Fibrolamellar Carcinoma

Synonyms and related keywords: fibrolamellar hepatoma, hepatocellular carcinoma with lamellar fibrosis, FLC, eosinophilic hepatocellular carcinoma with lamellar fibrosis, polygonal cell with fibrous stroma, eosinophilic glassy cell hepatoma, fibrolamellar oncocytic hepatoma, HCC, fibrolamellar carcinoma


INTRODUCTION

Background: Fibrolamellar hepatocellular carcinoma (FLC) is considered a histologic variant of hepatocellular carcinoma (HCC). In spite of this accepted classification, there is considerable evidence that FLC is distinct from HCC in its epidemiology, biology, and prognosis.

FLC is a rare primary hepatic malignancy, and has been described in the literature according to several names, including eosinophilic hepatocellular carcinoma with lamellar fibrosis, polygonal cell HCC with fibrous stroma, eosinophilic glassy cell hepatoma, and fibrolamellar oncocytic hepatoma. Edmonson first described FLC in 1956 when he published a review of infancy and childhood tumors. He included a 14-year-old girl with an unusually long survival following hepatic resection for liver cancer. Following two reports in 1980 by Craig et al and Berman et al, this HCC subtype became recognized as a distinct pathologic entity from the classic type of HCC based upon its clinical presentation and survival advantage.

Pathophysiology: The more typical form of HCC is often associated with active hepatic inflammation, hepatitis B or C viral infections, alcohol-related liver disease, nonalcoholic fatty liver disease, cirrhosis from any cause, or dietary aflatoxin B1. In contrast, the etiology of FLC remains unclear. It is associated with cirrhosis in less than 10% of patients and typically presents in the absence of underlying liver disease.

The histology of FLC strongly resembles focal nodular hyperplasia (FNH), a type of benign liver lesion, because both have similar presentations that are often in the setting of normal liver parenchyma. Based on this similarity, some have suggested that FNH may be a benign precursor to FLC. Moreover, some case reports have described foci of FNH adjacent to FLC tumors. This finding likely represents a secondary reaction to local ischemia-hypoperfusion abnormalities caused by the FLC mass. In summary, the etiological association between FNH and FLC remains unproven and is not widely accepted.

Frequency:

• Internationally: HCC is one of the most common malignancies worldwide, and its incidence is expected to rise over the next decade. Currently, HCC has the highest cancer-related prevalence and mortality with more than one million deaths per year. In contrast, FLC is rare, accounting for less than 1% of primary liver cancers.
• HCC is associated with cirrhosis and is most common in Asia and Africa where the prevalence of hepatitis B and C viruses is high. HCC predominantly occurs in males and typically presents in the fifth or sixth decade of life. In contrast, FLC is more common in the United States and Europe, and it is not associated with cirrhosis. FLC is also most common in young adults and occurs in both sexes with equal incidences.

Race: Compared to patients with typical HCC, patients with FLC are more likely to be white. According to a population-based study using the Surveillance, Epidemiology, and End Results (SEER) program in the United States between 1986 and 1999, El-Serag and Davila found that 85% of patients with FLC were white, while only 57% of patients with HCC were white.

Sex: El-Serag and Davila demonstrated that there was no sex predilection for FLC. This is in distinct contrast to the male predilection of HCC (74% male and 26% female).

Age: FLC is most common in younger adults (20-40 y) without prior liver disease. However, FLC can occur in all age groups. Compared with typical HCC, El-Serag and Davila reported that patients with FLC were more likely to be younger (mean age, 39 y vs 65 y).

CLINICAL

History: Patients usually present without symptoms. When symptoms do develop, they are most commonly abdominal pain and fullness. The latter is particularly true in the pediatric population.

• Less common presenting symptoms include the following:

• Weight loss

• Fatigue

• Malaise

• Fever

• Chills

• Abdominal distension

• Amenorrhea

• Other associated findings include the following:

• Migratory thrombophlebitis

• Hemobilia

• Obstructive jaundice

• Gynecomastia (believed to be from conversion of androgens to estrogens by the aromatase enzyme which can be produced by FLC)

Physical:

• Conduct a complete physical examination.

• Unlike patients with typical HCC, the ability to identify stigmata of chronic liver disease is uncommon in patients with FLC.

• A palpable abdominal mass occurs in patients when the tumor is large or extends inferiorly from the liver edge.

Causes:

• Unlike the more common HCC, FLC is not associated with hepatotoxins or cirrhosis.

• Less than 10-20% of cases of FLC are associated with hepatitis B viral infection.

• FLC is rarely associated with hepatitis C viral infection.

• FLC has not been associated with alpha1-antitrypsin deficiency or hemochromatosis.

