Well-differentiated Hepatocellular Carcinoma Research Articles

Correlation Between Indocyanine Green Fluorescence Patterns and Grade of Differentiation of Hepatocellular Carcinoma: A Western Prospective Cohort Study.

Background. Most of the available evidence on the use of indocyanine green (ICG) fluorescence in clinical practice consists of articles published by surgeons of the Asian-Pacific area. We performed a prospective cohort study to assess the patterns of ICG fluorescence in Western hepatocellular carcinoma (HCC) counterparts.Methods. From April 2019 to January 2022, a total of 31 consecutive patients who underwent laparoscopic liver resection (LLR) for superficial HCC were enrolled in this prospective study. All patients underwent laparoscopic staging with both laparoscopic ultrasound (LUS) and ICG fluorescence imaging.Results. A total of 38 hepatocellular carcinomas (HCCs) were enrolled: 23 superficial (surfacing at the liver's Glissonian capsule), 5 exophytic, 5 shallow (<8mm from the hepatic surface) and 5 deep (>10mm from the hepatic surface). The detection rate with preoperative imaging (abdominal CT/MRI), LUS, ICG fluorescence and combined modalities (ICG and LUS) was 97.4%, 94.9%, 89.7% and 100%, respectively. The five deep seated lesions underwent ultrasound-guided laparoscopic thermal ablation. The other 33 HCCs were treated with minimally invasive liver resection. Intraoperative ultrasound patterns were registered for each single nodule resected. The ICG fluorescence pattern was classified in two types: total fluorescence (all the tumoral tissue showed strong and homogeneous fluorescence), n = 9/33 (27.3%), and non-total fluorescence (partial and rim fluorescence), n = 24/33 (72.7%). There was a statistical correlation between ICG patterns and grade of differentiation. Almost all lesions with uniform fluorescence pattern were well-differentiated HCCs (G1-G2), while partial and rim-type fluorescence pattern were more common among moderately and poorly differentiated HCCs (G3-G4) (88.9% vs 11.1%, 37.5% vs 62.5%, P = .025, respectively).Conclusions. ICG fluorescence imaging could be used to identify early the grade of HCC, ie intraoperatively, thus influencing the intraoperative treatment.

Histopathologic findings and survival outcomes of dogs undergoing liver lobectomy as treatment for spontaneous hemoabdomen secondary to a ruptured liver mass: retrospective analysis of 200 cases (2012-2020).

To describe the distribution of histopathologic diagnoses in a large population of dogs undergoing surgical treatment for spontaneous hemoperitoneum secondary to a ruptured liver mass. Additionally, to describe survival outcomes and assess for prognostic factors for overall survival time in this population. 200 client-owned dogs with spontaneous hemoperitoneum resulting from a liver mass. Medical records from 19 veterinary referral hospitals were reviewed. Data collected included signalment, clinical signs, blood work, radiographic and ultrasonographic findings, surgical methods, intraoperative and postoperative complications, outcomes, and histopathologic findings. Follow-up information was obtained by contacting the referring veterinarian or owner. Well-differentiated hepatocellular carcinoma, benign masses, hemangiosarcoma, and other malignant tumors accounted for 36% (72/200), 27.5% (55/200), 25.5% (51/200), and 11% (22/200) of cases, respectively. Overall survival time for all dogs was 356 days and for the above categories was 897 days, 905 days, 45 days, and 109 days, respectively. Prognostic factors for survival included diagnosis, increased ALT, anemia, and whether a transfusion was received. Overall survival time in dogs with increased ALT was 644 versus 63 days with normal values. The majority of dogs (63.5%) were diagnosed with well-differentiated hepatocellular carcinoma or a benign process, resulting in favorable long-term survival. The distribution of histopathology for ruptured liver masses resulting in hemoperitoneum has not been previously reported and may be useful for client discussions prior to surgery.

Nickel chloride induces anticancer biological responses in hepatocellular carcinoma cell lines.

