Abstract
OBJECTIVES:
Fibrolamellar hepatocellular carcinoma is a rare primary malignant liver tumor that differs from conventional hepatocellular carcinoma in several aspects. The aim of this study was to describe the clinical, surgical and histopathological features of fibrolamellar hepatocellular carcinoma and to analyze the factors associated with survival.
METHODS:
We identified 21 patients with histopathologically diagnosed fibrolamellar hepatocellular carcinoma over a 22-year period. Clinical information was collected from medical records and biopsies, and surgical specimens were reviewed.
RESULTS:
The median age at diagnosis was 20 years. Most patients were female (67%) and did not have associated chronic liver disease. Most patients had a single nodule, and the median tumor size was 120 mm. Vascular invasion was present in 31% of patients, and extra-hepatic metastases were present in 53%. Fourteen patients underwent surgery as the first-line therapy, three received chemotherapy, and four received palliative care. Eighteen patients had “pure fibrolamellar hepatocellular carcinoma,” whereas three had a distinct area of conventional hepatocellular carcinoma and were classified as having “mixed fibrolamellar hepatocellular carcinoma.” The median overall survival was 36 months. The presence of “mixed fibrolamellar hepatocellular carcinoma” and macrovascular invasion were predictors of poor survival. Vascular invasion was associated with an increased risk of recurrence in patients who underwent surgery.
CONCLUSION:
Fibrolamellar hepatocellular carcinoma was more common in young female patients without chronic liver disease. Surgery was the first therapeutic option to achieve disease control, even in advanced cases. Vascular invasion was a risk factor for tumor recurrence. The presence of macrovascular invasion and areas of conventional hepatocellular carcinoma were directly related to poor survival.
Fibrolamellar hepatocellular carcinoma; Liver cancer; Liver neoplasms; Hepatocellular carcinoma (fibrolamellar variant)
INTRODUCTION
Fibrolamellar hepatocellular carcinoma (FLHCC) was first described by Edmondson in
1956 as “a rare, distinct form of primary hepatocellular carcinoma”
(11 Edmondson HA. Differential diagnosis of tumor and tumor-like
lesions of the liver in infancy and childhood. Am J Dis Child.
1956;91(2):168-86.). It is histologically characterized
by large polygonal hepatocytes with eosinophilic and granular cytoplasm surrounded
by abundant, thick fibrous bands, which are arranged in a parallel or lamellar
distribution (22 Berman MM, Libbey NP, Foster JH. Hepatocellular carcinoma.
Polygonal cell type with fibrous stroma - an atypical variant
with a favorable prognosis. Cancer.
1980;46(6):1448-55.,33 Craig JR, Peters RL, Edmonsdson HA, Omata M. Fibrolamellar
carcinoma of the liver: a tumor of adolescents and young adults with distinctive
clinico-pathologic features. Cancer. 1980;46(2):372-9,
http://dx.doi.org/10.1002/1097-0142(19800715)46:2<372::AID-CNCR2820460227>3.0.CO;2-S.
http://dx.doi.org/10.1002/1097-0142(1980...
). FLHCC represents 1 - 2% of all primary liver tumors, which
is a small percentage compared with that of conventional HCC, which represents
60-80% of liver cancers (44 Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular
carcinoma. Am J Gastroenterol. 2009;104(10):2617-24.,55 McLarney JK, Rucker PT, Bender GN, Goodman ZD, Kashitani N, Ros
PR. Fibrolamellar carcinoma of the liver: radiologic/pathologic correlation.
Radiographics. 1999;19(2):453-71,
http://dx.doi.org/10.1148/radiographics.19.2.g99mr09453.
http://dx.doi.org/10.1148/radiographics....
). To the best of our knowledge, there are
only four reports of FLHCC from Latin American populations (66 Arista-Nasr J, Gutierrez-Villalobos L, Nuncio J, Maldonaldo H,
Bornstein-Quevedo L. Fibrolamellar hepatocellular carcinoma in Mexican patients.
Pathol Oncol Res. 2002;8(2):133-7,
http://dx.doi.org/10.1007/BF03033723.
http://dx.doi.org/10.1007/BF03033723...
