Fibrolamellar Carcinoma

Fibrolamellar carcinoma is a rare primary hepatic malignancy that was first described as a pathological variant of hepatocellular carcinoma by Edmondson in 1956.[12]  In his review of liver tumors and tumorlike liver lesions, Edmondson included a report of a 14-year-old girl with an unusually long survival following hepatic resection for liver cancer. Fibrolamellar carcinoma was more widely recognized as a clinical entity distinct from conventional hepatocellular carcinoma after 2 simultaneous reports in 1980 by Craig et al[13]  and Berman et al,[14]  both of which again highlighted the young age of onset and the relatively good prognosis that continue to distinguish fibrolamellar carcinoma from conventional hepatocellular carcinoma.

In the literature, fibrolamellar carcinoma has been referred to by several names, based on its histological characteristics, as follows:

• Eosinophilic hepatocellular carcinoma with lamellar fibrosis ^[15]
• Polygonal cell hepatocellular carcinoma with fibrous stroma ^[14]
• Hepatocellular carcinoma with increased stromal fibrosis ^[16]
• Eosinophilic glassy cell hepatoma ^[15]
• Fibrolamellar oncocytic hepatoma ^[15]

The more typical form of hepatocellular carcinoma is often associated with active hepatic inflammation, hepatitis B or C viral infection, alcohol-related liver disease, nonalcoholic fatty liver disease (NAFLD), cirrhosis from any other cause, or dietary aflatoxin B1. In contrast, the etiology of fibrolamellar carcinoma remains unclear. Underlying liver inflammation or fibrosis is typically absent,[17] and no histological precursor lesion to fibrolamellar carcinoma has been identified.[18]

In 2014, Honeyman et al reported that FLC tumor samples from 11 patients expressed a novel fusion transcript, DNAJB1-PRKACA. Whole-genome sequencing revealed that the fusion resulted from a ∼400-kilobase (kb) deletion on chromosome 19 (chr19). The fusion transcript encodes a chimeric protein that couples a segment of the heat shock protein, DNAJB1, with the catalytic domain of protein kinase A (PKA) and exhibits full retention of PKA activity. Notably, the DNAJB1-PRKACA fusion was not detected in any of the matched nontumor liver tissue samples.[2]  

Multiple independent studies confirmed the findings of Honeyman et al by demonstrating the presence of the fusion gene in FLCs.[3, 5, 19]  In one of the studies, whole-genome sequencing of 10 FLC tumors showed no recurrent structural variations that contribute significantly to the tumor genotype, aside from the deletion of chromosome 19 determining the DNAJB1-PRKACA fusion protein.[19]  The apparent lack of a second-hit mutation in the genome of FLCs supports the role of DNAJB1-PRACA fusion protein as a major driver of this tumor and as a key diagnostic and therapeutic target.

Another study found that the DNAJB1-PRKACA transcript was expressed 10-fold higher than the wild type PRKACA transcript, resulting in clear overexpression of the mutant protein in tumors. Consequently, FLCs exhibited elevated cyclic adenosine monophosphate (cAMP)–stimulated PKA activity, compared with normal liver tissue, thus suggesting that aberrant PKA signaling contributes to liver tumorigenesis[7]  The analysis of RNA-sequencing data from The Cancer Genome Atlas (TCGA) for more than 9000 tumors across about 30 cancer types showed that the DNAJB1-PRKACA fusion is specific for FLCs. In addition, both the messenger RNA and long intergenic noncoding RNA signatures support a major role for PKA signaling in shaping the FLC gene expression landscape.[8]

A variant of FLC, known as mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) and characterized by the presence of both FLC and conventional HCC components within the same tumors, has also been reported. In these rare tumors, the DNAJB1-PRKACA fusion transcript is expressed at high levels.[6]  

Specific risk factors for fibrolamellar carcinoma remain unidentified. Unlike typical hepatocellular carcinoma (HCC), fibrolamellar carcinoma is not associated with hepatotoxins, cirrhosis, α1-antitrypsin deficiency, or hemochromatosis.