Nickel has long been known to have a toxic effect in humans and has been defined as a human carcinogen. However, recent studies have suggested that nickel chloride (NiCl2) may also possess anticancer properties. The liver is one of the target organs for nickel, and thus, the present study aims to evaluate the effect of NiCl2 on anticancer biological responses in hepatocellular carcinoma (HCC) cell lines. Both HuH-7, a well-differentiated HCC cell line, and Mahlavu cell line, a poorly differentiated HCC cell line, were exposed to NiCl2. It was determined that NiCl2 decreased cell viability in both cell lines in a dose- and time-dependent manner. Nickel chloride exposure at IC50 doses were observed to suppress the ability of HCC cells to produce colonies and also induce apoptosis of HCC cells by increasing Cleaved Caspase-3 protein levels. It was found that NiCl2 exposure affected cellular morphology, increased the LC3-II protein levels, and induced autophagy in parallel to increased apoptosis in HCC cells. It was also observed that NiCl2 suppressed cell migration, decreased the size and viability of HCC tumor spheroids generated in 3D cell cultures, and disrupted the spheroid structure of the tumor cells depending on E-cadherin expression levels. Furthermore, it was observed that all anticancer biological responses induced by NiCl2 occurred independently of the AKT signaling pathway. In conclusion, our results suggested that NiCl2 induced anticancer biological responses in HCC cell lines. Moreover, this study provided important new molecular and cellular biological basic data about the action mechanisms of NiCl2 in HCC.

Dual segmentation models for poorly and well-differentiated hepatocellular carcinoma using two-step transfer deep learning on dynamic contrast-enhanced CT images.

The aim of this study was to develop dual segmentation models for poorly and well-differentiated hepatocellular carcinoma (HCC), using two-step transfer learning (TSTL) based on dynamic contrast-enhanced (DCE) computed tomography (CT) images. From 2013 to 2019, DCE-CT images of 128 patients with 80 poorly differentiated and 48 well-differentiated HCCs were selected at our hospital. In the first transfer learning (TL) step, a pre-trained segmentation model with 192 CT images of lung cancer patients was retrained as a poorly differentiated HCC model. In the second TL step, a well-differentiated HCC model was built from a poorly differentiated HCC model. The average three-dimensional Dice's similarity coefficient (3D-DSC) and 95th-percentile of the Hausdorff distance (95% HD) were mainly employed to evaluate the segmentation accuracy, based on a nested fourfold cross-validation test. The DSC denotes the degree of regional similarity between the HCC reference regions and the regions estimated using the proposed models. The 95% HD is defined as the 95th-percentile of the maximum measures of how far two subsets of a metric space are from each other. The average 3D-DSC and 95% HD were 0.849 ± 0.078 and 1.98 ± 0.71mm, respectively, for poorly differentiated HCC regions, and 0.811 ± 0.089 and 2.01 ± 0.84mm, respectively, for well-differentiated HCC regions. The average 3D-DSC for both regions was 1.2 times superior to that calculated without the TSTL. The proposed model using TSTL from the lung cancer dataset showed the potential to segment poorly and well-differentiated HCC regions on DCE-CT images.

Simple Predictive Markers and Clinicopathological Features of Primary Liver Cancer following HCV Clearance with Direct-Acting Antivirals

Introduction: Simple predictive markers enabling even nonspecialized medical doctors and clinicopathological features of primary liver cancer (PLC) following HCV clearance with direct-acting antivirals (DAAs) are unclear. Methods: The subjects of this retrospective study were 2,476 patients following HCV clearance with DAAs. All patients were confirmed to be PLC-free before and during DAAs. Results: PLC was diagnosed in 73 patients during the follow-up, with an incidence rate per 1 000 person-years of 5.9. The annual rate of PLC during the first 6 years was 0.6%. Multivariate analysis identified gender, GGT, and FIB-4 index as the significant determinants of PLC. According to a combination of these risk factors, the cumulative PLC incidence rates were significantly different among the five subgroups based on the number of PLC risk scores. In 73 patients with PLC, the rates of abnormal AFP, PIVKAII, and serum TERT C228T positive were 37.0, 32.4, and 22.2%. PIVKAII levels in BCLC stage A and B were significantly higher than those in stage 0. In 41 patients, who underwent surgical resection for PLC, maximum tumor diameters of abnormal PIVKAII were significantly larger than those of normal PIVKAII. PLC of abnormal PIVKAII significantly indicated presence of vp more than that of normal PIVKAII, and did not contain well-differentiated HCC. Conclusions: Combination of simple markers, enabling even nonspecialized medical doctors, is useful for the evaluation of PLC risk following HCV clearance with DAAs. However, imaging studies are regularly recommended for the early detection of PLC.

