The Clinicopathological and Prognostic Significance of the Gross Classification of Hepatocellular Carcinoma

BACKGROUND: We aimed to determine the clinicopathological significance of the gross classification of hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association (KLCA) guidelines. METHODS: A retrospective analysis was performed on 242 cases of consecutively resected solitary primary HCC between 2003 and 2012 at Seoul National University Bundang Hospital. The gross classification (vaguely nodular [VN], expanding nodular [EN], multinodular confluent [MC], nodular with perinodular extension [NP], and infiltrative [INF]) was reviewed for all cases, and were correlated with various clinicopathological features and the expression status of “stemness”-related (cytokeratin 19 [CK19], epithelial cell adhesion molecule [EpCAM]), and epithelial-mesenchymal transition (EMT)–related (urokinase plasminogen activator receptor [uPAR] and Ezrin) markers. RESULTS: Significant differences were seen in overall survival (p=.015) and disease-free survival (p = .034) according to the gross classification; INF type showed the worst prognosis while VN and EN types were more favorable. When the gross types were simplified into two groups, type 2 HCCs (MC/NP/INF) were more frequently larger and poorly differentiated, and showed more frequent microvascular and portal venous invasion, intratumoral fibrous stroma and higher pT stages compared to type 1 HCCs (EN/VN) (p < .05, all). CK19, EpCAM, uPAR, and ezrin expression was more frequently seen in type 2 HCCs (p < .05, all). Gross classification was an independent predictor of both overall and disease-free survival by multivariate analysis (overall survival: p=.030; hazard ratio, 4.118; 95% confidence interval, 1.142 to 14.844; disease-free survival: p=.016; hazard ratio, 1.617; 95% confidence interval, 1.092 to 2.394). CONCLUSIONS: The gross classification of HCC had significant prognostic value and type 2 HCCs were associated with clinicopathological features of aggressive behavior, increased expression of “stemness”- and EMT-related markers, and decreased survival.

Donor Specific Antibody Negative Antibody-Mediated Rejection after ABO Incompatible Liver Transplantation / 대한이식학회지

Antibody-mediated rejection (AMR) is a major complication after ABO-incompatible liver transplantation. According to the 2016 Banff Working Group on Liver Allograft Criteria for the diagnosis of acute AMR, a positive serum donor specific antibody (DSA) is needed. On the other hand, the clinical significance of the histological findings of AMR in the absence of DSA is unclear. This paper describes a 57-year-old man (blood type, O+) who suffered from hepatitis B virus cirrhosis with hepatocellular carcinoma. Pre-operative DSA and cross-matching were negative. After transplantation, despite the improvement of the liver function, acute AMR was observed in the protocol biopsy on postoperative day 7; the cluster of differentiation 19+ (CD19+) count was 0% and anti-ABO antibody titers were 1:2. This paper presents the allograft injury like AMR in the absence of DSA after ABOi living donor liver transplantation with low titers of anti-ABO antibody and depleted serum CD19+ B cells.

Current Status of Laparoscopic Liver Resection: Experiences from Tertiary Center

Laparoscopic liver resection has been widely accepted nowadays for selective cases of liver diseases. Laparoscopic left lateral sectionectomy and minor LLR are considered standard practice worldwide and cautious introduction of major laparoscopic liver resections like hemihepatectomies, central sectionectomy etc.. in institutions having experienced liver surgeons. Because of increasing young liver donor, laparoscopic donor hepatectomy is becoming popular, which gives better cosmetic outcomes. Many clinical trials compared laparoscopic liver resection safety, long term outcomes with open procedures. More recently, advances in laparoscopic instruments and techniques encouraged Korean surgeons to choose a laparoscopic procedure as one of the treatment options for benign or malignant diseases of liver.

