[A Case of Synchronous-Metachronous Cancer of the Rectum, Stomach, Pharynx, Esophagus and Small Intestine].

A 71-year-old man presented with the chief complaint of fecal occult blood. Based on imaging studies, the patient was diagnosed advanced rectal cancer. He received laparoscopic low anterior resection. Three months after the rectal cancer operation, upper gastrointestinal endoscopy revealed gastric cancer. The patient had a diagnosis of synchronous cancer of the rectum and stomach, and received laparoscopic distal gastrectomy. Two years after the rectal cancer operation, liver metastasis(S4)was detected and resected. Three years after the rectal cancer operation, esophageal cancer and laryngeal cancer were detected synchronously and chemoradiotherapy was performed. Five years after the rectal cancer operation, small intestinal cancer with infiltration of descending colon and esophagus cancer were detected synchronously. Small intestinal resection and Hartmann procedure were performed for small intestinal cancer. ESD was performed for esophageal cancer. Six years after the rectal cancer operation, FDG-PET showed the peritracheal lymph node metastasis, lumbar spine metastasis and local recurrence in the pelvis. Currently, systemic chemotherapy is undergoing. We report a rare case of synchronous- metachronous cancer of the rectum, stomach, pharynx, esophagus and small intestine.

Honokiol Acts as a Potent Anti-Fibrotic Agent in the Liver through Inhibition of TGF-ß1/SMAD Signaling and Autophagy in Hepatic Stellate Cells.

Chronic liver injury may result in hepatic fibrosis, which can progress to cirrhosis and eventually liver failure. There are no drugs that are specifically approved for treating hepatic fibrosis. The natural product honokiol (HNK), a bioactive compound extracted from Magnolia grandiflora, represents a potential tool in the management of hepatic fibrosis. Though HNK has been reported to exhibit suppressive effects in a rat fibrosis model, the mechanisms accounting for this suppression remain unclear. In the present study, the anti-fibrotic effects of HNK on the liver were evaluated in vivo and in vitro. In vivo studies utilized a murine liver fibrosis model, in which fibrosis is induced by treatment with carbon tetrachloride (CCl4). For in vitro studies, LX-2 human hepatic stellate cells (HSCs) were treated with HNK, and expression of markers of fibrosis, cell viability, the transforming growth factor-ß (TGF-ß1)/SMAD signaling pathway, and autophagy were analyzed. HNK was well tolerated and significantly attenuated CCl4-induced liver fibrosis in vivo. Moreover, HNK decreased HSC activation and collagen expression by downregulating the TGF-ß1/SMAD signaling pathway and autophagy. These results suggest that HNK is a new potential candidate for the treatment of hepatic fibrosis through suppressing both TGF-ß1/SMAD signaling and autophagy in HSCs.

Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.

Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis.

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study's clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased ERRFI1 mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased ERRFI1 expression. EGFR degradation or inactivation represents a novel approach for NASH-HCC treatment and prevention, and the GR-MIG6 axis is a newly defined target that can be activated by HNK and related compounds.

Influence of the Retrocolic Versus Antecolic Route for Alimentary Tract Reconstruction on Delayed Gastric Emptying After Pancreatoduodenectomy: A Multicenter, Noninferiority Randomized Controlled Trial.

OBJECTIVE: This study aimed to determine whether retrocolic alimentary tract reconstruction is noninferior to antecolic reconstruction in terms of DGE incidence after pancreatoduodenectomy (PD) and investigated patients' postoperative nutritional status. SUMMARY OF BACKGROUND DATA: The influence of the route of alimentary tract reconstruction on DGE after PD is controversial. METHODS: Patients from 9 participating institutions scheduled for PD were randomly allocated to the retrocolic or antecolic reconstruction groups. The primary outcome was incidence of DGE, defined according to the 2007 version of the International Study Group for Pancreatic Surgery definition. Noninferiority would be indicated if the incidence of DGE in the retrocolic group did not exceed that in the antecolic group by a margin of 10%. Patients' postoperative nutrition data were compared as secondary outcomes. RESULTS: Total, 109 and 103 patients were allocated to the retrocolic and antecolic reconstruction group, respectively (n = 212). Baseline characteristics were similar between both groups. DGE occurred in 17 (15.6%) and 13 (12.6%) patients in the retrocolic and antecolic group, respectively (risk difference; 2.97%, 95% confidence interval; -6.3% to 12.6%, which exceeded the specified margin of 10%). There were no differences in the incidence of other postoperative complications and in the duration of hospitalization. Postoperative nutritional indices were similar between both groups. CONCLUSIONS: This trial could not demonstrate the noninferiority of retrocolic to antecolic alimentary tract reconstruction in terms of DGE incidence. The alimentary tract should not be reconstructed via the retrocolic route after PD, to prevent DGE.