Circular RNAs hsa_circ_0001438 and hsa_circ_0000417 are downregulated and upregulated, respectively, in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most predominant type of liver cancer and is frequently fatal. Alpha-fetoprotein, alpha-fetoprotein-L3, and protein induced by vitamin K absence or antagonist-II are used as biomarkers to diagnose HCC. However, these biomarkers are not highly specific, especially for early-stage HCC diagnosis; therefore, more specific biomarkers are needed. Recently, circular RNA (circRNA) biomarkers have been used to diagnose several intractable diseases. In this study, we sought to identify circRNA biomarkers for the specific diagnosis of HCC. To this end, we compared the expression levels of circRNAs in primary HCC and normal tissues using publicly available RNA-seq data. Our analysis revealed that the expression levels of eight circRNAs were altered in primary HCC tissues compared with normal tissues. To confirm our findings, we examined the expression levels of selected circRNAs in HCC cell lines and normal hepatocytes. The expression level of hsa_circ_0001438, a circRNA that was downregulated in primary HCC, was lower in poorly and well-differentiated HCC cell lines than in normal hepatocytes. By contrast, the expression level of hsa_circ_0000417, which was increased in primary HCC, was strongly upregulated in a well-differentiated HCC cell line compared with normal hepatocytes. Thus, hsa_circ_0001438 and hsa_circ_0000417 might be potential biomarkers for the specific diagnosis of HCC. The experimental strategy described here, using publicly available RNA-seq data, is a useful and cost-effective method of identifying circRNA biomarkers.

Recurrent hepatocellular carcinoma with osteoclast-like giant cells: a case report

BackgroundHepatocellular carcinoma with osteoclast-like giant cells is very rare and has an extremely poor prognosis. Here, we report a case of hepatocellular carcinoma with osteoclast-like giant cells that had a relatively better prognosis.Case presentationA 70-year-old Japanese man with hepatitis B virus-related liver cirrhosis was admitted to our hospital for the treatment of recurrent hepatocellular carcinoma. At the age of 60 years, he was first diagnosed as having hepatocellular carcinoma in the right lobe (9 cm in diameter), and liver resection of segment 7/8 was performed. Histological findings showed well-differentiated hepatocellular carcinoma. Since then, imaging studies have been performed every 3 or 4 months. One year later, hepatocellular carcinoma recurred in the lateral segment, and radiofrequency ablation was performed. Nine years after the first presentation, hepatocellular carcinoma recurrences were detected in the caudate lobe and segment 5 by imaging studies. Surgical resection of the caudate lobe was performed, and ultrasonography-guided radiofrequency ablation was subsequently performed for the segment 5 tumor. The resected tumor was simple nodular, well-differentiated HCC; it measured 21 × 21 mm and contained many osteoclast-like giant cells. As neither vascular nor bile duct invasion was found, we believe that radical resection was achieved. Since then, the hepatocellular carcinoma has not recurred for over a year and a half.ConclusionHepatocellular carcinoma with osteoclast-like giant cells is very rare and the prognosis is extremely poor, but early detection can lead to a better clinical course.

Deep Learning-Based Classification of Hepatocellular Nodular Lesions on Whole-Slide Histopathologic Images

Hepatocellular nodular lesions (HNLs) constitute a heterogeneous group of disorders. Differential diagnosis among these lesions, especially high-grade dysplastic nodules (HGDNs) and well-differentiated hepatocellular carcinoma (WD-HCC), can be challenging, letalone biopsy specimens. We aimed to develop a deep learning system to solve these puzzles, improving the histopathologic diagnosis of HNLs (WD-HCC, HGDN, low-grade DN, focal nodular hyperplasia, hepatocellular adenoma), and background tissues (nodular cirrhosis, normal liver tissue). The samples consisting of surgical and biopsy specimens were collected from 6 hospitals. Each specimen was reviewed by 2 to 3 subspecialists. Four deep neural networks (ResNet50, InceptionV3, Xception, and the Ensemble) were used. Their performances were evaluated by confusion matrix, receiver operating characteristic curve, classification map, and heat map. The predictive efficiency of the optimal model was further verified by comparing with that of 9 pathologists. We obtained 213,280 patches from 1115 whole-slide images of 738 patients. An optimal model was finally chosen based on F1 score and area under the curve value, named hepatocellular-nodular artificial intelligence model (HnAIM), with the overall 7-category area under the curve of 0.935 in the independent external validation cohort. For biopsy specimens, the agreement rate with subspecialists' majority opinion was higher for HnAIM than 9 pathologists on both patch level and whole-slide images level. We first developed a deep learning diagnostic model for HNLs, which performed well and contributed to enhancing the diagnosis rate of early HCC and risk stratification of patients with HNLs. Furthermore, HnAIM had significant advantages in patch-level recognition, with important diagnostic implications for fragmentary or scarce biopsy specimens.

