Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a malignant liver tumor which is thought to be a variant of conventional hepatocellular carcinoma (HCC). It accounts for a small proportion of HCC cases and occurs in a distinctly different group of patients which are young and usually not in the setting of chronic liver disease. The diagnosis of FL-HCC requires the integration of clinical information, imaging studies, and histology. In terms of the treatment options, the only potentially curative treatment option for patients who have resectable disease is surgery either liver resection (LR) or liver transplantation (LT). When performed in a context of aggressive therapy, long-term outcomes after surgery, particularly liver resection for FL-HCC, were favorable. The clinical outcome of patients with unresectable disease is suboptimal with median survival of less than 12 months. The aim of this review is to update the available evidence on diagnosis, treatment options, outcome predictors, and recent developments of patients with this rare disease and to provide a summarized overview of the available literature.


Background
Fibrolamellar hepatocellular carcinoma (FL-HCC) is thought to be a rare variant of conventional hepatocellular carcinoma (HCC), accounting for 0.85 to 16 % of all hepatocellular carcinomas [1][2][3][4][5][6][7]. It occurs in a distinctly different group of patients which are young and usually not in the setting of chronic liver disease ( Table 1). The majority of such cases offer vague and nonspecific clinical symptoms, including weight loss, fatigue, abdominal pain, and a mass lesion. Alternatively, patients can be asymptomatic and had their disease discovered incidentally during diagnostic workup of an unrelated medical condition. Thus, the biological behavior of FL-HCC can range from an indolent, clinically insignificant disease to an aggressive pattern of locally invasive disease or distant metastasis [1,4,6,[8][9][10]. The main goal in the assessment of patients with FL-HCC is to distinguish FL-HCC from other malignancies of the liver particularly HCC and liver metastases and other benign liver lesions such as focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA). This requires the integration of clinical information with conventional diagnostic techniques such as ultrasound (US), computed tomography (CT) scans, magnetic resonance imaging (MRI), and histology. The only potentially curative treatment option for patients who have resectable disease is surgery either liver resection (LR) or liver transplantation (LT). Because it is increasingly safe and offers a truly curative therapy, liver resection remains the standard of care for patients with locoregional disease in a non-cirrhotic liver. When performed in a context of aggressive therapy, long-term outcomes after surgery, particularly liver resection for FL-HCC, were favorable. Unfortunately, disease recurrence is high, at 33-100 % [11]. Even after curative-intent surgery, disease recurrence is frequent, often in the first 4 years postsurgical [12]. However, it can also occur after 5 years or even longer [6,11]. Thus, after treatment for FL-HCC, prolonged follow-up is necessary because recurrence and death can occur years after diagnosis. For patients with resectable FL-HCC, 5-year survival rates as high as 80 % and 5-year disease-free survival rates of 18 to 50 % have been reported ( Table 2). The clinical outcome of patients with unresectable disease is suboptimal with median survival of only 12 months and no patient surviving beyond 5 years [6,10]. Furthermore, the role of neoadjuvant and adjuvant therapies, including systemic chemotherapy and radiotherapy, remains poorly defined and has been reported to have only a modest or no therapeutic effect [2,10,13]. Reports on the characteristics of patients with FL-HCC as well as predictors of recurrence and survival are scarce, probably due to the rarity of this tumor, and are limited to case series, small cohorts, and few systematic reviews. The aim of this review is to update the available evidence on diagnosis, treatment options, and outcome of patients with this rare disease and to provide a summarized overview of the available literature.

Clinical finding
Diagnosis of FL-HCC requires consideration of the clinical conditions, imaging studies, and histologic evaluation.
Patients with FL-HCC are typically young, without underlying liver disease, and asymptomatic. Therefore, this tumor forms a difficult problem in diagnosis. When patients with FL-HCC are symptomatic, they typically present with nonspecific abdominal pain or discomfort, weight loss, a palpable liver mass, ascites, and lower edema [3,5,14]. There may also be a constellation of symptoms, including anorexia, fever, and jaundice, and this subject has been recently reviewed by Darcy et al. [15]. These authors reported that the most common presenting symptom is abdominal pain (72 %) followed by abdominal distention (44 %), anorexia (32 %), fever, and jaundice (20 %). Craig et al. 1980 [8] reported that abdominal pain as the main presenting symptom is highly variable in duration ranging from 1 to more than 6 months preceding the diagnosis of FL-HCC. In general, symptoms are usually present 3 to 12 months before diagnosis [16].
The routine biochemical and hematological values of FL-HCC patients are mostly normal or mildly elevated in a nonspecific fashion [1,17].

