Steatohepatitic Hepatocellular Carcinoma Research Articles

Imaging and prognostic characterization of fat-containing hepatocellular carcinoma subtypes.

Steatohepatitic hepatocellular carcinoma (SH-HCC) is characterized by intratumoral fat with > 50% inflammatory changes. However, intratumoral fat (with or without inflammation) can also be found in not-otherwise specified HCC (NOS-HCC). We compared the imaging features and outcome of resected HCC containing fat on pathology including SH-HCC (> 50% steatohepatitic component), NOS-HCC with < 50% steatohepatitic component (SH-NOS-HCC), and fatty NOS-HCC (no steatohepatitic component). From September 2012 to June 2021, 94 patients underwent hepatic resection for fat-containing HCC on pathology. Imaging features and categories were assessed using LIRADS v2018. Fat quantification was performed on chemical-shift MRI. Recurrence-free and overall survival were estimated. Twenty-one patients (26%) had nonalcoholic steatohepatitis (NASH). The median intra-tumoral fat fraction was 8%, with differences between SH-HCC and SH-NOS-HCC (9.5% vs. 5% p = 0.03). There was no difference in major LI-RADS features between all groups; most tumors were classified as LR-4/5. A mosaic architecture on MRI was rare (7%) in SH-HCC, a fat in mass on CT was more frequently depicted (48%) in SH-HCC. A combination of NASH with no mosaic architecture on MRI or NASH with fat in mass on CT yielded excellent specificity for diagnosing SH-HCC (97.6% and 97.7%, respectively). The median recurrence-free and overall survival were 58 and 87months, with no difference between groups (p = 0.18 and p = 0.69). In patients with NASH, an SH-HCC may be suspected in L4/LR-5 observations with no mosaic architecture at MRI or with fat in mass on CT. Oncological outcomes appear similar between fat-containing HCC subtypes.

Challenges in Diagnosis of Steatohepatitic Hepatocellular Carcinoma on a Biopsy Specimen

Abstract Introduction/Objective Hepatocellular carcinoma (HCC) is the most common primary liver tumor. Steatohepatitic hepatocellular carcinoma (SH-HCC) is a subtype that is associated with metabolic syndrome and alcoholic hepatitis. Diagnosing SH-HCC can be extremely challenging on a biopsy specimen, given that steatohepatitis-like changes can be seen in focal nodular hyperplasia and hepatic adenoma. Herein, we present a very challenging case of SH-HCC that was initially diagnosed as a well-differentiated lesion after multi-institutional consultations. Methods/Case Report A 54-year-old female with past medical history of diabetes and hypertension presented with flank pain and a 2.7 cm liver mass in a background of diffuse hepatic steatosis by CT scan, concerning for malignancy. Viral hepatitis serology workup was negative. Results (if a Case Study enter NA) The liver core biopsy reveals a well-differentiated hepatic lesion with areas of steatosis, fibrosis, and features of steatohepatitic changes including ballooning hepatocytes and Mallory-Denk bodies. No significant cytological atypia is identified. No definitive loss of reticulin is seen by reticulin stain. The cytological or architectural atypia was insufficient in isolation to diagnose HCC. The lesion cells are positive for HepPar-1 and Arginase-1, while negative for Glypican. Diffuse sinusoidal CD34 staining is present. Ki-67 proliferative index is approximately 2%. These changes did not permit a confident diagnosis of hepatic adenoma or hepatocellular carcinoma. The case was sent for consultation by multiple institutions with a consensus diagnosis of well-differentiated hepatic lesion/neoplasm. A follow-up liver wedge resection shows a hepatic neoplasm with areas of loss of reticulin staining. Focal stromal invasion is present. The neoplastic cells are positive for HepPar-1, Arginase-1, glutamine synthetase and Glypican (patchy). Final diagnose was rendered as SH-HCC. Conclusion The diagnosis of SH-HCC requires high level of suspicion on a biopsy specimen, especially in a background of steatohepatitis. A reticulin stain and immunohistochemical stains may not be helpful. Clinical- radiological correlation should always be considered.