Hepatocellular neoplasms with loss of liver fatty acid binding protein: Clinicopathologic features and molecular profiling

HNF1A-inactivated hepatocellular adenomas (H-HCA) show steatosis, no atypia and loss of liver fatty acid binding protein (LFABP). LFABP loss also occurs in hepatocellular carcinoma (HCC). This study examines 68 LFABP-negative tumors: 33 typical H-HCA, 10 atypical hepatocellular neoplasms (AHN), 7 well-differentiated (WD) HCC, 18 moderately or poorly differentiated (MD/PD) HCC. Capture based sequencing was performed in 13 cases (8 AHN, 5 WD-HCC). Patients with HCA, AHN and WD-HCC were nearly all women. AHN and WD-HCC resembled H-HCA but had higher degree of atypia and/or reticulin loss. Variant features like inconspicuous fat (59% vs. 12%, p=0.03), predominance of eosinophilic cells (59% vs. 21%, p=0.01) and pseudoacini were more common in AHN and WD-HCC. Myxoid change and prominent lipofuscin were more common in WD-HCC (29% each) than H-HCA and AHN combined (2% and 7% respectively). Compared to WD-HCC, LFABP-negative MD/PD HCC were more commonly associated with male gender, viral hepatitis and cirrhosis. Biallelic HNF1A alterations were seen in all 13 (100%) sequenced cases. Additional mutations and/or copy number alterations were observed in 38% of AHN and 100% of WD-HCC. Diffuse glutamine synthetase (GS) staining was seen in 13% of cases, with no nuclear β-catenin or Wnt signaling alterations. In conclusion, variant features such as lack of fat, peliosis, myxoid change, pseudoacini and abundant lipofuscin are more common in AHN and/or WD-HCC. LFABP-negative MD/PD HCC have different clinicopathologic features compared to WD-HCC. The significance of diffuse GS in a subset of these cases is unclear.

Non-Cirrhotic Hepatocellular Carcinoma with Duodenal Metastasis in Chronic Hepatitis B: Case Report

Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer-related death. The extrahepatic extension is also more common in non-cirrhotic HCC. It most commonly metastases to the regional lymph nodes, bone, and lungs. Metastasis to the small bowel is rare. Further, hematogenous metastasis to the duodenum is incredibly rare. Case: A 67-year-old man was admitted with a recurrence of hematemesis melena, weight loss, weakness, and decreased appetite. There was a history of hepatitis and a family history of liver diseases. Abdominal examination revealed a palpable liver (8 cm below the right costal margin, firm, irregular, and tender). Laboratory studies revealed Hb 5.2 g/dL, SGOT 301.1 u/L, SGPT 244.7 u/L, albumin 2.7 g/dL, HbsAg was reactive with HBV DNA 2.01 x 104 IU/ml. EGD showed that esophageal varices were not visible, the duodenum showed an irregular mass, bleeding on touch, and many blood clots. Abdominal USG revealed hepatomegaly with suspicion of multifocal hepatoma, while a CT scan suggested the appearance of HCC and no local invasion into the small bowel. The result of the fibro scan was severe fibrosis, not cirrhosis. At laparotomy, a hepatic tumor and duodenum were discovered. The histopathological study of the tumor revealed a well-differentiated HCC. The resection of the tumor could not be done. He was given palliative and symptom treatment HCC on non-cirrhotic liver remains an exceptional condition. Conclusion: We report a non-cirrhotic HCC in chronic hepatitis B infection.

Development of a Deep Learning Model to Assist With Diagnosis of Hepatocellular Carcinoma.

