DOI: 10.1148/rg.282075153
RadioGraphics 2008;28:609-613
© RSNA, 2008
Best Cases from the AFIP
Fibrolamellar Hepatocellular Carcinoma1
Mitchell T. Smith, MD,
Ellen R. Blatt, MD,
Paul Jedlicka, MD, PhD,
John D. Strain, MD, and
Laura Z. Fenton, MD
1 From the Department of Radiology, University of Colorado Health Sciences Center, 12631 E 17th Ave, MS 8200, Bldg L15, Room 2414, PO Box 6511, Aurora, CO 80045 (M.T.S.), and the Department of Radiology, Children’s Hospital, Denver, Colo (E.R.B., P.J., J.D.S., L.Z.F.). Received July 3, 2007; revision requested August 7 and received September 21; accepted September 24. All authors have no financial relationships to disclose.
Address correspondence to M.T.S. (e-mail: mitch.smith{at}uchsc.edu).
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History
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A 13-year, 10-month-old boy presented with a low energy level, depression, and intermittent diarrhea. According to his growth chart, at age 7 years he was in the 25–50 percentile for height. At the time of presentation, he had fallen to the fifth percentile. Results of a bone age study indicated that his bone age, according to the standards of Gruelich and Pyle, was within 2 months of his chronologic age. Laboratory studies revealed the levels of free thyroxine and thyroid-stimulating hormone to be 12.6 pmol/L (normal range, 10.3–21.9 pmol/L) and 7.08 mIU/L (normal range, 0.36–5.4 uIU/mL), respectively. He began taking 50 mcg of Levothyroxine, which had a positive effect on his energy level. Results of physical examination at this time were remarkable for gynecomastia; the patient was referred for an endocrine evaluation.
A month and a half later, the patient presented to the emergency department with shortness of breath and tachycardia. In addition, he experienced vomiting and diarrhea without fever over the previous 2 days. The patient’s level of estrone was elevated at 777 pmol/L (normal range, 55.5–925 pmol/L), with estradiol at 8.1 pmol/L (normal range, 1.84–5.9), androstenedione at 2.2 nmol/L (normal range, 1.1–2.3), cortisol at 402.8 nmol/L (normal range, 140–690), and 
-fetoprotein at 2.8 µg/mL. Chest and abdominal computed tomography (CT) was ordered for a suspected pulmonary embolus and for liver abnormalities.
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Imaging Findings
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CT images of the chest demonstrated mild dependent edema and a small, right pleural effusion. There was no evidence of a pulmonary embolus or of nodules, which would suggest metastatic disease.
Abdominal CT images showed a 12-cm lesion involving the anterior segment of the right lobe of the liver (Fig 1). The lesion almost completely replaced the anterior segment, had an irregular and nodular enhancing border, was low attenuating (approximately 40 HU), and had multiple septa (Fig 1). The posterior segment of the right lobe and the left lobe were unremarkable, and lymphadenopathy was noted at the esophageal hiatus. In addition, minimal amounts of periportal and pelvic free fluid were identified. Ultrasonography (US) demonstrated a solitary, heterogeneous 9.5 x 11.2-cm mass with significant vascular flow involving the anterior segment of the right lobe of the liver (Fig 2). The hepatic artery and the portal vein had increased diameters, and the aorta decreased in caliber after the take-off of the celiac axis.
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Figure 1. Contrast material–enhanced abdominal CT scan demonstrates a mass in the dome of the liver; the mass enhances in a peripheral and nodular pattern. The irregular enhancing internal soft tissue and adjacent lower attenuation are indicative of necrosis.
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Figure 2a. (a) Transverse US image through the dome of the liver helps confirm that the hepatic lesion is a soft tissue mass. (b) Spectral Doppler US image reveals low resistance arterial flow in the lesion, which indicates a hypervascular tumor with arteriovenous shunting.
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Figure 2b. (a) Transverse US image through the dome of the liver helps confirm that the hepatic lesion is a soft tissue mass. (b) Spectral Doppler US image reveals low resistance arterial flow in the lesion, which indicates a hypervascular tumor with arteriovenous shunting.
