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Gastrointestinal Imaging |
1 From the Departments of Radiology (T.I., M.P.F., L.G.) and Surgery (W.M.), University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213-2582; and the Department of Radiology, Yamanashi Medical University, Japan (T.I.). Received October 26, 1999; revision requested December 7; revision received January 4, 2000; accepted January 27. Address correspondence to M.P.F. (e-mail: federlemp@radserv.arad.upmc.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Thirty-one patients with fibrolamellar HCC underwent pretherapy computed tomography (CT); 11 underwent pretherapy magnetic resonance (MR) imaging. All 40 patients underwent posttherapy CT; four, follow-up MR imaging. Imaging, surgical, and histopathologic findings were correlated.
RESULTS: Twenty-five (81%) patients had solitary tumors (mean maximum diameter, 13 cm). Thirteen (42%) patients had intrahepatic biliary obstruction; 27 (87%) patients had involvement of the portal or hepatic veins. Thirteen (42%) had extrahepatic tumor spread, nine (29%) had distant metastases on pretherapy images, and 20 (65%) had lymphadenopathy. Thirty-two (80%) of 40 patients underwent exploration surgery; curative resection was attempted in 25 (62%), including four patients who underwent liver transplantation. Only 17 patients were considered to have had hepatic and extrahepatic tumors completely excised. Tumor recurred in all eight of the 17 patients who had extrahepatic disease at pretherapy CT and in four of the seven patients who seemed to have tumor limited to the liver. A combination of repeat tumor resection and adjuvant chemotherapy resulted in prolonged tumor-free survival in some cases.
CONCLUSION: Fibrolamellar HCC frequently demonstrates aggressive local invasion and nodal and distant metastases. Pretherapy and follow-up imaging are important for staging, surveillance, and optimal management. Aggressive surgical resection may be helpful to control fibrolamellar HCC and to prolong survival in appropriately selected cases.
Index terms: Liver neoplasms, CT, 761.12113, 761.12114, 761.12115 • Liver neoplasms, MR, 761.121411, 761.12143 • Liver neoplasms, staging, 761.323, 761.324 • Liver neoplasms, therapy, 761.1267, 761.323, 761.324
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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In, to our knowledge, the largest (41-patient) study with published findings of fibrolamellar HCC treated by the same team of physicians over 27 years, the authors found that the TNM stage of the fibrolamellar HCC was significantly associated with tumor-free survival (12). Patients who had tumor invading lymph nodes, adjacent viscera, or blood vessels had shorter survival than patients who had tumor limited to the liver and free of vessels. These authors (12) stressed the need for aggressive surgical treatment of all hepatic and adjacent disease whenever feasible and the potential benefit of surgical excision of recurrent tumor.
Others and we have described various computed tomographic (CT) and magnetic resonance (MR) imaging features of fibrolamellar HCC that appear to be characteristic and that may allow distinction from other types of liver tumors (13,14). However, to our knowledge, there have been few published reports on the prevalence of advanced hepatic and extrahepatic involvement by fibrolamellar HCC (15). We conducted this review of our patients with fibrolamellar HCC to determine these features, along with their effect on immediate surgical management and tumor recurrence.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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-fetoprotein levels were elevated in only three patients, while serum neurotensin levels were abnormally elevated in two of the three patients tested. Evidence of hepatitis C infection was established in only one patient, while none had serum markers for hepatitis B infection. All patients had histopathologic proof of fibrolamellar HCC in percutaneous 20- or 18-gauge core-needle biopsy specimens; the 32 patients who underwent surgery had histopathologic proof in specimens obtained at laparotomy and/or resection. The tumors were composed of cords, sheets, and pseudoglands of polygonal hepatocyte-like cells separated by irregularly arranged fibrolamellar bands of dense collogen.
All patients underwent pretherapy CT evaluation, but only 31 patients underwent dynamic incremental or helical CT after the injection of a bolus of contrast material. All 40 patients had postoperative or posttherapy CT scans available for review.
Of the 31 patients with contrast material–enhanced pretherapy CT scans, 10 had conventional nonhelical nonenhanced and contrast-enhanced scans; 21 had multiphase helical CT scans of the liver, which consisted of nonenhanced scans followed by hepatic arterial dominant phase and portal venous dominant phase images obtained during the bolus infusion (4–5 mL/sec) of 120–150 mL of iodinated contrast medium (either iothalamate meglumine or ioversol [Conray 60 or Optiray 350, respectively, Mallinckrodt Medical, St Louis, Mo]). Hepatic arterial dominant phase and portal venous dominant phase imaging was initiated with a scanning delay of 25 and 60 seconds, respectively. All helical CT scans were obtained with a commercial CT scanner (HiSpeed Advantage; GE Medical Systems, Milwaukee, Wis) by using a section thickness of 5 or 7 mm and a pitch of 1 to 1.5, which are sufficient to scan the entire liver in one breath hold.
