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Ovaries are a common niche for metastasis. Metastatic malignancies account for 5–30% of all ovarian malignancies. Hepatocellular carcinoma (HCC) is one of the rare malignancies to metastasize to the ovaries. Of all the variants of HCC, fibrolamellar HCC (FLHCC) variant is extremely uncommon and accounts for around 1% of all HCC cases. FLHCC metastasizing to ovaries, at presentation, is an exceptional occurrence. We present a case of a young female who presented with bilateral adnexal masses and was diagnosed as metastatic FLHCC on histopathological examination and confirmed by immunohistochemistry. In addition, a thorough literature review highlighting the previously reported cases is also presented. [ABSTRACT FROM AUTHOR]

Fibrolamellar carcinoma (FLC) is a rare and poorly understood malignancy, which seems to be more prevalent in young patients compared with conventional hepatocellular carcinoma (HCC). Performing prospective clinical trials recruiting patients diagnosed with FLC has proven challenging with scarce data available guiding clinical management. The use of a number of chemotherapy compounds in these patients, including cisplatin, epirubicin, 5-fluorouracil (5-FU) and recombinant interferon α-2B (IFN-α-2B), has been reported in the literature, mainly in the form of case reports. The most promising systemic therapy tested so far is the combination of 5-FU infusion and 3-weekly IFN-α-2B, based on results from a phase II clinical trial. This article provides an overview of our own experience with this treatment schedule for patients with FLC, confirming its activity and treatment-derived benefit in the real world. Current challenges being faced by healthcare professionals treating patients with advanced FLC are discussed, especially the increasingly limited access to IFN-α-2B, which could compromise the access to an active therapy in the coming future, and the difficulties in the development of new treatment options for advanced FLC. • Fibrolamellar carcinoma is a liver cancer. • Evidence supporting systemic therapy is scarce. • Most promising systemic therapy is based on 5-fluorouracil infusion and interferon α-2B (IFN-α-2B). • There is an increasingly limited access to IFN-α-2B. [ABSTRACT FROM AUTHOR]

DNAJB1 - PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) that occurs in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered. A series of 151 liver tumors including 126 HCC, 15 FLC, and 10 mixed-FLC/HCC were analyzed by RNAseq and whole-genome- or whole-exome sequencing. Western blots were performed to validate genomic discoveries. Results were validated using the TCGA database. Most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of 17 tumors, which all had mutations or translocations inactivating BAP1 , the gene encoding BRCA1-associated protein-1. Like FLC, BAP1-HCC were significantly enriched in females, patients with a lack of chronic liver disease, and fibrotic tumors compared to non-BAP1 HCC. However, patients were older and had a poorer prognosis than those with FLC. BAP1 tumors were immune hot, showed progenitor features and did not show DNAJB1 - PRKACA fusion, while almost none of these tumors had mutations in CTNNB1 , TP53 and TERT promoter. In contrast, 80% of the BAP1 tumors showed a chromosome gain of PRKACA at 19p13, combined with a loss of PRKAR2A (coding for the inhibitory regulatory subunit of PKA) at 3p21, leading to a high PRKACA/PRKAR2A ratio at the mRNA and protein levels. We have characterized a subgroup of BAP1 -driven HCC with fibrolamellar-like features and a dysregulation of the PKA pathway, which could be at the root of the clinical and histological similarities between BAP1 tumors and DNAJB1 - PRKACA FLCs. Herein, we have defined a homogeneous subgroup of hepatocellular carcinomas in which the BAP1 gene is inactivated. This leads to the development of cancers with features similar to those of fibrolamellar carcinoma. These tumors more frequently develop in females without chronic liver disease or cirrhosis. The presence of PKA activation and T cell infiltrates suggest that these tumors could be treated with PKA inhibitors or immunomodulators. • BAP1 -inactivating alterations define a homogeneous subgroup of HCC characterized by fibrolamellar-like features. • These tumors frequently develop in females, with non-cirrhotic livers. • Patients with BAP1-inactivated HCC could benefit from drugs inactivating PKA and immunomodulators. [ABSTRACT FROM AUTHOR]