A Case Treated with Extracorporeal Membrane Oxygenation for Disseminated Cytomegalovirus Infection after Liver Transplantation / 대한이식학회지

Cytomegalovirus (CMV) is a clinically important pathogen in immunocompromised patients, especially after organ transplantation. However, there have been several reports of severe CMV infections in immunocompetent patients. This report presents a case of an immunocompetent patient who presented with fulminant hepatitis requiring liver transplantation. Because CMV was detected upon histopathologic review of the explanted liver, it was later assumed that CMV may be the primary cause of hepatitis. However, at the time of transplantation, we did not suspect CMV hepatitis. Following transplantation and initiation of immunosuppression, the patient developed viral sepsis with a disseminated CMV infection. Respiratory failure because of CMV pneumonia worsened despite antiviral therapy, and venovenous extracorporeal membrane oxygenation (ECMO) was initiated. Although ECMO has been traditionally contraindicated in patients with sepsis, this patient recovered and was successfully weaned off ECMO. CMV should be included in the differential diagnosis of fulminant hepatitis, even in immunocompetent patients, especially when liver transplantation is considered.

A Case of Rapid Progressive Extrahepatic Metastasis of Hepatocellular Carcinoma after Surgical Resection for Huge Single Mass

Hepatocellular carcinoma (HCC) shows a poor prognosis with high recurrence rate even after surgical resection. To improve prognosis of HCC patient, regular surveillance for high-risk group is recommended, but cost-benefit of the surveillance under 40 years old Asian male with hepatitis B infection is unclear. We share a 39-year-old male case which showed early recurrence and rapid extrahepatic metastasis after surgical resection for single huge HCC. Based on the pathologic finding, this case was diagnosed with 'stemness'-related marker-expressing HCC. Further molecular classification for HCC could be beneficial to estimate individual risk for HCC recurrence and to predict prognosis.

The Role of Laparoscopic Necrosectomy in the Era of Minimally Invasive Treatment for Necrotizing Pancreatitis: A Case Series and Review of the Literature

PURPOSE: Despite the recent increasing application of minimally invasive techniques to treat necrotizing pancreatitis, few reports on laparoscopic necrosectomy have appeared. The aim of the present study was to evaluate the role played by laparoscopic necrosectomy in treatment of necrotizing pancreatitis. We review our own experience and the relevant literature. METHODS: All patients undergoing laparoscopic necrosectomy at Seoul National University Bundang Hospital from March 2005 to January 2016 were included in the study. Data on patient demographics, CT severity index score, American Society of Anesthesiologists' score, preoperative procedures, operative methods, operation time, estimated blood loss, postoperative complications, and length of hospital stay were retrospectively analyzed. We also performed an up-to-date review of the relevant literature. RESULTS: Laparoscopic necrosectomy was performed on four patients with infective pancreatic necrosis that was inadequately treated by percutaneous drainage. A transgastrocolic, transmesocolic, or retrocolic approach was used. The median time from diagnosis to operation was 57 days (range, 34~109 days) and the median operation time 203 min (range, 180~255 min). There was no operative mortality. The necrotic tissue was successfully removed in a single operation in three of the four patients. Three patients experienced postoperative complications, including pleural effusion and recurrence of necrosis. The median postoperative hospital stay was 39 days (range, 16~99 days). CONCLUSION: Laparoscopic necrosectomy is safe and effective when used to treat necrotizing pancreatitis. Such treatment is especially useful for patients with solid, necrotic pancreatic components that are not removed by percutaneous or endoscopic drainage.

Peri-Transplant Change in AFP Level: a Useful Predictor of Hepatocellular Carcinoma Recurrence Following Liver Transplantation

Pretransplant alpha-fetoprotein (AFP) is a useful tumor marker predicting recurrence of hepatocellular carcinoma (HCC). Little is known, however, about the relationship between changes in AFP concentration and prognosis. This study investigated the clinical significance of change in peri-transplant AFP level as a predictor of HCC recurrence. Data from 125 HCC patients with elevated pretransplant AFP level who underwent liver transplantation (LT) between February 2000 and December 2010 were retrospectively reviewed. Patients with AFP normalization within 1 month after LT were classified into the rapid normalization group (n = 97), with all other patients classified into the non-rapid normalization group (n = 28). Tumor recurrence was observed in 17 of the 97 patients (17.5%) with rapid normalization; of these, 11 patients had high AFP levels and six had normal levels at recurrence. In contrast, tumor recurrence was observed in 24 of the 28 patients (85.7%) without rapid normalization, with all 24 having high AFP levels at recurrence. Multivariate analysis showed that non-rapid normalization (harzard ratio [HR], 4.41, P < 0.001), sex (HR, 3.26, P = 0.03), tumor size (HR, 1.15, P = 0.001), and microvascular invasion (HR, 2.65, P = 0.005) were independent risk factors for recurrence. In conclusion, rapid normalization of post-LT AFP level at 1 month is a useful clinical marker for HCC recurrence. Therefore, an adjuvant strategy and/or intensive screening are needed for patients who do not show rapid normalization.