Steatohepatitic hepatocellular carcinoma: Two cases report with literature review

Steatohepatitic hepatocellular carcinoma (SH-HCC) is one of the most common hepatocellular carcinoma (HCC) subtypes, with a frequency of 5-20%. These tumor are well-differentiated and show distinct histologic features resembling steatohepatitis: Macrovesicular steatosis, inflammation, balloon cells, Mallory-Denk bodies and pericellular fibrosis. Because of their similar characteristics, distinguishing SH-HCC from background fatty liver can be a diagnostic challenge. The histology of SH-HCC has been described in resection specimens. Unfortunately, diagnostic criteria to aid in the evaluation of biopsy specimens have not been well established; therefore, the diagnosis of SH-HCC in biopsies remains challenging. On diagnostic imaging tests, SH-HCC may be difficult to distinguish from surrounding liver parenchyma in patients with severe hepatic steatosis or other fat-containing liver lesions such as angiomyolipoma or clear cell HCC. We report two cases of SH-HCC that we documented along with diagnostic difficulties.

Pathology and Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatic Tumors.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the livers of patients without a history of alcohol abuse. It is classified as either simple steatosis (nonalcoholic fatty liver) or nonalcoholic steatohepatitis (NASH), which can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, it was suggested that the terms "metabolic dysfunction-associated steatotic liver disease (MASLD)" and "metabolic dysfunction-associated steatohepatitis (MASH)" should replace the terms "nonalcoholic fatty liver disease (NAFLD)" and "nonalcoholic steatohepatitis (NASH)", respectively, with small changes in the definitions. MASLD, a hepatic manifestation of metabolic syndrome, is rapidly increasing in incidence globally, and is becoming an increasingly important cause of HCC. Steatohepatitic HCC, a histological variant of HCC, is characterized by its morphological features resembling non-neoplastic steatohepatitis and is closely associated with underlying steatohepatitis and metabolic syndrome. Variations in genes including patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), and membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) are associated with the natural history of MASLD, including HCC development. The mechanisms of HCC development in MASLD have not been fully elucidated; however, various factors, including lipotoxicity, inflammation, reactive oxygen species, insulin resistance, and alterations in the gut bacterial flora, are important in the pathogenesis of MASLD-associated HCC. Obesity and MASLD are also recognized as risk factors for hepatocellular adenomas, and recent meta-analyses have shown an association between MASLD and intrahepatic cholangiocarcinoma. In this review, we outline the pathology and pathogenesis of MASLD-associated liver tumors.

Clinico-histological and molecular features of hepatocellular carcinoma from nonalcoholic fatty liver disease.

Patients with nonalcoholic fatty liver disease (NAFLD) continue to increase with the epidemics of obesity, and NAFLD is estimated to become the most prevalent etiology of hepatocellular carcinoma (HCC). Recently, NAFLD-HCC has been recognized to have clinico-histologically and molecularly distinct features from those from other etiologies, including a lower incidence rate of HCC and less therapeutic efficacy to immune checkpoint inhibitors (ICIs). Consistent with the clinical observations that up to 50% of NAFLD-HCC occurs in the absence of cirrhosis, the imbalance of pro- and antitumorigenic hepatic stellate cells termed as myHSC and cyHSC can contribute to the creation of an HCC-prone hepatic environment, independent of the absolute fibrosis abundance. Immune deregulations by accumulated metabolites in NAFLD-affected livers, such as a fatty-acid-induced loss of cytotoxic CD4 T cells serving for immune surveillance and "auto-aggressive" CXCR6+ CD8 T cells, may promote hepatocarcinogenesis and diminish therapeutic response to ICIs. Steatohepatitic HCC (SH-HCC), characterized by the presence of fat accumulation in tumor cells, ballooned tumor cells, Mallory-Denk body, interstitial fibrosis, and intratumor immune cell infiltration, may represent a metabolic reprogramming for adapting to a lipid-rich tumor microenvironment by downregulating CPT2 and leveraging its intermediates as an "oncometabolite." Genome-wide analyses suggested that SH-HCC may be more responsive to ICIs given its mutual exclusiveness with β-catenin mutation/activation that promotes immune evasion. Thus, further understanding of NAFLD-specific hepatocarcinogenesis and HCC would enable us to improve the current daily practice and eventually the prognoses of patients with NAFLD.

Pathological overview of steatohepatitic hepatocellular carcinoma in a surgical series.