BackgroundAn accurate pathological diagnosis of hepatocellular carcinoma (HCC), one of the malignant tumors with the highest mortality rate, is time-consuming and heavily reliant on the experience of a pathologist. In this report, we proposed a deep learning model that required minimal noise reduction or manual annotation by an experienced pathologist for HCC diagnosis and classification.MethodsWe collected a whole-slide image of hematoxylin and eosin-stained pathological slides from 592 HCC patients at the First Affiliated Hospital, College of Medicine, Zhejiang University between 2015 and 2020. We propose a noise-specific deep learning model. The model was trained initially with 137 cases cropped into multiple-scaled datasets. Patch screening and dynamic label smoothing strategies are adopted to handle the histopathological liver image with noise annotation from the perspective of input and output. The model was then tested in an independent cohort of 455 cases with comparable tumor types and differentiations.ResultsExhaustive experiments demonstrated that our two-step method achieved 87.81% pixel-level accuracy and 98.77% slide-level accuracy in the test dataset. Furthermore, the generalization performance of our model was also verified using The Cancer Genome Atlas dataset, which contains 157 HCC pathological slides, and achieved an accuracy of 87.90%.ConclusionsThe noise-specific histopathological classification model of HCC based on deep learning is effective for the dataset with noisy annotation, and it significantly improved the pixel-level accuracy of the regular convolutional neural network (CNN) model. Moreover, the model also has an advantage in detecting well-differentiated HCC and microvascular invasion.

Quantification of contrast agent uptake in the hepatobiliary phase helps to differentiate hepatocellular carcinoma grade

This study aimed to assess the degree of differentiation of hepatocellular carcinoma (HCC) using Gd-EOB-DTPA-assisted magnetic resonance imaging (MRI) with T1 relaxometry. Thirty-three solitary HCC lesions were included in this retrospective study. This study's inclusion criteria were preoperative Gd-EOB-DTPA-assisted MRI of the liver and a histopathological evaluation after hepatic tumor resection. T1 maps of the liver were evaluated to determine the T1 relaxation time and reduction rate between the native phase and hepatobiliary phase (HBP) in liver lesions. These findings were correlated with the histopathologically determined degree of HCC differentiation (G1, well-differentiated; G2, moderately differentiated; G3, poorly differentiated). There was no significant difference between well-differentiated (950.2 ± 140.2 ms) and moderately/poorly differentiated (1009.4 ± 202.0 ms) HCCs in the native T1 maps. After contrast medium administration, a significant difference (p ≤ 0.001) in the mean T1 relaxation time in the HBP was found between well-differentiated (555.4 ± 140.2 ms) and moderately/poorly differentiated (750.9 ± 146.4 ms) HCCs. For well-differentiated HCCs, the reduction rate in the T1 time was significantly higher at 0.40 ± 0.15 than for moderately/poorly differentiated HCCs (0.25 ± 0.07; p = 0.006). In conclusion this study suggests that the uptake of Gd-EOB-DTPA in HCCs is correlated with tumor grade. Thus, Gd-EOB-DTPA-assisted T1 relaxometry can help to further differentiation of HCC.

Comparing the CT and MRI findings for canine primary hepatocellular lesions.

Triple-phase CT and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) MRI have been used to differentiate hepatocellular carcinomas (HCCs) in dogs. This retrospective case series aimed to compare the CT findings with MRI findings of 20 canine hepatocellular lesions, including eight poorly/moderately-differentiated HCCs, eight well-differentiated HCCs and four hyperplasias. CT data were analysed, and the following parameters were noted: vessel enhancement, enhancement pattern in the equilibrium phase, maximal transverse diameter, the lowest enhancement, and the attenuation values of each hepatocellular lesion in the precontrast and triple-phase series, including the arterial phase, portal phase and equilibrium phase. MRI data were analysed, and the following parameters were noted: signal intensities of each hepatocellular lesion on T2-weighted images and T1-weighted images, and signal intensity ratio of the hepatocellular lesions in the hepatobiliary phase. In 62.5% of poorly/moderately-differentiated HCC and 75% of well-differentiated HCC, presumptive necrosis was detected on CT and MRI. In the hepatobiliary phase on MRI, the median signal intensity ratio of poorly/moderately-differentiated HCC (0.54 [range: 0.3-0.71]) was significantly lower than that of well-differentiated HCC (0.75 [range: 0.6-0.96]) and hyperplasia (0.79 [range: 071-0.98]; p=0.02 and p=0.02, respectively). Gd-EOB-DTPA-enhanced MRI may be a superior modality for differentiating hepatocellular origin lesions.