Less than 10-20% of cases of fibrolamellar carcinoma are associated with hepatitis B viral infection, and even this association may simply reflect the high worldwide prevalence of hepatitis B.[18]  Fibrolamellar carcinoma is rarely associated with hepatitis C viral infection.

Based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the age-adjusted incidence rate of fibrolamellar carcinoma in the United States is 0.02 per 100,000 per year, which is 100-fold lower than the 1.99 per 100,000 annual incidence rate of typical hepatocellular carcinoma (HCC).[20]  Fibrolamellar carcinoma has been reported all over the world,[21] but worldwide incidence data are not available.

In the United States, patients with fibrolamellar carcinoma are overwhelmingly (> 85%) non-Hispanic whites, with smaller numbers of cases seen among Chinese Americans (6%), Blacks (4%), and white Hispanic persons (4%).[20] In contrast, typical HCC occurs in non-Hispanic white patients 57% of the time, with significant numbers of cases diagnosed in Blacks (13%), Chinese Americans (8%), white Hispanics (7%), and other ethnic groups.[20]

The average age at presentation is 25 years, but there is a second smaller peak in incidence between 70 and 79 years.[9]  HCC in general is typically diagnosed in adults between 40 and 70 years of age, and is more common in males, while fibrolamellar carcinoma does not have a gender bias.[20, 9]

Prognosis after surgical therapy is superior to that with any medical management alone. Patients with unresectable metastatic fibrolamellar carcinoma have a median survival of 14 months.[22]

The population-based relative survival of patients with fibrolamellar carcinoma in the United States is 73% at 1 year and 32% at 5 years.[20]  In contrast, hepatocellular carcinoma relative survival is 26% at 1 year and 7% at 5 years.[20]  However, these figures include death from all causes. For example, because hepatocellular carcinoma patients tend to be older than those with fibrolamellar carcinoma, they may be at higher risk of death related to medical comorbidities (eg, heart disease or stroke). Nevertheless, even when only patients younger than 40 years are analyzed, fibrolamellar carcinoma still appears to portend a better prognosis than typical hepatocellular carcinoma.[20]

More importantly, fibrolamellar carcinoma usually occurs in the setting of a normal liver parenchyma (see the image below), while 80% of typical hepatocellular carcinoma occurs in the setting of a cirrhotic liver. Because cirrhosis is an independent risk factor for mortality, the observed difference in survival between fibrolamellar carcinoma and typical hepatocellular carcinoma may not in fact reflect differences in tumor biology or cancer-specific mortality.[18]

Two studies have found that in children, fibrolamellar carcinoma and hepatocellular carcinoma have similar prognoses and responses to therapy.[23, 24]  Two studies in adults have found that fibrolamellar carcinoma and typical hepatocellular carcinoma in noncirrhotics have similar prognoses after resection,[25, 9]  supporting the viewpoint that the survival differences seen in older groups may be confounded by competing causes of death.

Using data from the Surveillance, Epidemiology, and End Results (SEER) program, Mayo et al studied surgical treatment and prognosis in patients with fibrolamellar carcinoma or hepatocellular carcinoma: 7135 (99%) had hepatocellular carcinoma and 90 (1%) had fibrolamellar carcinoma. Patients with fibrolamellar carcinoma were younger (25 years vs 59 years) and more were women (44% vs 27%). Regional disease was nearly twice as common in patients with fibrolamellar carcinoma (42.2%) than in those with hepatocellular carcinoma (22.1%).[10]

Patients with fibrolamellar carcinoma were more often treated with a hemihepatectomy compared with patients with hepatocellular carcinoma, who were more often managed with a liver transplant. However, despite a higher likelihood of advanced disease at the time of diagnosis, surgically treated fibrolamellar carcinoma patients had better long-term outcomes than patients with conventional hepatocellular carcinoma, surviving a median of 75 months vs 43 months, respectively.[10]

In another study using SEER data, which included 225 patients with fibrolamellar carcinoma, survival decreased with increasing age. Median survival was 85 months in patients age ≤ 19 years, 29 months in those age 20-59 years, and 12 months in those age ≥ 60 years. Although patients age ≤ 19 years presented with more advanced disease, they were more likely to receive surgical interventions (eg, wedge or segmental resection, lobectomy or extended lobrectomy, liver transplantation.[26]