Diagnostic accuracy of combined biomarker measurements and vibration-controlled transient elastography (VCTE) for predicting fibrosis stage of non-alcoholic fatty liver disease.

BACKGROUND: Numerous biomarkers have been developed for assessing the presence and severity of liver fibrosis associated with non-alcoholic fatty liver disease (NAFLD). Fibrosis can be assessed by liver stiffness measurement (LSM) using vibration-controlled transient elastography (VCTE). Here we examined whether diagnostic accuracy and applicability can be further improved by combining various biomarker measurements with LSM. METHODS: A total of 278 patients with biopsy-confirmed Japanese NAFLD patients were enrolled. Area under the receiver operator characteristic curve (AUROC) was evaluated for obtaining the optimum interpretation criteria for LSM by VCTE and comparing various biomarkers alone and in combination with LSM. RESULTS: Liver stiffness measurements including cases with interquartile range (IQR)/median (M) < 30% or LSM ≤ 7.1 kPa demonstrated high applicability (90% of patients with NAFLD) and accuracy (AUROC: 0.891) for predicting stage ≥ 3 fibrosis. For all biomarkers tested, the AUROC values for predicting stage ≥ 3 fibrosis were increased when combined with LSM [platelet count, 0.734 vs. 0.912; type-4 collagen 7s (T4C7s), 0.894 vs. 0.921; aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), 0.774 vs. 0.906; AST to platelet ratio index, 0.789 vs. 0.902; FIB-4 index, 0.828 vs. 0.922; NAFLD fibrosis score, 0.800 vs. 0.906; CA index-fibrosis, 0.884 vs. 0.913; FM-fibro index, 0.920 vs. 0.943; FIB-4 index + T4C7s, 0.901 vs. 0.930], demonstrating the advantage of concurrent LSM. CONCLUSIONS: While VCTE has slightly limited applicability (90%) for patients with NAFLD, concurrent measurement with certain biomarkers (especially FM-fibro, T4C7s, and FIB-4) greatly improves the diagnostic accuracy.

Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers.

The genetic factors affecting the natural history of nonalcoholic fatty liver disease (NAFLD), including the development of nonalcoholic steatohepatitis (NASH) and NASH-derived hepatocellular carcinoma (NASH-HCC), are still unknown. In the current study, we sought to identify genetic factors related to the development of NAFLD, NASH, and NASH-HCC, and to establish risk-estimation models for them. For these purposes, 936 histologically proven NAFLD patients were recruited, and genome-wide association (GWA) studies were conducted for 902, including 476 NASH and 58 NASH-HCC patients, against 7,672 general-population controls. Risk estimations for NAFLD and NASH were then performed using the SNPs identified as having significant associations in the GWA studies. We found that rs2896019 in PNPLA3 [p = 2.3x10-31, OR (95%CI) = 1.85 (1.67-2.05)], rs1260326 in GCKR [p = 9.6x10-10, OR (95%CI) = 1.38(1.25-1.53)], and rs4808199 in GATAD2A [p = 2.3x10-8, OR (95%CI) = 1.37 (1.23-1.53)] were significantly associated with NAFLD. Notably, the number of risk alleles in PNPLA3 and GATAD2A was much higher in Matteoni type 4 (NASH) patients than in type 1, type 2, and type 3 NAFLD patients. In addition, we newly identified rs17007417 in DYSF [p = 5.2x10-7, OR (95%CI) = 2.74 (1.84-4.06)] as a SNP associated with NASH-HCC. Rs641738 in TMC4, which showed association with NAFLD in patients of European descent, was not replicated in our study (p = 0.73), although the complicated LD pattern in the region suggests the necessity for further investigation. The genetic variants of PNPLA3, GCKR, and GATAD2A were then used to estimate the risk for NAFLD. The obtained Polygenic Risk Scores showed that the risk for NAFLD increased with the accumulation of risk alleles [AUC (95%CI) = 0.65 (0.63-0.67)]. CONCLUSIONS: We demonstrated that NASH is genetically and clinically different from the other NAFLD subgroups. We also established risk-estimation models for NAFLD and NASH using multiple genetic markers. These models can be used to improve the accuracy of NAFLD diagnosis and to guide treatment decisions for patients.