According to the last WHO classification, steatohepatitic hepatocellular carcinoma (SH-HCC) is recognized as a distinct HCC subtype, even though a consensual definition is still lacking. The objectives of the study were to carefully describe the morphological features of SH-HCC and evaluate its impact on prognosis. We conducted a single-centre retrospective study including 297 surgically resected HCC. Pathological features including SH criteria (steatosis, ballooning, Mallory-Denk bodies, fibrosis, and inflammation) were assessed. SH-HCC was defined by the presence of at least four of the five SH criteria and the SH component represented >50% of the tumour area. According to this definition, 39 (13%) HCC cases corresponded to SH-HCC and 30 cases (10%) corresponded to HCC with an SH component (<50%). SH criteria in SH-HCC and non-SH-HCC were distributed as follows: ballooning (100% versus 11%), fibrosis (100% versus 81%), inflammation (100% versus 67%), steatosis (92% versus 8%), and Mallory-Denk bodies (74% versus 3%). Inflammation markers (c-reactive protein [CRP] and serum amyloid A [SAA]) were significantly more expressed in SH-HCC compared to non-SH-HCC (82% versus 14%, P = <0.001). Five-year recurrence-free survival (RFS) and 5-year overall survival (OS) were similar for SH-HCC and non-SH-HCC (P = 0.413 and P = 0.866, respectively). The percentage of SH component does not impact OS and RFS. We confirm in a large cohort the relatively high prevalence (13%) of SH-HCC. Ballooning is the most specific criteria for this subtype. The percentage of the SH component does not impact prognosis.

Steatotic hepatocellular carcinoma: Association of MRI findings to underlying liver disease and clinicopathological characteristics

Fatty change is commonly observed in hepatocellular carcinoma (HCC); however, the characteristics of steatotic and steatohepatitic HCCs are not well understood. This retrospective study included patients with HCCs who underwent resection between January 2014 and December 2019 to evaluate clinicopathological and magnetic resonance imaging features. Tumours were categorized as magnetic resonance imaging-steatotic, pathology-steatotic and steatohepatitic HCCs and were defined as HCCs with ≥50% steatosis on in-and-oppose phase images, ≥34% tumour cells with lipid droplets and ≥50% tumour areas with steatohepatitic features on light microscopy respectively. Of 465 HCCs, 38 (8%), 23 (5%) and 15 (3%) were diagnosed as magnetic resonance imaging-steatotic, pathology-steatotic and steatohepatitic HCCs respectively. These HCC variants were less likely to be associated with hepatitis B virus infections than with type 2 diabetes mellitus, metabolic syndrome, non-tumour liver steatosis and steatohepatitis. Moreover, microvascular invasion was less likely to be associated with them than either tumour size or differentiation. Type 2 diabetes and non-tumour steatosis were independent risk factors for magnetic resonance imaging-steatotic HCCs. Pathology-steatotic HCCs and steatohepatitic HCCs were significantly associated with magnetic resonance imaging-steatotic HCCs. A targetoid appearance in the transitional or hepatobiliary phase was also more prevalent in steatohepatitic-HCCs than in non-steatohepatitic-HCCs. When magnetic resonance imaging-steatotic HCCs were combined with one or more ancillary features, the sensitivity and specificity were 60% and 97% respectively. Underlying fatty liver disease and metabolic syndrome are strongly associated with both steatotic and steatohepatitic HCCs. Clinicoradiological characteristics help identify steatohepatitic HCC with high specificity.

Contrast-Enhanced Imaging Features and Clinicopathological Investigation of Steatohepatitic Hepatocellular Carcinoma