A multi-institutional study that included 35 patients (13 female; median age, 32 years) with fibrolamellar carcinoma who underwent hepatectomy found that for curative-intent surgery (n=30), overall and recurrence-free survivals at 5 years were 62% and 45%, respectively. None of the patients who achieved a 4-year disease-free interval developed recurrence, suggesting possible freedom from disease thereafter. These authors concluded that in patients with recurrent resectable disease, repeat surgery should be strongly considered.[27]

Patients with fibrolamellar carcinoma (FLC) typically present with nonspecific symptoms or no symptoms at all. When symptoms develop, they are most commonly the following:[13, 14, 28, 29, 30]

• Abdominal pain
• Weight loss
• Malaise

Uncommonly, presenting signs and symptoms may include the following:

• Migratory thrombophlebitis (Trousseau syndrome) or venous thrombosis as a result of direct invasion of the hepatic veins and inferior vena cava (IVC) or mass effect on the IVC ^[31]
• Pain and fever simulating a hepatic abscess ^[32]
• Obstructive jaundice due to biliary compression ^{[33, 34]}
• Gynecomastia, due to aromatase production by FLC cells and resultant conversion of circulating androgens to estrogens ^{[28, 35, 36]}

Other unusual presentations of fibrolamellar carcinoma have been summarized by Torbenson.[18]

The most common physical finding is an abdominal mass or fullness due to hepatomegaly.[28]

Unlike patients with typical hepatocellular carcinoma, the stigmata of chronic liver disease and portal hypertension are usually absent in patients with fibrolamellar carcinoma.

Hepatic enzymes

Mild elevations of serum aspartate and alanine aminotransferases (AST and ALT)[13] and alkaline phosphatase may be identified but are commonly absent.[29]

Elevation of serum bilirubin is rarely identified, but subclinical biliary obstruction may be relatively common, as 40% of cases demonstrate intrahepatic biliary ductal dilatation on imaging studies.[50]

Other circulating tumor markers

α-Fetoprotein (AFP) levels are typically normal but may be elevated. Less than 10% of patients with fibrolamellar carcinoma (FLC) have AFP levels greater than 200 ng/mL,[46] and even this finding may in part represent misclassification of hepatocellular carcinoma (HCC) as FLC.[18, 9]

Serum carcinoembryonic antigen (CEA) can be elevated on occasion.

An association between FLC and increased serum binding capacity of vitamin B-12 has been reported.[51, 52, 31] Likewise, elevated serum neurotensin levels have been reported in association with FLC.[53] Neither test can accurately differentiate FLC from other liver tumors, and neither test is useful as a screening modality. However, these levels may have utility for following a tumor's response to chemotherapy or for monitoring disease recurrence in patients following tumor resection.

For full discussion of radiologic findings in fibrolamellar carcinoma (FLC), see Fibrolamellar Hepatocellular Carcinoma Imaging.

Radiography

FLC is typically found as a solitary mass in an otherwise normal-appearing liver. FLCs can be quite large, and a visible central scar is noted in 20-60% of cases.[54]  On abdominal radiographs, calcifications in a nodular or stellate pattern may be seen in up to 40% of cases. The radiologic differential diagnosis of FLC includes the following benign and malignant hepatic tumors:

• Focal nodular hyperplasia (FNH)
• Hepatocellular adenoma
• Hepatocellular carcinoma (HCC)
• Intrahepatic cholangiocarcinoma
• Giant hepatic hemangioma
• Hypervascular metastases

FLC must be carefully differentiated from focal nodular hyperplasia because their management differs. Epidemiologic characteristics are similar in that both lesions occur in young, healthy patients who usually do not have a history of cirrhosis or liver disease. However, FLC requires aggressive treatment by liver resection, while focal nodular hyperplasia, a benign disease, does not require treatment unless the patient is symptomatic.

Computed tomography (CT) scan

The imaging technique of choice for staging is computed tomography (CT).