Activation of apoptosis inhibitor of macrophage is a sensitive diagnostic marker for NASH-associated hepatocellular carcinoma.

BACKGROUND: A diagnostic marker is needed enabling early and specific diagnosis of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH). Our recent findings have indicated that circulating apoptosis inhibitor of macrophage (AIM), which usually associates with IgM pentamer in the blood, is activated by its dissociation from IgM. We investigated the serum levels of IgM-free AIM for AIM activation and its possible relationship with development of HCC in NASH. METHODS: Serum levels of IgM-associated and IgM-free AIM were evaluated in patients with non-alcoholic fatty liver, NASH, and NASH-HCC using enzyme-linked immunosorbent assays and immunoblots. Liver biopsy specimens were graded and staged using Brunt's classification. RESULTS: Forty-two patients with fatty liver, 141 with NASH, and 26 with NASH-HCC were evaluated. Patients with stage 4 or grade 3 NASH (with or without HCC) exhibited significantly higher levels of both IgM-free and total AIM than those with fatty liver, whereas the ratio of IgM-free-to-total AIM was equivalent in these groups. Among patients with the same fibrosis stage of NASH, those with HCC had significantly higher IgM-free but not total AIM levels, resulting in a proportional increase in the IgM-free/total AIM ratio. Analysis of the areas under the receiver operating characteristic curves indicated the high sensitivity of the IgM-free AIM for NASH-HCC. CONCLUSIONS: Our observations suggest the activation of AIM in blood in the presence of NASH-HCC, with a significant increase in IgM-free AIM levels. IgM-free AIM serum levels appear to be a sensitive diagnostic marker for NASH-HCC.

Analysis of fecal microbiota, organic acids and plasma lipids in hepatic cancer patients with or without liver cirrhosis.

BACKGROUND & AIMS: Changes in the microbiota composition are able to affect nutrient absorption and energy metabolism, but there are few human studies. The aims were to analyze fecal constituents quantitatively and compare them with liver dysfunction in hepatic cancer patients and to evaluate the relationships among intestinal microbiota, fecal organic acids and plasma lipid composition. METHODS: Fecal samples collected from 46 hepatic cancer patients (with liver cirrhosis, chronic hepatitis or liver fibrosis and normal liver) were evaluated for fecal constituents. Blood organic acid, lipid and fatty acid concentrations were analyzed. RESULTS: Fecal microbiota and organic acids showed no significant differences among different liver dysfunction patients. In normal liver patients, fecal Candida was positively correlated with plasma phospholipid while Bifidobacterium was negatively correlated with plasma eicosapentaenoic acid and eicosapentaenoic acid/arachidonic acid ratio (all p < 0.05). In cirrhotic liver patients, positive correlations were noted for Lactobacillus and docosahexaenoic acid and Candida and eicosapentaenoic acid or eicosapentaenoic acid/arachidonic acid ratio (all p < 0.01). It was suggested that intestinal biota affected serum fatty acid metabolism and were modified by liver disorders. CONCLUSIONS: Intestinal microbiota and organic acid concentrations in hepatic cancer patients had positive and/or negative correlations with serum lipid levels.

[A case of hepatocellular carcinoma( Vp3)-planned radiotherapy after extended right hepatectomy].