Steatohepatitic hepatocellular carcinoma (SH-HCC) is a distinctive histologic variant of HCC for the presence of steatohepatitis. This study intended to evaluate the contrast-enhanced imaging features and clinicopathological characteristics of 26 SH-HCCs in comparison with 26 age-and-sex-matched non-SH-HCCs. The frequency of obesity (34.6%, p = 0.048) and type 2 diabetes mellitus (23.1%, p = 0.042) were significantly higher in SH-HCC patients. As seen via B-mode ultrasound (BMUS), SH-HCCs were predominantly hyperechoic (65.4%, p = 0.002) lesions, while non-SH-HCCs were mainly hypo-echoic. As seen via contrast-enhanced ultrasound (CEUS), 96.2% of SH-HCCs exhibited hyperenhancement in the arterial phase. During the portal venous and late phase, 88.5% of SH-HCCs showed late and mild washout. Consequently, most SH-HCCs and all non-SH-HCCs were categorized as LR-4 or LR-5. As seen via magnetic resonance imaging (MRI), a signal drop in the T1WI opposed-phase was observed in 84.6% of SH-HCCs (p = 0.000). Notably, diffuse fat in mass was detected in 57.7% (15/26) SH-HCCs (p < 0.001). As seen via contrast-enhanced MRI (CEMRI), most of the SH-HCCs and non-SH-HCCs exhibited heterogeneous hyperenhancement in the arterial phase (80.8% versus 69.2%, p = 0.337). During the delayed phase, 76.9% SH-HCCs and 88.5% non-SH-HCCs exhibited hypo-enhancement. Histopathologically, the rate of microvascular invasion (MVI) was significantly lower in SH-HCCs than non-SH-HCCs (42.3% versus 73.1%, p = 0.025). The frequency of hepatic steatosis >5% in non-tumoral liver parenchyma of SH-HCCs was significantly higher than in non-SH-HCCs (88.5% versus 26.9%, p = 0.000). Additionally, the fibrotic stages of S0, S1 and S2 in SH-HCCs were significantly higher than in non-SH-HCCs (p = 0.044). During follow-up, although the PFS of SH-HCC patients was significantly longer than non-SH-HCC patients (p = 0.046), for the overall survival rate of SH-HCC and non-SH-HCC patients there was no significant difference (p = 0.162). In conclusion, the frequency of metabolism-related diseases in SH-HCC patients was significantly higher than in non-SH-HCC patients. The imaging features of SH-HCCs combined the fatty change and typical enhancement performance of standard HCC as seen via CEUS/CEMRI.

Histological subtypes of hepatocellular carcinoma: Their clinical and prognostic significance

Assigning a hepatocellular carcinoma (HCC) to an appropriate subtype is important because this guarantees the diagnosis and treatment and allows decisions regarding the prognosis of the patient. HCC subtyping is usually based on the World Health Organization (WHO) classification and the 2019 fifth edition is the latest version. However, the WHO classification system is still in evolution and has limited clinical relevance. We aimed to evaluate the clinical relevance of HCC subtyping and to reappraise some of the major subtypes of HCC. Our archived cases (n = 589) were reclassified according to the 2019 WHO system. The percentage of each subtype was mostly similar to that in the WHO classification. However, on the contrary to the 2019 WHO system, clear cell type HCC was associated with more frequent recurrence or metastasis. Meanwhile, macrotrabecular massive HCC was related to poor prognosis as demonstrated in the 2019 WHO system and should be described in the pathology report. For steatohepatitic HCC, there is a debate on whether it is a true subtype because the steatohepatitis morphology may or may not be present in the background liver. In our study, 44 % of steatohepatitic HCCs (n = 19/43) presented underlying steatohepatitis. Additionally, the background cirrhosis did not influence survival in the HCC patients, although the 2019 WHO system indicates the presence of cirrhosis as a poor prognostic factor. In conclusion, although it is not perfect yet, HCC subtyping based on the 2019 WHO system provides valuable information to manage patients with HCC.