The role of tumor markers
Alpha-fetoprotein (AFP) is the most well-studied serum marker widely used in diagnostic and screening of HCC. Unlike HCC, FL-HCC rarely produces AFP. Consequently,  [17]. Elevated levels of serum vitamin B 12 -and serum unsaturated vitamin B 12 -binding capacities have been described as associated with FL-HCC by some authors [18,19]. However, additional evidence and experience are needed to determine the strength of this association. Elevated serum neurotensin was found to have a role as a biomarker in some cases, but did not prove to be sensitive or specific enough for diagnosis [15,20].

Imaging diagnostic
Imaging of the liver which is an integral part of every diagnosis is largely performed by cross-sectional imaging modalities including US, CT, and MRI.
Nuclear medicine studies such as FDG PET can be utilized once a liver lesion is detected and/or there is a clinical suspicion for extrahepatic manifestation and may be helpful in narrowing the differential diagnosis. However, the role of nuclear medicine in the imaging diagnostic of FL-HCC has not been fully evaluated [21].
Thus, when a liver mass is detected, characterization can be performed by several different imaging techniques. Multiphasic examinations are required with acquisition of images before and dynamically after the administration of contrast media to characterize the mass and to determine the extent of disease. In general, the technique employed is usually determined by institutional preference and experience as well as other clinical factors such as patient history and comorbid conditions such as kidney failure. US is the initial diagnostic modality for evaluating the liver. It can detect an intrahepatic mass and intrahepatic or extrahepatic ductal dilation. However, US is nonspecific and less accurate than CT or MRI to differentiate FL-HCC from other mass-forming lesions of the liver. Although CT is adequate for initial pretreatment imaging of FL-HCC, particularly for evaluation of metastatic lesions, MRI may be helpful for initial workup when FL-HCC is first discovered as an initial liver mass [22]. In general, FL-HCC tends to present as a large, heterogeneous enhancing mass that may contain a central scar and/or calcifications on imaging. Details about imaging findings have been reviewed extensively in previous publications [14,16,[21][22][23][24][25][26][27][28][29] and summarized in Table 3. Portal vein thrombosis and biliary TP time period, YP year of publication, ♂:♀ male to female ratio, CD number of patients with chronic liver disease particularly liver cirrhosis in percent of the total number of patients, AFP↑ number of patients with pathologic elevation of alpha-fetoprotein in relation to tested patients, LR liver resection, LT liver transplantation, 5y-OS 5-year overall survival (numbers in bracket indicate the average survival in months for any treatment), DR disease recurrence, DSF disease free survival, nr not reported, na not applicable obstruction are extremely rare occurring in only 5-10 % of cases [14,16,23,26,28]. Nodal metastatic lesions are most commonly seen at the hepatic hilum and hepatodudenal ligament occurring in up to 50 to 60 % of cases [6,14,21]. Distant metastatic disease from FL-HCC, mostly to the lungs, peritoneum, and adrenal gland has been reported on imaging in up to 20-30 % of cases [4,21,30].

The role of biopsy
Histologic appearances are the most objective and widely accepted differences between FL-HCC and HCC [31,32]. Therefore, histologic confirmation is needed to be able to diagnose FL-HCC with certainty. This is particularly important if there is diagnostic uncertainty about the imaging diagnosis. It enhances the ability to select patients properly for aggressive surgical intervention by excluding the subset of patients who do not appear to benefit from surgical therapy, such as those with extensive metastatic disease or with underlying medical conditions that preclude surgery. Fine needle aspiration has low yields and may aspirate malignant hepatocytes without the characteristic fibrotic lamellae resulting in a diagnosis of HCC and not FL-HCC [33]. Thus, the preferred technique of biopsy is either percutaneous core biopsy or open biopsy via laparoscopy.

Differential diagnosis
The differential diagnosis of FL-HCC includes a wide spectrum of nonneoplastic and neoplastic lesions of the liver such as FNH, HCA, and HCC [34]. Differentiation of other liver lesions from FL-HCC permits optimal patient treatment. Some of these entities may show characteristic imaging findings including morphology that permit their diagnosis (Table 4). However, radiologic findings are generally inconclusive for a differential diagnosis because the appearance of the lesions on the various imaging studies of FL-HCC patients may closely simulate that of FNH, HCA, HCC, or metastasis [29]. Correlation with clinical and demographic data may help narrow the differential diagnosis in patients with FL-HCC. Overall, however, biopsy may be required to achieve definitive histopathologic characterization in most cases.