The patient was a 57-year-old man who was diagnosed as having hepatocellular carcinoma (HCC). The tumor, 13 cm in diameter, occupied almost the entire right lobe and directly permeated the gallbladder. In addition, invasion of the portal vein umbilical region was seen from an inside area progress department. Because of the small remnant liver volume due to 3 procedures for right area excision and because liver failure was a concern after the operation, we decided to perform extended right hepatectomy for which we retained one S4 Glisson's capsule. Radiotherapy was planned for portal vein tumor thrombus after the operation. We started radiotherapy( 2.0 Gy×25) on postoperative day 14, and the patient was discharged without complications on postoperative day 55. We initiated the internal administration of tegafur-uraci(l UFT 400 mg/day) on postoperative day 44 and continued the treatment for half a year; however, metastasis was frequently noted in the lungs on computed tomography (CT) at 9 months after the operation. We administered low-dose 5-fluorouracil plus cisplatin( FP, intravenous) therapy combined with sorafenib( 800 mg/day), and the patient is being followed up. No recurrence has been noted in the liver at 16 months after the operation.

[A case of hepatocellular carcinoma (Vp4)-combination therapy prolonged survival in a patient with advanced hepatocellular carcinoma with a tumor thrombus in the portal vein trunk].

A 44-year-old man with advanced hepatocellular carcinoma (HCC) was admitted to our institution. Abdominal computed tomography( CT) revealed diffuse HCC in the right lobe, with a tumor thrombus in the main trunk and contralateral branch of the portal vein. Right lobectomy and tumor thrombectomy were performed. Three months later, oral tegafur-uraci( l UFT) administration( 300 mg/day) was initiated. Twelve months after surgery, intrahepatic recurrence was detected on CT scans. Therefore, the patient was treated with transcatheter arterial infusion( TAI) and percutaneous ethanol injection therapy (PEIT). Since then, no evidence of HCC recurrence has been noted for 46 months after the initial treatment.

Clinical and pathological progression of non-alcoholic steatohepatitis to hepatocellular carcinoma.

AIM: Non-alcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to examine the clinical and pathological course of how NASH progresses to HCC. METHODS: In this retrospective multicenter study conducted in Japan, we examined 19 patients (53% female), who had been previously diagnosed with histologically proven NASH and developed HCC during the follow-up period. The median age of the patients at the time of initial diagnosis of NASH was 65 years. RESULTS: NASH progressed to HCC after a median follow-up period of 3.8 years (range: 0.5-11.6 years). All patients had been identified as having HCC during screening, which included 12 patients assessed by ultrasound, four patients assessed with computerized tomography, two patients that underwent serum des-γ-carboxy prothrombin testing and one patient that underwent serum α-fetoprotein testing. The median diameter of HCC tumors was 1.8 cm (range: 0.8-3.0 cm). The majority of patients (n = 13; 68%) presented with only one HCC tumor. The stage of liver fibrosis was significantly more advanced at the time of diagnosis of HCC than at the time of initial diagnosis of NASH, whereas there were no significant differences in the degree of steatosis. CONCLUSION: Screening for HCC with imaging is necessary not only in NASH patients with advanced fibrosis, but also in those with less advanced forms of fibrosis, particularly if they are old men. Liver fibrosis progresses to a more advanced stage during the development of HCC in NASH patients.

Effects of perioperative synbiotic treatment on infectious complications, intestinal integrity, and fecal flora and organic acids in hepatic surgery with or without cirrhosis.

BACKGROUND: The aim of this study was to assess the effect of preoperative and postoperative synbiotic treatment in hepatectomy patients with or without liver cirrhosis. METHODS: Sixty-one patients with hepatic cancer were assigned randomly to receive either oral synbiotics that consisted of Bifidobacterium, Lactobacillus, and galactooligosaccharides or no synbiotics (control) preoperatively for 14 days and postoperatively for 11 days. Infectious complications, intestinal mucosal integrity as measured by serum diamine oxidase (DAO) activity, and fecal flora and organic acid concentrations were compared between synbiotic treatment (n = 32) and control (n = 29) groups. RESULTS: Fecal flora culture and organic acid concentrations were changed after hepatectomy in both groups. The postsurgery decrease in DAO activity was less profound in the synbiotic-treated group (P < .01) and was correlated negatively with serum interleukin 6 and C-reactive protein concentrations (P < .001). Infectious complications occurred in 5 (17.2%) patients in the control group and no patients in the synbiotic-treated group (P < .05). CONCLUSION: Perioperative synbiotic treatment attenuated the decrease in intestinal integrity and reduced the rate of infectious complications in patients with or without liver cirrhosis who underwent hepatic surgery.

Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to characterize the clinical features of NASH patients with HCC. METHODS: In a cross-sectional multicenter study in Japan, we examined 87 patients (median age, 72 years; 62% male) with histologically proven NASH who developed HCC. The clinical data were collected at the time HCC was diagnosed. RESULTS: Obesity (body mass index ≥25 kg/m(2)), diabetes, dyslipidemia, and hypertension were present in 54 (62%), 51 (59%), 24 (28%), and 47 (55%) patients, respectively. In nontumor liver tissues, the degree of fibrosis was stage 1 in 10 patients (11%), stage 2 in 15 (17%), stage 3 in 18 (21%), and stage 4 (ie, liver cirrhosis) in 44 (51%). The prevalence of cirrhosis was significantly lower among male patients (21 of 54, 39%) compared with female patients (23 of 33, 70%) (P = .008). CONCLUSIONS: Most patients with NASH who develop HCC are men; the patients have high rates of obesity, diabetes, and hypertension. Male patients appear to develop HCC at a less advanced stage of liver fibrosis than female patients.

[A successfully resected case of rectal cancer with liver metastases treated with mFOLFOX6 and bevacizumab].

A sixties-man had complained of melena. Colonoscopy revealed type 2 tumor at rectum. Computed tomography (CT)demonstrated lymph node metastasis in front of sacrum and two low density areas which were suspected metastases in the liver. The patient was diagnosed stageIV rectal cancer and resected primary focus and lymph node metastasis.[ Ra-RS, ant, type 2, moderately differentiated adenocarcinoma, ly1, v3, pSE, pN2, sH1(Grade C), sP0, pM1(No. 270)]without liver resection. It was due to high level of CEA and remote lymph node metastasis. The patient was treated with mFOLFOX6 and bevacizumab after the operation. The level of CEA decreased to normal level and CT revealed a partial response after 4 cycles of systemic chemotherapy. Liver resection was performed safely. Histological response was Grade 2 at liver metastases.

Superiority of CT arterioportal angiography to contrast-enhanced CT and MRI in the diagnosis of hepatocellular carcinoma in nodules smaller than 2 cm.

To evaluate the effectiveness of computed tomography (CT) arterioportal angiography in the diagnosis of hepatocellular carcinoma (HCC) in nodules smaller than 2 cm, we compared the findings of CT during arteriography (CTA) and CT during arterial portography (CTAP) with those of enhanced CT and enhanced magnetic resonance imaging (MRI). Sixty-eight nodules smaller than 2 cm in 53 patients with liver cirrhosis were classified into three groups of CTA and CTAP: (group 1) hyperattenuation on CTA, and hypoattenuation on CTAP (56 nodules, 41 patients); (group 2) hypoattenuation on CTA, and hypoattenuation on CTAP (10 nodules, 10 patients); (group 3) hypoattenuation on CTA, and hyperattenuation on CTAP (2 nodules, 2 patients). Histologically, 96% (54/56), 80% (8/10), and 100% (2/2) of the nodules in groups 1, 2 and 3, respectively, were diagnosed as HCC. In group 1, enhanced CT or enhanced MRI confirmed hypervascularity in only 77% (30/39) and venous washout in 21% (8/39). In groups 2 and 3, enhanced CT or enhanced MRI on 7 and 2 nodules, respectively, revealed no hypervascularity (0%). The results suggested that CT arterioportal angiography is superior to enhanced CT and MRI in nodules smaller than 2 cm for diagnosing HCC (p < 0.01 group 1, p < 0.01 group 2).

Well-to moderately-differentiated HCC manifesting hyperattenuation on both CT during arteriography and arterial portography.