7 Silva H, León G, Náquira N. Fibrolamellar
hepatocellular carcinoma: report of 4 cases. Rev Med Chil.
1988;116(2):153-6.-88 Moreno-Luna LE, Arrieta O, García-Leiva J, Martinez B, Torre
A, Uribe M, et al. Clinical and pathologic factors associated with survival in
young adult patients with fibrolamelar hepatocarcinoma. BMC Cancer. 2005;5:142,
http://dx.doi.org/10.1186/1471-2407-5-142.
http://dx.doi.org/10.1186/1471-2407-5-14...
) and no previous
reports from Brazil. The actual incidence of FLHCC in Latin America remains
unknown.
FLHCC differs from conventional HCC in several aspects, such as demographics, risk
factors and tumor markers (44 Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular
carcinoma. Am J Gastroenterol. 2009;104(10):2617-24.,55 McLarney JK, Rucker PT, Bender GN, Goodman ZD, Kashitani N, Ros
PR. Fibrolamellar carcinoma of the liver: radiologic/pathologic correlation.
Radiographics. 1999;19(2):453-71,
http://dx.doi.org/10.1148/radiographics.19.2.g99mr09453.
http://dx.doi.org/10.1148/radiographics....
). FLHCC typically occurs in younger patients,
with a median age at diagnosis of 25 years old, and has a controversial gender
predilection (99 Toberson M. Review of the clinicopathologic features of
fibrolamellar carcinoma. Adv Anat Pathol. 2007;14(3):217-23.
10 El-Serag HB, Davila JA. Is fibrolamellar carcinoma different
from hepatocellular carcinoma? A US population-based study.
Hepatology. 2004;39(3):798-803,
http://dx.doi.org/10.1002/hep.20096.
http://dx.doi.org/10.1002/hep.20096...
-1111 El-Gazzaz G, Wong W, El-Hadary MK, Gunson BK, Mirza DF, Mayer
AD, et al. Outcome of liver resection and transplantation for fibrolamellar
hepatocellular carcinoma. Transpl Int. 2000;13(Suppl 1):S406-9.). In contrast to conventional HCC, the vast majority of
cases occur in patients without chronic liver disease or cirrhosis (44 Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular
carcinoma. Am J Gastroenterol. 2009;104(10):2617-24.,99 Toberson M. Review of the clinicopathologic features of
fibrolamellar carcinoma. Adv Anat Pathol. 2007;14(3):217-23.,1212 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR,
D′Angelica M, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer. 2006;106(6):1331-8,
http://dx.doi.org/10.1002/cncr.21703.
http://dx.doi.org/10.1002/cncr.21703...
). Conventional tumor markers
for HCC, such as alpha-fetoprotein (AFP), are normal in the majority of patients
(44 Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular
carcinoma. Am J Gastroenterol. 2009;104(10):2617-24.).
Controversy exists regarding whether FLHCC has a better prognosis than conventional
HCC. Several studies had formerly described FLHCC as more indolent and associated
with a better prognosis (1010 El-Serag HB, Davila JA. Is fibrolamellar carcinoma different
from hepatocellular carcinoma? A US population-based study.
Hepatology. 2004;39(3):798-803,
http://dx.doi.org/10.1002/hep.20096.
http://dx.doi.org/10.1002/hep.20096...
,1313 Wetzel WJ, Costin JL, Petrino RL. Fibrolamellar carcinoma:
distinctive clinical and morphologic variant of hepatoma. South Med J.
1983;76(6):796-8,
http://dx.doi.org/10.1097/00007611-198306000-00028.
http://dx.doi.org/10.1097/00007611-19830...
14 Hemming AW, Langer B, Sheiner P, Greig PD, Taylor BR. Aggressive
surgical management of fibrolamellar hepatocellular carcinoma. J Gastroinst
Surg. 1997;1(4):342-6,
http://dx.doi.org/10.1016/S1091-255X(97)80055-8.
http://dx.doi.org/10.1016/S1091-255X(97)...
-1515 Lack EE, Neave C, Vawter GF. Hepatocellular carcinoma. Review of
32 cases in childhood and adolescence. Cancer.