Update in Pathology of Practically Encountered Lesions and Diseases in the Liver

This issue of the American Journal of Surgical Pathology, Reviews and Reports is devoted to recent advances and update in the pathology of the liver. The articles provide insights into the current nomenclature, classification, diagnosis, differential diagnoses, clinical and prognostic aspects of various liver diseases, and lesions that are informative to pathologists in their daily practice. Hepatocellular adenomas (HCAs) is generally a benign liver neoplasm that typically arises in the noncirrhotic liver; however, malignant transformation does occur, and hence, subtyping is critical. Drs Jung and Liu present a case of HCA that was initially diagnosed as inflammatory HCA on a biopsy and subsequently was confirmed to be β-catenin–activated inflammatory HCA on the resection specimen. They then comprehensively review recent updates on molecular classification and the key histologic features of each subtype and discuss common diagnostic pitfalls. Over the past decades, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have been recognized to be heterogeneous in morphology, molecular features, and biological behavior. Recent World Health Organization classification describes various histomorphological subtypes of HCC and iCCA, some with characteristic molecular profiles, clinical correlates, and prognostic implications. In their review, Drs Hwang and Kim nicely discuss recently described subtypes of HCC and iCCA: macrotrabecular HCC, steatohepatitic HCC, scirrhous HCC, and small duct iCCA. Congestive hepatopathy shows a unique pattern of fibrosis, that is, pericentral fibrosis at early stage, which may progress to bridging fibrosis and cirrhosis. Making a diagnosis of congestive hepatopathy and staging its fibrosis are important tasks for pathologists, as patients may undergo liver biopsies before cardiac transplantation to assess the degree of liver fibrosis, which may impact clinical decision-making. Besides patients' own cardiac dysfunction, congestive hepatopathy can also be seen after a Fontan procedure. Drs Gosse and Bosch describe a case of congestive hepatopathy due to altered circulation with a Fontan procedure. They then discuss the fibrosis scoring systems recently described for Fontan-associated liver disease and congestive heart disease–associated hepatopathy. Combined hepatocellular-cholangiocarcinoma is a rare primary liver tumor with neoplastic components of both hepatocytic and cholangiocytic differentiation within the same tumor. There is recent consensus paper and World Health Organization classification of this unique tumor. Drs Kondo, Akiba, and Yano herein report a case of this tumor and thoughtfully review the terminology, classification, and clinical and pathological characteristics of combined hepatocellular-cholangiocarcinoma and its differential diagnosis. Hemophagocytic lymphohistiocytosis is a rare disease with a high mortality. Liver involvement is common, with most patients demonstrating acute hepatitis. Therefore, liver biopsies are frequently performed when this entity is suspected. Dr Xiong and colleagues summarize the clinical features of hemophagocytic lymphohistiocytosis, emphasizing its hepatic manifestations. They describe the highly variable histologic patterns and address difficulties encountered by pathologists. We are extremely grateful to all the contributors for sharing their expertise and knowledge in forming this issue. We hope that the information provides highlights and elucidates the practically encountered lesions in the liver. Guest Editors

Histomorphological Subtypes of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Review and Update

Abstract Primary liver cancers comprise a heterogeneous group of neoplasms, with the 2 main entities being hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Over the past decades, HCC and iCCA have been recognized to be heterogeneous in morphology, molecular features, and biological behavior, and the most recent World Health Organization classification of digestive system tumors describes various histomorphological subtypes of HCC and iCCA, some of which also have characteristic molecular features, clinical correlates, and prognostic implications. In this review, we discuss 4 recently described subtypes of HCC and iCCA—macrotrabecular HCC, steatohepatitic HCC, scirrhous HCC, and small duct iCCA—based on a series of cases.

Transcriptomic Analysis of Cirrhosis-Like Hepatocellular Carcinoma Reveals Distinct Molecular Characteristics and Pathologic Staging Implications.

Cirrhosis-like hepatocellular carcinoma (CL-HCC) is a rare hepatocellular malignancy characterized by multiple tumor nodules that clinically, radiologically, macroscopically, and microscopically mimic cirrhosis. We aimed to elucidate the molecular biology of CL-HCC and determine tumor nodule clonality. We performed RNA sequencing on formalin-fixed, paraffin-embedded tissue from confirmed CL-HCC cases (n = 6), along with corresponding nonneoplastic hepatic tissue (n = 4) when available. Transcriptomes from our previous work on steatohepatitic hepatocellular carcinoma and The Cancer Genome Atlas (TCGA) were used for comparison purposes. Histologically, CL-HCC displayed innumerable nodules and extensive vascular invasion. Intratumoral nodule comparison indicated that the multiple nodules were all clonally related, not independent primaries. The unique histomorphologic appearance corresponded with a distinct transcriptome compared with other HCCs, including fibrolamellar HCC (n = 6), steatohepatitic HCC (n = 8), and conventional HCC in TCGA (n = 424). Tumor-normal gene expression analysis revealed consistent overexpression of several genes involved in degradation of tissue matrix. No recurrent translocations or point mutations were identified. CL-HCC showed a gene expression profile indicative of zone 2 hepatocytes. CL-HCC's distinctive clinicopathologic features correspond to a unique gene expression profile, increased expression of invasive markers, features of zone 2 hepatocytes, and features suggestive of intratumoral nodule monoclonality.

State-of-the-art review on the correlations between pathological and magnetic resonance features of cirrhotic nodules.

