Evaluation of surgical strategies and long-term outcomes in pediatric hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC), the second most common pediatric malignant liver tumor after hepatoblastoma, represents 1% of all pediatric tumors. METHODS: A retrospective study was conducted on children with HCC treated at our center from March 2002 to October 2022, excluding those with inadequate follow-up or records. Demographic data, initial complaints, alpha-fetoprotein (AFP) values, underlying disease, size and histopathological features of the masses, chemotherapy, and long-term outcomes were analyzed. RESULTS: Fifteen patients (8 boys, 7 girls) with a mean age of 11.4 ± 4.1 years (0.8-16.4 years) were analyzed. The majority presented with abdominal pain, with a median AFP of 3.9 ng/mL. Hepatitis B cirrhosis in one patient (6.6%) and metabolic disease (tyrosinemia type 1) in two patients (13.3%) were the underlying diseases. Histopathological diagnoses were fibrolamellar HCC (n:8; 53.3%), HCC (n:6; 40%). Four of the 15 patients underwent liver transplantation, and 9 underwent surgical resection. Due to late diagnosis, two patients were considered inoperable (13.3%). The survival rate for the four patients who underwent liver transplantation was found to be 75%. CONCLUSION: Surgical treatment of various variants of HCC can be safely performed in experienced centers with a multidisciplinary approach, and outcomes are better than in adults.

Decoding the rhabdoid riddle in liver: A rare case of primary hepatic malignant rhabdoid tumor with a comprehensive literature review.

Malignant rhabdoid tumor of the liver is a rare, highly aggressive primary hepatic malignancy occurring primarily in infants. Establishing a definitive diagnosis is challenging due to its rarity, non-specific clinicoradiologic findings, and overlapping morphologic features. Herein, we present the cytomorphologic and immunocytochemical characteristics of a rare case of primary hepatic Malignant rhabdoid tumor (MRT) in an infant. A 5-month-old female child presented with progressively increasing firm mass in the upper abdomen, progressive pallor, sudden onset respiratory distress, and difficulty feeding. On examination, the child had massive, firm nodular hepatomegaly. Ultrasonography of the abdomen revealed a heterogeneously hypoechoic lesion in the left lobe of the liver. Serum alpha-fetoprotein levels were within normal limits. An ultrasound-guided fine-needle aspiration cytology (FNAC) from the liver mass showed predominantly dispersed large, markedly pleomorphic tumor cells with round to oval eccentrically placed nuclei, prominent nucleoli, and moderate cytoplasm. On immunocytochemistry, tumor cells showed positivity for vimentin, cytokeratin, and EMA and demonstrated a loss of INI1, confirming the diagnosis of MRT. The index report highlights the distinctive clinicopathological features of a hepatic malignant rhabdoid tumor along with the key differential diagnoses, which may pose a diagnostic conundrum. A high index of clinical suspicion and a thorough understanding of its cytomorphological and immunochemical characteristics are crucial for an accurate diagnosis.

Surgical Pathology Diagnostic Pitfalls of Hepatoblastoma.

Hepatoblastoma (HB) is the most common malignancy within the rare cohort of pediatric primary liver tumors. It may arise sporadically or in association with germline mutations in specific genetic syndromes. Histogenesis recapitulates fetal hepatic development, however, this tumor can exhibit a markedly heterogeneous appearance both macroscopically and under the microscope. Histologic subtypes are classified based on morphologic appearance, with additional discrimination based on emerging molecular and immunohistochemical features. Numerous diagnostic pitfalls exist from clinical presentation through to ancillary testing; at all stages, the surgical pathologist must be discerning and open to collaboration with colleagues of different specialties. Problematic areas include the adequacy of tissue sampling, correlation of histology with radiologic appearance and alpha feto-protein (AFP) serology, forming a diagnostic consensus within the pediatric pathology community and choosing a shrewd immunohistochemical panel. This review discusses the sequence of events leading up to histologic assessment, and the nuances of microscopic evaluation. Along the way, pitfalls are highlighted, providing a tool for the surgical pathologists to support their individual approach.

