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Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare liver cancer that displays features that make it very different in its behavior and clinical findings from conventional hepatocellular carcinoma (HCC)[1]. FL-HCC accounts for less than 1% of all primary hepatic malignancies. Unlike conventional HCC, FL-HCC is more common in younger patients and has a significantly lower incidence. This activity describes the evaluation and treatment of FL-HCC and highlights the role of an interprofessional team in evaluating and treating patients with this malignancy. Objectives: Identify the common physical exam findings associated with FLC. Identify the gold standard for the treatment of FLC. Determine the typical imaging findings associated with FLC. Communicate the importance of collaboration and coordination among the interprofessional team that can enhance patient care when deciding the treatment and management of patients with advanced disease. Access free multiple choice questions on this topic.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare cancer of the liver. It displays features that make it very different in its behavior and clinical findings from conventional hepatocellular carcinoma (HCC).[1] FL-HCC accounts for a negligible percentage of primary liver cancers (1%). Patients affected by FL-HCC are usually in a lower age group than HCC. The presenting complaints, blood tests, radiological evaluation, and treatment strategies differ from HCC. Prompt diagnosis and initiation of appropriate care plans play an important role in this disease entity, eventually affecting the outcome. This article aims at reviewing the salient features of FL-HCC, comparing it to HCC.[2]

No certain underlying trigger is detected in FL-HCC. These patients do not have a history of cirrhosis or chronic liver disease. Less than 10% of patients with a diagnosis of FL-HCC have cirrhotic liver morphology.[3] This is very different from underlying cirrhosis/liver fibrosis seen in patients diagnosed with conventional HCC.[2]

Patients affected by FL-HCC most commonly are in the second or the third decade.[4][5] In contrast, the patients with HCC are most commonly in an older age group, usually around the sixth decade. A very small percentage of primary liver cancer is attributed to Fl-HCC (1%). Although HCC appears to be more common in men, FL-HCC does not demonstrate any gender preference. More than half of the patients affected by FL-HCC are white, while greater than 80% of patients with HCC are white.[4]

At diagnosis, most FL-HCC masses are approximately slightly greater than 10cm. At the time of the histopathological examination, four-tenths of the patients have a positive margin and vascular invasion after resection. Metastasis to locoregional lymph nodes has been demonstrated in about half the patients. On examination, these tumors are usually large, single, yellow, with well-defined margins, and demonstrate features of rapid growth, outgrowing the blood supply, and having a central scar.

Patients usually present with symptoms and signs ranging from pain to a liver mass detected while evaluating some other clinical condition.[7][8] The most common symptoms seem to be abdominal pain or a palpable mass. Symptoms commonly seen with a malignant process such as conventional HCC are not seen in FL-HCC.[9][10] Serum tumor markers do not have an important role in the evaluation or diagnosis of FL-HCC and are elevated in less than one-tenth of the patient population.[11][7]

Radiological evaluation appears to be the most useful evaluation tool. The most commonly used techniques include ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). Sonographic features include a lobulated mass with varied echotexture. These findings are non-specific and may not help differentiate them from other hepatic neoplasms. The central scar is not easily discernible and, if present, can be seen as an area of increased echogenicity.[12] Computed Tomography usually shows a single tumor with well-demarcated margins, with most of these tumors showing decreased attenuation. Greater than 70% of the patients demonstrate a calcified central scar. Liver mass CT protocol commonly involves different intravenously acquisitions at different time points following contrast administration to highlight features in the arterial, portal venous, and delayed phases. Greater than 80% of the patients demonstrate masses that have increased contrast avidity in the arterial phase, reflecting the high blood supply of these tumors. Almost half of these masses enhance similarly to the background liver in the venous phase, and about one-third of the tumors have higher contrast avidity. Almost two-thirds of these masses enhance similar to the background liver on the delayed phase and can be difficult to differentiate. The central fibrous scar in these masses can show contrast avidity in this later phase.[5] Magnetic resonance imaging shows a decreased signal on T1-weighted sequences in about two-thirds of the patients. The fibrous nature of the scar often demonstrates decreased signals on both T1 and T2 weighted sequences. The enhancement characteristics of the tumor and the central scar are similar to those described above on CT imaging.[13] Like many other malignant tumors, these also can show restricted diffusion with increased signal on diffusion-weighted imaging sequences (DWI).[14] In addition to the above findings, radiological evaluation plays an important role in detecting additional distant diseases that are not apparent otherwise.[5]