1983;52(8):1510-5.),
but subsequent studies found that survival after resection was similar in patients
with FLHCC and conventional HCC without cirrhosis (1616 Kakar S, Burgart LJ, Batts KP, Garcia J, Jain D, Ferrel LD.
Clinicopathologic features and survival in fibrolamellar carcinoma: comparison
with conventional hepatocellular carcinoma with and without cirrhosis. Mod
Pathol. 2005;18(11):1417-23,
http://dx.doi.org/10.1038/modpathol.3800449.
http://dx.doi.org/10.1038/modpathol.3800...
17 Ringe B, Wittekind C, Weimann A, Tusch G, Pichlmayr R. Results
of hepatic resection and transplantation for fibrolamellar carcinoma. Surg
Gynecol Obstet. 1992;175(4):299-305.-1818 Nagorney DM, Adson MA, Weiland LH, Knight CD Jr., Smaley SR,
Zinsmeister AR. Fibrolamellar hepatoma. Am J Surg.
1985;149(1):113-9.). It is conceivable that a
better outcome for FLHCC would be derived from the absence of cirrhosis, high
resectability rates, and a younger age at presentation rather than from the distinct
biological and clinicopathological features of the tumor itself (44 Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular
carcinoma. Am J Gastroenterol. 2009;104(10):2617-24.,99 Toberson M. Review of the clinicopathologic features of
fibrolamellar carcinoma. Adv Anat Pathol. 2007;14(3):217-23.,1616 Kakar S, Burgart LJ, Batts KP, Garcia J, Jain D, Ferrel LD.
Clinicopathologic features and survival in fibrolamellar carcinoma: comparison
with conventional hepatocellular carcinoma with and without cirrhosis. Mod
Pathol. 2005;18(11):1417-23,
http://dx.doi.org/10.1038/modpathol.3800449.
http://dx.doi.org/10.1038/modpathol.3800...
). A recent multicenter
French study has suggested that the presence of some tumor heterogeneity, with
classical FLHCC intermingled with conventional HCC, would be responsible for a worse
prognosis in a subgroup they called “mixed FLHCC” (1919 Malouf GG, Brugieres L, Le Deley MC, Faivre S, Fabre M, Paradis
V, et al. Pure and mixed fibrolamellar hepatocellular carcinoma differ in
natural history and prognosis after complete surgical resection. Cancer.
2012;118(20):4981-9, http://dx.doi.org/10.1002/cncr.27520
http://dx.doi.org/10.1002/cncr.27520...
).
The aim of this study was to describe the clinical, surgical, and histopathological features from a series of 21 cases of fibrolamellar hepatocellular carcinoma, with an emphasis on prognostic factors for survival.
MATERIALS AND METHODS
Medical records from 21 patients with histopathologically diagnosed FLHCC from 1990
to 2012 were reviewed and searched for patient demographics, medical histories, the
results of imaging studies, laboratory tests, surgical procedures, and outcomes. An
experienced liver pathologist (VAFA) reviewed all biopsies and surgical specimens.
Patients were staged according to the 7th edition of the American Joint
Committee on Cancer (AJCC) staging criteria (2020 Sobin LH, Compton CC. TNM seventh edition: what's new,
what's changed: communication from the International Union Against Cancer
and the American Joint Committee on Cancer. Cancer. 2010;116(22):5336-9,
http://dx.doi.org/10.1002/cncr.25537.
http://dx.doi.org/10.1002/cncr.25537...
). The study was approved by the Hospital das Clínicas from the
University of São Paulo School of Medicine Ethics Committee and was conducted
in accordance with the Declaration of Helsinki.
The pathological diagnosis of FLHCC was based on the presence of the following criteria: 1) large tumor cells with deeply eosinophilic cytoplasm; 2) the presence of central macronucleoli; and 3) abundant, fibrous stroma arranged in thin, parallel lamellae around the tumor cells (44 Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular carcinoma. Am J Gastroenterol. 2009;104(10):2617-24.).
Similarly to the proposal by Malouf et al. (1919 Malouf GG, Brugieres L, Le Deley MC, Faivre S, Fabre M, Paradis
V, et al. Pure and mixed fibrolamellar hepatocellular carcinoma differ in
natural history and prognosis after complete surgical resection. Cancer.
