Pediatric hepatic vascular tumors: clinicopathologic characteristics of 33 cases and proposed updates to current classification schemes.

Pediatric hepatic vascular tumors (HVTs) are rare neoplasms with features distinct from their cutaneous counterparts. Their behavior ranges from benign to malignant, with each subtype having therapeutic differences. Histopathologic descriptions of large cohorts are scarce in the literature. Thirty-three putative HVTs diagnosed from 1970 to 2021 were retrieved. All available clinical and pathologic materials were reviewed. Lesions were reclassified according to the World Health Organization (WHO) classification of pediatric tumors [1] as hepatic congenital hemangioma (HCH; n = 13), hepatic infantile hemangioma (HIH; n = 10), hepatic angiosarcoma (HA; n = 3), and hepatic epithelioid hemangioendothelioma (HEH; n = 1). Vascular malformations (n = 5) or vascular-dominant mesenchymal hamartoma (n = 1) were excluded. HCH frequently showed involutional changes, whereas HIH often had anastomosing channels and pseudopapillae formation. HA had solid areas with epithelioid and/or spindled endothelial morphology, significant atypia, increased mitoses, high proliferation index, and occasionally necrosis. On morphology analysis, a subset of HIH showed features worrisome for progression to HA including solid glomeruloid proliferation, increased mitoses, and epithelioid morphology. The widely metastatic and fatal HEH was observed in a 5-year-old male with multiple liver lesions. Immunohistochemically, HIHs and HA were Glucose transporter isoform 1 (GLUT-1) positive. One HIH patient died from postoperative complications, whereas 3 are alive without disease. Five HCH patients are alive and well. Two of three HA patients died of disease, and 1 is alive without recurrence. To our knowledge, this is the largest series of pediatric HVTs reviewing clinicopathologic features based on current Pediatric WHO nomenclature [1]. We highlight diagnostic challenges and propose inclusion of an intermediate category between HIH and HA which warrants closer follow-up.

Imaging of Fontan-associated liver disease.

The Fontan operation has dramatically altered the natural history of functionally single ventricle congenital heart disease. Patients who have undergone the Fontan operation are living longer and, thus, noncardiac morbidity resulting from the Fontan operation is increasingly being recognized. Fontan-associated liver disease (FALD), one of the chief morbidities following the Fontan operation, is believed to be a multifactorial process that manifests as hepatic congestion and fibrosis, portal hypertension, and development of focal liver lesions, including malignant tumors. This article reviews the imaging findings of FALD in the pediatric and young adult population, reviews the literature related to the imaging of FALD and discusses possible screening algorithms for this population. The need for further research to better understand the causes of FALD, to establish if early liver stiffness measurements (or their change over time) predict long-term outcomes and complications, and to define optimal liver screening procedures is highlighted.

Pediatric trichodysplasia spinulosa: A report of 2 cases and review of the literature.

Trichodysplasia spinulosa is a rare disorder caused by the ubiquitous trichodysplasia spinulosa-associated polyomavirus (TSPyV) and characterized clinically by predominately centrofacial, but often generalized, folliculocentric papules with protuberant keratinaceous spines. Although seroprevalence reaches up to 70% in adult populations, TSPyV causes clinical manifestations in a small percentage of patients who are immunosuppressed. Diagnosis can be made using typical clinical and histologic features, SV40T antibody immunostaining, and PCR of various tissues including the keratinaceous spine, skin, serum, urine, and CSF. Various topical and systemic medications have demonstrated variable success. Decreasing or discontinuing immunosuppression has also been shown to improve or alleviate clinical manifestations.

Two-dimensional ultrasound shear wave elastography for identifying and staging liver fibrosis in pediatric patients with known or suspected liver disease: a clinical effectiveness study.