Liver Procurement / 대한이식학회지

With increasing demand for liver transplantation, liver grafts are used from marginal donors who were not considered suitable. This trend toward the use of marginal donors reinforces the need to balance the recipient's condition and graft quality and to perform a liver retrieval process with a proper method for preservation of liver function. Although the issues in organ procurement are debatable, rapid and high pressure perfusion for the aorta only with a cold dissection method can be an optimal method for the successful recipient outcome in liver transplantation using a marginal graft.

SALL4 Expression in Hepatocellular Carcinomas Is Associated with EpCAM-Positivity and a Poor Prognosis

BACKGROUND: There is increasing interest in hepatocellular carcinomas (HCC) expressing "stemness"-related markers, as they have been associated with aggressive behavior and poor prognosis. In this study, we investigated the usefulness of Sal-like protein 4 (SALL4), a recently proposed candidate marker of "stemness." METHODS: Immunohistochemical stains were performed for SALL4, K19, and epithelial cellular adhesion molecule (EpCAM) on tissue microarrays constructed from 190 surgically resected HCCs, and the results were correlated with the clinicopathological features and patient survival data. RESULTS: Nuclear SALL4 expression was observed in 39/190 HCCs (20.5%), while K19 and EpCAM were expressed in 30 (15.9%) and 92 (48.7%) HCCs, respectively. The nuclear expression was generally weak, punctate or clumped. SALL4 expression was significantly associated with a poor overall survival compared to SALL4-negative HCCs (p = .014) compared to SALL4-negative HCCs. On multivariate analysis adjusted for tumor size, multiplicity, vascular invasion, and pathological tumor stage, SALL4 remained as a significant independent predictor of decreased overall survival (p= .004). SALL4 expression was positively correlated with EpCAM expression (p = .013) but not with K19 expression. HCCs that expressed both SALL4 and EpCAM were associated with significantly decreased overall survival, compared to those cases which were negative for both of these markers (p = .031). CONCLUSIONS: Although SALL4 expression was not significantly correlated with other clinicopathological parameters suggestive of tumor aggressiveness, SALL4 expression was an independent predictor of poor overall survival in human HCCs, and was also positively correlated with EpCAM expression.

Correction: Liver Procurement / 대한이식학회지

This erratum is being published to correct of contents.

Optimal Tailored Screening Protocol after Living Donor Liver Transplantation for Hepatocellular Carcinoma

The indication for hepatocellular carcinoma (HCC) is expanding in living donor liver transplantation (LDLT). Early detection and effective management of recurrence has become an important issue in LDLT for HCC. This study aimed to find an optimal screening protocol in terms of screening interval and screening tools by analyzing recurrence pattern after LDLT for HCC. A total of 205 LDLT patients in two centers from February 1999 to October 2010 was reviewed. Recurrence appeared in 55 cases. Six risk factors for recurrence were identified: preoperative alpha-fetoprotein >400, Edmonson grade 3 or 4, tumor size >7 cm, tumor number > or =7, minimal tumor necrosis in the transarterial chemoembolization group and positive micro-vascular invasion. Four groups with different ranges of index scores showed different recurrence-free survival and median time to recurrence. Group I showed low and late recurrence. Groups II and III showed linearly increased rate of recurrence until 18 months. Group IV showed very early recurrence within 6 months. Across the groups, extra-hepatic recurrence developed in more than 40% of cases and multi-organ recurrence rate was 20%. The screening interval should be different based on the risk of recurrence. Screening should include work-up for extra-hepatic recurrence as well as intra-hepatic recurrence.

Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation

BACKGROUND/AIMS: The most commonly used immunosuppressant therapy after liver transplantation (LT) is a combination of tacrolimus and steroid. Basiliximab induction has recently been introduced; however, the most appropriate immunosuppression for hepatocellular carcinoma (HCC) patients after LT is still debated. METHODS: Ninety-three LT recipients with HCC who took tacrolimus and steroids as major immunosuppressants were included. Induction with basiliximab was implemented in 43 patients (46.2%). Mycophenolate mofetil (MMF) was added to reduce the tacrolimus dosage (n=28, 30.1%). The 1-year tacrolimus exposure level was 7.2 +/- 1.3 ng/mL (mean +/- SD). RESULTS: The 1- and 3-year recurrence rates of HCC were 12.9% and 19.4%, respectively. Tacrolimus exposure, cumulative steroid dosages, and MMF dosages had no impact on HCC recurrence. Induction therapy with basiliximab, high alpha fetoprotein (AFP; >400 ng/mL) and protein induced by vitamin K absence/antagonist-II (PIVKA-II; >100 mAU/mL) levels, and microvascular invasion were significant risk factors for 1-year recurrence (P<0.05). High AFP and PIVKA-II levels, and positive 18fluoro-2-deoxy-d-glucose positron-emission tomography findings were significantly associated with 3-year recurrence (P<0.05). CONCLUSIONS: Induction therapy with basiliximab, a strong immunosuppressant, may have a negative impact with respect to early HCC recurrence (i.e., within 1 year) in high-risk patients.

Histopathologic factors affecting tumor recurrence after hepatic resection in colorectal liver metastases

PURPOSE: Hepatic resection is a standard method of treatment for colorectal liver metastases (CRLM). However, the pathologic factors of metastatic lesions that affect tumor recurrence are less well defined in CRLM. The aim of this study was to evaluate the risk factors for recurrence of CRLM, focusing on histopathologic factors of metastatic lesions of the liver. METHODS: From January 2003 to December 2008, 117 patients underwent curative hepatic resection for CRLM were reviewed. Tumor size and number, differentiation, tumor budding, angio-invasion, dedifferentiation and tumor infiltrating inflammation of metastatic lesions were investigated. RESULTS: The mean number of hepatic tumors was 2 (range, 1-8). The mean size of the largest tumor was 2.9 cm (range, 0.3-18.5 cm) in diameter. The moderate differentiation of the hepatic tumor was the most common in 86.3% of the patients. Tumor budding, angio-invasion, and dedifferentiation were observed in 81%, 34%, and 12.8% of patients. Inflammation infiltrating tumor was detected in 6.8% of patients. Recurrence after hepatic resection appeared in 69 out of 117 cases (58.9%). Recurrence-free survival at 1, 2 and 5 years were 62.4%, 43.6%, and 34.3%. The multivariate analysis showed the number of metastases > or =3 (P = 0.007), the tumor infiltrating inflammation (P = 0.047), and presence of dedifferentiation (P = 0.020) to be independent risk factors for tumor recurrence. CONCLUSION: Histopathological factors, i.e., dedifferentiation and tumor infiltrating inflammation of the metastatic lesion, could be one of the risk factors of aggressive behavior as well as the number of metastases even after curative resection for CRLM.

The Characteristics and Treatment of Bone Loss after Liver Transplant / 대한이식학회지

BACKGROUND: Bone loss after liver transplant (LT) is a long-term problem associated with an increased morbidity due to pathologic fractures. We reviewed our management of post-LT bone loss. METHODS: We collected retrospective data from 82 adult LT recipients between January 2006 and December 2009 who had preoperative and postoperative (12 to 24 months) bone mineral density (BMD) data measured by dual energy X-ray absorptiometry (DXA). BMD was decreased in 52 out of 82 patients before LT. These patients were managed with calcium plus alendronate, calcium only, or no treatment. We compared the efficacy of these three modalities and the factors influencing BMD changes and investigated the incidence of pathologic fractures. RESULTS: In decreased BMD patients (n=52), the postoperative spinal BMD was increased with all three treatment modalities. A more significant increase was found with ALN treatment (+0.103) compared to NO treatment (+0.029) (P-value: 0.016). However, femoral BMD decreased despite ALN treatment. Alendronate use was a significant factor for post-LT spinal BMD improvement in the univariate and multivariate analysis. There were significant newly-developed pathologic fractures after LT especially in osteoporotic patients (28%). CONCLUSIONS: Weekly alendronate with daily calcium may be helpful for the spinal bone mineral protection in preoperative patients with decreased BMD.