Hepatocellular carcinoma (HCC) has become the second greatest cause of cancer-related mortality worldwide and the newest advancements in liver imaging have improved the diagnosis of both overt malignancies and premalignant lesions, such as cirrhotic or dysplastic nodules, which is crucial to improve overall patient survival rate and to choose the best treatment options. The role of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) has grown in the last 20 years. In particular, the introduction of hepatospecific contrast agents has strongly increased the definition of precursor nodules and detection of high-grade dysplastic nodules and early HCCs. Nevertheless, the diagnosis of liver tumours in cirrhotic patients sometimes remains challenging for radiologists, thus, in doubtful cases, biopsy and histological analysis become critical in clinical practice. This current review briefly summarizes the history of imaging and histology for HCC, covering the newest techniques and their limits. Then, the article discusses the links between radiological and pathological characteristics of liver lesions in cirrhotic patients, by describing the multistep process of hepatocarcinogenesis. Explaining the evolution of pathologic change from cirrhotic nodules to malignancy, the list of analyzed lesions provides regenerative nodules, low-grade and high-grade dysplastic nodules, small HCC and progressed HCC, including common subtypes (steatohepatitic HCC, scirrhous HCC, macrotrabecular massive HCC) and more rare forms (clear cell HCC, chromophobe HCC, neutrophil-rich HCC, lymphocyte-rich HCC, fibrolamellar HCC). The last chapter covers the importance of the new integrated morphological-molecular classification and its association with radiological features.

Steatohepatitic Variant of Hepatocellular Carcinoma-Incidental and Rare Finding on Autopsy

Hepatocellular carcinoma (HCC) constitutes 70-85% of all primary liver tumors and ranks as the fifth most common cancer and the second most common cause of cancer deaths worldwide [1, 2]. Steatohepatitic hepatocellular carcinoma (SH-HCC) is a variant of hepatocellular carcinoma (HCC) with established association with nonalcoholic steatohepatitis (NASH), while its association with alcoholic steatohepatitis (ASH) is unclear. The steatohepatitic variant of HCC (SH-HCC) typically presents in patients with metabolic risk factors and either cirrhotic or non-cirrhotic NAFLD and shares many of the histological features found in non-alcoholic steatohepatitis (NASH). It accounts for 5-20% of HCCs, and the background liver may show steatohepatitis [3, 4]. We present a case of a 53-year-old deceased male. Part of liver was received after autopsy, which appeared nodular grossly and histopathological diagnosis of Steatohepatitic variant of Hepatocellular Carcinoma was made.

Clinicopathological assessment of steatohepatitic hepatocellular carcinoma

AimTo compare the clinicopathological features of typical steatohepatitic HCC (SH-HCC) with other HCCs. MethodsSubjects were 486 patients with untreated HCC who underwent hepatectomy at our hospital from January 2015 to December 2020. We compared patient backgrounds, preoperative laboratory data, imaging findings (ultrasonography, computed tomography [CT], and magnetic resonance imaging [MRI]), and postoperative pathological findings (tumor and background of liver). The Liver Imaging Reporting And Data System (LI-RADS) was used to examine CT and MRI findings. ResultsTypical SH-HCCs were significantly different from other HCCs with respect to age, hepatitis B virus (HBV) infection, and nonalcoholic steatohepatitis (NASH). Diabetes and hyperlipidemia were also significantly more common. Regarding histopathology, tumor size and background steatosis were significantly different between groups. Although ultrasonography, CT, and MRI could each alone diagnose SH-HCCs with a diameter < 20 mm in ≥ 50% of patients, the combined use of these tests improved diagnostic accuracy. By LI-RADS, 87% of SH-HCC cases were classified as LR-5, which are considered to be malignant tumors. ConclusionsIt seems possible to diagnose SH-HCC by combining ultrasonography, CT, and MRI.

Steatotic and Steatohepatitic Hepatocellular Carcinomas: Features in a Series With Predominantly Viral Etiology.