Primary treatment of this tumor involves a treatment strategy that aims at a cure. When possible, complete resection is the preferred treatment, which appears to favor the outcome.[15] However, a high percentage of patients (greater than two-thirds) eventually show recurrent disease.[15] A good portion of these patients have locoregional diagnosis during the surgical treatment, and these additional sites of disease are also treated along with the primary tumor resection, which has shown to have a better prognostic value.[16] These tumors are often very aggressive in their behavior, and a failed surgical attempt at resection, the necessity of second surgical intervention, and finally, hepatic transplantation are often encountered. These additional interventions can hurt the outcome.[17] Chemotherapy has served as a treatment tool before and following surgical resection. Due to the limited incidence of FL-HCC, no RCT has elucidated the most efficacious chemotherapeutic regimen. Of note is that no neoadjuvant/adjuvant systemic therapies have yet been reported, showing an improved survival benefit in patients with resectable FL-HCC.[15] Chemotherapy with agents such as gemcitabine, cisplatin, 5-fluorouracil, interferon, and oxaliplatin have to be utilized and have shown varying degrees of response.[18][19] Combined treatment strategies, including surgery, chemotherapy, and radiation, have shown better outcomes.[20] Decreasing the mass size before surgical resection with percutaneous radioembolization has been studied.[21] A novel targeted therapy that has demonstrated efficacy in treating HCC, sorafenib, was evaluated retrospectively in FL-HCC, showing limited effectiveness.[19] Potential targets in the mTOR pathway and/or Aurora A kinase were recently identified. Currently, no controlled trials have evaluated these targets. There has been a favorable outcome in utilizing rapamycin (mTOR inhibitor) in an unresectable patient.[22] Checkpoint inhibition has shown reasonable efficacy in a Phase II study of advanced HCC.[23] Controlled trials evaluating checkpoint inhibitors in FL-HCC are lacking, and case reports to date are limited and unequivocal.[15][19]

The differential diagnosis of this disease includes: Focal nodular hyperplasia Giant cavernous hemangioma Hepatocellular carcinoma (HCC) Imaging plays a crucial role in differentiating these lesions. Focal nodular hyperplasia demonstrates characteristics that follow the normal surrounding liver parenchyma on the portal venous and later delayed phase imaging. In the early arterial phase, it can show hyperenhancement which is usually uniform.[24] Calcification is not a common feature. The Hyperintense signal on T2-weighted is seen in the central scar that can be seen in these masses and is attributed to biliary ductules as opposed to the scar related to FL-HCC described above.[25] Cavernous hemangiomas follow the enhancement characteristics of blood vessels in all 3 phases. The classic pattern seen is a discontinuous and nodular enhancement pattern in the periphery of these masses in the early phases with subsequent contrast filling of the center.[26] Conventional HCC includes prompt enhancement in the arterial phase with a contrast washout in the delayed phases. These patients often have a cirrhotic liver, which is reflected in the imaging.

Identifying a recurrent DNAJB1-PRKACA chimeric transcript in FLC by Honeyman et al initiated the growth in our ability to differentiate FL-HCC from conventional HCC. It may lead to insight into FL-HCC’s pathogenesis.[27] DNAJB1-PRKACA rearrangements are absent in conventional HCC and cholangiocellular tumors. DNAJB1-PRKACA and PRKACA rearrangement detection by break-apart fluorescence in situ hybridization (FISH) probe or polymerase chain reaction (PCR) provides both sensitive and specific elucidation in the context of primary hepatocellular neoplastic processes.[28] Engelholm et al found that introducing the DNAJB1-PRKACA fusion gene into wild-type mice was sufficient to initiate hepatic tumors in mice with features consistent with human FLC.[29]

Successful surgical treatment is associated with a better overall outcome. However, if there is a locoregional or distant disease, there is a negative impact on outcomes[30][31]. As expected, survival decreases as the number of disease site involvement increases.[32] If patients have findings of conventional HCC along with FL-HCC, which can rarely occur, there is a negative impact on prognosis.[6] The overall prognosis is superior to conventional HCC in the setting of underlying cirrhosis when compared to patients with a non-cirrhotic liver.[33] There is a statistically significant difference in the survival of patients diagnosed with FL-HCC compared to those with conventional HCC. Factors correlated with improved outcomes include disease confined to the liver, completed removal of the tumor at surgery, and treatment with different modalities as described above.[1][34][20]

Surgical complications are often encountered in these patients, especially those requiring complicated surgical treatment. Most patients affected with this disease are in a younger age group with a disease extent that is often higher than other liver malignancies. This necessitates a complex and aggressive approach to treatment, resulting in a higher rate of surgical complications.

These patients benefit from a treatment approach integrating different clinical teams familiar with treating complex malignancies with an evidence-based approach in a higher-level care center with the resources necessary to manage these patients.[35][36]