FLC usually appears as a hypoattenuated, well-defined, solitary mass on a nonenhanced CT scan. When a dynamically enhanced CT scan is used with arterial- and portal venous-phase contrast, the cellular portion enhances prominently and is heterogeneous, consistent with its vascular characteristics.

The central scar, if present, can be viewed on nonenhanced and arterial-phase scans; however, it is best viewed on delayed images because the unscarred portion of the mass becomes more homogeneous. Note that the fibrous scar in FLC typically does not enhance.[55] This is in contrast to focal nodular hyperplasia, in which the central scar, which is in reality a vascular entity, enhances on arterial-phase CT scan images.[56] This difference generally distinguishes FLC from focal nodular hyperplasia but is not absolute, as up to 25% of FLCs may in fact demonstrate delayed enhancement of the central scar. See the image below.

Calcifications are present in 33-55% of FLC and are usually located within the central scar but may less commonly be located at the tumor periphery.[54, 57]

Pseudoencapsulation of the tumor, caused by compression of adjacent liver parenchyma, is present in up to 15% of cases. However, true encapsulation is more characteristics of typical hepatocellular carcinoma.

Retraction of the adjacent Glisson capsule can occur in up to 10% of FLC cases, but it is also found with other primary liver malignancies. However, Glisson capsule retraction argues against a benign lesion such as focal nodular hyperplasia.[58]

As noted above, the ability to differentiate FLC from other lesions that also demonstrate central scars is useful. In a blinded retrospective review of CT scans of 64 patients with liver tumors (20 FLC, 29 focal nodular hyperplasia, and 15 hemangiomas), findings that were useful in differentiating FLC from focal nodular hyperplasia and large hemangiomas were as follows[59] :

• Tumor size greater than 10 cm (focal nodular hyperplasia is usually < 5 cm)

• Nodular centripetal enhancement (typical of hemangioma)

• Invasion of hepatic vessels or bile ducts (rules out focal nodular hyperplasia and hemangioma)

• Scar width greater than 2 cm (suggests fibrolamellar carcinoma or hemangioma over focal nodular hyperplasia)

• Heterogeneity (typical of FLC, also found in hemangioma but in a characteristic pattern of nodular centripetal enhancement, uncommon in focal nodular hyperplasia)

• Isoattenuation with blood vessels (suggests focal nodular hyperplasia over FLC or hemangioma)

• Extrahepatic metastases (rules out focal nodular hyperplasia and hemangioma)

• Calcification (suggests FLC over focal nodular hyperplasia or hemangioma)

• Surface lobulation (suggests FLC or hemangioma over focal nodular hyperplasia)

• Almost isoattenuating on portal venous phase images (favors FLC or focal nodular hyperplasia over hemangioma)

Magnetic resonance imaging (MRI)

MRI commonly shows a large, lobulated, homogeneous mass, as depicted in the first image below, that is hypointense relative to normal liver parenchyma on T1-weighted images. T2-weighted images, as depicted in the second image below, show a hyperintense mass relative to the liver and a heterogeneous pattern in most patients.

If a fibrous scar is present, it is usually hypointense on all MRI images.[55, 60] The fact that fibronodular hyperplasia demonstrates a hyperintense scar on MRI can be used to differentiate these tumors, although FLC scars can uncommonly demonstrate hyperintensity on T2-weighted images.[61, 62]

The enhancement pattern seen for FLC on gadolinium-enhanced MRI parallels that seen on CT scan.

Ultrasonography

Ultrasonography, which is often the initial study performed for right upper quadrant abdominal pain, commonly shows FLC as a solitary, well-defined mass with variable echotexture. Tumors with mixed echotexture are most common (60%) and are predominantly hyperechoic or isoechoic. The sensitivity of ultrasonography for detecting a central scar is only 33-60% (as compared with CT and pathological analysis),[54, 57] and when present is visualized as a central area of hyperechogenicity. Ultrasonography is less accurate than CT scan or MRI for evaluation of lymph node involvement and staging.[63, 64, 65, 66]

Angiography

Angiography may demonstrate a hypervascular lesion with a dense tumor blush and an avascular region corresponding to the central scar. However, it is of limited value in diagnosing FLC. On the other hand, it does have utility for defining portal venous and hepatic arterial anatomy and may aid in preoperative planning by allowing assessment of vascular invasion.