DIFFERENTIALS

Hemangiomas, Hepatic
Hepatocellular Adenoma

Other Problems to be Considered:

Focal nodular hyperplasia
Hepatic adenoma
Hepatocellular carcinoma (HCC)
Intrahepatic cholangiocarcinoma
Hepatic metastases

Isolated case reports of synchronous and/or metachronous liver tumors in patients with FLC

Focal nodular hyperplasia
Hepatic adenoma
HCC
Intrahepatic cholangiocarcinoma

Lab Studies:

• Hepatic enzymes

• Results may show mild elevations of serum transaminases (AST and ALT) and alkaline phosphatase levels.

• Elevation of bilirubin is rarely identified.

• Alpha-fetoprotein (AFP): Although commonly elevated with HCC, less than 10% of patients with FLC have an AFP level greater than 200 ng/mL.

• Other circulating tumor markers

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

• Some patients have an elevation in their binding capacity of serum vitamin B-12. Paradina et al found that 10 of 107 patients with primary liver cancer had an elevated binding capacity of serum vitamin B-12. Seven of those 10 patients had FLC.

• Patients may have increased level of plasma neurotensin. Collier et al performed a serum analysis of patients with liver tumors and found elevated neurotensin levels in 5 of 20 patients. Four of those 5 patients were diagnosed with FLC.

• Despite these findings, neither elevated serum neurotensin nor increased binding capacity of vitamin B-12 can accurately differentiate FLC from other liver tumors. Moreover, neither test is useful as a screening test. However, they may have utility for following a tumor's response to chemotherapy or for monitoring disease recurrence in patients following tumor resection.

Imaging Studies:

• Radiography

• This tumor typically presents as a solitary mass in an otherwise normal appearing liver. FLC can be quite large, and a visible central scar is occasionally noted.

• The radiologic differential diagnosis of FLC includes the following benign and malignant hepatic tumors:
  • FNH
  • Hepatocellular adenoma
  • HCC
  • Intrahepatic cholangiocarcinoma
  • Giant hepatic hemangioma
  • Hypervascular metastases

• FLC must be carefully differentiated from FNH because their management differs. Epidemiologic characteristics are similar because 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 FNH, a benign disease, does not require treatment unless the patient is symptomatic.

• CT scan

• 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, when present, does not enhance as expected. This is in contradiction to FNH, in which the central scar, which is in reality a vascular entity, enhances on arterial-phase CT scan images. This difference distinguishes the two masses. However, this finding is not absolute.

• In a large retrospective radiographic analysis of 58 cases of FLC from the archives of the Armed Forces Institute of Pathology, McLarney et al found that 25% of central scars showed some enhancement.

• Other findings more characteristic of a malignant tumor (eg, calcification, pseudoencapsulation, retraction of the adjacent Glisson capsule) can occur in FLC. These findings can be used to differentiate FLC from FNH.
• In a blinded retrospective review of CT scans of 64 patients with liver tumors, based upon CT findings, the diagnosis of FLC was most accurate. Findings that were significant for differentiating these tumors from others included the following:
  • Tumor size larger than 10 cm
  • Width of the tumor scar greater than 2 cm
  • Surface lobulatation
  • Intralesional calcifications (may be seen with any tumor but the high frequency in FLC makes this an important differentiating feature)
  • Tumor heterogeneity is typical in 90% of cases and results from the mixed content of eosinophilic neoplastic cells interspersed in collagen and fibrotic tissue, as well as from intratumoral necrosis and hemorrhage.
  • Marked hyperattenuation on arterial phase images
  • Isoattenuation or hypoattenuation without heterogeneity on portal venous phase images compared with normal liver tissue
  • Lymphadenopathy is present in 50-70% of cases. This almost always involves the hepatic hilum and hepatoduodenal ligament and may be extensive, involving multiple abdominal and retroperitoneal sites.
  • Invasion of the hepatic vessels or bile ducts occurs in less than 5% of FLC.
  • Portal vein thrombosis
  • Lack of evidence for cirrhosis
  • Lack of multifocal disease

• MRI

• This commonly shows a large, lobulated, homogeneous mass that is hypointense relative to normal liver parenchyma on T1-weighted images. T2-weighted images show a hyperintense mass relative to the liver and a heterogeneous pattern in most patients.

• If a fibrous scar is present, it usually is hypointense on either T1- or T2-weighted images. This characteristic seems to be specific for FLC and is used to differentiate it from other lesions (eg, FNH).

• In the Armed Forces Institute of Pathology study of patients with FLC, a central scar was viewed in 12 of 14 tumors. Of these tumors, 10 of the 12 exhibited a hypointense scar, while one scar was hyperintense and another was heterogeneous.

• For FLC, MR imaging with gadolinium-enhancement often parallels the findings seen with contrast-enhanced CT scanning.