Hepatocellular carcinomas (HCCs) with steatohepatitis and steatosis are reported with varying definitions and clinicopathologic features. We aimed to search the attributes of steatohepatitic hepatocellular carcinoma (SH-HCC) and steatotic-HCC in our series. A retrospective clinicopathologic analyses of 150 HCCs and immunostaining for C-reactive protein (CRP) and serum amyloid A (SAA) were performed. Tumors were reclassified as all SH-HCC, limited SH-HCC, typical SH-HCC (steatohepatitic features in >5%, 5% to 50%, and ≥50% of the tumor, respectively), steatotic-HCC, and classic HCC (C-HCC). Group comparisons were made using Kruskal-Wallis and Kaplan-Meier tests. The background etiology in all SH-HCCs was pure viral in 51.4%, nonalcoholic steatohepatitis (NASH)/alcoholic liver disease (ALD) alone/mixed in 34.3%, and unidentified in normal liver in 14.3%. All SH-HCCS (n=35, 23.3%) and typical SH-HCCs (n=13, 8.6%) had higher NASH/ALD. Limited SH-HCCs (n=22, 14.6%) had higher ALD (all P<0.05). Typical SH-HCCs tended to have more NASH (P=0.054). Steatotic-HCCs (n=13, 9%) and C-HCCs (n=102, 68%) had higher pure viral etiology and serum CRP (all P<0.05). CRP and SAA were positive in 69% and 27% of the tumors, respectively. SAA positivity correlated with ALD (P=0.026). In the overall group disease-free survival rates at 1, 5, 10, and 20 years were 97.0%, 82.3%, 79.6%, and 77.2%, respectively. Demographics, tumor characteristics, CRP and SAA positivity, and survival were similar between the groups (P>0.05). SH-HCC is heterogenous in terms of underlying etiologies, and can be seen in NASH/ALD, pure viral and noncirrhotic/normal background. The ≥50% cutoff for the definition of SH-HCC can lead to overlook ALD-related SH-HCC. Steatotic-HCC seems more similar to C-HCC rather than SH-HCC, but none of them feature as a different prognostic group.

Steatohepatitic hepatocellular carcinoma: imaging findings with clinicopathological correlation

To evaluate the clinicopathological and computed tomography (CT) and magnetic resonance imaging (MRI) findings of steatohepatitic hepatocellular carcinoma (SH-HCC). Clinicopathological and radiological features were evaluated in 20 patients with SH-HCC. The diagnosis of SH-HCC was made histologically if the tumour had four of the following five characteristics: steatosis (>5% tumour cells), ballooning, Mallory-Denk bodies, interstitial fibrosis, and inflammation. All patients underwent dynamic CT and MRI. CT and MRI images were reviewed for morphological features including tumour size, presence, and distribution of fat, and patterns and degree of contrast enhancement. Obesity, hypertension, and history of heavy alcohol intake were common clinical findings observed in 10 (50%), 13 (65%), and 11 (55%) of the 20 patients, respectively. Steatosis and steatohepatitis were pronounced in the background liver in 12 (60%) and 10 (50%) patients, respectively. SH-HCC was moderately differentiated in 18 patients (90%) and well differentiated in two (10%). Pathologically, steatohepatitic features were diffuse in 12 (60%) of the 20 tumours and focal in eight (40%). Tumour size and the percentage of intratumoural steatosis were not correlated (r=0.17, p=0.47). On CT, 16 (80%) patients showed arterial phase enhancement and delayed washout. On MRI, 16 (80%) of 20 tumours showed prominent fatty deposition (10 diffusely, six focally) with arterial phase enhancement. SH-HCC is likely to show prominent fatty deposits with arterial phase enhancement on CT and MRI. A hypervascular lesion with prominent fatty change should raise the diagnostic suspicion of SH-HCC.

Transcriptomic and Proteomic Analysis of Steatohepatitic Hepatocellular Carcinoma Reveals Novel Distinct Biologic Features.

Steatohepatitic hepatocellular carcinoma is a distinct variant of hepatocellular carcinoma strongly associated with underlying nonalcoholic steatohepatitis. The molecular biology of steatohepatitic hepatocellular carcinoma is not fully elucidated, and thus we aimed to investigate the molecular underpinnings of this entity. Transcriptomic analysis using RNAseq was performed on eight tumor-nonneoplastic pairs of steatohepatitic hepatocellular carcinoma with comparison to conventional hepatocellular carcinoma transcriptomes curated in The Cancer Genome Atlas. Immunohistochemistry was used to validate key RNA-level findings. Steatohepatitic hepatocellular carcinoma demonstrated a distinctive differential gene expression profile compared with The Cancer Genome Atlas curated conventional hepatocellular carcinomas (n = 360 cases), indicating the distinctive steatohepatitic hepatocellular carcinoma morphology is associated with a unique gene expression profile. Pathway analysis comparing tumor-nonneoplastic pairs revealed significant upregulation of the hedgehog pathway based on GLI1 overexpression and significant downregulation of carnitine palmitoyltransferase 2 transcript. Glutamine synthetase transcript was significantly upregulated, and fatty acid binding protein 1 transcript was significantly downregulated and immunohistochemically confirmed, indicating steatohepatitic hepatocellular carcinoma tumor cells display a zone 3 phenotype. Steatohepatitic hepatocellular carcinoma demonstrates a distinctive morphology and gene expression profile, phenotype of zone 3 hepatocytes, and activation of the hedgehog pathway and repression of carnitine palmitoyltransferase 2, which may be important in tumorigenesis.