Positron emission tomography (PET) scanning

Positron emission tomography (PET) scanning is generally of limited value in typical hepatocellular carcinoma because of its low sensitivity, but more aggressive or dedifferentiated hepatocellular carcinoma tumors demonstrate enhanced tracer uptake.[67] Because FLCs are generally well-differentiated tumors, PET scanning is unlikely to be of great utility. One case report has demonstrated the successful use of PET scanning to stage FLC, but this case involved a relatively large and aggressive tumor.[68, 69]

Fine-needle aspiration biopsy

In some patients, fine needle aspiration biopsy (FNAB) can allow a histopathologic diagnosis to be made prior to operative intervention.[70]

FNAB should not be performed if the tumor is deemed resectable based on imaging studies. But, if the tumor is unresectable, FNAB may facilitate a tissue diagnosis in order for the oncologist to select the appropriate chemotherapy regimen.

FNAB should be used in cases when the diagnosis is unclear, such as when focal nodular hyperplasia is considered in an asymptomatic patient. This is important because distinguishing fibrolamellar carcinoma from focal nodular hyperplasia has implications for treatment and prognosis.

The cytologic findings of fibrolamellar carcinoma are very characteristic:[71, 72, 73, 74, 75]

• Large polygonal tumor cells: A single cell aspirated from a fibrolamellar carcinoma is 3 times the size of a normal hepatocyte and 1.6 times the size of a single cell aspirated from a well-differentiated typical hepatocellular carcinoma.

• Large nuclei and prominent nucleoli

• Abundant eosinophilic, granular cytoplasm, such that the N/C ratio is not as high as that for typical hepatocellular carcinoma (despite the large nucleus)

• Parallel bands of fibrous tissue may be seen in tumor fragments.

Core needle biopsy

The indications for core needle biopsy and the cytologic appearance of the tumor are as for FNAB. Core needle biopsy is more likely than FNAB to preserve the fibrous lamellae that are important to distinguish fibrolamellar carcinoma from typical hepatocellular carcinoma. As such, core needle biopsy is preferred over FNAB when a percutaneous biopsy is needed.[76]

Fibrolamellar carcinoma has a distinct macroscopic and microscopic appearance. Macroscopically, it typically appears as a yellow to pale tan mass ranging in texture from soft to hard and arising in a background of normal, noncirrhotic liver parenchyma.[18] The tumors are often large, growing up to 10-20 cm in size,[65, 77, 30, 46] and usually solitary (80-90%),[30, 46, 65] although small satellite lesions are occasionally observed. Pseudoencapsulation occasionally occurs, but a true capsule is more suggestive of typical hepatocellular carcinoma. A visible central scar, representing fibrosis rather than a vascular entity as in focal nodular hyperplasia, is noted in 20-60% of cases.[54, 78, 79] Hemorrhage and necrosis are occasionally observed.[78]

Microscopically, fibrolamellar carcinoma appears as tumor cells growing in sheets or small trabeculae that are separated by fibrous collagen. This results in a characteristic lamellar pattern (see the images below).[74] These lamellar bands of fibrosis may coalesce, forming the fibrous central scars seen on gross examination.[18]

The defining cytologic features of fibrolamellar carcinoma are as follows:[12, 13, 14, 18, 74]

• Large polygonal cells with abundant eosinophilic cytoplasm

• Large vesiculated nuclei

• Large nucleoli

Tumor cells may also demonstrate "pale bodies," which are round amphophilic cytoplasmic inclusions, and hyaline bodies.[13] Both features are found in roughly 50% of fibrolamellar carcinomas but are not specific for fibrolamellar carcinoma, as they may also be found in typical hepatocellular carcinoma.[13] Mitotic figures are less common than in typical hepatocellular carcinoma.[18] Copper deposition is often seen in fibrolamellar carcinoma, as in typical hepatocellular carcinoma.[18]

