cells and fibrous tissue. These features are diagnostic of a ciliated hepatic foregut cyst, a rare congenital malformation with histologic similarities to bronchogenic cysts. The young age of our patient, prenatal detection, large size of the cyst, and a clear communication with the biliary tree have not been previously described with ciliated hepatic foregut cysts.

Kasai portoenterostomy--new insights from hepatic morphology.

BACKGROUND/PURPOSE: The aim of this paper was to investigate the mechanism of long-term biliary drainage after Kasai portoenterostomy by clinicopathologic study of hepatic morphology in explanted livers. METHODS: Explanted livers from 13 consecutive children undergoing transplantation for biliary atresia were examined in detail using a standardized protocol. Group 1 (n = 6) had no Kasai procedure before transplantation at a median age of 8 m. Group 2 (n = 4) were transplanted at a median age of 10 m after a failed Kasai portoenterostomy. Group 3 (n = 3) had a successful Kasai but required transplantation for complications of chronic liver disease at 12-14 years. Pathology findings were correlated with hepatic morphology determined by pretransplant magnetic resonance imaging. RESULTS: Large perihilar regenerative nodules (8-14 cm diameter) were observed in 2 patients after successful Kasai portoenterostomy, less well-defined perihilar nodules in group 2 patients, and no regenerative nodules in group 1. Microscopically, group 1 had diffuse biliary cirrhosis with evidence of progressive ductopenia during infancy. In group 2, perihilar regenerative nodules showed variable portal fibrosis but no cirrhosis and bile ducts were present with 68%-100% of hepatic arteries; in peripheral cirrhotic areas, bile ducts were absent in patients older than 9 m. The perihilar regenerative nodules in group 3 patients had a noncirrhotic architecture with preserved bile ducts, but the peripheral parenchyma was cirrhotic; one patient had diffuse macronodular cirrhosis. These morphologic findings correlated well with magnetic resonance images, highlighting the preservation of relatively normal perihilar liver architecture after successful Kasai portoenterostomy. CONCLUSIONS: Unoperated biliary atresia is associated with progressive intrahepatic ductopenia leading to diffuse biliary cirrhosis. Kasai portoenterostomy can result in the growth of large perihilar regenerative nodules, probably as a consequence of surviving intrahepatic ducts in this region. In some patients, long-term success after Kasai portoenterostomy may depend on hyperplasia of the perihilar liver.