BACKGROUND: Ultrasound shear wave elastography (SWE) measures liver stiffness noninvasively, but few studies have defined cutoff values for detecting liver fibrosis in pediatric patients using 2-D ultrasound SWE. OBJECTIVE: To evaluate the diagnostic performance of 2-D ultrasound SWE and define cutoff values for liver fibrosis in pediatric patients, using Canon (Toshiba) Aplio ultrasound systems. MATERIALS AND METHODS: This was an institutional review board-approved retrospective study of patients (≤18 years old) who had undergone both liver 2-D ultrasound SWE and percutaneous liver biopsy within 6 months. Liver biopsies were staged using the METAVIR (fibrosis) scoring system. Continuous data were compared using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was used to evaluate diagnostic performance. RESULTS: Forty-six patients, with a median age of 11.5 years (interquartile range: 8.0-14.3 years), were included. Twenty-three patients were male (50%). Twenty-seven patients had a METAVIR fibrosis score of F0-1, and 19 patients had a score of F2-4. For differentiating METAVIR F0-1 from F2--4, the area under the ROC (AuROC) was 0.75 (95% confidence interval [CI]: 0.60-0.90). A cutoff of >1.89 m/s yielded sensitivity of 73.7% (95% CI: 51.2-88.2) and specificity of 77.8% (95% CI: 59.2-89.4). For the subset of patients without histological hepatic steatosis (n=35), the AuROC was 0.86 (95% CI: 0.71-1.0). The same cutoff of >1.89 m/s yielded a sensitivity of 80.0% (95% CI: 54.8-93.0) and specificity of 95.0% (95% CI 76.4-99.7). CONCLUSION: Two-dimensional ultrasound SWE distinguishes patients with no/mild fibrosis from those with moderate/severe fibrosis with good sensitivity and specificity. Diagnostic performance is comparable to that published for magnetic resonance elastography and is likely adversely impacted by steatosis.

Clinical heterogeneity of pediatric hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is often a chemoresistant neoplasm with a poor prognosis. Pediatric HCC may reflect unique biological and clinical heterogeneity. PROCEDURE: An IRB-approved retrospective institutional review of patients with HCC treated between 2004 and 2015 was undertaken. Clinical, radiographic, and histologic data were collected from all patients. RESULTS: Thirty-two patients with HCC, median age 11.5 years (range 1-20) were identified. Seventeen patients had a genetic or anatomic predisposition. Histology was conventional HCC (25) and fibrolamellar HCC (7). Evans staging was 1 (12); 2 (1); 3 (10); 4 (9). Sixteen patients underwent resection at diagnosis and five patients after neoadjuvant chemotherapy. Surgical procedures included liver transplantation (LT, 11), hemihepatectomy (9), and segmentectomy (1). Eighteen patients had medical therapy (13 neoadjuvant, 5 adjuvant). Most common initial medical therapy included sorafenib alone (7) and cisplatin/doxorubicin-based therapy (8). Overall, 14 (43.8%) patients survived with a median follow-up of 58.8 months (range 26.5-157.6). Cause of death was most often linked to lack of primary tumor surgery (11). Of the survivors, Evans stage was 1 (11), 2 (1), and 3 (2, both treated with LT). Four of 18 patients (22%) who received medical therapy, 8 of 17 patients with a predisposition (47%), and 14 of 21 patients (66%) who underwent surgery remain alive. CONCLUSIONS: Genetic and anatomic predisposing conditions were seen in over half of this cohort. Evans stage 1 or 2 disease was linked to improved survival. LT trended toward improved survival. Use of known chemotherapy agents may benefit a smaller group of pediatric HCC and warrants formal prospective study through cooperative group trials.

Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes.