The 10 patients who underwent conventional transverse CT evaluation had scans obtained after a bolus infusion of 150 mL of contrast medium at 2.5–3.0 mL/sec and a section thickness of 7 mm (Hilight Advantage, GE Medical Systems). Conventional (nonhelical) scanning was initiated in a cephalocaudal direction with an initial scanning delay of 50 seconds. A series of clustered scans was obtained during breath hold through the liver, with scanning completed within 60 seconds (50–110 seconds total).
All 11 patients who underwent pretherapy MR imaging examinations and the four who underwent follow-up MR imaging had imaging sequences that included T1-weighted spin-echo imaging (140–700/12–20 [repetition time msec/echo time msec]) and T2-weighted spin-echo (n = 4) or fast spin-echo (n = 7) imaging (4,000–9,230/70–140, echo train length of eight or 16). Fat-suppression techniques were not used.
Nine of the 11 patients who underwent pretherapy imaging had imaging sequences repeated following contrast material administration, including five patients who received gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ) at a dose of 0.1 mmol per kilogram of body weight. Four of the five patients who received gadopentetate dimeglumine underwent biphasic MR imaging during the hepatic arterial dominant (25-second delay) and portal venous dominant (60–70-second delay) phases. Three of the 11 patients underwent repeated MR imaging following the intravenous administration of mangafodipir trisodium (Teslascan; Nycomed-Amersham, Princeton, NJ) at a dose of 5 µmol/kg. One pretherapy patient underwent MR imaging before and after intravenous administration of gadobenate dimeglumine (MultiHance; Bracco, Milan, Italy) at a dose of 0.1 mmol/kg.
The T1- and T2-weighted sequences used were the same regardless of which contrast agent was used. All MR examinations were performed by using 1.5-T imagers (Signa; GE Medical Systems) and a variety of software upgrades that continuously evolved over the period of the study.
The timing of posttherapy CT and MR imaging was not uniform for various reasons. Some patients had relatively "early" repeat CT or MR evaluations (at 1–14 days) because of acute symptoms or signs (eg, fever, abnormal liver function test results), while others had uneventful posttherapy courses. Many patients received only episodic care at our institution and received their primary and follow-up care in their home communities. We were able to follow the clinical course of all patients for a minimum of 6 months and were able to follow up most patients until their death (n = 19) or for a mean interval of 4 years (follow-up range, 6 months to 9 years).
All CT and MR images were interpreted independently by two radiologists (T.I., L.G.) in a retrospective fashion with knowledge of the diagnosis of fibrolamellar HCC but without knowledge of specific clinical, surgical, or histopathologic findings. In cases of interobserver disagreement, final decisions were reached by consensus. Because we were not attempting to determine the sensitivity or specificity of CT and because only minor variations in interpretation were noted between the two readers, we did not calculate 
statistics for the interobserver difference.
The features that we evaluated included the number, size, and distribution of tumors. We tried to correlate all tumor characteristics that were shown at CT or MR imaging with those found at surgical exploration or pathologic analysis.
The imaging features that were of particular interest in this study were those that we considered as "aggressive" and that have been cited by other investigators as indicating a relatively poor prognosis (12,15). These included vascular involvement, extrahepatic tumor extension, lymphadenopathy, intrahepatic metastases (satellite lesions), and intrahepatic biliary dilatation. Vascular involvement was judged as either tumor thrombus (distending the vessel or showing contrast medium enhancement) or compression or occlusion (vessel narrowed or occluded by the contiguous tumor). Vascular involvement was further classified as that of the main, right, or left portal vein; the right, left, or middle hepatic vein; or the inferior vena cava (IVC). Extrahepatic tumor extension was defined as contiguous spread to an adjacent organ, with obliteration of an intervening fat plane and distortion of the visceral contour, or hematogenous metastases to the lung or other organs. Lymphadenopathy was defined as lymph nodes greater than 1 cm in the short axis in any of the upper abdominal or thoracic locations. Hepatic metastases were satellite masses in the liver in addition to the primary or largest hepatic mass. Biliary dilatation indicated visible intrahepatic bile ducts peripheral to a hepatic mass.
