Fibrolamellar Carcinoma Workup

Updated: Oct 17, 2022
  • Author: Michael A Choti, MD, MBA, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Laboratory Studies

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.


Imaging Studies

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


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.

CT scan showing fibrolamellar carcinoma with a lar CT scan showing fibrolamellar carcinoma with a large stellate central scar.

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.

T1-weighted MRI of a fibrolamellar carcinoma in th T1-weighted MRI of a fibrolamellar carcinoma in the left lobe of the liver.
T2-weighted MRI of a fibrolamellar carcinoma in th T2-weighted MRI of a fibrolamellar carcinoma in the left lobe of the liver, demonstrating a heterogeneous appearance with a central scar.

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, 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 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]


Histologic Findings

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]

Hematoxylin and eosin photomicrograph of fibrolame Hematoxylin and eosin photomicrograph of fibrolamellar carcinoma. Note the thick fibrous lamellae within the tumor stroma.
Masson trichrome stain photomicrograph of fibrolam Masson trichrome stain photomicrograph of fibrolamellar carcinoma depicting the collagen-containing lamellae within the tumor stroma.

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.