Doxorubicin in combination with cisplatin, 5-flourouracil, and vincristine is feasible and effective in unresectable hepatoblastoma: A Children's Oncology Group study.

BACKGROUND: The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. METHODS: In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. RESULTS: One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. CONCLUSIONS: The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Undifferentiated sarcoma of the liver: Multicenter international experience of the Cooperative Soft-Tissue Sarcoma Group and Polish Paediatric Solid Tumor Group.

BACKGROUND: Undifferentiated embryonal sarcomas of the liver (UESL) are extremely rare and continue to pose a diagnostic and therapeutic challenge. The aim of the study was to present a multicenter experience of the German CWS and Polish PPSTG groups in the treatment of UESL in children. PROCEDURE: Twenty-five patients were treated according to the CWS-96, CWS-2002, and CYVADIC protocols. Distant metastases were observed in four cases (16%). In four cases, an initial disease presentation mimicked other entities. A pure cystic appearance of liver mass led to misdiagnosis of hydatid cyst in three cases. In one case, laparotomy was performed due to the signs of appendicitis, and bleeding from ruptured liver tumor was found. All these patients were finally diagnosed as UESL. RESULTS: Thirteen patients received preoperative chemotherapy. Partial response was observed in 10 cases. Tumor resection was performed in 20 patients (primary resections, 12; delayed resections-, 8). In five patients, the primary tumor never became operable. The macroscopically complete resection rate was 95% (19/20). Postoperative chemotherapy was given to 20 children. Local radiotherapy was used in three children. After a median follow-up time of 136 months, 17 patients (68%) were alive with no evidence of disease. All children with unresectable tumor and three out of four patients with distant metastases died. The five-year overall survival (OS) rate was 72%. CONCLUSIONS: In summary, a complete tumor excision plays the central role in the treatment of UESL. A cystic presentation of the liver lesion on imaging does not exclude the diagnosis of malignant tumor.

The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.

PURPOSE: Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification. METHODS: We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors. RESULTS: Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture. CONCLUSION: Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.

Pediatric intrahepatic bile duct adenoma - rare liver tumor: A case report.

BACKGROUND: Intrahepatic bile duct adenoma (BDA) is one of the rarest of the rare benign tumors of the liver in the pediatric age group. It arises from the epithelial lining of intrahepatic bile ducts. The overall incidence of BDA is 1.3% of all primary benign liver tumors. Few case reports of this rare tumor occurring in adult population are present in the literature and to date, only one pediatric case has been reported worldwide. CASE SUMMARY: An 18-month-old male child presented with chief complaints of mass per abdomen for 8 mo. Computerized tomography abdomen revealed a well-defined exophytic solid tumor arising from the posteroinferior margin of the right lobe of the liver with heterogenous enhancement and cystic changes, suggesting a suspicion of hepatoblastoma. Non-anatomical liver resection was done and a tumor of 10 cm × 9.5 cm was excised. Histopathology of the specimen was conclusive with the diagnosis of intrahepatic bile duct adenoma, which was further supported by immunohistochemistry panel testing. The post-operative period was uneventful. On follow-up, the child was doing well and had no post-operative complication. CONCLUSION: Intrahepatic bile duct adenoma in children is very rare and to date only one case has been reported. This is the second pediatric case of intrahepatic bile duct adenoma in the world. Additionally this is the first ever case of such a large tumor presenting in a child.

mTOR inhibition affects Yap1-ß-catenin-induced hepatoblastoma growth and development.