The 40 patients who underwent posttherapy CT and/or MR evaluation had their images reviewed for the same aggressive intra- and extrahepatic criteria. In addition, any recurrent hepatic mass was evaluated for tumor features that have been described (12,13) as characteristic for primary fibrolamellar HCC, which include the presence of a central or eccentric scar and calcification, in addition to tumor size, number, and location. CT features of recurrent tumors were also compared with those of untreated tumors.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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The 31 patients who underwent contrast-enhanced pretherapy CT (n = 31) or MR imaging (n = 11) had the following aggressive tumor findings. Intrahepatic biliary dilatation was found in 13 patients (42%) and was judged subjectively to be slight in eight, moderate in two, and marked in three. In two of the three patients with marked biliary dilatation, a biliary stent was placed to help relieve obstructive jaundice.
Compression, occlusion, or invasion of major hepatic vessels was noted in 27 patients (87%). The main portal vein or its major branches were compressed or obstructed in 25 patients (Fig 1): the main portal vein in nine patients, the right portal vein in 13 patients, and/or the left portal vein in 14 patients. Two patients had involvement of both right and left portal venous branches. Three patients had portal venous tumor thrombus that caused distention of the lumen and contrast medium enhancement of the thrombus. The IVC or one of the three main hepatic veins was compressed, occluded, or invaded by tumor in 20 patients. The IVC was compressed by tumor in 13 patients and had intraluminal thrombus in three patients (Fig 2). Hepatic venous involvement included the right hepatic vein in 12 patients, the middle hepatic vein in 13 patients, and the left hepatic vein in 14 patients. One patient had tumor thrombus within the right hepatic vein. The presence of tumor thrombus was confirmed histopathologically in all patients except for one of the patients with IVC thrombus.
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Extrahepatic distant metastases, including lung (n = 5) and adrenal (n = 4) involvement, were found in nine (29%) of the 31 patients with pretherapy contrast-enhanced studies. Lymphadenopathy was found in 20 of the 31 patients (65%) (Fig 3) at the hepatic hilum (n = 16), hepatoduodenal ligament (n = 15), other intraabdominal sites (n = 9), and retroperitoneum (n = 10). Three patients had nodal spread beyond the abdomen to the pelvic, cardiophrenic, and mediastinal nodes in one patient each.
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Of the 32 patients who underwent surgery, four underwent orthotopic liver transplantation and 16 underwent attempted resection soon after diagnosis with no adjuvant therapy before surgery. Before surgery, 12 patients received neoadjuvant chemotherapy (two to 18 courses), with systemic intravenous administration, selective hepatic arterial administration, or both. Of the 32 patients who underwent surgery, tumor resection was not performed in seven (22%) because of various factors, which included diffuse liver metastases (n = 2), IVC thrombus (n = 1), peritoneal dissemination and IVC thrombus (n = 1), adrenal and nodal metastases (n = 1), and severe lymph node metastases (n = 2) that could not be resected completely.
Curative resection was attempted in 25 of the 32 patients (78%), which constitutes 62% (25 of 40) of all patients with fibrolamellar HCC whom we evaluated. Four of these 25 patients underwent orthotopic liver transplantation, and 13 underwent partial hepatic resection along with resection of involved lymph nodes. In the eight remaining patients, the primary hepatic tumor was resected, but the surgery was deemed palliative because tumor was known to be left in various sites, which included the liver (n = 2), liver and peritoneum (n = 1), lymph nodes and adrenal gland (n = 1), lymph nodes (n = 2), and lung metastases (n = 2).
Among the 17 patients with a curative resection, seven had tumor limited to the liver, while the remaining 10 had extrahepatic tumors that included lymph node metastases (n = 10), cardiophrenic lymphadenopathy (n = 1), and IVC tumor thrombus (n = 1).
Correlation between preoperative imaging and surgical findings was limited by our inability to correlate specific hepatic, nodal, or vascular lesions when these were multiple. Nevertheless, in all patients in whom CT or MR imaging demonstrated multiple lymph nodes larger than 1 cm in short axis diameter who underwent nodal resection, at least one node was found to have metastatic fibrolamellar HCC at histopathologic examination. Some lymph nodes were enlarged because of reactive hyperplasia.