2012;118(20):4981-9, http://dx.doi.org/10.1002/cncr.27520
http://dx.doi.org/10.1002/cncr.27520...
), the cases were divided into two groups: pure FLHCC, in which the
diagnostic criteria described above were present throughout all samples available
from the tumor, and mixed FLHCC, in which at least one focus of conventional HCC was
found in a tumor with extensive areas of typical FLHCC. The presence of micro- or
macrovascular invasion, satellite nodules, and extra-hepatic disease was also
evaluated.
Immunohistochemical staining for the markers Hep-Par, Arginase-1, Muc-1, CK19, CK7, and chromogranin was performed in all specimens. To avoid endogenous avidin-biotin interactions, which might yield undesirable background staining, signal amplification was achieved by the use of a short-polymer peroxidase complex (Novolink, Novocastra, U.K.). The immunoprofile was used to confirm the diagnosis: classical FLHCC was expected to be positive for Hep-Par, Arginase-1, and CK-7 and to present only focal staining for Muc-1 and CK19, whereas the neuroendocrine marker chromogranin was expected to be negative.
Overall survival (OS) was defined as the interval between the diagnosis and the last
follow up or death from any cause. A survival analysis was conducted using the
Kaplan-Meier method (2121 Kaplan E, Meier P. Non-parametric estimation from incomplete
observations. J Am Stat Assoc. 1958;53(282):457-81,
http://dx.doi.org/10.1080/01621459.1958.10501452.
http://dx.doi.org/10.1080/01621459.1958....
) and compared by
simple and multiple Cox Regression analyses using R version 2.15.2. Differences were
considered significant at p < 0.05. Whenever it was not possible to use the Cox
regression, differences were evaluated by the Log-Rank test using R version 2.15.2
(R Core Team, R Foundation for Statistical Computing, Vienna, Austria, 2011)(2222 R Core Team R: A language and environment for statistical
computing. R Foundation for Statistical Computing, Vienna, Austria (2013). URL
http://WWW.R-project.org/.
http://WWW.R-project.org/...
). We analyzed the impact of the following
factors on OS: treatment (surgical vs. nonsurgical), AJCC staging (I/II vs. III/IV),
recurrence, and radiological and pathological features (macro- and microvascular
invasion, extra-hepatic disease, and pathologic classification - pure FLHCC vs.
mixed FLHCC).
RESULTS
The clinicopathologic features and tumor staging, based on imaging studies and histopathological examination, of 21 patients with FLHCC are summarized in Table 1.
The diagnosis was made by percutaneous biopsy in 62% of cases and by surgical biopsy or surgical specimen examination in 38%. The histological review confirmed the diagnosis of FLHCC in all 21 specimens. Using the proposed sub-classification by Malouf et al., 18 patients had “pure FLHCC,” whereas three patients (14%) had at least one distinct area of conventional HCC and were thus classified as having “mixed FLHCC”. Macrovascular invasion was analyzed according to radiological and pathological findings. Additionally, histological assessment was performed to search for microvascular invasion.
None of the patients had tumor-associated chronic liver disease or cirrhosis or a history of hepatic adenoma, and the AFP level was normal in all patients at diagnosis. Two patients had portal hypertension associated with portal vein thrombosis. All patients had symptoms at the time of presentation, and the most common symptoms were abdominal pain (65%), weight loss (60%), abdominal mass (50%) and nausea (35%). Two patients in our series had been pregnant but had delivered shortly before tumor diagnosis.
Using imaging studies, tumor staging was evaluated in 20 patients (Figure 1). In radiological studies at diagnosis, most patients had a single nodule (90%), and the median tumor size was 120 mm (6.6-19 cm). Vascular invasion was present in 30% of patients, and extra-hepatic metastases were present in 53%; all cases with extra-hepatic metastases involved metastasis to regional lymph nodes. One patient had also an image suggestive of lung metastasis, whereas 3 patients had mediastinal lymph node metastases.
Abdominal computerized tomography of a patient with fibrolamellar hepatocellular carcinoma. (A) Contrast-enhanced, arterial-phase computed tomography showing heterogeneous enhancement of a large solid mass with small necrotic foci in segments IV and V of the liver. (B) Contrast-enhanced, arterial-phase computed tomography showing an enlarged lymph node in the hepatic portal (arrow).