BACKGROUND: Congenital portosystemic shunt (CPSS) is a rare malformation in which splanchnic venous flow bypasses the liver. CPSS is associated with other congenital anomalies and syndromes and can be associated with life-threatening complications. CPSS and their management remain underreported in the literature. Here, we review the clinical characteristics, management, and outcomes of a cohort of children and young adults with CPSS from two pediatric centers. METHODS: Cases of CPSS from Cincinnati Children's Hospital Medical Center and C.S. Mott Children's Hospital were reviewed to define CPSS anatomy, associated anomalies, complications, interventions, and outcomes. The imaging features and histopathology of liver lesions were characterized in detail. RESULTS: A total of 11 cases were identified. Median age was 10 years (range 0-26); 8 (73%) cases were female. Associated anomalies included six patients with heterotaxy (55%), five patients with congenital heart disease (45%), three patients with Turner syndrome (27%), and two patients with omphalocele, exstrophy, imperforate anus, spinal defects (OEIS) complex (18%). Eight (73%) cases had hyperammonemia ± encephalopathy. A 4-month-old presented with hepatopulmonary syndrome, and 12-year-old presented with pulmonary hypertension. Eight patients (73%) had liver lesions including five with premalignant adenomas and three with well-differentiated hepatocellular carcinoma (HCC). Four children underwent successful CPSS occlusion/ligation. Three children underwent liver transplant (2) or resection (1) for HCC without recurrence at extended follow-up. CONCLUSIONS: CPSS is associated with multiple anomalies (heterotaxy, congenital heart disease) and syndromes (Turner syndrome). CPSS liver lesions should be very carefully evaluated due to risk of premalignant adenomas and HCC. Serious complications of CPSS can occur at a young age but can be managed endovascularly or with open surgery.

Risk Factors Associated With Upper Aerodigestive Tract or Coliform Bacterial Overgrowth of the Small Intestine in Symptomatic Patients.

INTRODUCTION: The clinical relevance of bacterial types identified in small bowel aspirate cultures during diagnostic evaluation of small intestinal bacterial overgrowth (SIBO) is unclear. AIM: The main purpose of this study was to assess associations between risk factors for upper aerodigestive tract (UAT) or coliform SIBO and SIBO diagnosis by culture. MATERIALS AND METHODS: Small bowel aspirates were cultured in patients with suspected SIBO, defined as ≥10 colony-forming units/mL coliform or ≥10 colony-forming units/mL UAT bacteria. History was reviewed for risk factors and potential SIBO complications. Symptoms, quality of life, psychological traits, and laboratory values were assessed. We compared groups by 2-sample t test, Wilcoxon rank sum test, and the Fisher exact test. Overall associations of primary and secondary endpoints with type of bacterial overgrowth were assessed by analysis of variance F-test, Kruskal-Wallis test, and the Fisher exact tests. Associations of risk factors with type of overgrowth were explored using multinomial logistic regression. RESULTS: Among 76 patients, 37 had SIBO (68% coliform, 33% UAT) and 39 did not. Conditions (P=0.02) and surgery (P<0.01) associated with decreased gastric acid were associated with SIBO. In multinomial logistic regression, conditions of decreased acid was associated with UAT SIBO [odds ratio (OR), 5.8; 95% confidence interval, 1.4-33.3]. Surgery causing decreased acid was associated with UAT [OR, 9.5 (1.4-106)] and coliform SIBO [OR, 8.4 (1.6-86.4)]. Three patients with discontinuous small bowel had coliform SIBO [OR, 17.4 (1.2-2515)]. There were no differences in complications, overall symptoms, quality of life, or psychological traits. CONCLUSIONS: Conditions or surgeries associated with decreased gastric acid are associated with SIBO diagnosis by culture.

