Continuing Education Activity

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare cancer of the liver and it 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 a younger patient population 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:

• Explain the common physical exam findings associated with FLC.
• Identify the gold standard for the treatment of FLC.
• Describe the typical imaging findings associated with FLC.
• Outline 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.

Introduction

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare cancer of the liver and 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 as opposed to HCC. The presenting complaints, blood tests, radiological evaluation, and treatment strategies are different from HCC. Prompt diagnosis and initiation of appropriate care plans play a very important role in this disease entity, which eventually affects the outcome. This article aims at reviewing the salient features of FL-HCC, comparing it to HCC.[2]

Etiology

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]

Epidemiology

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]

Pathophysiology

At the time of 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 have a central scar.

Histopathology

Under microscopic examination, these tumors have big cells that have eosinophilic cytoplasm, large central nuclei, a central lamellated scar that surrounds these large cells.[6]

History and Physical

Patients usually present with a range of symptoms and signs ranging from pain to a liver mass that is detected during the evaluation of 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 is 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]

Evaluation

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 to differentiate 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 the majority of these tumors showing decreased attenuation. Greater than 70% of the patients demonstrate a calcified central scar. Liver mass CT protocol commonly involves different acquisitions performed at different time points following contrast administration intravenously 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 similar 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 that can be seen 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 the characteristics 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 disease that is not apparent otherwise.[5] 

Treatment / Management

Primary treatment of this tumor involves a treatment strategy that aims at cure. When possible, complete resection is the preferred treatment and this appears to have a favorable effect on the outcome.[15] However, a high percentage of patients (greater than two-thirds) eventually go on to 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 is often encountered. These additional interventions can have a negative impact on 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, there are no neoadjuvant/adjuvant systemic therapies yet reported that have shown 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 that include surgery, chemotherapy, and radiation have shown better outcomes.[20] Decreasing the size of the mass before surgical resection with percutaneous radioembolization has been studied.[21] A novel targeted therapy that has demonstrated efficacy in the treatment of HCC, sorafenib, was evaluated in a retrospective manner in FL-HCC, showing limited effectiveness.[19] Potential targets in the mTOR pathway and/or Aurora A kinase were recently identified. Currently, there are no controlled trials that have evaluated these targets. There has been on favorable outcome 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]

Differential Diagnosis

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 three phases. The classic pattern seen is a discontinuous and nodular enhancement pattern in the periphery of these masses on the early phases with subsequent contrast filling of the center.[26]

Conventional HCC includes prompt enhancement in the arterial phase with a washout of contrast in the delayed phases. These patients often have a cirrhotic liver which is reflected in the imaging.

Medical Oncology

The identification of 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 and 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) provide both sensitive and specific elucidation in the context of primary hepatocellular neoplastic processes.[28] Engelholm et al. found that the introduction of the DNAJB1-PRKACA fusion gene into wild-type mice was sufficient to initiate hepatic tumors in mice with features consistent with human FLC.[29]

Prognosis

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 as the number of disease site involvement increases, survival decreases.[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 as opposed 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]

Complications

Surgical complications are often encountered in these patients, especially patients who require 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.

Deterrence and Patient Education

Patient education on the risks of this disease is essential as there is a high rate of recurrence. 

Enhancing Healthcare Team Outcomes

These patients benefit from a treatment approach that includes integration of different clinical teams that are familiar with treating complex malignancies with an evidence-based approach in a higher level care center with resources that are necessary for the management of these patients.[35][36]