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Pathologic Evaluation
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Analysis of the needle biopsy specimen from the lesion showed clusters and islands of large polygonal cells with granular eosinophilic cytoplasm and large nuclei with prominent nucleoli in a background of densely collagenized fibrous tissue. Although the size of the specimen was very limited, the histologic features were characteristic of the lamellar variant of hepatocellular carcinoma. Possible differential diagnoses (although remote)—metastatic occult steroid-producing adrenal cortical or testicular tumor, or a neuroendocrine tumor—were excluded by means of immunohistochemical staining, which revealed the tumor cells to be cytokeratin-positive and neurospecific enolase-, synaptophysin-, and chromogranins-negative. A diagnosis of fibrolamellar hepatocellular carcinoma was rendered.
Because of the results of the biopsy, the patient underwent surgical tumor resection, which included an extended right trisegmentectomy. The resected liver specimen showed a poorly circumscribed tumor mass that measured 12 x 11.5 x 7.5 cm; involved the liver parenchyma; and exhibited a tan, yellow, and green solid cut surface (Fig 3). The histologic features of the tumor were identical to those of the needle biopsy specimen; thus, the diagnosis of hepatocellular carcinoma, fibrolamellar variant, was confirmed (Fig 4). The tumor was completely resected with close but negative margins.
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Figure 3a. Gross and histologic features of the liver tumor. (a) Photograph of an intact trisegmentectomy resected specimen shows a large tumor distending an intact liver capsule. (b) Photograph of the cut specimen reveals a tan, yellow, and green surface of the tumor and its irregular interface with adjacent liver parenchyma.
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Figure 3b. Gross and histologic features of the liver tumor. (a) Photograph of an intact trisegmentectomy resected specimen shows a large tumor distending an intact liver capsule. (b) Photograph of the cut specimen reveals a tan, yellow, and green surface of the tumor and its irregular interface with adjacent liver parenchyma.
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Figure 4. Photomicrograph (original magnification, x200; hematoxylineosin stain) of the resected specimen demonstrates classic morphologic features of a fibrolamellar hepatocellular carcinoma. Collagenized/fibrous stroma are arranged in a parallel lamellar pattern.
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Discussion
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Fibrolamellar carcinoma was first described as an entity distinct from hepatocellular carcinoma in 1956 by Edmondson (1). Among the 181 reported cases, the disease has a unimodal distribution, beginning in late adolescence, with a peak incidence at 24.8 ± 13 years (2). According to the Surveillance, Epidemiology, and End Results database, fibrolamellar carcinoma has no apparent sex bias but does show a predilection for Caucasians (3).
These patients tend to present with nonspecific symptoms and commonly complain of abdominal pain, malaise, and weight loss (4–7). At physical examination, either an abdominal mass or hepatomegaly is most commonly seen (5). Less frequently, gynecomastia, elevated levels of estrone, and lower than expected growth chart values have also been associated with fibrolamellar hepatocellular carcinoma (8). In one instance, the cause of elevated estrone levels and subsequent gynecomastia was linked to aromatase expression within the tumor (9).
At CT, more than 80% of fibrolamellar carcinomas have a lobulated surface (10). Calcifications are seen in 35%–68% of the tumors and tend to be centrally located, small (<5 mm), and fewer than three in number (10–13). The majority of the tumors are heterogeneous with areas of low attenuation on unenhanced CT scans (10). During the hepatic arterial phase of contrast enhancement, these lesions are hyperattenuating 80% of the time (10). A central scar is seen in 20%–71% of the cases and can be either stellate or amorphous (10–13). Finally, significant lymphadenopathy is seen more than 50% of the time, usually in the hepatic hilum or in the hepaticoduodenal ligament (10–13).
Although it is not commonly a first-line imaging modality for known tumors, US has been shown to demonstrate a well-defined lesion of mixed echogenicity (11). The central scar, with or without associated calcification, is variably visualized as a central hyperechoic region (11). US is less sensitive for evaluating central necrosis and regional lymphadenopathy (11).
