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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Hepatology. Author manuscript; available in PMC 2010 December 21.
Published in final edited form as:
PMCID: PMC3005350
NIHMSID: NIHMS250029

Treatment of Fibrolamellar Hepatoma With Subtotal Hepatectomy or Transplantation

Abstract

Fibrolamellar hepatoma (FL-HCC) is an uncommon variant of hepatocellular carcinoma (HCC), distinguished by histo-pathological features suggesting greater differentiation than conventional HCC. However, the optimal treatment and the prognosis of FL-HCC have been controversial. Follow-up studies are available from 1 year to 27 years, after 41 patients with FL-HCC were treated with partial hepatectomy (PHx) (28 patients) or liver transplantation (13 patients). In this retrospective study, the effect on outcome was determined for the pTNM stage and other prognostic factors routinely recorded at the time of surgery. Cumulative survival at 1, 3, 5, and 10 years was 97.6%, 72.3%, 66.2%, and 47.4%. Tumor-free survival at these times was 80.3%, 49.4%, 33%, and 29.3%. The TNM stage was significantly associated with tumor-free survival. Patients with positive nodes had a shorter tumor-free survival than those with negative nodes (P < .015). Patient survival was most adversely affected by the presence of vascular invasion (P < .05). FL-HCC is an indolently growing tumor of the liver, which usually was diagnosed in our patients at a stage too advanced for effective surgical treatment of most conventional HCC. Nevertheless, long-term survival frequently was achieved with aggressive surgical treatment. When a subtotal hepatectomy could not be performed, total hepatectomy (THx) with liver transplantation was a valuable option.

Fibrolamellar hepatoma (FL-HCC) was first described by Edmondson1 as a rare histological variant of hepatocellular carcinoma (HCC). Although several reports have emphasized the indolent growth of this subtype as well as a higher survival than with surgical treatment of conventional HCC, the better postoperative prognosis has been questioned or denied. 2,3

Resolution of this controversy has been hampered by the paucity of long-term follow-up data after surgical therapy for FL-HCC. Exclusive of the 41 patients described herein (some previously reported46), less than 100 such cases can be found in the literature.2,3,717 In our series, we have compared the survival of patients with FL-HCC with that of patients with conventional HCC who were treated by the same team over a 27 -year period.

PATIENTS AND METHODS

Case Material

Between 1968 and 1995,477 patients with hepatoma underwent hepatic resection or orthotopic liver transplantation (OLT). Forty-one (8.9%) of the 477 patients had FL-HCC. Four were treated at the University of Colorado (before 1980), and the remaining 37 at the University of Pittsburgh Medical Center. There were 23 males and 18 females. The 41 patients were 29.5 ± 13.7 (SD) years old (range, 9–66; median, 25) (Fig. 1). The median follow-up was 58 ± 9.3 months.

FIG. 1
HCC-FL: age and gender distribution by decades of age. (An external file that holds a picture, illustration, etc.
Object name is nihms250029ig1.jpg) All patients; (■) male patients; and (□) female patients.

Clinicopathological Characteristics

The pathology reports and operative findings were used to determine: the principal tumor size, number of lesions, lobar distribution, vascular and lymphatic tumor extension, surgical margins, distant metastases, and the presence or absence of associated cirrhosis. When available, the tumor markers were recorded as well as the virus markers (hepatitis C virus, hepatitis B virus).

Staging was with the pTNM classification proposed by the International Union Against Cancer and the American Joint Committee on Cancer.18,19 Thirty-seven of the 41 patients had stage IV tumors at the time of surgery (Table 1).

TABLE 1
Patient Distribution According to pTNM Stage

Surgical Procedures

Partial hepatectomy (PHx) was the procedure of choice. Total hepatectomy (THx) and OLT were performed when tumor extension or the presence of underlying liver disease precluded PHx. Both PHx and THx were frequently performed under highly unfavorable conditions, such as lymph node involvement and/or direct invasion of tumor into the adjacent organs.4

Subtotal Hepatectomy (PHx)

In 8 of the 28 patients, resection included one or more surrounding organs in an attempt to secure tumor-free margins. The types of PHx performed in this group are summarized in Table 2, using surgical techniques that have been described elsewhere.20,21

TABLE 2
Surgical Treatment of FL-HCC

THx and OLT

In 6 of these 13 patients, the THx was extended to adjacent organs (Table 2). Two patients had upper abdominal exenteration and organ cluster transplantation.22,23 In 1 patient, OLT was combined with pancreaticoduodenectomy (Whipple procedure). The surgical techniques for OLT and the immunosuppression used thereafter have been described elsewhere.2226 Immunosuppression was with cyclosporine and prednisone (n = 9), imuran and prednisone (n =1), or tacrolimus and prednisone (n = 3).

