January 16, 2007

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


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.


  • 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).


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.




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
Intrahepatic cholangiocarcinoma

Lab Studies:

Imaging Studies:

    • 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.


  • 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-.


Medical Care:

Surgical Care:


Further Outpatient Care:


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