Nuclear medicine imaging can also be useful in differentiating fibrolamellar hepatocellular carcinoma from other primary liver neoplasms (11). Because Kupffer cells are neither present nor metabolically active in these tumors, there is no uptake of technetium 99m (99mTc)-labeled sulfur colloid (11). The background liver and spleen demonstrate normal increased uptake with sulfur colloid, and the fibrolamellar hepatocellular carcinoma is visualized as an area of photopenia (11). With 99mTc-labeled red blood cells, fibrolamellar hepatocellular carcinoma appears as an area of increased uptake during the arterial phase, which washes out on more delayed phase images; this pattern is opposite of that seen in hemangiomas (11).
On magnetic resonance (MR) images, fibrolamellar hepatocellular carcinoma appears as a mass with a central scar (14). On T1-weighted images, the mass is isointense relative to liver parenchyma, and on T2-weighted images the appearance varies from hypointense to slightly hyperintense (14). The central scar of fibrolamellar hepatocellular carcinoma has a low signal intensity with all pulse sequences, which helps to distinguish it from focal nodular hyperplasia, which may have a central scar that demonstrates high signal intensity on T2-weighted images (14).
At gross examination, fibrolamellar hepatocellular carcinomas are pale tan to yellow, with a central scar present in approximately 75% of cases (2). Unlike classic hepatocellular carcinoma, however, the background liver is not usually fibrotic or cirrhotic in fibrolamellar hepatocellular carcinoma (15). Histologic analysis of fibrolamellar hepatocellular carcinoma typically shows large polygonal cells with prominent eosinophilic cytoplasm, large vesiculated nuclei, and large nucleoli against a background of lamellar fibrosis (2). Immunohistochemistry can be used to help diagnose fibrolamellar hepatocellular carcinoma. These tumors tend to be positive for Hepatocyte Paraffin; cytokeratin 8, 18, and 7; chromogranins; metalloproteinase 2; and several collagens; they tend to be negative for -fetoprotein (2).
Differential diagnoses for the imaging appearance of fibrolamellar carcinoma include focal nodular hyperplasia, a large cavernous hemangioma, and hepatocellular carcinoma.
Focal nodular hyperplasia usually shows homogeneous hypervascular enhancement on hepatic arterial phase images. In addition, in the absence of hemorrhage, the attenuation of focal nodular hyperplasia tends to be similar to that of surrounding liver tissue on unenhanced portal venous images and on delayed phase images (15). Calcification tends to be rare in focal nodular hyperplasia, but it can be seen in up to 68% of cases of fibrolamellar hepatocellular carcinoma (10,11). A central scar is commonly seen in focal nodular hyperplasia, but it tends to be smaller and to have signal characteristics that are not typical for fibrolamellar hepatocellular carcinoma; the scar is usually hyperintense on T2-weighted images (16). Finally, lymphadenopathy is more frequently seen with fibrolamellar hepatocellular carcinoma than it is with focal nodular hyperplasia (10).
Cavernous hemangiomas can have a central scar or necrosis and may occasionally have central calcifications. The enhancement pattern of hemangiomas tends to follow the blood vessels during all phases of enhancement and is peripheral, nodular, and discontinuous, with eventual filling-in on delayed phase images.
Conventional hepatocellular carcinoma usually has substantially different demographics, as well as different clinical and radiologic features. Patients with the fibrolamellar variant of hepatocellular carcinoma do not typically have underlying liver disease. Conventional hepatocellular carcinoma tends to affect older adults and those with underlying chronic liver disease. Fibrolamellar hepatocellular carcinoma is more likely to have a central scar, calcification, and fibrosis, and it is less likely to have necrosis and bleeding (10).
Resectability is the most important prognostic factor affecting the outcome of both hepatocellular carcinoma and fibrolamellar carcinoma (17). The median 5-year survival rate for patients with a resectable fibrolamellar hepatocellular carcinoma is 76%, with a median survival of 112 months; the median 5-year survival rate for patients with nonresectable fibrolamellar carcinoma is 0%, with a median survival of 12 months (17). Other prognostic factors have various effects on outcome and include lymph node metastatic disease, absence of vascular invasion, age at presentation, and normal liver function tests (17).