Adjuvant Therapy

Sixteen patients received adjuvant radiotherapy or chemotherapy before and/or after surgery (Table 3). These regimens were highly variable in the long period of the study. Adriamycin ± Cis-Platinum were most commonly used.

TABLE 3
Adjuvant Therapy in Patients with FL-HCC

Statistical Analysis

Cumulative overall survivals and tumor-free survivals were calculated by the method of Kaplan-Meier with adjustment for types of surgery (OLT vs. PHx).27 Potential risk factors studied by univariate analysis were tumor size, number of lesions, lobar involvement, vascular invasion, lymph node invasion, distant metastases, pTNM stage, surgical margins, and adjuvant chemotherapy. P < .05 was considered significant. The small number of patients with different potential risk factors precluded multivariate analysis.

RESULTS

Pathological Characteristics

Tumor Size, Number, and Lobar Distribution

The principal tumors had a median diameter of 13 cm (mean ± SD = 12.4 ± 4.3 cm) with a range between 3 to 25 cm. Thirty patients (73%) had a single tumor. The remaining 11 patients (27%) had two or more lesions. The tumor(s) was bilobar in 30 patients (73%). The tumor(s) involved only the left lobe in 7 patients and the right lobe in 4 (Tables 4 and and55).

TABLE 4
Tumor-Free Survival
TABLE 5
Patient Survival

Vascular Invasion

Ten patients (24.4%) had no evidence of vascular invasion (V0), 21 (51.2%) had microvascular invasion (V1). and 10 (24.4%) had gross vascular invasion (V2) (Tables 4 and and5).5). The main branch of the portal vein or the portal vein trunk was involved in 7 of the 10 cases with V2. There was one example of inferior vena cava invasion, and two of the hepatic vein.

Margins

The margins of resection were free of tumor (R0) in 34 cases. The margins of resection were microscopically positive (R1) in 4 other patients and grossly positive (R2) in the remaining 3 (Tables 4 and and55).

Metastases

Thirteen patients (31.7%) had regional meta-static disease (M1) at the time of surgery (Tables 4 and and5),5), which was resected in continuity with the principal tumor (Table 6).

TABLE 6
Sites of Metastatic Lesions of FL-HCC at the Time of Surgery

Cirrhosis, Tumor Markers, and Serology

Three patients in the OLT group had associated cirrhosis (7.3%). One of these patients is alive 120 months after OLT, 1 died with tumor recurrence at 25 months, and the third patient died at 66 months with tumor recurrence.

Nineteen patients were tested for α-fetoprotein, with only 2 (10.5%) elevations. However, all of the 10 patients tested for Des-γ-carboxy prothrombin28 had elevated serum levels despite normal levels of α-fetoprotein.

Of the 30 patients tested for hepatitis B virus, none had a positive serology. The positive rate for hepatitis C virus was 1 of 17 tested.

TNM Stage

The pTNM stages of the 41 patients are summarized in Tables 1 and and4;4; 90.2% presented with pTMN stage IVA or IVB. One of the 2 patients with stage II was transplanted for decompensated cirrhosis; the FL-HCC was an incidental finding in the surgical specimens.

Survival Rate

There were no deaths within 6 months after either PHx or OLT. Thereafter, survival after PHx was consistently superior, and, at 5 years, the gap was 44% (Fig. 2). However, because the conditions dictating the use of THx and OLT were different than those for PHx, comparison of survival with these therapeutic modalities has little value. Of the 18 patients who died after the surgical treatment, 16 died from causes related to the tumor occurrences. Two patients, both in the OLT group, died from sepsis.

FIG. 2
FL-HCC: patient survival after PHx and THx with OLT.