Focal nodular hyperplasia
Focal nodular hyperplasia is a hyperplastic nodule that contains scar-like tissue [35]. It is believed to originate from hepatocyte proliferation around a congenital arteriovenous malformation and is the second most common benign hepatic lesion after hemangioma, mostly seen in women and incidentally detected [36,37]. Its growth is may be promoted by oral contraception (OC) but has no evidenced causal relationship to OC. Because of macroscopic similarities, common age, and gender to FL-HCC, FNH is often confused for FL-HCC [33]. Distinction between these two diagnoses is important because the clinical approach regarding both is different.

Hepatocellular adenoma
Hepatocellular adenoma is a rare benign neoplasm of the liver that occurs typically in young women of child-bearing age who have a long history of estrogen-based oral contraceptive use [38,39]. Owing to hormone-induced growth, these lesions may rupture and bleed spontaneously leading to massive hemorrhage [40]. Besides the risk of rupture and bleeding, about 4.2 % of HCAs have the potential to undergo malignant transformation into HCC [41]. Thus, the preferred treatment option is liver resection particularly if lesions are >5 cm in diameter [42]. The diagnosis of HCA is usually made based on the clinical and imaging findings and the findings of core biopsies obtained for diagnostic workup of a liver mass [33,[43][44][45]. However, HCA may sometimes show overlapping diagnostic features with FL-HCC posing a diagnostic challenge.

Hepatocellular carcinoma
There are major differences in the clinicopathologic characteristics between conventional HCC and its variant FL-HCC (Table 1). HCC accounts for significant global morbidity and mortality, especially in endemic areas of chronic viral infection [46]. Contrary to FL-HCC, HCC has well-defined major risk factors such as chronic viral infection with hepatitis B and C and aflatoxin B1 intake with contaminated food that lead to liver cirrhosis [47][48][49]. The majority of cases of HCC develop in liver cirrhosis, making liver cirrhosis the strongest predisposing factor [50]. Furthermore, HCC predominantly occurs in older patients with significant sex predilection (more often in men over the age of 60), whereas FL-HCC typically affects adolescents and young adults with a nearly even sex distribution [19,21].

Surgical treatment
Data in the literature shows that patients with FL-HCC are good candidates for aggressive surgical treatment; these patients can expect a reasonable likelihood of durable survival [12]. Liver resection and liver transplantation are aggressive approaches to the treatment of patients for FL-HCC and are the only known potentially curative treatment options for this tumor.

Liver resection
Liver resection is the treatment of choice for FL-HCC unless it arises in the setting of liver cirrhosis which is extremely rare. In the absence of liver cirrhosis, patients with FL-HCC have a high resectability rate (  survival of 66 % at 5 years and 47 % at 10 years. According to these authors, this survival advantage was attributed to indolent growth, favorable biological behavior, and suitability to extensive liver resection including adjacent structures initially as well as to treat recurrence. Disease recurrence after complete surgical resection is high in this patient population ranging 33-100 % [1-3, 7, 9, 11-15]. The median time to recurrence is relatively short at between 10 and 33 months [1,3,6,13,14]. However, recurrence of disease more than 5 years after surgery is a rare event [2,12]. The high recurrence rate after surgery may seem somewhat surprising, especially given that patients were treated aggressively and at highly specialized hepatobiliary centers. However, quite often patients with FL-HCC are referred to these centers at an advanced stage, with large primary tumors and evidence of lymph node metastases, both factors which has been identified as negative prognostic indicators [2,3,6,12,13,15]. Furthermore, for those patients with recurrence after liver transplantation, in addition to advanced tumor stage, the issue of immunosuppression should also be considered because it may significantly increase the recurrence rate [52].
Repeat surgery has been considered by many to be the most effective treatment for recurrence [6][7][8]12]. Reresection aimed at recurrent or metastatic disease, when possible, may provide patients with good long-term results. For example, in a study of Stipa et al. [6], 28 patients with FL-HCC underwent LR with an overall recurrence rate of 61 %. The mean time to recurrence was 37 months. Recurrence was exclusively intrahepatic in approximately half of the 17 patients with disease recurrence. Despite this high recurrence rate, all patients were amenable to treatment with re-resection that resulted in median survival of 26 months. In the study of Kaseb et al. [7], metastasectomy was done in 18 cases and was found to be significantly associated with longer OS. The median OS was 145 months for those who underwent surgery versus 35 months for those who did not. In the study of Maniaci et al. [13] that included 10 patients, disease recurrence occurred in all patients following initial surgery with a median time to recurrence of 2.2 years. In seven patients, disease recurrence was managed surgically that resulted in a median survival of 4.7 years and an OS of 48 % at 5 years. Therefore, as such, tumor recurrence should not preclude resection when complete removal can be achieved because it carries a relatively good prognosis. Patient selection and an emphasis on surgical technique to achieve complete removal are pivotal to optimizing the best chance for the best possible outcome.