Hepatoblastoma (HB) is the most common pediatric liver malignancy. Around 80% of HB demonstrate simultaneous activation of ß-catenin and Yes-associated protein 1 (Yap1). The mechanism by which these signaling pathways contribute to HB pathogenesis remain obscure. Recently, mTORC1 activation was reported in human HB cells and in a murine HB model driven by ß-catenin and Yap1. Here, we directly investigate the therapeutic impact of mTOR inhibition following HB development in the Yap1-ß-catenin model. HB were established by hydrodynamic tail vein injection of Sleeping Beauty transposase and plasmids coding for ΔN90-ß-catenin and S127A-Yap1. Five weeks after injection, when HB were evident, mice were randomized into Rapamycin diet-fed or basal-diet-fed groups for 5-weeks. Tumor growth was monitored via ultrasound imaging and mice in both groups were euthanized after 5-weeks for molecular analysis. Transcriptomic analysis showed a strong correlation in gene expression between HB in the Yap1-ß-catenin model and HB patient cohorts. Rapamycin treatment decreased HB burden, almost normalizing liver weight to body weight ratio. Ultrasound imaging showed reduction in tumor growth over the duration of Rapamycin treatment as compared to controls. Majority of HB in the controls exhibited crowded fetal or embryonal histology, while remnant tumors in the experimental group showed well-differentiated fetal morphology. Immunohistochemistry confirmed inhibition of mTORC1 in the Rapamycin group. Thus, Rapamycin reduces HB in a clinically relevant model driven by ß-catenin and Yap1, supporting use of mTORC1 inhibitors in their therapy. We also show the utility of standard and 3D ultrasound imaging for monitoring liver tumors in mice.

The genetic and epigenetic landscapes of hepatoblastomas

Primary liver cancers are rare in children, and the most common type is hepatoblastoma (HB), an embryonal tumor with histological features that resemble different stages of liver cell differentiation. However, mainly because of its rarity, molecular data on HB tumorigenesis remain scarce. This article reviews the current knowledge regarding genetic and epigenetic alterations reported in HB cases, with emphasis on the recent findings of next-generation sequencing studies (AU)

Intraoperative ultrasound for liver tumor resection in children.

BACKGROUND: Primary hepatic neoplasms in children are rare tumors. All malignant and medically refractive benign primary pediatric liver tumors ultimately require surgical resection for cure. Accurate preoperative imaging including multidetector helical computerized tomography or magnetic resonance imaging (MRI) is necessary to determine resectability. In the literature intraoperative ultrasound (IOUS) has proven to be a vital adjunct to liver surgery in adults, but this is not well established in children. MATERIALS AND METHODS: Between April 2003 and November 2014, children (<18-y-old) with a primary liver neoplasm, preoperatively evaluated with multidetector helical computerized tomography or MRI, who had IOUS used at the time of surgery were retrospectively reviewed. RESULTS: Preoperative evaluation with high-resolution MRI and IOUS were discordant in 4 of 19 patients (21%). In one case, right hepatic vein involvement was not accurately assessed with MRI. Two cases showed tumor involvement in segment IV by MRI; however, IOUS revealed no medial segment involvement. The final patient had a large (>5 cm), solitary hepatic adenoma on MRI, but IOUS in this case revealed diffuse adenomatosis. The operative management was altered in three of these cases. CONCLUSIONS: Although MRI can provide a detailed view of the hepatic anatomy and is an invaluable tool for preoperative planning for the pediatric patient with a primary liver neoplasm, IOUS may provide further and more up to date delineation of tumor extent and should be considered a crucial element in operative planning for hepatectomy in children.

Calcified telangiectatic hyperplastic nodule associated with vascular malformation in a child: a case report.

This is a case report of an asymptomatic 4-year-old girl who was found to have a nodule at the lateral left lobe of the liver. She underwent transabdominal liver ultrasound and abdominal MRI that showed calcification and intense arterial enhancement but they failed to clearly exclude malignancy. The patient underwent an unremarkable laparoscopic wedge liver resection of the lesion because of its location and size. Pathological examination showed features compatible with a benign telangiectatic hyperplastic nodule with vascular malformation and calcification. CD34 immunostained the proliferative vascular lining cells while CK7 and CK19 highlighted the normal bile ducts present within the lesion. The diagnosis of a telangiectatic hyperplastic nodule associated with vascular malformation has been scarcely reported in children and our case shows for the first time that it can also present with calcifications.