Immunohistochemical staining can differentiate fibrolamellar carcinoma from non-hepatocellular carcinoma liver tumors but not from typical hepatocellular carcinoma. Fibrolamellar carcinoma demonstrates positive staining for α1-antitrypsin and fibrinogen in most cases and at higher levels than typical hepatocellular carcinoma, while AFP immunoreactivity is usually absent (except in the uncommon circumstance of elevated serum AFP).[80] Consistent with their high degree of differentiation, fibrolamellar carcinoma cells express hepatocellular differentiation markers (HepPar) and biliary differentiation markers (cytokeratin 7),[17] as well as CD99.[81]

CT scan is the imaging study of choice for the staging of fibrolamellar carcinoma. The American Joint Commission on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for fibrolamellar carcinoma is the same as for typical hepatocellular carcinoma. Metastatic spread to regional lymph nodes may be more common in fibrolamellar carcinoma than in typical hepatocellular carcinoma.

Surgical resection or transplantation is the standard of care for fibrolamellar carcinoma (FLC) for eligible patients.[82] Trans-arterial chemo-embolization (TACE) may be a useful option in patients who have unresectable disease.[83, 84] TACE has also been used as neoadjuvant therapy, to facilitate subsequent tumor resection.[85]

The role of neoadjuvant or adjuvant chemotherapy is controversial. FLC is not typically responsive to chemotherapy. In some cases, chemotherapy had no effect on survival or recurrence in patients who received chemotherapy after surgery. In contrast, other studies have found that patients who received chemotherapy in neoadjuvant and adjuvant settings fared better than those with surgery only.[76]  

While not well studied, radiation therapy has been used to treat recurrent FLC in isolated case reports. Peacock et al demonstrated an 85.9% decrease in tumor volume of FLC metastases using 40 Gy in 10 fractions over a 13-day period.[86]

In addition to systemic chemotherapy, research has also focused on taking advantage of the new understanding of the pathogenesis and molecular genetics of FLC. For example, anecdotal reports of FLC response to rapamycin analogs have been substantiated by laboratory evidence of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activation in these tumors.[87, 88] However, a phase II multi-institutional, three-arm trial of estrogen deprivation therapy, alone or in combination with the mTOR inhibitor everolimus, did not demonstrate clinical activity in advanced FLC.[89]

In another study using SEER data, which included 225 patients with fibrolamellar carcinoma, survival decreased with increasing age. Median survival was 85 months in patients age ≤ 19 years, 29 months in those age 20-59 years, and 12 months in those age ≥60 years. Although patients age ≤ 19 years had more advanced disease, with positive lymph nodes, they were more likely to receive surgical interventions (eg, wedge or segmental resection, lobectomy or extended lobrectomy, liver transplantation.[26]

Chemotherapy for metastatic fibrolamellar carcinoma (FLC) is as for metastatic typical hepatocellular carcinoma (HCC). Single-agent chemotherapy or combinations of chemotherapeutic drugs give responses of no more than 25%, with questionable benefit for overall survival.

Sorafenib is an orally delivered small molecule that inhibits several different protein kinases, including Raf-1 and B-Raf, platelet-derived growth factor β (PDGFR-β), and vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. Sorafenib targets both tumor growth (Raf-MEK-ERK pathway) and neoangiogenesis (VEGFRs, PDGFR-β), both of which are thought to be important in the pathogenesis of typical HCC.

A randomized controlled trial of sorafenib in 602 patients with advanced typical HCC and well-compensated cirrhosis demonstrated a survival benefit with sorafenib as compared with placebo, corresponding to a 3-month increase in median survival (10.7 versus 7.9 mo).[90]  A similar study will likely never be performed in FLC due to the rarity of the disease. It is unclear whether the data on sorafenib for typical HCC are generalizable to FLC. There are not yet any reports in the literature describing sorafenib use in FLC.

A phase II clinical trial reported in 2003 evaluated 21-day courses of systemic continuous 5-fluorouracil repeated monthly and thrice-weekly subcutaneous recombinant interferon α-2b in a mixed population of 43 patients with FLC or typical HCC.[91] All of these patients were ineligible for surgical therapy due to extent of hepatic disease as determined by CT scan, but none had extrahepatic disease. Of nine patients with FLC, eight were radiologically assessed for response, which showed one complete response (CR), four partial responses (PR), and one minor response (MR). The median survival of the FLC patients was 23 months, compared with 15.5 months for typical HCC (statistical significance not reported).