• Other imaging studies

• Ultrasonography, which often is 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 predominantly contain hyperechoic and isoechoic components. The central scar, if present, is visualized as a central area of hyperechogenicity. However, this only occurs in 30-60% of patients when compared with CT scan results and pathologic analysis. Ultrasonography may also reveal calcifications commonly within a central scar and may demonstrate regional adenopathy. Overall, ultrasonography is less accurate than CT or MRI for clinical staging.

• Plain abdominal radiographs have only a limited role in diagnosing or distinguishing liver lesions. However, FLC can be associated with calcifications in a nodular or stellate pattern in up to 40% of abdominal radiographs of patients with FLC.

• Angiography, like plain radiographs, has a limited role in making the diagnosis of FLC. On the other hand, it has utility for defining portal venous and hepatic arterial anatomy. Preoperatively, it may indicate the presence of vascular invasion.

Procedures:

• Fine-needle aspiration biopsy

• In some patients, fine needle aspiration biopsy (FNAB) can allow a histopathologic diagnosis to be made prior to operative intervention.
• FNAB should not be performed if the tumor is deemed resectable based upon 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 FNH is considered in an asymptomatic patient. This is important because distinguishing FLC from FNH has implications for treatment and prognosis.

• The cytologic findings of FLC are very characteristic:
  • Large tumor cells (a single cell aspirated from a FLC is 3 times the size of a normal hepatocyte and 1.6 times the size of a single cell aspirated from a well-differentiated HCC)
  • Large nuclear and nucleolar sizes
  • Low nuclear-to-cytoplasmic (N/C) ratio

Histologic Findings: FLC has a distinct macroscopic and microscopic appearance, including the presence of thick fibrous lamellae within the tumor stroma. Overall, it appears as a single, firm, tan-white, nonencapsulated mass in a background of normal, noncirrhotic liver parenchyma. The tumors can be large, growing up to 10-15 cm in size.

Approximately 50-60% of FLC lesions are solitary, while the remainder have smaller satellite lesions adjacent to the large dominant mass. Diffuse liver involvement is rarely observed. Interestingly, a predominance of left lobe involvement has been noted.

Histologically, features include large, polygonal tumor cells arranged in a trabecular formation with eosinophilic and granular cytoplasm. These cells are surrounded by prominent hypocellular stromal fibrosis composed mainly of collagen. Infiltrating collagen deposition and lamella formation result in the compartmentalization of cellular elements, as well as the formation of a central fibrous scar. Mitochondria are abundant, and the cells commonly have macronuclei that demonstrate prominent intranuclear cytoplasmic invaginations and peripheralized chromatin.

Immunohistochemical staining can differentiate FLC from non-HCC liver tumors because FLC demonstrates positive staining for copper and fibrinogen in most cases, while AFP immunoreactivity is uniformly absent. Moreover, immunohistochemical analysis shows that FLC cells express hepatocellular differentiation markers (ie, HepPar) and biliary markers (ie, cytokeratin 7), as well as CD99. Additionally, specific electron microscopy findings may be used to differentiate FLC from HCC.

An important characteristic of FLC is the presence of a central stellate scar similar to that in the benign liver lesion, FNH. In contrast to the true central scar of FLC, the scar of FNH is a vascular abnormality and not due to fibrosis. A central scar is reported in 20-60% of patients with FLC. Similar scars are found in lymph nodes with metastatic FLC. The etiology of the central scar is unclear, but it likely represents necrosis due to a diminished central blood supply.

Cytogenetic findings

Chromosomal imbalances are frequently found in HCC. Four alterations that are more frequent in FLC than other types of liver tumors include 4q⁺, 9p^-, 16p^-, and Xq^-.

TREATMENT

Medical Care:

• Neoadjuvant management: Although tumor resection remains the standard of care for patients with FLC, Patt et al reported a phase II clinical trial of systemic, continuous 5-fluorouracil and thrice-weekly subcutaneous recombinant interferon alfa-2b for liver cancers. This study demonstrated that this regimen was an effective treatment for patients with FLC, suggesting that neoadjuvant chemoimmunotherapy may play a previously unappreciated role in treatment of FLC and that further investigation is warranted for the study of this and other regimens as a primary treatment in some patients with FLC.

Surgical Care:

• Optimal management

• Optimal management for most hepatic malignancies, including HCC and FLC, is complete surgical resection (eg, anatomic liver resection, wedge resection, orthotopic liver transplantation).
• There appears to be occasional utility for treating FLC with neoadjuvant or adjuvant chemotherapy or transarterial chemoembolization (TACE).