Hepatic Adenomatosis in a Young Asymptomatic but High-risk Patient: An Incidental Diagnosis with Potentially Severe Clinical Implications.

Hepatic adenomatosis (HA) is a very rare condition and defined as the presence of 10 or more adenomas in an otherwise normal liver. HA has an incidence of 10–24% in patient with hepatic adenoma and it is more common in women. Most patients with HA are asymptomatic with a normal liver function test and half of cases are detected incidentally on imaging. Although HA is considered a benign disease, some patients may develop potentially fatal complications, such as hypovolaemic shock due to rupture of the liver lesion or malignant transformation to hepatocellular carcinoma.We report the case of a 29-year-old woman who presented to the emergency room after a car accident. Whole-body computed tomography revealed multiple focal hepatic hypervascular lesions in the right lobe of the liver together with a fatty liver. Subsequent hepatic magnetic resonance imaging suggested the diagnosis of HA with a suspicion of focal nodular hyperplasia (FNH). The patient refused to undergo liver biopsy, so we instituted a 3-month surveillance program, which included clinical assessment, liver function tests, tumour marker assessment and blood tests as well as sonographic evaluation for follow-up of the liver lesions.LEARNING POINTSHepatic adenomatosis is an extremely rare disease which predominantly affects women and is associated with hormone consumption, liver steatosis, glycogen storage disease, obesity, metabolic syndrome, abnormalities of hepatic vasculature and maturity onset diabetes of the young (MODY).The two main differential diagnoses include focal nodular hyperplasia (FNH) and well-differentiated hepatocellular carcinoma. Histological confirmation is required when MRI findings are inconclusive or when a malignancy is suspected.In men, resection of adenomas is mandatory due to the high risk of malignant transformation. In woman, a conservative approach with contraceptive discontinuation and biannual follow-up with MRI and alpha-fetoprotein is recommended; resection is needed in case of positive immunohistochemical staining for β-catenin on biopsy, symptomatic adenomas, adenoma increasing in size, and when malignancy cannot be ruled out.

S2611 When FNH Is Not FNH: The Value of the Multidisciplinary Conference for Management of Hepatic Masses

Introduction: While hepatocellular carcinoma (HCC) can arise spontaneously, the majority of cases are observed in patients with cirrhosis or chronic hepatitis infection. Hepatocellular adenoma is also an important cause of liver mass, but is often found in women and associated with exposure to estrogens. Adenomas can be seen in males, especially those with history of anabolic androgen use. Focal nodular hyperplasia (FNH) is another benign cause of liver mass usually seen in females. We report a case of an undifferentiated liver mass in a healthy male patient that was originally thought to be FNH but turned out to be a more serious condition. Case Description/Methods: An asymptomatic 36-year-old man with unremarkable medical history presented with a liver mass after routine blood work revealed an elevated alkaline phosphatase. Risk factors for liver disease included obesity and hyperlipidemia. Imaging demonstrated a mass in the right hepatic lobe (8.1 x 7.1 x 9.0 cm), with arterial hyperenhancement, followed by isointensity to the liver after the arterial phase. The surrounding parenchyma appeared normal. He had no exposure to hepatitis B or C and his chronic liver disease evaluation was negative. Alpha fetoprotein was normal. Given these findings, the lesion was initially deemed most consistent with FNH. Multidisciplinary review instead favored adenoma or HCC, due to male gender, lesion size, T2 hyperintensity relative to liver, and central areas of high signal intensity that did not fill like a classic central scar. The patient subsequently underwent right hepatectomy. Surgical pathology revealed a well-differentiated hepatocellular neoplasm without invasion of the surrounding vasculature. The lesion had a prominent capsule and consisted of sheets and nodules of well-differentiated hepatic cells. The remainder of the liver parenchyma showed mild steatosis without inflammation or fibrosis. Pathology was reviewed at multiple institutions, with results favoring a well-differentiated HCC or atypical adenoma. Unfortunately, it was difficult to determine whether this mass was benign or malignant. Discussion: In this case, presentation at a multidisciplinary conference was lifesaving. Given that adenomas of this size carry high risk for malignant transformation or rupture, and large HCC often metastasize and can be terminal, surgery was indicated regardless of diagnosis. However, FNH can typically be observed. The patient now follows with Oncology and Hepatology for surveillance imaging and labs every 3 months.Figure 1.: A. Contrast-enhanced MRI demonstrates a large (8.1 x 7.1 x 9.0 cm) right hepatic lobe mass with heterogeneous hyperenhancement in the arterial phase. B. Gross pathology of 9.7cm tumor in right hepatic lobe. C. High magnification of the tumor (H&E) showing unpaired arteries without abnormal thickening of hepatocellular plates.