Of note, a major reason the authors chose this treatment regimen was that they anticipated it would be well tolerated by patients with cirrhosis. Although the regimen was in fact well tolerated in this trial, none of the FLC patients had cirrhosis. Because FLC patients generally do not have cirrhosis, chemotherapeutic regimens that might not be appropriate for typical HCC might be of use in FLC.

In a study of immunochemotherapy with 5-fluorouracil, interferon, and nivolumab in adolescent and young adult patients (22 treated, 14 evaluable) with unresectable, metastatic, refractory, or relapsed FLC, median progression-free survival was 9 months. After 26 months, over 90% of patients were still alive; 5 patients had achieved clinical remission, 8 patients were stable or improving, and 1 patient had experienced progression.[92]

 

Optimal management for most hepatic malignancies, including typical hepatocellular carcinoma and fibrolamellar carcinoma, is complete surgical resection (eg, wedge resection, anatomic liver resection, or total hepatectomy with orthotopic liver transplantation). There may be occasional utility in treating fibrolamellar carcinoma with neoadjuvant chemotherapy or trans-arterial chemo-embolization (TACE) with the goal of downstaging the tumor to allow resection.[83]

Hepatic resection

Cirrhosis often limits the feasibility of liver resection in patients with typical hepatocellular carcinoma (HCC) because cirrhotic patients have increased perioperative risk and require a larger future liver remnant to be left behind to allow adequate liver function. In contrast, fibrolamellar carcinoma (FLC) is rarely associated with cirrhosis, and patients are often young and otherwise healthy. For this reason, aggressive liver resections can be more readily undertaken in patients with FLC than in those with typical HCC.

Several factors are associated with a better prognosis following surgery, including younger age at diagnosis, earlier tumor stage at diagnosis, and absence of large vessel invasion or thrombosis.[20] ​ The ability to perform complete resection has been reported to be one of the most important and well-described prognostic factors for FLC.[20, 46, 24] Factors associated with a particularly poor prognosis include lymph node metastasis, multiple tumors, metastatic disease at presentation, and vascular invasion.[20, 77]

Patients with resected FLC generally have a prognosis similar to that for noncirrhotic patients with resected typical HCC.[9, 25] Aggressive surgical approaches, even for recurrent disease, can be undertaken with good results.[29]

Orthotopic liver transplantation

Total hepatectomy followed by orthotopic liver transplantation (OLT) should be considered in patients with unresectable FLC that is confined to the liver.  An analysis of 63 patients who received liver transplanation for FLC between October 1988 and January 2013 had an overall survival at 1, 3, and 5 years of 96%, 80%, and 48%, respectively, while comparable rates in HCC patients were 89%, 77%, and 68%. Six patients had tumor recurrence (10%). Model for End-stage Liver Disease (MELD) score and cold ischemic time were the strongest predictors of overall survival in FLC patients.[93]  

Even among patients who develop tumor recurrence, the time to recurrence is significantly longer in patients with FLC than in those with typical HCC.[94] This may be a result of more indolent behavior by FLC versus typical HCC. Alternatively, it may result from the fact that accompanying cirrhosis in typical HCC increases the risk of recurrence (including development of a second primary tumor) via a field effect.

Orthotopic liver transplantation can result in long-term survival but is a resource-intensive treatment approach. In typical HCC, orthotopic liver transplantation confers the advantage of removing the at-risk cirrhotic liver in addition to the tumor itself. In FLC, this theoretical advantage is likely not present because no such field effect is present (due to the lack of cirrhosis in most cases).

As such, it is not clear that the use of donor organs in patients with FLC is an appropriate use of this scarce resource.[90] Newer innovative approaches (eg, adult living-related donations, split-liver techniques, and potential use of marginal donor organs) may allow for a future increase in the use of orthotopic liver transplantation for FLC.