• Hepatic resection

• Cirrhosis is present in 90% of patients with typical HCC and is a poor prognostic indicator because cirrhotic patients have increased perioperative morbidity and mortality following resection.
• Unlike typical HCC, FLC is rarely associated with cirrhosis. For this reason, the resectability rate is higher in these patients. Moreover, the postoperative mortality rate in patients with HCC and cirrhosis ranges from 7-25%, while the postoperative mortality rate in patients without cirrhosis (including those with FLC) is generally less than 5%.
• Positive prognostic factors for HCC are as follows:
  • Small tumor size (less than 5 cm)
  • Favorable tumor location
  • Well-differentiated histologic grade
  • Presence of a tumor capsule
  • Lack of vascular invasion
  • Most significant predictor of resectability and long-term survival is the histopathologic diagnosis of FLC.

• Published series show overall 5-year survival rates of 25-63% for both resectable and unresectable liver tumors, with median patient survival time of 21-45 months.
• The reported resection rates for FLC are 47-100%. The 5-year survival rate after curative resection is 40-65%, with a median survival rate of 33-50 months. On the other hand, survival rates for patients with HCC are significantly lower. For patients with HCC, the 5-year overall survival rate is 0-26% (median survival rate of 4-7 mo) and the 5-year survival rate following an attempted curative resection is only 17-25%.
• Although an improved survival rate exists for patients with FLC as compared to those with HCC, this is largely due to the increased resectability rate and the lack of associated cirrhosis in patients with FLC. In addition, some studies suggest that FLC has a less aggressive biologic behavior than HCC.
• Recently, this has come under debate. A study by Kakar et al suggested that the prognosis of FLC is similar to typical HCC. In patients without metastatic disease they found that the prognosis was better for FLC and HCC without cirrhosis compared to HCC. However, the 5-year survival and overall survival were similar for patients with FLC and HCC without cirrhosis. This study concluded that the absence of cirrhosis rather than FLC's distinct clinical and pathologic features were beneficial for patient survival.

• In general, it is thought that prolonged survival can be achieved in patients with FLC despite an advanced tumor stage or metastatic disease.
• Wood et al showed that the median patient survival was 50 months for patients with resectable FLC versus 7 months for patients with noncirrhotic resectable HCC.
• Nagorney et al reported a significantly greater survival rate for patients with resectable FLC than for patients without cirrhosis who had resectable nonfibrolamellar HCC.

• Orthotopic liver transplantation

• A total hepatectomy followed by orthotopic liver transplantation (OLT) can be considered in patients with unresectable FLC that is confined to the liver. In earlier OLT series, the operative mortality rate was reportedly 24-70%. More recently, OLT has improved and is considered more common in patients not amenable to partial hepatectomy, including patients with FLC.
• Pichlmayr et al reported on 135 liver transplants performed on patients with HCC. Patients in this series had 1-year, 5-year, and 10-year survival rates of 53%, 28%, and 14%, respectively. The subset of patients with FLC (n=8) had the most favorable prognosis following transplantation, with 1-year, 5-year, and 10-year survival rates of 63%, 38%, and 25%, respectively. The median survival rate was 35.1 months, and no patients died from postoperative complications.

• Overall, FLC has less aggressive behavior than other tumor types, and patients tend to do well following OLT. However, given that most patients lack cirrhosis and late recurrences are common, debate remains regarding the allocation of donor organs for patients with FLC.

• OLT can result in long-term survival, but long waiting times, high costs, and limited donor availability temper enthusiasm for this approach, particularly in patients without cirrhosis who have large unresectable tumors (eg, FLC). Newer innovative approaches (eg, adult living-related donors, split liver techniques, potential use of marginal donor organs) may allow for a future increase in the use of OLT for FLC.

FOLLOW-UP

Further Outpatient Care:

• Contraindications to liver resection include metastatic disease, periportal or peridiaphragmatic lymphadenopathy, or involvement of the hilar structures. In some cases, radiation and regional or systemic chemotherapy may result in responses sufficient to convert the tumor stage to resectable disease.

• Radioablation may be advantageous in some clinical settings.

• Soyer et al reported on 4 cases and found a 50% tumor response rate to intra-arterial transcatheter oily chemoembolization (TOCE).

• A study from the Johns Hopkins Hospital reported that patients with unresectable FLC had a longer survival rate than matched controls with typical unresectable HCC following multimodality treatment (intra-arterial chemotherapy, external beam radiotherapy, and isotopic immunoglobulin-directed radiotherapy). The median patient survival rate was 14 months versus 7.7 months. In some patients, tumors were converted from unresectable to resectable.

Prognosis:

• Poor prognostic factors that affect survival include the following:

• Diagnosis before age 23 years

• Lack of surgical resection

• Positive surgical margins

• Vascular invasion

• Altered hepatic enzymes

• Overall, FLC is considered a pathologic subset of HCC. However, it is associated with its own distinct features related to diagnosis and treatment, as well as - an ultimate survival advantage. Aggressive surgical resection improves long-term survival while liver transplantation is a possible option when indicated. Most patients (80%) can be treated by resection with curative intent. In patients with unresectable disease, FLC can respond to aggressive chemoradiation therapy or chemoimmunotherapy.