Applying criteria for hepatocellular neoplasm of uncertain malignant potential reclassifies more than half of hepatocellular adenomas

ObjectivesHepatocellular adenoma (HCA) is a benign well-differentiated hepatocellular neoplasm that can be difficult to distinguish from well-differentiated hepatocellular carcinoma (HCC). The term “well-differentiated hepatocellular neoplasm of uncertain malignant potential” (HUMP) has been proposed for neoplasms resembling HCAs, but arising in atypical clinical situations (in females over 50 years old or under 15, in males, with anabolic steroid use, or in some congenital conditions), and/or with atypical pathological features (focal cytological/architectural atypia, β-catenin activation, or focal reticulin loss) insufficient for an unequivocal diagnosis of HCC. MethodsThis study evaluated HUMP criteria on 42 previously diagnosed HCAs from 33 patients. ResultsTwenty-six (62%) masses from 21 patients were classified as HUMPs. Eleven (42%) had focal cytological atypia, and two (8%) had focal architectural atypia. Four (15%) showed focal reticulin loss. Five (19%) showed evidence of β-catenin activation. Four (12%) HUMP patients were male. ConclusionsIn this series, HUMP did not correlate with an increased rate of synchronous or metachronous HCC compared to HCA. Clinical colleagues may not accept such a high rate of tumors placed in a category of “uncertain malignant potential”. Additional study is warranted to refine criteria for designating well-differentiated hepatocellular neoplasms as of uncertain malignant potential.

Significance of hepatocyte atypia in liver fine needle aspiration.

Fine needle aspiration (FNA) of the liver is frequently the diagnostic procedure of choice for sampling hepatic lesions. One of the main diagnostic challenges in the interpretation of liver FNA is distinguishing dysplastic lesions and well-differentiated hepatocellular carcinoma (WD-HCC) from benign processes, as they share significant cytomorphologic overlap. Furthermore, the diagnosis of HCC often requires evaluation of stroma for invasion, which may not be present on cytology and small needle biopsy specimens. A reporting system for liver cytopathology has yet to be instituted. Without standardized and well-defined criteria for hepatocyte atypia, we recommend limiting the use of atypia in evaluation of liver FNA specimens to describe a diagnosis of exclusion, in which all known benign and neoplastic processes have been ruled out. The cytologic findings on the FNA of a liver nodule may be best reported as atypical hepatocytes in the absence of a core needle biopsy or cell block sufficient to render a definitive diagnosis of HCC.

Possible spontaneous regression of hepatocellular carcinoma with unique histopathological features confirmed by surgical resection: a case report

BackgroundSpontaneous regression of hepatocellular carcinoma (HCC) is a rare event, and its clinicopathological features and underlying mechanism are not fully understood.Case presentationAn 84-year-old female with hepatitis C virus infection and diabetes mellitus was referred to our hospital for further examination. Abdominal ultrasonography showed a 3.4-cm solid tumor with a heterogeneous irregular center and no fibrous capsule in liver segment 8 (S8). An enhanced computed tomography (CT) scan revealed a tumor in S8 with heterogeneous enhancement in the arterial phase and washed out insufficiently in the portal and equilibrium phase. The enhanced pattern on magnetic resonance imaging was similar to that of CT. Although the imaging findings were not typical for HCC, liver resection (S8) was performed with HCC as the most probable diagnosis. Histopathological examination of the resected specimen showed that the tumor was well to moderately differentiated HCC with unique features. Approximately half of the tumor was composed of well-differentiated HCC that was focally accompanied by dense lymphocyte infiltration. The other half of the tumor was fibrotic tissue that resembled an inflammatory pseudotumor. Several foci of moderately differentiated HCC were scattered within the tumor with a nodule-in-nodule appearance, and the foci totally showed coagulative necrosis. On immunostaining, lymphocytes in the tumor stroma were positive for CD8 and programmed death 1. The expression of programmed death-ligand 1 was observed in carcinoma cells and macrophages specifically within the lymphocyte-rich area of HCC.ConclusionsWe consider this case representative of spontaneous regression of HCC, and the immune response against HCC might contribute to tumor regression, leading to complex histopathological appearances. This case may provide insight into the mechanism of spontaneous regression of HCC.