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) involves development of hepatic steatosis, fibrosis, and steatohepatitis. Because hepatic steatosis appears first in NAFLD animal models, the current therapy development focuses on inhibition of hepatic steatosis, suggesting that further steps of NAFLD will be also inhibited. In this report, we show that the first event of NAFLD is liver proliferation, which drives fibrosis in NAFLD. We have deleted a strong driver of liver proliferation, gankyrin (Gank), and examined development of NAFLD in this animal model under conditions of a high-fat diet (HFD). We found that proliferating livers of wild-type mice develop fibrosis; however, livers of Gank liver-specific knockout (GLKO) mice with reduced proliferation show no fibrosis. Interestingly, an HFD causes the development of strong macrovesicular steatosis in GLKO mice and is surprisingly associated with improvements in animal health. We observed that key regulators of liver biology CCAAT/enhancer binding protein α (C/EBPα), hepatocyte nuclear factor 4α (HNF4α), p53, and CUG repeat binding protein 1 (CUGBP1) are elevated due to the deletion of Gank and that these proteins support liver functions leading to healthy conditions in GLKO mice under an HFD. To examine the role of one of these proteins in the protection of liver from fibrosis, we used CUGBP1-S302A knockin mice, which have a reduction of CUGBP1 due to increased degradation of this mutant by Gank. These studies show that reduction of CUGBP1 inhibits steatosis and facilitates liver proliferation, leading to fibrosis and the development of liver tumors. Conclusion: Liver proliferation drives fibrosis, while steatosis might play a protective role. Therapy for NAFLD should include inhibition of proliferation rather than inhibition of steatosis.

Prognostic value of hypersensitivity reactions on epidural steroid injection outcomes: a phenotypic signature? A prospective cohort study.

BACKGROUND: Studies have found that diffuse pain, indicative of central sensitization, portends poor interventional outcomes. Multiple chemical sensitivities are associated with signs of central sensitization. We sought to prospectively determine whether hypersensitivity reactions (HR) were associated with epidural steroid injection (ESI) outcomes. METHODS: HR were classified as immune-related or non-immune-related and categorized by number (0=low, 1 or 2=intermediate, ≥3=high). The primary outcome measure was mean reduction in average leg pain score 1 month post-procedure. A positive outcome was defined as a two-point or greater decrease in average leg pain accompanied by satisfaction 1 month post-procedure. RESULTS: The mean number of immune-mediated and non-immune-mediated HR were 0.6±1.2 and 0.8±1.4, respectively. Individuals in the high (n=24) total HR group had a mean reduction in average leg pain of 0.1±2.7, compared with those in the low (n=61; 1.8±2.1, p=0.025) and intermediate groups (n=52; 1.6±3.1, p=0.060). For back pain and categorical successful outcome, those with fewer HR experienced greater benefit. There were no differences in outcomes when patients were stratified by immune-related HR. Among participants in the low, intermediate and high non-immune-mediated HR groups, the mean reductions in average leg pain scores were 1.7±2.5, 1.6±3.0, and -0.2±2.3, respectively (p = 0.002). 51%, 35%, and 12% of people with low, intermediate and high numbers of non-immune-mediated HR experienced a positive categorical outcome, respectively (p=0.007). CONCLUSIONS: Non-immune-related HR were inversely correlated with some ESI outcome measures.

Transarterial radioembolization with yttrium-90 of unresectable primary hepatic malignancy in children.

BACKGROUND: Primary malignant liver tumors are rare, accounting for 1% to 2% of all childhood cancers. When chemotherapy fails, transarterial radioembolization with yttrium-90 (TARE-Y90) may offer an alternative therapy as a bridge to surgical resection or liver transplant or for palliation. METHODS: We conducted a retrospective review of 10 pediatric patients with histologically confirmed primary liver malignancy who received treatment with TARE-Y90. RESULTS: The median age at treatment was 5.5 years (range, 2-18 years). Median patient survival from initial diagnosis was 12.5 months (range, 10-28 months), and median patient survival after TARE-Y90 was 4 months (range, 2-20 months). Retreatment was well tolerated in three of 10 patients, with these patients demonstrating the longest survival times (range, 17-20 months). One patient was transplanted 6 weeks after TARE-Y90. By RECIST 1.1 criteria of all target lesions, eight of nine patients had stable disease, and one of nine had progressive disease. By mRECIST criteria (requiring postcontrast arterial phase imaging), two of seven patients had a partial response, four of seven had stable disease, and one of seven had progressive disease. CONCLUSION: TARE-Y90 of unresectable primary liver malignancy is both technically feasible and demonstrates an anticancer effect, and retreatment is well tolerated. TARE-Y90 could be considered as adjunctive therapy in pediatric patients with unresectable hepatic malignancies and could be used as a bridge to surgical resection or liver transplant. More research is required to determine the efficacy of this treatment in children and to define the clinical scenarios where benefit is likely to be optimized.

Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice.

BACKGROUND AND AIMS: The transcription factors FOXF1 and FOXF2 have been implicated in the development of the gastrointestinal tract but their role in adults or in gastrointestinal diseases is poorly understood. We have recently shown that expression of serum response factor (SRF), a transcription factor whose activity is modulated by FOXF proteins, is decreased in the stomach muscularis of patients with gastroparesis. The aim of the current study was to determine whether FOXF expression is decreased in gastroparesis patients and whether loss of FOXF1 and/or FOXF2 from adult smooth muscle is sufficient to impair gastric emptying in mice. METHODS: Full-thickness stomach biopsy samples were collected from control subjects and from patients with gastroparesis. mRNA was isolated from the muscularis externa, and FOXF mRNA expression levels were determined by quantitative reverse transcriptase (RT)-PCR. Foxf1 and Foxf2 were knocked out together and separately from smooth muscle cells in adult mice, and the subsequent effect on liquid gastric emptying and contractile protein expression was determined. KEY RESULTS: Expression of FOXF1 and FOXF2 is decreased in smooth muscle tissue from gastroparesis patients. Knockout of Foxf1 and Foxf2 together, but not alone, from mouse smooth muscle resulted in delayed liquid gastric emptying. Foxf1/2 double knockout mice had decreased expression of smooth muscle contractile proteins, SRF, and myocardin in stomach muscularis. CONCLUSIONS AND INFERENCES: Our findings suggest that decreased expression of FOXF1 and FOXF2 may be contributing to the impaired gastric emptying seen in gastroparesis patients.

Reactive Ductules Are Associated With Angiogenesis and Tumor Cell Proliferation in Pediatric Liver Cancer.

While reactive ductules (RDs) have been observed in viral hepatitis, biliary atresia, nonalcoholic fatty liver disease, and adult hepatocellular carcinoma (HCC), RDs in pediatric liver cancer remain uncharacterized. This study investigated the relationship of RDs with angiogenic paracrine factors, the extent of angiogenesis, and tumor cell proliferation in pediatric hepatoblastoma (HBL)/HCC livers. We quantified the extent of RDs and their expression of paracrine factors that include vascular endothelial growth factor (VEGF), vascular endothelial growth factor D (VEGFD), platelet-derived growth factor C, and angiopoietin 1 (ANGPT1). In addition, we performed immunohistochemical detection of the endothelial marker clusters of differentiation (CD)34 and the proliferation marker Ki67 followed by correlation analyses. In HBL, we found the percentage of RDs with Ki67 expression (% Ki67+ RDs) significantly correlated with intratumoral Ki67+ areas (r = 0.5138, P = 0.0349) and % ANGPT1+ RDs positively correlated with % Ki67+ RDs (r = 0.5851, P = 0.0136). In HCC, the high ANGPT1+ RDs group (i.e., cases with % ANGPT1+ RDs ≥50) exhibited high intratumoral Ki67+ areas compared to the low ANGPT1+ RDs group. In the combined HBL and HCC liver tumor group, there was a positive association between % platelet-derived growth factor C+ RDs and intratumoral Ki67+ areas (r = 0.4712, P = 0.0099) and the high VEGFD+ RDs group (≥50%) exhibited a high number of peritumoral CD34+ vessels compared to the low VEGFD+ RDs group. Conclusion: Paracrine factor-expressing RDs are associated with angiogenesis and proliferation of pediatric liver tumors.

Hepatocyte-specific contrast media: not so simple.