The Characteristics and Treatment of Bone Loss after Liver Transplant / 대한이식학회지

BACKGROUND: Bone loss after liver transplant (LT) is a long-term problem associated with an increased morbidity due to pathologic fractures. We reviewed our management of post-LT bone loss. METHODS: We collected retrospective data from 82 adult LT recipients between January 2006 and December 2009 who had preoperative and postoperative (12 to 24 months) bone mineral density (BMD) data measured by dual energy X-ray absorptiometry (DXA). BMD was decreased in 52 out of 82 patients before LT. These patients were managed with calcium plus alendronate, calcium only, or no treatment. We compared the efficacy of these three modalities and the factors influencing BMD changes and investigated the incidence of pathologic fractures. RESULTS: In decreased BMD patients (n=52), the postoperative spinal BMD was increased with all three treatment modalities. A more significant increase was found with ALN treatment (+0.103) compared to NO treatment (+0.029) (P-value: 0.016). However, femoral BMD decreased despite ALN treatment. Alendronate use was a significant factor for post-LT spinal BMD improvement in the univariate and multivariate analysis. There were significant newly-developed pathologic fractures after LT especially in osteoporotic patients (28%). CONCLUSIONS: Weekly alendronate with daily calcium may be helpful for the spinal bone mineral protection in preoperative patients with decreased BMD.

Serongative Acute Hepatic Failure-associated Aplastic Anemia in Pediatric Liver Transplantation / 대한이식학회지

Aplastic anemia (AA) is a rare complication of liver transplantation. The causes of AA have not yet been identified, and optimal treatment for AA after liver transplantation has not been firmly established. We experienced two cases of AA accompanied with fulminant hepatitis among 157 pediatric recipients (1.3%) and among 17 recipients of Korean Network of Organ Sharing (KONOS) status 1 (11.8%). The patients were a 16-year-old girl and a 3-year-old boy who had jaundice and lethargy due to non-A, non-B, non-C fulminant hepatitis. The girl underwent split liver transplantation involving the liver of a 24-year-old man, and the boy underwent an emergency living donor liver transplantation with a liver obtained from his 16-year-old cousin. Each transplantation procedure was uneventful. However, both patients were diagnosed with AA caused by thrombocytopenia and neutropenia at 140 and 26 days, respectively, after liver transplantation. The girl recovered completely after undergoing bone marrow transplantation and was followed up for 70 months. However, the boy was conservatively treated because of the development of hyperbilirubinemia and pyrexia. He died of multi-organ failure 74 days after liver transplantation. AA is not a rare complication of pediatric liver transplantation for fulminant hepatic failure. Therefore, AA must be suspected in pediatric cases of cytopenia even after liver transplantation. Our findings indicate bone marrow transplantation is the treatment of choice for AA even in cases where AA develops after liver transplantation.

Serongative Acute Hepatic Failure-associated Aplastic Anemia in Pediatric Liver Transplantation / 대한이식학회지