Twenty patients underwent surgery. In six cases, the tumor was considered unresectable, due either to extensive liver involvement or to the presence of extra-hepatic disease. Of these, four patients received palliative care, and two received chemotherapy. One patient who did not undergo surgery due to the presence of supraclavicular lymph node metastasis. Fourteen patients underwent resection as the first-line therapy. Nine patients (43%) underwent only surgical resection. Five patients (24%) received surgery plus chemotherapy.
Pathological staging was studied in 13 patients who underwent resection (Figure 2). The median tumor size was 12 cm (6-19 cm) in the surgical specimens. Vascular invasion was present in 5/13 (38%) patients, microvascular invasion was present in 3 patients, and macrovascular invasion was present in 2 patients. One patient had satellite nodules. Extra-hepatic metastases were observed in 6/13 (46%) patients, and the most common sites of metastasis were intra-abdominal lymph nodes (5/6, 83%). A positive surgical margin was present in 5/13 (38%) patients.
Pathological aspects of fibrolamellar hepatocellular carcinoma. (A) Surgical specimen of a large, well-circumscribed, yellow, heterogeneous mass with areas of necrosis and a central scar. (B) Histopathology of “pure fibrolamellar hepatocellular carcinoma”: large tumor cells with deeply eosinophilic cytoplasm, round, central macronucleoli, and abundant fibrous stroma arranged in thin parallel lamellae around the tumor cells. (C): Fibrolamellar hepatocellular carcinoma showing microvascular invasion; (D): “Mixed fibrolamellar hepatocellular carcinoma”: classical fibrolamellar hepatocellular carcinoma cells are found intermingled with neoplastic cells with features of conventional hepatocellular carcinoma.
Recurrence after resection was evaluated in 10 patients; eight of them presented FLHCC recurrence. The median time from resection to recurrence was 12 months (Figure 3A). The most common sites of recurrence were the liver (3/8) and abdominal lymph nodes (3/8). One patient had recurrence in both the liver and lymph nodes, and one had peritoneal implants. Two patients underwent surgery for liver recurrences, and both evolved new recurrences. One of them underwent another resection; this patient has now been living disease free for 20 years. The other patient had peritoneal mass recurrence, which evolved to progressive disease and death. Three patients with recurrences received chemotherapy, and the other three received palliative care. As depicted in Figure 3A, the presence of either macro- or microvascular invasion on anatomopathological examination was found to be significantly related to an increased risk of recurrence (p = 0.01). All patients without recurrence were still alive at the end of the study.
(A) Overall disease-free survival of resected patients with fibrolamellar hepatocellular carcinoma according to vascular invasion. Vascular invasion, either macro- or microscopic, was associated with an increased risk of tumor recurrence (Cox regression, p<0.01). (B) The overall survival of patients with fibrolamellar hepatocellular carcinoma according to the presence of vascular invasion. On the one hand, the presence of macrovascular invasion had a significant impact on survival; on the other hand, although the microvascular invasion data may suggest a trend, the small number of cases (33 Craig JR, Peters RL, Edmonsdson HA, Omata M. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer. 1980;46(2):372-9, http://dx.doi.org/10.1002/1097-0142(19800715)46:2<372::AID-CNCR2820460227>3.0.CO;2-S.
http://dx.doi.org/10.1002/1097-0142(1980... ) did not allow for a significant discrimination with cases without any vascular invasion.
The tumor staging of the 21 patients using the TNM system, according to radiological and pathological findings, was as follows: stage I (TNM) in 5 patients, stage II in one, stage III in three patients and stage IV in 12 patients (60%) (Table 1).
Nineteen patients were followed, with a mean follow-up of 24 months. Fourteen patients died; five patients are still alive, three of whom are disease-free. Two patients are being treated with chemotherapy and are experiencing progressive disease. The median overall survival of the entire series was 36 months (6-228 months). The presence of macrovascular invasion, according to radiological and pathological findings (Figure 3B), and the presence of areas of conventional HCC in “mixed FLHCC” (Figure 4) were associated with a worse survival, as assessed by the Log-Rank test.