We present a rare case of well- to moderately-differentiated hepatocellular carcinoma (HCC) in a 71-year-old woman with hepatitis C virus-related cirrhosis and unusual radiologic features. A 20-mm hypoechoic nodule disclosed by ultrasound in segment two showed hyperattenuation on both computed tomography hepatic arteriography and computed tomography during arterial portography. Contrast-enhanced ultrasound revealed hypervascularity in the early vascular phase and defect in the post-vascular phase, with the same pattern detected by the two imaging techniques. SPIO-MRI revealed a hyperintense nodule. These findings were compatible with those of moderately-differentiated HCC. An ultrasound-guided biopsy showed histological features of well- to moderately-differentiated HCC characterized by more than two-fold the cellularity of the non-tumorous area, fatty change, clear cell change and mild cell atypia with a thin to mid-trabecular pattern. Further studies may provide insights into the correlation between tumor neovascularity in multistep hepatocarcinogenesis and dual hemodynamics, including the artery and the portal vein.

Small hepatocellular carcinoma presenting with massive metastasis in the peritoneum, mimicking sarcomatous tumor.

The case of a 51-year-old man with hepatitis C virus (HCV)-related hepatocellular carcinoma metastasizing to the peritoneal cavity and mimicking a sarcomatous tumor is presented. A 12 x 12 cm mass, disclosed by computed tomography (CT), in the peritoneal cavity was predominantly isodense to muscle but had hypodense areas that suggested necrosis. T1-weighted magnetic resonance imaging (MRI) showed a large mass, slightly hyperintense to muscle, with local hyperintense areas of suspected hemorrhagic necrosis.T2-weighted MRI of the same region revealed a markedly non-homogeneous and hyperintense mass with inner high signals and peripheral brush-like linear striations. From such imaging studies, sarcomatous tumors, such as fibrosarcoma, leiomyosarcoma, and gastrointestinal stromal tumors, can be distinguished. Pathological findings at autopsy revealed necrotic tissue with a small portion of moderately differentiated HCC. Further studies may provide insights into the metastatic modes of HCC.

Multistep hepatocarcinogenesis from a dysplastic nodule to well-differentiated hepatocellular carcinoma in a patient with alcohol-related liver cirrhosis.

We describe a rare case of the transformation of a dysplastic nodule into well-differentiated hepato-cellular carcinoma (HCC) in a 56-year-old man with alcohol-related liver cirrhosis. Ultrasound (US) disclosed a 10 mm hypoechoic nodule and contrast enhanced US revealed a hypovascular nodule, both in segment seven. US-guided biopsy revealed a high-grade dysplastic nodule characterized by enhanced cellularity with a high N/C ratio, increased cytoplasmic eosinophilia, and slight cell atypia. One year later, the US pattern of the nodule changed from hypoechoic to hyperechoic without any change in size or hypovascularity. US-guided biopsy revealed well-differentiated HCC of the same features as shown in the first biopsy, but with additional pseudoglandular formation and moderate cell atypia. Moreover, immunohistochemical staining of cyclase-associated protein 2, a new molecular marker of well-differentiated HCC, turned positive. This is the first case of multistep hepatocarcinogenesis from a dysplastic nodule to well-differentiated HCC within one year in alcohol-related liver cirrhosis.

Genome-wide microsatellite analysis of focal nodular hyperplasia: a strong tool for the differential diagnosis of non-neoplastic liver nodule from hepatocellular carcinoma.

Allelic imbalance (AI), which represents certain chromosomal gains or losses, has been described in hepatocellular carcinoma (HCC), but the significance of AI analysis in focal nodular hyperplasia (FNH) has not been fully clarified. We hypothesized, therefore, that comprehensive allelotyping of FNH could be a useful tool for differentiating FNH from HCC. A 27-year-old man was admitted to the hospital because of general fatigue. A computed tomography (CT) scan disclosed a hepatic nodule 8 cm in diameter. No definite diagnosis was made after imaging or by biopsy before surgery. Macroscopically and microscopically, the surgical specimen showed typical features of FNH. Comprehensive microsatellite analysis was carried out with 382 microsatellite markers distributed throughout all chromosomes. To detect AI effectively, the cutoff value of the AI index was set at 0.70. Among the 382 microsatellite markers, 212 loci were informative, but no AI was detected. The absence of gross chromosomal alterations strongly suggested that the large nodule was FNH rather than HCC, in terms of its genetic background. The patient's subsequent clinical course revealed the nodule to be benign. The results suggest that this genome-wide microsatellite analysis is a useful tool for the differential diagnosis of non-neoplastic liver nodules from HCC.