Steatohepatitic Variant of Hepatocellular Carcinoma Is Associated With Both Alcoholic Steatohepatitis and Nonalcoholic Steatohepatitis: A Study of 2 Cohorts With Molecular Insights.

Steatohepatitic hepatocellular carcinoma (SH-HCC) is a variant of hepatocellular carcinoma (HCC) with established association with nonalcoholic steatohepatitis (NASH), while its association with alcoholic steatohepatitis (ASH) is unclear. We studied 2 cohorts of patients who underwent resection for HCC in the setting of steatohepatitis. In our Mount Sinai (New York) cohort, we found SH-HCC in 17/24 (71%) patients with NASH and in 14/19 (74%) patients with ASH, while SH-HCC was the predominant tumor morphology in 12/24 (50%) in the NASH group and 9/19 (47%) in the ASH group. Upon review, 12/19 patients diagnosed with ASH also had diabetes and/or a body mass index >30. When these patients were removed, we still found similar rates of SH-HCC (6/7 [86%] showed SH-HCC, while SH-HCC was predominant in 3/7 [43%]. Interestingly, glycogenated hepatocyte nuclei were seen in the nontumor liver in 4/7 (57%) of these cases. In our Japan cohort, we also found similar rates of SH-HCC in NASH and ASH patients with HCC, 15/58 (26%), and 16/45 (36%), respectively. We determined molecular subclassification of tumors from the Japan cohort and found no difference in the distribution of S1, S2 and S3 subclasses among the ASH and NASH groups, though, among cases of SH-HCC, there was a trend toward an association of ASH with S1 (P=0.054) and NASH with S3 (P=0.052). Our study shows that SH-HCC is common in both ASH and NASH and that both underlying liver diseases produce tumors with similar molecular profiles, though different pathways may underlie the development of SH-HCC in ASH versus NASH.

Hepatocellular carcinoma in non-alcoholic fatty liver disease (NAFLD) - pathological evidence for a predominance of steatohepatitic inflammatory non-proliferative subtype.

This study evaluated clinical and pathological aspects of patients with hepatocellular carcinoma (HCC) secondary to non-alcoholic fatty liver disease (NAFLD) and related these factors to immunohistochemical markers representative of the proliferative class. We evaluated 35 HCC nodules from 21 patients diagnosed with NAFLD undergoing liver resection (n=12) or liver transplantation (n=8) or both (n=1). Demographic, clinical and biochemical data were compared to histological features and to immunohistochemical reactivity for K19 and Ki-67. Cirrhosis was present in 58% of patients. Ages ranged from 50 to 77 years. Sixteen patients (76%) were male and had type 2 diabetes mellitus, 81% had arterial hypertension, and 90% had BMI above 25 kg/m². Alpha-fetoprotein levels were normal in 62% of patients. Twenty-five (70%) nodules were diagnosed as "steatohepatitic HCC". Only 32% of the nodules presented high levels of Ki-67 (>10%) and/or K19 (>5%), although 63% were poorly differentiated (G.3/G.4) according to Edmondson & Steiner grading system. K19 positivity (>5%) was associated with higher degree of intratumoral inflammation (G.2/G.3), and with fibrosis, both at the center of the tumor and at the tumor front, whereas Ki-67 positivity (>10%) was associated with ballooning of neoplastic cells and occurred in more than 70% in non-cirrhotic patients. NAFLD-related HCC was found in non-cirrhotic patients in 42% of cases, alpha-fetoprotein level was normal in 63% and "steatohepatitic HCC" was the predominant histological type. Immunoexpression of K19 and/or Ki-67 occurred in 32% of the nodules and were associated with intratumoral inflammation and ballooning, suggesting that HCC in MtS may be preferentially "an inflammatory, non-proliferative subtype of HCC".