Liver transplantation
LT is an effective treatment for HCC, and its indications are expanding [53]. On the contrary, only FL-HCC which is not amenable to resection but confined to the liver is considered a suitable indication for LT by the majority of investigators [2,3,11]. Thus, the use of LT for advanced disease is unique to FL-HCC. However, owing to its rarity and the infrequent need for LT, available data is limited. Theoretically, LT has the potential to readily achieve a clean margin, accomplish a radical removal of the tumor, and treat underlying liver disease when present. In 1997, Pinna et al. [2] examined the results of 13 patients who underwent LT for FL-HCC. The overall 3-and 5-year survival rates were 45 and 36 %, respectively. However, disease recurrence was confirmed in 9 (69 %) out of 13 Patients. These authors analyzed the specific factors that might serve as predictors of disease recurrence after LT. Patients with regional lymph node involvement (N1), those with the presence of metastasis (M1), and those with stage IVB disease were more likely to develop recurrent disease. Interestingly, the use of chemotherapy in an adjuvant setting was also associated with earlier intrahepatic recurrence.
In a series which included nine patients with FL-HCC treated by LT, El-Gazzaz et al. [3] reported 1-, 3-, and 5year survival rates of 90, 75, and 50 %, respectively. Disease recurrence occurred in five (56 %) out of nine transplanted patients. Two of the nine transplanted patients received chemotherapy in neoadjuvant and adjuvant setting, and chemotherapy had no detectable effect on survival or recurrence-free survival.
In a systematic review published in 2012, Mavros et al. [11] reported the results of 14 studies that included 109 patients after LT for FL-HCC. Six studies reported specific survival data on 79 patients. Survival after 1, 3, and 5 years ranged from 63 to 100 %, 43 to 75 %, and 29 to 55 %.
In a meta-analysis of 17 studies involving 368 patients with FL-HCC and 9877 patients with conventional HCC, Njei et al. [54] found significantly higher 5-year survival rates in those patients with FL-HCC treated by LR than did those with conventional HCC. But, they found no difference in survival in patients undergoing liver transplantation.
Overall, patients who underwent LR for FL-HCC did better than patients who underwent LT. However, with the number of published trials increasing, the aggregate data indicated acceptable outcomes for patients who underwent LT as well. Thus, given the advanced stage of disease in transplanted patients, LT for FL-HCC does not appear to be an inferior treatment option in comparison with LR and may have more indications than the current standard of care. However, given the rarity of the disease and the retrospective nature of data collection from different institutions with a very small sample size, most published series lack sufficient power for statistical analysis and the results are inconclusive. Thus, the perception of good survival outcomes after LT despite the advanced stage of disease is probably inaccurate and should therefore be interpreted with caution.

Chemotherapy
The role of neoadjuvant or adjuvant chemotherapy is controversial. In some cases, chemotherapy had no effect on survival or recurrence in patients who received chemotherapy after surgery [2,3]. Contrary to this, in other studies, patients who had chemotherapy in neoadjuvant and adjuvant settings fared better than those with surgery only with patients who had front-line surgery followed by chemotherapy having the longest OS [7,55]. In one report [56], the use of platinum-based chemotherapy in pediatric patients with FL-HCC resulted a partial response in 31 % of patients on imaging but a 3-year survival of only 22 %. Thus, although some different types of systemic chemotherapy for FL-HCC have been tried, the advances in tumor downstaging with this therapeutic option have not proven effective. The most difficult aspect of understanding the utility of chemotherapy for FL-HCC is that no prospective trials have investigated different types of chemotherapy options. Instead, most knowledge about the effectiveness of chemotherapy is based on anecdotal evidence and single-patient experience.