The cumulative survival and the tumor-free survival of the combined cohorts are shown in Fig. 3. The mean cumulative survival was 126.93 ± 16.34 (SE) months. The mean tumor-free survival was 86.93 ± 15.24 (SE) months. The cumulative survivals and the tumor-free survivals, stratified according to the pTNM stages, are shown in Table 7. The differences in the cumulative survivals and tumor-free survivals among the pTNM stages were statistically Significant (Table 7).

FIG. 3
FL-HCC: cumulative overall patient and tumor-free survival after surgery
TABLE 7
Cumulative and Tumor-Free Survivals According to pTNM Stages

Prognostic Factors

The influence of nine clinicopathological factors on tumor-free and overall survivals were examined by univariate analysis (Tables 4 and and5).5). The involvement of regional lymph nodes (N1), the presence of metastasis (M1), and advanced pTNM stage were statistically significant prognostic factors reducing tumor-free survivals. Although these factors did not individually influence the overall survival at a statistically significant level, survival of the patients with Stage IVB was significantly lower than that of those with stages II and III combined (P < .05) (Table 7). The presence of macrovascular invasion of the tumor was a statistically significant prognostic factor reducing overall survival, but it did not influence tumor-free survival. Unexpectedly, adjuvant chemotherapy tended to decrease the tumor-free survival (Tables 4 and and55).

Tumor Recurrence and Treatment

Recurrence of FL-HCC was confirmed in 27 (65.8%) of the 41 patients during the study period: 18 (64.2%) of the 28 treated with PHx and 9 (69.2%) of the 13 treated with THx and OLT. The time and site of tumor recurrence, treatment used for recurrence, and survival after diagnosis are summarized in Table 8. The liver was the organ most often involved, followed by the lungs and intra-abdominal lymph nodes.

TABLE 8
Time and Site of Recurrence, Treatment of Recurrence, and Survival After the Diagnosis of Recurrence

Attempts at re-resection were made in 6 patients whose original surgery was PHx, and 3 who already had undergone THx and OLT. The secondary surgeries ranged from minor procedures to the drastic step of complete liver replacement in 3 cases, followed by survival of 2, 12, and 30 months (Table 8). After the diagnosis of tumor recurrence, the 18 patients initially treated with PHx lived for 1 to 80 months; the 9 first treated with OLT lived for 0 to 43 months. The overall actuarial postrecurrence survival in the combined group (n = 27) at 1, 3, and 5 years was 75%, 48%, and 28%, respectively (Fig. 4). The survival of the 9 patients whose recurrence was treated by surgical resection with or without combined chemotherapy was slightly better than that of the 13 patients who were treated with chemotherapy alone, but the difference was not statistically significant.

FIG. 4
Patient survival after recurrence. (An external file that holds a picture, illustration, etc.
Object name is nihms250029ig2.jpg) All patients (n = 28); (An external file that holds a picture, illustration, etc.
Object name is nihms250029ig3.jpg) surgery (n =9) and (An external file that holds a picture, illustration, etc.
Object name is nihms250029ig4.jpg) chemotherapy (n =13).

Five-Year Survivors

Of the 31 patients treated more than 5 years ago, 19 (61.3%) achieved actual survival of at least 5 years; 15 (75%) of the 20 patients in the hepatic resection group and 4 (36.3%) of the 11 treated with OLT (Table 9 and Fig. 2). All 4 patients with tumor stage II or III survived for more than 5 years compared with 12 (63.1%) of the 19 with tumor stage IVA, and only 3 (37.5%) of 8 with tumor stage IVB. One of the 3 long survivors in the IVB group died after 7 years; the other 2 are alive with tumor after 7 and 9 years (PHx 10 and 14) (Table 9). The time of survival postrecurrence in these unusual cases has been 6.67 and 4.33 years.

TABLE 9
List of 19 Five-Year Survivors

DISCUSSION

FL-HCC was first identified by its unique histological features1 and distinctive clinical behavior.1,7 In our study (see Fig. 1), as well as in collected cases from the literature, FL-HCC showed a unimodal age distribution with the peak in the third decade. In contrast, common HCC has a bimodal age distribution when it occurs in the noncirrhotic liver with the peaks in the third and in the sixth decade,29,30 and a unimodal peak in the fifth or sixth decade when cirrhosis is present.30 The conventional HCC is more frequent in males than females, but the FL-HCC is found almost equally in females (44% in our series). FL-HCC is rarely found in the cirrhotic liver,3,5,9 as was exemplified by only 3 (7.3%) of the 41 cases reported herein.