In all seven patients in whom CT or MR imaging demonstrated major intravascular tumor, this was confirmed at surgery or histopathologic analysis (six patients, including three with portal venous, two with IVC, and one with hepatic venous tumor) or with clinical and imaging follow-up (one with IVC tumor). Vessel compression or occlusion was difficult to differentiate at imaging and to prove at surgery or histopathologic analysis because the surgeons frequently performed meticulous dissection ("skeletonization") of vessels near the porta hepatis in spite of adjacent tumor and because the status of major hepatic vessels deep within resected hepatic lobes was not always described in sufficient detail in pathology reports.
In general, direct local invasion and peritoneal seeding were more evident at surgery than at preoperative imaging. In only two of the 12 patients with ascites did CT demonstrate definite peritoneal tumor, while 10 of these 12 patients had carcinomatosis at surgery.
Posttherapy Imaging and Follow-up Findings
All 17 patients who underwent curative resection underwent subsequent CT (n = 17) and/or MR (n = 4) evaluation, with a mean follow-up period of 4 years (range, 6 months to 9 years). Twelve patients (71%) had recurrent or metastatic disease. With preoperative CT or MR evaluation as the standard of reference, recurrence was found in four of the seven patients who were judged to have had tumor only within the liver and in all eight patients who had extrahepatic tumor (Figs 3, 4). One of the four patients who underwent liver transplantation had tumor recurrence within the transplanted liver and lymph nodes.
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Additional surgical therapy was attempted in some patients with recurrent or metastatic tumor. Two patients with isolated hepatic tumor recurrence underwent repeated hepatic resection, with no subsequent evidence of recurrence at the time this article was written. One patient had two recurrent hepatic lesions and underwent surgical resection but developed lung metastases 24 months later. Another patient with multiple hepatic recurrent lesions was treated with intraarterial chemotherapy, with slow progression of disease. One other patient with recurrence apparently limited to the liver was being considered for liver transplantation at the time this article was written. The patient with the 16-cm lymph node metastases underwent attempted curative resection of the mass but had adrenal and lymph node recurrence 27 months later. The remaining six patients received chemotherapy or supportive therapy alone because of extensive extrahepatic metastases.
The four patients with pulmonary metastases had between two and 10 nodules at the lung bases. Thoracoscopic surgical resection of all or some of the lesions was attempted for palliation and for confirmation of metastases. Three of these four patients had disease recurrence apparently limited to the lungs. Metastatic disease was confirmed, and additional lung and nodal recurrences developed within 12–30 months.
The appearance of the recurrent hepatic masses was compared with that of untreated fibrolamellar HCC. Seven patients had intrahepatic recurrence: multiple lesions in four patients and solitary lesions in three. All tumors were hypoattenuating to liver on nonenhanced CT images and were heterogeneously enhancing, with areas of hypervascularity evident in five of the seven patients (Fig 4). Central scar was present in four of the seven patients, but only one of the four had calcification. One other patient had a tumor with massive intratumoral hemorrhage evident on CT and MR images.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Stevens et al (15) reported on the Mayo Clinic experience in 10 patients with fibrolamellar HCC who received aggressive surgical management in spite of imaging features that would generally be regarded as indicating unresectability. Because surgeons may attempt curative resection in patients with advanced disease, they emphasized the importance of accurate imaging to assess not only the intrahepatic disease but also the extent of local and distant metastases.
Our experience with 40 patients with fibrolamellar HCC reinforces the impressions and recommendations of the Mayo Clinic investigators (15). We found that contrast-enhanced CT, particularly helical multiphase CT, allowed excellent characterization and staging of fibrolamellar HCC. MR imaging seems to provide similar information (16), accurately depicting hepatic involvement, although evaluation for distant metastases and lymph node involvement might be more challenging and expensive with MR imaging.
At the time of presentation or referral to our institution, most patients had a large primary hepatic tumor (mean, 13 cm) and 19% had multiple hepatic masses. Dilatation of intrahepatic bile ducts was seen in 42% of our patients. Portal venous, hepatic venous, or even IVC involvement was found in more than 80% of our patients at pretherapy evaluation, and seven patients had intraluminal tumor thrombus. It is apparent that vascular and biliary invasion can occur in patients with fibrolamellar HCC, although these invasive features have been regarded as more characteristic of conventional HCC. Our experience suggests that CT and MR imaging accurately demonstrate major vascular tumor thrombi. Distinction of vascular compression from actual encasement or obstruction is more difficult and may not constitute an absolute contraindication to attempted surgical resection.