The overall survival of patients with fibrolamellar hepatocellular carcinoma according to the presence of areas of conventional hepatocellular carcinoma (mixed hepatocellular carcinoma vs. pure fibrolamellar hepatocellular carcinoma).
In the univariate and multivariate analyses, the presence of “mixed FLHCC” was a predictor of poor survival (p = 0.04). Patients who underwent surgery had a better one-year survival rate (87.5%) compared with those who underwent chemotherapy, surgery plus chemotherapy, and palliative care (66%, 60%, and 50%, respectively, p = 0.05) (Figure 5).
The overall survival of patients with fibrolamellar hepatocellular carcinoma according to treatment.
DISCUSSION
FLHCC is an infrequent primary liver tumor presenting significant epidemiological and
clinical differences compared with conventional hepatocellular carcinoma. Although
the real incidence and clinicopathological features of FLHCC in Latin America remain
poorly understood due to scarce available information (66 Arista-Nasr J, Gutierrez-Villalobos L, Nuncio J, Maldonaldo H,
Bornstein-Quevedo L. Fibrolamellar hepatocellular carcinoma in Mexican patients.
Pathol Oncol Res. 2002;8(2):133-7,
http://dx.doi.org/10.1007/BF03033723.
http://dx.doi.org/10.1007/BF03033723...
7 Silva H, León G, Náquira N. Fibrolamellar
hepatocellular carcinoma: report of 4 cases. Rev Med Chil.
1988;116(2):153-6.-88 Moreno-Luna LE, Arrieta O, García-Leiva J, Martinez B, Torre
A, Uribe M, et al. Clinical and pathologic factors associated with survival in
young adult patients with fibrolamelar hepatocarcinoma. BMC Cancer. 2005;5:142,
http://dx.doi.org/10.1186/1471-2407-5-142.
http://dx.doi.org/10.1186/1471-2407-5-14...
), the present study
of 21 cases from a single tertiary hospital suggests either that the incidence of
cases at this particular hospital might be increased due to increased referrals or
that FLHCC may be less rare than expected. In our series, as observed in other
studies, FLHCC occurred in young patients with a median age of 20 years and without
associated chronic liver disease (1111 El-Gazzaz G, Wong W, El-Hadary MK, Gunson BK, Mirza DF, Mayer
AD, et al. Outcome of liver resection and transplantation for fibrolamellar
hepatocellular carcinoma. Transpl Int. 2000;13(Suppl 1):S406-9.
12 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR,
D′Angelica M, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer. 2006;106(6):1331-8,
http://dx.doi.org/10.1002/cncr.21703.
http://dx.doi.org/10.1002/cncr.21703...
13 Wetzel WJ, Costin JL, Petrino RL. Fibrolamellar carcinoma:
distinctive clinical and morphologic variant of hepatoma. South Med J.
1983;76(6):796-8,
http://dx.doi.org/10.1097/00007611-198306000-00028.
http://dx.doi.org/10.1097/00007611-19830...
14 Hemming AW, Langer B, Sheiner P, Greig PD, Taylor BR. Aggressive
surgical management of fibrolamellar hepatocellular carcinoma. J Gastroinst
Surg. 1997;1(4):342-6,
http://dx.doi.org/10.1016/S1091-255X(97)80055-8.
http://dx.doi.org/10.1016/S1091-255X(97)...
15 Lack EE, Neave C, Vawter GF. Hepatocellular carcinoma. Review of
32 cases in childhood and adolescence. Cancer.
1983;52(8):1510-5.
16 Kakar S, Burgart LJ, Batts KP, Garcia J, Jain D, Ferrel LD.
Clinicopathologic features and survival in fibrolamellar carcinoma: comparison
with conventional hepatocellular carcinoma with and without cirrhosis. Mod
Pathol. 2005;18(11):1417-23,
http://dx.doi.org/10.1038/modpathol.3800449.
http://dx.doi.org/10.1038/modpathol.3800...
17 Ringe B, Wittekind C, Weimann A, Tusch G, Pichlmayr R. Results
of hepatic resection and transplantation for fibrolamellar carcinoma. Surg
Gynecol Obstet. 1992;175(4):299-305.