Aplastic anemia (AA) is a rare complication of liver transplantation. The causes of AA have not yet been identified, and optimal treatment for AA after liver transplantation has not been firmly established. We experienced two cases of AA accompanied with fulminant hepatitis among 157 pediatric recipients (1.3%) and among 17 recipients of Korean Network of Organ Sharing (KONOS) status 1 (11.8%). The patients were a 16-year-old girl and a 3-year-old boy who had jaundice and lethargy due to non-A, non-B, non-C fulminant hepatitis. The girl underwent split liver transplantation involving the liver of a 24-year-old man, and the boy underwent an emergency living donor liver transplantation with a liver obtained from his 16-year-old cousin. Each transplantation procedure was uneventful. However, both patients were diagnosed with AA caused by thrombocytopenia and neutropenia at 140 and 26 days, respectively, after liver transplantation. The girl recovered completely after undergoing bone marrow transplantation and was followed up for 70 months. However, the boy was conservatively treated because of the development of hyperbilirubinemia and pyrexia. He died of multi-organ failure 74 days after liver transplantation. AA is not a rare complication of pediatric liver transplantation for fulminant hepatic failure. Therefore, AA must be suspected in pediatric cases of cytopenia even after liver transplantation. Our findings indicate bone marrow transplantation is the treatment of choice for AA even in cases where AA develops after liver transplantation.

Is neoadjuvant chemotherapy necessary for patients with initially resectable colorectal liver metastases in the era of effective chemotherapy?

BACKGROUNDS/AIMS: Hepatic resection has only guaranteed long-term survival in patients with colorectal liver metastasis (CRLM) even in the era of effective chemotherapy. The definite role of neoadjuvant chemotherapy (NCT) is to improve outcomes of unresectable CRLMs, but it its role has not been defined for initially resectable CRLMs (IR-CRLMs). METHODS: We reviewed the medical records of 226 patients, who had been diagnosed and treated for IR-CRLM between 2003 and 2008; the patients had the following pathologies: 10% had more than 4 nodules, 11% had tumors larger than 5 cm, and 61% had synchronous CRMLs. Among these patients, 20 patients (Group Y) were treated with NCT, and 206 (Group N) did not receive NCT according to their physician's preference. The median follow-up time was 34.1 months. RESULTS: The initial surgical plans were changed after NCT to further resection in 20% and to limited resection in 10% of 20 patients. Complication rates of Groups Y (30%) were indifferent from Group N (23%) (p=0.233), but intraoperative transfusions were more frequent in Group N (15%) than in Group Y (5%) (p=0.006). There was one case of hospital mortality (0.44%). Disease-free survival rates in Groups Y and N were 23% and 39%, respectively, and patient survival rates were 42% and 66% (p>0.05). By multivariate analysis, old age (> or =60 years), differentiation of primary tumor (poorly/mucinous), resection margin involvement, and no adjuvant chemotherapy were associated with poor patient survival; the number of CRLMs (> or =4) was associated with poor disease-free survival. CONCLUSIONS: NCT had neither a positive impact nor a negative impact on survival, even with intraoperative transfusion, as observed on operative outcomes for patients with IR-CRLM. Further study is required to elucidate the role of NCT for treatment of patient with IR-CRLMs.

Isolated Unconjugated Hyperbilirubinemia after Liver Transplantation

PURPOSE: In our experience, post-LT persistent isolated unconjugated hyperbilirubinemia (IUH) has been frequently observed even after liver transplantation (LT) from normal donors. The present study was performed to evaluate the incidence and clinical significance of post-LT IUH. METHODS: Eighty-five patients were enrolled, and they had undergone adult-to-adult living donor LT between Jan 1999 and Jun 2003 and they had been followed-up for more than 2 years. Persistent post-LT IUH was defined as the case that showed repeated IUH 3 times or more per year. We excluded those cases that had other liver function abnormality, biliary complication, active infection or hemolysis. The donor's condition and the long-term prognosis of the post-LT IUH patients were investigated. RESULTS: Sixteen patients (18.8%) showed post-LT IUH. Seven of them underwent LT from donors who had IUH preoperatively. Nine (10.6%) of them, however, underwent LT from normal donors, that is, there was newly developed IUH postoperatively. There was no clinical factor associated with post-LT IUH for those nine patients, yet they developed no graft failure and major complications. A gradual increasing tendency of the bilirubin level during follow-up duration was observed for 3 of these 9 patients. CONCLUSION: Although about 10% patients developed post-LT IUH from normal donors, they all showed a good prognosis. Therefore, post-LT IUH was likely to be benign. However, close observation may be required because a gradual increasing tendency of bilirubin level was observed in some patients.