Local extrahepatic tumor spread, including invasion of adjacent organs, was seen in 42% of our patients with pretherapy contrast-enhanced CT scans. Ascites was present in 39% of the patients with pretherapy contrast-enhanced CT scans, although it was difficult to diagnose peritoneal tumor dissemination with CT or MR. Extrahepatic distant metastases, including lung, adrenal, and thoracic nodal disease, were found in 29% of our pretherapy evaluations. Abdominal lymphadenopathy was encountered in 65% of our preoperative evaluations and was confirmed at surgery in all patients.
In spite of these ominous CT features, 32 of our 40 patients (80%) underwent abdominal surgical exploration and 25 (62%) underwent attempted curative resection. In 17 patients, the surgeons believed they had resected all apparent tumor, whether limited to the liver or also involving upper abdominal lymph nodes. In eight patients, only palliative resection was possible because of unresectable tumor outside the liver. Four patients were treated with orthotopic liver transplantation, either because of otherwise unresectable tumor limited to the liver or because of fibrolamellar HCC that occurred within an end-stage cirrhotic liver.
The rationale for successful or failed attempts at resection of advanced fibrolamellar HCC may not be readily apparent. In patients with obvious distant metastases, surgery to treat major vessel tumor thrombosis or peritoneal carcinomatosis is generally futile. However, pretherapy imaging is not always successful in distinguishing vessel invasion and mere compression and usually fails to demonstrate peritoneal tumor implants. Conversely, the apparent presence of perihepatic tumor invasion or lymphadenopathy indicates neither definite extrahepatic malignancy nor unresectable disease. In many such cases, meticulous dissection resulted in no apparent residual tumor.
The clinical and radiologic features of our cases seem very similar to those reported by the Mayo Clinic group (15), while being more advanced than those reported by other investigators (4–6,9,10) (see Table). Perhaps this reflects the tertiary referral nature of our institutions. Nevertheless, it is apparent that fibrolamellar HCC is a deadly disease with a high rate of recurrence, even after aggressive surgical therapy. All of the patients we and others have examined who have had extrahepatic disease at the time of resection have had recurrent or metastatic disease documented.
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Tumor recurred within 3–25 months (all sites) and often changed dramatically in size within several months. Intrahepatic and nodal masses up to 16 cm in size developed between CT examinations performed 12 months apart. We agree with recommendations (15) that patients be followed up with CT every 2–4 months for at least 12–18 months after initial resection of fibrolamellar HCC. We recommend that follow-up CT scans include the thorax for the detection of pulmonary or mediastinal nodal metastases.
There would be little reason for close surveillance of patients with fibrolamellar HCC if therapy were totally ineffective. In spite of its aggressive nature, however, fibrolamellar HCC has a reported 5-year survival rate of 25%–30% and up to 63% in patients whose tumors are resected (9–12). In the largest study (12) we know of, with follow-up of 1–27 years, the cumulative survival rates at 1, 3, 5, and 10 years were 97.6%, 72.3%, 66.2%, and 47.4%, respectively. The tumor-free survival rates at these times were 80.3%, 49.4%, 33%, and 29.3%, respectively. The investigators (12) emphasized the need for accurate tumor staging and an aggressive surgical approach, which included transplantation, for resectable disease. They reported a significantly shorter tumor-free survival rate in those with vascular invasion or lymphadenopathy. An aggressive surgical approach toward tumor recurrence after primary treatment can also extend patient survival time (12,15).
Our results suggest that current CT and MR techniques allow accurate assessment of major hepatic vascular invasion and lymphadenopathy and are useful for both initial assessment and surveillance for recurrence. We stress that fibrolamellar HCC is a deadly disease, although it has a better prognosis than conventional HCC. Optimal management of fibrolamellar HCC requires accurate and specific diagnosis and staging of the primary hepatic tumor, as well as of the involvement of extrahepatic tissues, lymph nodes, and distant metastases. Many, but not all, patients may benefit from attempted curative resection of the initial tumor, as well as recurrences.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, T.I., M.P.F.; study concepts and design, T.I., M.P.F.; definition of intellectual content, T.I., M.P.F.; literature research, T.I.; clinical studies, T.I., L.G., W.M.; data acquisition and analysis, T.I., L.G.; manuscript preparation, T.I., M.P.F.; manuscript editing and review, M.P.F.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  Z.-H. Fan, M.-H. Chen, Y. Dai, Y.-B. Wang, K. Yan, W. Wu, W. Yang, and S.-S. Yin Evaluation of primary malignancies of the liver using contrast-enhanced sonography: correlation with pathology. Am. J. Roentgenol., June 1, 2006; 186(6): 1512 - 1519. [Abstract] [Full Text] [PDF]
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