Hepatocellular adenoma in men: A nationwide assessment of pathology and correlation with clinical course.

Background & AimsHepatocellular adenomas (HCA) rarely occur in males, and if so, are frequently associated with malignant transformation. Guidelines are based on small numbers of patients and advise resection of HCA in male patients, irrespective of size or subtype. This nationwide retrospective cohort study is the largest series of HCA in men correlating (immuno)histopathological and molecular findings with the clinical course.MethodsDutch male patients with available histological slides with a (differential) diagnosis of HCA between 2000 and 2017 were identified through the Dutch Pathology Registry (PALGA). Histopathology and immunohistochemistry according to international guidelines were revised by two expert hepatopathologists. Next generation sequencing (NGS) was performed to confirm hepatocellular carcinoma (HCC) and/or subtype HCA. Final pathological diagnosis was correlated with recurrence, metastasis and death.ResultsA total of 66 patients from 26 centres fulfilling the inclusion criteria with a mean (±SD) age of 45.0 ± 21.6 years were included. The diagnosis was changed after expert revision and NGS in 33 of the 66 patients (50%). After a median follow‐up of 9.6 years, tumour‐related mortality of patients with accessible clinical data was 1/18 (5.6%) in HCA, 5/14 (35.7%) in uncertain HCA/HCC and 4/9 (44.4%) in the HCC groups (P = .031). Four B‐catenin mutated HCA were identified using NGS, which were not yet identified by immunohistochemistry and expert revision.ConclusionsExpert revision with relevant immunohistochemistry may help the challenging but prognostically relevant distinction between HCA and well‐differentiated HCC in male patients. NGS may be more important to subtype HCA than indicated in present guidelines.

Hepatocellular adenomas in the Turkish population: reclassification according to updated World Health Organization criteria

Hepatocellular adenoma (HCA) is an uncommon liver neoplasm, and studies of HCA subtypes have been primarily limited to France, the USA, and Japan. The aim of this study was to describe the clinicopathological features of HCA subtypes in Turkey. The resection specimens of 59 cases diagnosed as 'hepatocellular adenoma' collected from 15 institutions were reviewed to confirm the diagnosis and to classify them according to the current World Health Organization 2019 classification. Immunostaining for glutamine synthetase, liver fatty acid-binding protein, C-reactive protein, β-catenin and reticulin was performed. Of the 59 cases, 48 (81%) were diagnosed as HCA. We identified 24 (50%) hepatocyte nuclear factor 1α (HNF1α)-inactivated HCAs, five (10%) inflammatory HCAs, 15 (32%) β-catenin-activated HCAs, three (6%) β-catenin-activated inflammatory HCAs, and one (2%) unclassified HCA. HCA patients were predominantly female (female/male ratio of 5:1); they had a median age of 34years and a median tumour diameter of 60mm. In the β-catenin-activated HCA group, nine cases (19%) showed cytoarchitectural atypia, and were also referred to as atypical hepatocellular neoplasms. In the β-catenin-activated HCA group, three cases (6%) showed focal areas supportive of transition to HCA. The original diagnosis of HCA was changed to well-differentiated hepatocellular carcinoma in nine cases and to focal nodular hyperplasia in two cases. In our series, the major HCA subtype was HNF1α-inactivated HCA. We found a low incidence of inflammatory-type HCA. Our data also showed that β-catenin-activated hepatocellular neoplasms, including cases with atypical histology, constituted a relatively high proportion of the cases. These findings are in contrast to those of most other studies of HCA subtypes.