Outcome and prognostic factors
Although FL-HCC patients often present with an advanced disease, approximately 50-84 % of affected patients are amenable to surgical treatment and have an OS as high as 76 % at 5 years (Table 2). Thus, patients with FL-HCC appear to have a better prognosis than those with HCC which have a far worse prognosis with a 5-year survival of only 6.8 % [4]. However, considering similar stage disease, patients with FL-HCC do not have a favorable prognosis and do not respond any differently to treatment than patients with HCC in non-cirrhotic livers [9,10,51,54,57]. This suggests that the apparent better outcome seen in FL-HCC may be related to the absence of liver cirrhosis. Thus, as indicated by some of the reviewed studies, along with the indolent nature of the disease and younger age, the most likely reason for this favorable outcome is the absence of liver cirrhosis that allows aggressive surgical treatment [4,6,8,10,17]. Individual tumor stage, number and size of tumors, vascular invasion, regional lymph node metastasis, the presence of extrahepatic disease, non-White race, and female gender have been thought to be negative predictors of outcome after surgery [1,2,6,10,12,15,58]. Of these, the initial stage of the tumor at the time of treatment seems to be the most significant determinant of prognosis. Patients with stage I-III disease tended to fare better than patients with stage IV disease [1,2,6,23], and in some cases, this difference attains statistical significance [2,12,23]. Overall, however, additional studies with large number of patients are needed, since the existing data does not result in a differentiation firm enough to base treatment decisions on.

Recent developments
Currently, researchers are attempting to provide some insights into the molecular characteristics of FL-HCC. Using genomic analysis, some patterns of genomic aberrations which are different from other liver malignancies have been shown and possible pathways and candidate genes as therapeutic targets have been identified. However, these discoveries of molecular pathways and genetic mutations that characterize FL-HCC have not yet enhanced the ability to design specific anticancer therapies. DNAJB1-PRKACA: this recently described predominant fusion protein has been proved to retain the kinase activity of PRKACA, the catalytic subunit of protein kinase A (PKA) [59][60][61]. DNAJB1-PRKACA may represent a potential therapeutic target as high levels of DNAJB1-PRKACA protein expression (amplified in more than 70 % of FL-HCC) have been found in FL-HCC compared to a normal liver or HCC [59]. Because of the many oncogenic signaling pathways regulated by PKA [62,63], kinase inhibitors which bind near the active site of the PKA catalytic subunit can target several oncogenic proteins in parallel [64]. Currently, however, no known drug trials are using such inhibitors specifically against FL-HCC. mTOR: the mammalian target of rapamycin (mTOR) is an intracellular protein kinase (PK) expressed in mammalian cells and is critical in the development of many malignant tumors [65]. The mTOR pathway is responsible for regulating cell growth and survival. It mediates signaling transduction downstream of receptor tyrosine kinases. If this pathway becomes dysfunctional, mTOR becomes upregulated, leading to increased cell proliferation, angiogenesis, and evasion of apoptosis [66]. Consequently, inhibitors of this pathway have been assessed and evaluated for their safety and efficacy in cancer patients. For example, the mTOR inhibitor everolimus in combination with octereotide has been shown to be effective for low-and intermediate-grade neuroendocrine tumors. Most patients experienced either a partial response or stable disease, with a minority experiencing tumor progression [67].
Anticancer agents that induce durable remissions are needed particularly for those FL-HCC patients whose tumors are not amenable to aggressive surgery. Currently, it has been shown that mTOR signaling significantly activated in FL-HCC compared to other liver malignancies [61]. This suggests that mTOR inhibitors may have anticancer activity in FL-HCC as well. Recently, however, there have been no published trials using mTOR inhibitors that target its dysregulated pathways for patients diagnosed with FL-HCC. Thus, given the present results in drug research regarding the treatment of FL-HCC, it is highly unlikely that a marked prolongation of life in patients with advanced FL-HCC is on the immediate horizon.

Conclusions
A familiarity with the diagnosis, treatment, and overall management of FL-HCC is necessary for all those dealing with these patients. The optimal approach to management involves accurate diagnosis and staging, followed by assessment of candidacy for liver resection or transplantation. The diagnosis of FL-HCC is often difficult, and it requires careful assessment of the clinical findings and multiple, complimentary, imaging modalities and biopsy. Liver resection is the preferred treatment option; however, in selected patients, liver transplantation can also be considered as an option. With few presented conflicting results of retrospective studies, the role of other therapeutic options such as chemotherapy is controversial. For now, it seems that these options are uniformly ineffective in prolonging survival. The resistance of FL-HCC to these treatment options likely contributes to poor outcomes in patients presenting with extensive metastatic disease. Surgery for recurrent disease, even when present with regional metastases, can achieve a meaningful survival benefit. Thus, surveillance must be maintained, even beyond 5 years. The more indolent course of this tumor and its good response to aggressive surgical therapy suggest that future research and treatment strategy should be designed in a manner that addresses more appropriately the treatment of patients who have tumors that may be less sensitive and not amenable to surgical therapy. Because of its very low incidence, research on targeted therapy is difficult and has not yet been successful. Therefore, national and international collaborations are required to achieve this objective.

Ethics approval
Not applicable.

Availability of data and materials
This manuscript is a literature review, and all used literature is referenced appropriately in the "References" section.