The tumor markers of FL-HCC have a characteristic pattern. In our series, only 10.5% of the patients tested had elevated serum α-fetoprotein levels, while the Des-γ-carboxy prothrombin serum level was elevated in all who were tested. The Des-γ-carboxy prothrombin level also identified tumor recurrence, whereas the AFP did not. High levels of neurotensin and vitamin B12 binding capacity also have been reported with FL-HCC,11,13,31 but these were not determined in our cases.

The indolent growth of FL-HCC and an excellent long-term survival after surgery was first emphasized by Craig et al.7 and by Berman et al.8 in 1980, based largely on cases collected from the literature. Although Nagorney et al. were the first to question the prognostic Significance of this diagnosis in 1985,2 our report 1 year later4 contained evidence that patients with FL-HCC were excellent candidates for aggressive surgery. Since then, the clinical Significance of a histopathological diagnosis of FL-HCC has been debated among investigators, analyzing small numbers of their own cases in combination with reviews of the literature. Some authors have not found the diagnosis of FL-HCC to confer a survival advantage.3,14 but others confirmed the original claims. 11,12,17

The 41 patients with FL-HCC reported herein of whom 31 were operated upon more than 5 years ago constitute the largest series with the longest follow-up known to exist. The cases were accrued over a 3-decade period by a Single group of surgeons committed to aggressive treatment of these neoplasms. Despite the fact that 90% of tumors presented with pTNM stage IVA or IVB, our overall actuarial survival was 66.2% at 5 years and 47.4% at 10 years. The higher survival compared with that reported by others 2,3 could be explained in part by our wide use of extensive hepatic resection (including adjacent structures) at the original surgery, and an aggressive surgical approach to the recurrent tumors.

However, the most important factor obviously was the biological behavior of FL-HCC, the results with which can be compared with our contemporaneous experience with conventional HCC. In patients with HCC in noncirrhotic liver, 5-year global survival was 43.7% after hepatic resection and 26% after transplantation.6 However, the 5-year survival when the HCC was stage IVA was only 16.8% after PHx and 10.9% after OLT,6 similar to the experience of others.3238

The indolent growth of FL-HCC was especially obvious when recurrences developed. Even after the diagnosis of tumor recurrence, survival was 75% at 1 year, 48% at 3 years, and 28% at 5 years (Fig. 4). Surgical excision of recurrent tumor with or without chemotherapy may have prolonged survival, but, if so, only minimally. Cytoreductive chemotherapy was clearly ineffective. Adjuvant chemotherapy from the outset did not improve survival. However, the impression that it may have been harmful (see Tables 4 and and5)5) reflected in part the selection for chemotherapy of patients with advanced tumor stage. Of the 16 patients who received adjuvant chemotherapy, 6 had stage IVA and 10 had stage IVB tumor. Eleven patients had positive lymph nodes, and 15 patients had vascular invasion by the tumor.

Because of the limited number of cases at stages II and III, a conventional analysis of stratification-specific prognostic factors could not be performed. However, the good results obtained with hepatic resection or transplantation for FL-HCC that was staged at IVA or IVB in >90% of cases can be construed as evidence of the indolent growth, favorable natural behavior, and suitability for aggressive treatment of these tumors.

In conclusion, the therapeutic approach that we recommend for FL-HCC is wide hepatic resection including the adjacent structures if they are invaded by the tumor. PHx is the treatment of choice if at least one liver segment can be saved. If the presence of underlying liver disease or the location of the tumor preclude PHx, THx with OLT should be considered. Adjuvant chemotherapy so far has not shown any benefit in patient survival and tumor-free interval. An aggressive surgical approach of tumor recurrences after primary treatment can extend the patient survival.

Acknowledgment

The authors thank Dr. Mohamed A. Virji for his assistance in compiling the data on blood tumor markers, and advice on their interpretation.

Supported by Project Grant DK 29961 from the National Institutes of Health, Bethesda, MD.

Abbreviations

FL-HCC
fibrolamellar hepatoma
HCC
hepatocellular carcinoma
OLT
orthotopic liver transplantation
PHx
partial hepatectomy
THx
total hepatectomy

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