Hepatocyte-specific contrast media are gadolinium chelates that are taken up by hepatocytes and partially cleared via the biliary tree. The absence of lesional uptake of the contrast media in the hepatobiliary phase is a marker of either the absence of hepatocytes or of poorly functioning, neoplastic hepatocytes. Uptake of the contrast media in the hepatobiliary phase, whether equal to or greater than background liver, reflects the presence of hepatocytes but does not equate to absence of neoplasia. Accurate diagnosis of liver lesions utilizing hepatocyte-specific contrast media requires an understanding of the mechanisms of uptake and clearance of the contrast media to avoid misdiagnosis. In this review we discuss the mechanisms of hepatocellular transport of hepatocyte-specific contrast media and utilize an understanding of those mechanisms to discuss the imaging appearance of a subset of hepatocellular lesions that can be seen in the pediatric and young adult liver. We pay particular attention to lesions that appear iso- to hyperintense in the hepatobiliary phase but have the potential for adverse clinical outcomes. We also discuss strategies for identifying these lesions.

Acquired ornithine transcarbamylase deficiency in pediatric and adolescent patients with fibrolamellar hepatocellular carcinoma.

Ornithine transcarbamylase deficiency (OTCD) disrupts the metabolic pathway responsible for converting nitrogenous waste to urea, allowing for excretion. When impaired, ammonia levels accumulate in the blood resulting in severe, sometimes life-threatening toxicities. Abnormalities of the urea cycle are often inherited, though there are some rarer acquired forms. We describe two cases of acquired OTCD in pediatric patients with fibrolamellar hepatocellular carcinoma (FL-HCC). We detail its presentation and management, explore potential underlying pathophysiology, and propose a practice change to optimize care of FL-HCC patients.

Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that is often chemoresistant. Complete surgical resection remains the mainstay of therapy. The role of liver transplantation (LT) in pediatric HCC is in evolution, as is the role of adjuvant chemotherapy for stage I disease. METHODS: A retrospective review of patients < 18 years of age with completely resected HCC treated with surgical intervention alone at our institution from 2004 to 2015 was conducted. RESULTS: Twelve patients with a median age of 12 years (range = 1-17; number of females = 7) with upfront resected HCC (Evans stage I) were identified. Four patients had HCC without identifiable risk factors (fibrolamellar-HCC = 2; early HCC arising in focal nodular hyperplasia = 1, well-differentiated [wd] HCC = 1). Four patients had early or wd-HCC in the context of portosystemic shunts (Abernethy = 2; mesocaval shunt and portal vein thrombosis = 2). Four patients had moderate to wd-HCC in the context of pre-existing liver disease with cirrhosis (progressive familial intrahepatic cholestasis type-2 = 2, alpha-1 antitrypsin deficiency = 1, Alagille syndrome = 1). Seven patients underwent LT (multifocal = 5; solitary = 2); five exceeded Milan criteria (MC) by imaging. Five patients underwent complete resection (segmentectomy = 2; hemihepatectomy = 3). Ten patients received no adjuvant chemotherapy. All patients are alive without evidence of disease with a median follow-up of 54.1 months (range = 28.1-157.7 months). CONCLUSIONS: Pediatric and adolescent patients with upfront, completely resected HCC can be effectively treated without chemotherapy. LT should be considered for nonmetastatic HCC, especially in the context of pre-existing chronic liver disease, even when the tumor exceeds MC. Distinct pediatric selection criteria are needed to identify patients most suitable for LT.

Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma.