Background: Fibrolamellar carcinoma (FLC) and conventional hepatocellular carcinoma (HCC) share the same American Joint Committee on Cancer (AJCC) staging. The worse survival with HCC is attributed to the underlying cirrhosis.The aim of this study was to compare stage-matched prognosis after resection of FLC and non-cirrhotic HCC.Methods: Outcomes after resection of 65 consecutive patients with FLC and 158 non-cirrhotic patients with HCC were compared. Patients were staged according to the 7th edition AJCC staging.Results: The AJCC stage distributions for FLC and HCC demonstrated a predominance of stage IV disease in FLC and stage I in HCC (FLC stage I-23 %, II-15 %, III-15 %, IV-46 % vs. HCC stage I-42 %, II-32 %, III-20 %, IV-6 %, p < 0.001). Among stage IV FLC patients, 81 % had isolated nodal metastases, which did not affect overall survival (OS) or recurrence-free survival (RFS). In FLC, OS was significantly affected by the number of tumors and vascular invasion (p < 0.05). Recurrent disease developed in 56 (86 %) FLC patients and was treated with repeat surgical resection in 25 (45 %) patients. Vascular invasion was associated with recurrent FLC, with 3-year RFS rates of 9 % and 35 %, with and without vascular invasion (p = 0.034). With respect to RFS, the AJCC staging did not stratify FLC patients, compared to non-cirrhotic HCC.Conclusions: When compared to non-cirrhotic HCC, patients with FLC are not adequately stratified by AJCC staging with respect to RFS. Our results support classifying lymph node metastases in FLC as regional disease, rather than systemic disease. Important prognostic factors in FLC are the number of tumors and vascular invasion. [ABSTRACT FROM AUTHOR]

Fibrolamellar carcinoma (FLC) is a rare pathologically distinct primary liver cancer. Surgical resection is the only treatment associated with prolonged survival. Trans-arterial embolization (TAE), which is a recognised treatment for hepatocellular carcinoma has been used to treat FLC. We present a case and performed a literature review of patients with FLC treated with TAE. We present a 19-year old female with a large potentially resectable FLC which was initially treated with trans-arterial chemo-embolization (TACE) with drug eluting beads. The TACE was followed by surgical resection. Histology confirmed tumour necrosis related to the previous TACE. We identified seven case reports and one case series of TAE for FLC. TAE was either used as a neo-adjuvant therapy to facilitate subsequent tumour resection or as a palliative treatment modality. We propose an algorithm for the treatment of FLC that includes TAE. The rarity of FLC and the paucity of data precludes establishing clear evidence-based standards of care. We propose an algorithm for the treatment of FLC. The establishment of an international registry may facilitate the collection of better quality evidence. • Fibrolamellar carcinoma (FLC) is a rare primary liver tumour that predominantly occurs in young patients. • Surgical resection of the tumour and liver transplantation are the only potentially curative treatment modalities. • Trans-arterial embolization has been used as neo-adjuvant and palliative treatment modalities. • We propose a management algorithm which includes trans-arterial embolization for selected patients with FLC. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and its prognosis depends largely on early detection and management. The diagnosis of HCC can be challenging, especially when dealing with scant biopsy specimens and unusual morphology. This review describes HCC subtypes with emphasis on their distinguishing histological features. Furthermore, it incorporates recently described immunohistochemical markers into an algorism for the initial approach of challenging HCC cases. [Copyright &y& Elsevier]

Summary: Anterior gradient-2 expression is critical in normal embryonic development. Aberrant expression of anterior gradient-2 in adult tissues has been linked to breast, prostate, esophageal, and pancreatic carcinoma. To define the role of anterior gradient-2 in primary hepatocellular neoplasms, we used tissue microarrays and examined protein expression in typical hepatocellular carcinomas (n = 44), fibrolamellar carcinomas (n = 12), and hepatic adenomas (n = 9). In nonneoplastic liver tissues, anterior gradient-2 was expressed in the septal-sized bile ducts and weakly in zone 3 hepatocytes in 11 (18%) of 61 cases. In tumors, anterior gradient-2 was overexpressed by only 1 (2%) of 44 hepatocellular carcinomas. In contrast, 6 (75%) of 8 fibrolamellar and 3 (75%) of 4 metastatic fibrolamellar carcinomas were positive. All 9 hepatic adenomas were negative. Further analysis of mRNA in fibrolamellar carcinomas identified 2 novel splice variants, but expression levels were very low. Sequencing of the anterior gradient-2 gene in fibrolamellar carcinomas identified several polymorphisms (refSNP Ids: rs6842, rs8071, rs1051905) but no mutations. In conclusion, anterior gradient-2 is overexpressed in the majority of fibrolamellar carcinomas but is only rarely overexpressed in hepatocellular carcinomas. [Copyright &y& Elsevier]