For conventional hepatocellular carcinoma, resection, chemotherapy, and local ablative techniques have all been proposed as treatments. The current standard, and the only curative approach, however, is surgical resection: Patients with resected hepatocellular carcinoma have a 5-year survival rate of 37%–56% (18). Factors that are associated with a negative prognosis following resection include multiple lesions, lesions that are larger than 5 cm, vascular invasion, -fetoprotein greater than 2000 µg/mL, and positive resection margins (18).
Our patient underwent a trisegmentectomy followed by four cycles of chemotherapy. Ten months after surgery he is disease-free with no evidence of recurrence on CT images.
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Footnotes
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Editor’s Note.—Everyone who has taken the course in radiologic pathology at the Armed Forces Institute of Pathology (AFIP) remembers bringing beautifully illustrated cases for accession to the Institute. In recent years, the staff of the Department of Radiologic Pathology has judged the "best cases" by organ system, and recognition is given to the winners on the last day of the class. With each issue of RadioGraphics, one or more of these cases are published, written by the winning resident. Radiologic-pathologic correlation is emphasized, and the causes of the imaging signs of various diseases are illustrated.
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References
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- Torbenson M. Review of the clinicopathological features of fibrolamellar carcinoma. Adv Anat Pathol 2007;14(3):217–223.[CrossRef][Medline]
- El-Serag HB, Davila JA. Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology 2004; 39(3):798–803.[CrossRef][Medline]
- Craig JR, Peters RL, Edmondson HA, et al. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinicopathologic features. Cancer 1980;46(2):372–379.[CrossRef][Medline]
- Saab S, Yao F. Fibrolamellar hepatocellular carcinoma: case reports and a review of the literature. Dig Dis Sci 1996;41(10):1981–1985.[CrossRef][Medline]
- Hemming AW, Langer B, Sheiner P, et al. Aggressive surgical management of fibrolamellar hepatocellular carcinoma. J Gastrointest Surg 1997;1(4): 342–346.[CrossRef][Medline]
- El-Gazzaz G, Wong W, El-Hadary MK, et al. Outcome of liver resection and transplantation for fibrolamellar hepatocellular carcinoma. Transpl Int 2000;13(suppl 1):S406–S409.[CrossRef][Medline]
- Hany MA, Betts DR, Schmugge M, et al. A childhood fibrolamellar hepatocellular carcinoma with increased aromatase activity and a near triploid karyotype. Med Pediatr Oncol 1997;28(2):136–138.[CrossRef][Medline]
- Agarwal VR, Takayama K, Van Wyk JJ, Sasano H, Simpson ER, Bulun SE. Molecular basis of severe gynecomastia associated with aromatase expression in a fibrolamellar hepatocellular carcinoma. J Clin Endocrinol Metab 1998;83(5):1797–1800.[Abstract/Free Full Text]
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- Friedman AC, Lichtenstein JE, Goodman Z, Fishman EK, Siegelman SS, Dachman AH. Fibrolamellar hepatocellular carcinoma. Radiology 1985; 157(3):583–587.[Abstract/Free Full Text]
- Brandt DJ, Johnson CD, Stephens DH, Weiland LH. Imaging of fibrolamellar hepatocellular carcinoma. AJR Am J Roentgenol 1988;151(2):295–299.[Abstract/Free Full Text]
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- Rummeny E, Weissleder R, Sironi S, et al. Central scars in primary liver tumors: MR features, specificity and pathologic correlation. Radiology 1989; 171(2):323–326.[Abstract/Free Full Text]
- Stipa F, Yoon SS, Liau KH, et al. Outcome of patients with fibrolamellar hepatocellular carcinoma. Cancer 2006;106(6):1331–1338.[Medline]
- Palesty JA, Al-kasspooles M, Gibbs J. Patient selection for surgical management of primary and metastatic liver cancers: current perspectives. Semin Interv Radiol 2006;23(1):13–20.[CrossRef]
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History
Imaging Findings