Angiosarcoma is an aggressive malignancy of vascular origin that occurs de novo or in the context of previous cancer therapy. Despite multi-modal aggressive treatment including surgical resection, chemotherapy, and radiation, five-year overall survival remains poor at 35%. Due to its rarity, little is known about its molecular pathology and clinical trials have been extremely difficult to conduct. Development of animal models for rare diseases like angiosarcoma is critical to improve our understanding of tumorigenesis and to test novel treatment regimens. A genetically engineered mouse model for angiosarcoma was generated by conditional deletion of Trp53, Pten, and Ptpn12 in endothelial cells. Tumors arising from these mice recapitulate the histology and molecular pathology of the human disease including hyperactivation of the PI3K/mTOR and MAPK signaling pathways. Treatment of tumor-bearing mice with mTOR or MEK inhibitors effectively inactivated signaling and resulted in reduced proliferation and elevated apoptosis leading to tumor regression. The effect of treatment on tumor growth was transient and proliferation was restored after a period of dormancy. However, combined inhibition of mTOR and MEK resulted in profound tumor regression which was sustained for the duration of treatment. These results suggest that angiosarcoma may be effectively treated by this drug combination. .

Intrahepatic cholangiocarcinoma after Fontan procedure in an adult with visceral heterotaxy.

Hepatic dysfunction, including development of hepatocellular carcinoma and other liver lesions has been increasingly reported following Fontan procedure for congenital heart disease. We report a unique case of intrahepatic cholangiocarcinoma 28 years after a Fontan procedure in a 31year old female with heterotaxy syndrome. The subcapsular mass-forming tumor was composed of poorly differentiated tumor cells arranged in small vague glandular or slit-lumen nests, and focally fused or anastomosing large trabecular patterns within the prominent fibrotic stroma. The tumor cells with immunoreactivity to CK7, CK19, Cam5.2, COX2, EMA, BCL-2, MOC-31 and AE1/AE3, supported a diagnosis of intrahepatic cholangiocarcinoma. Focal atypical ductular proliferation within the background liver may represent a precursor lesion to this tumor. Dysmorphic cilia observed by electron microscopy examination in the background liver may suggest cholangiociliopathy in heterotaxy. MYST3 mutation at Q1388H detected in intrahepatic cholangiocarcinoma is reported for the first time.

C/EBPα-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer.

Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular carcinoma (HCC) is caused by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT/enhancer binding protein α (C/EBPα) at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPα-S193A, in a large cohort of human HBL samples, and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPα that is dephosphorylated at Ser190/193. We found that dephosphorylated C/EBPα creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C/EBPα-dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta-like 1 homolog-positive intranuclear inclusions. We further isolated C/EBPα-dependent multinucleated hepatocytes and found that they possess characteristics of tumor-initiating cells, including elevation of stem cell markers. C/EBPα-dependent cancer stem cells are observed in patients with aggressive HBL and in patients with a predisposition for liver cancer. CONCLUSION: The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C/EBPα into an oncogenic isoform, which further creates preneoplastic foci where hepatocytes dedifferentiate into cancer cells, giving rise to liver cancer. (Hepatology 2018;67:1857-1871).

Germline APC mutations in hepatoblastoma.

BACKGROUND: Conflicting reports on the frequency of germline adenomatous polyposis coli (APC) gene mutations in patients with hepatoblastoma (HB) have called into question the clinical value of APC mutation testing on apparently sporadic HB. METHODS: An Institutional Review Board approved retrospective review of clinical data collected from patients with HB who received APC testing at our institution was conducted. All HB patients seen at Cincinnati Children's Hospital Medical Center were eligible for testing. Potential genotype/phenotype correlations were assessed. RESULTS: As of July 2015, 29 patients with HB had received constitutional APC testing. Four (14%) were found to have APC pathogenic truncations of the APC protein and in addition two (7%) had APC missense variants of unknown clinical significance. Two patients (7%) had family histories indicative of familial adenomatous polyposis (FAP). Response to chemotherapy tracked differently in APC pathogenic cases, with a slower imaging response despite an equivalent or slightly faster α-fetoprotein (AFP) response. CONCLUSION: The prevalence of pathogenic APC variants in apparently sporadic HB may be higher than previously detected. Differences in time to imaging response, despite similar AFP response, may impact surgical planning. All patients with HB warrant germline APC mutation testing for underlying FAP.