Summary: Fibrolamellar carcinomas (FLC) are a rare type of primary hepatocellular carcinoma found in younger individuals. FLC are known to have relatively few consistent chromosomal alterations, although a gain of chromosome 1q has been reported. The gene expression of 4 FLC (2 primary FLC and 2 metastatic deposits) were studied using Affymetrix DNA microarray technology (Santa Clara, CA). Selected genes were confirmed by real-time polymerase chain reaction. Relatively few genes were significantly overexpressed—447 genes, case 1; 1298 genes, case 2—corresponding to approximately 0.8% and 2.3%, respectively, of the 56000 transcripts present in the arrays. Of these, 155 genes were overexpressed simultaneously by both tumors. The number of significantly overexpressed genes more than doubled in the 2 metastatic deposits (2777 and 2855 genes compared with 1298 in the primary tumor). Proteins involved in the RAS, MAPK, PIK3, and xenobiotic degradation pathways were commonly overexpressed. Because chromosome 1q is thought to contain an important oncogene, additional attention was focused on this region. Of 114 total genes found overexpressed in common among all primary and metastatic tumors, 11 of 114 genes were located on chromosome 1q: ARF1, CD46, CNIH4, ENSA, FH, NICE-3, PSMB4, RGS2, RGS5, TIMM17A, and UFC1. Primary FLC show overexpression of genes involved in the RAS, MAPK, PIK3, and xenobiotic degradation pathways. Eleven common genes were consistently overexpressed on chromosome 1q among all tumors and metastases and warrant further study as potential oncogenes. [Copyright &y& Elsevier]

Abstract: The liver is an important site for primary and secondary tumours. In western countries, the commonest malignant neoplasm of the liver is metastatic carcinoma, but hepatocellular carcinoma is a common and important cause of death elsewhere. There is a strong association with infection by hepatitis-B and -C; the latter explains the growing incidence of hepatocellular carcinoma in western countries. It is a complication of cirrhosis of any cause; male sex is an important risk factor. Such associations do not exist for the rare variant fibrolamellar carcinoma, which carries a better prognosis than the common form (where survival is measured in weeks). Cholangiocarcinoma, a malignant tumour of bile ducts, accounts for about 15% of primary intrahepatic malignancies; recent epidemiological studies have shown dramatic increases in its incidence. There is a strong association with primary sclerosing cholangitis and, in the Far East, with hepatolithiasis and infection by liver flukes. Epithelioid haemangioendothelioma and angiosarcoma are the commonest malignant mesenchymal tumours in the liver. A number of benign tumours and tumour-like lesions may mimic malignant neoplasms. [Copyright &y& Elsevier]

Summary: There is an increasing understanding of the aetiology, molecular pathogenesis and pathology of tumours and tumour-like lesions of hepatocytes; this is due in part to advances in radiology, the examination of resected and explanted liver tissue, and modern techniques in molecular biology. The migration of populations from regions that are endemic for hepatitis B and the rising incidence of hepatitis C in the West entail an increase in cases of hepatocellular carcinoma as well as putative preneoplastic lesions. Terminology related to many of these lesions has changed in recent years, as has the importance of surveillance and prognosis. The purpose of this review is to highlight these concepts while reviewing the various pathological features that are of importance to the practicing pathologist. [Copyright &y& Elsevier]

Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit a distinct gene expression profile, the chromatin regulatory landscape and the genes most critical for tumor cell survival remain unclear. Here, we use chromatin run-on sequencing to discover ∼7,000 enhancers and 141 enhancer hotspots activated in FLC relative to nonmalignant liver. Bioinformatic analyses reveal aberrant ERK/MEK signaling and candidate master transcriptional regulators. We also define the genes most strongly associated with hotspots of FLC enhancer activity, including CA12 and SLC16A14. Treatment of FLC cell models with inhibitors of CA12 or SLC16A14 independently reduce cell viability and/or significantly enhance the effect of the MEK inhibitor cobimetinib. These findings highlight molecular targets for drug development, as well as drug combination approaches. • ChRO-seq reveals that FLC tumors have unique enhancer and super enhancer profiles • AP-1 and CREB are among the candidate master transcriptional regulators in FLC • FLC tumors exhibit a chromatin and gene signature of aberrant MAPK/ERK signaling • Inhibition of CA12 or SLC16A14 synergizes with MEK inhibitor in FLC disease models Fibrolamellar carcinoma (FLC) is an aggressive liver cancer with limited treatment options. Dinh et al. use chromatin run-on sequencing to identify FLC-specific super enhancers and associated pathways. Inhibition of the superenhancer-associated genes CA12 and SLC16A14 each reduces cell viability and enhances the effect of MEK inhibition in FLC models. [ABSTRACT FROM AUTHOR]