18 Nagorney DM, Adson MA, Weiland LH, Knight CD Jr., Smaley SR,
Zinsmeister AR. Fibrolamellar hepatoma. Am J Surg.
1985;149(1):113-9.
19 Malouf GG, Brugieres L, Le Deley MC, Faivre S, Fabre M, Paradis
V, et al. Pure and mixed fibrolamellar hepatocellular carcinoma differ in
natural history and prognosis after complete surgical resection. Cancer.
2012;118(20):4981-9, http://dx.doi.org/10.1002/cncr.27520
http://dx.doi.org/10.1002/cncr.27520...
20 Sobin LH, Compton CC. TNM seventh edition: what's new,
what's changed: communication from the International Union Against Cancer
and the American Joint Committee on Cancer. Cancer. 2010;116(22):5336-9,
http://dx.doi.org/10.1002/cncr.25537.
http://dx.doi.org/10.1002/cncr.25537...
21 Kaplan E, Meier P. Non-parametric estimation from incomplete
observations. J Am Stat Assoc. 1958;53(282):457-81,
http://dx.doi.org/10.1080/01621459.1958.10501452.
http://dx.doi.org/10.1080/01621459.1958....
22 R Core Team R: A language and environment for statistical
computing. R Foundation for Statistical Computing, Vienna, Austria (2013). URL
http://WWW.R-project.org/.
http://WWW.R-project.org/...
-2323 Maniaci V, Davidson BR, Rolles K, Dhillon AP, Hackshaw A, Begent
RH, et al. Fibrolamellar hepatocellular carcinoma - prolonged survival with
multimodality therapy. Eur J Surg Oncol.
2009;35(7):617-621.). Most patients in our study were female
(14/21, 67%), similarly to some other studies (88 Moreno-Luna LE, Arrieta O, García-Leiva J, Martinez B, Torre
A, Uribe M, et al. Clinical and pathologic factors associated with survival in
young adult patients with fibrolamelar hepatocarcinoma. BMC Cancer. 2005;5:142,
http://dx.doi.org/10.1186/1471-2407-5-142.
http://dx.doi.org/10.1186/1471-2407-5-14...
,1111 El-Gazzaz G, Wong W, El-Hadary MK, Gunson BK, Mirza DF, Mayer
AD, et al. Outcome of liver resection and transplantation for fibrolamellar
hepatocellular carcinoma. Transpl Int. 2000;13(Suppl 1):S406-9.); however, other series did
not show a gender predilection for FLHCC (99 Toberson M. Review of the clinicopathologic features of
fibrolamellar carcinoma. Adv Anat Pathol. 2007;14(3):217-23.,1010 El-Serag HB, Davila JA. Is fibrolamellar carcinoma different
from hepatocellular carcinoma? A US population-based study.
Hepatology. 2004;39(3):798-803,
http://dx.doi.org/10.1002/hep.20096.
http://dx.doi.org/10.1002/hep.20096...
,2323 Maniaci V, Davidson BR, Rolles K, Dhillon AP, Hackshaw A, Begent
RH, et al. Fibrolamellar hepatocellular carcinoma - prolonged survival with
multimodality therapy. Eur J Surg Oncol.
2009;35(7):617-621.). Two patients in our series had been pregnant shortly
before tumor diagnosis. Some cases of FLHCC have been reported during pregnancy
(2424 Dahan MH, Kastell P. Fibrolamellar hepatic carcinoma with a
presentation similar to that of septic pregnancy. A case
report. J Reprod Med. 2002;47(1):47-9.,2525 Gemer O, Segal S, Zohav E. Pregnancy in a patient with
fibrolamelar hepatocellular carcinoma. Arch Gynecol Obstret. 1994;255(4):211-2,
http://dx.doi.org/10.1007/BF02335087.
http://dx.doi.org/10.1007/BF02335087...
), and some studies have associated FLHCC with the use of oral
contraceptives (44 Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular
carcinoma. Am J Gastroenterol. 2009;104(10):2617-24.,88 Moreno-Luna LE, Arrieta O, García-Leiva J, Martinez B, Torre
A, Uribe M, et al. Clinical and pathologic factors associated with survival in
young adult patients with fibrolamelar hepatocarcinoma. BMC Cancer. 2005;5:142,
http://dx.doi.org/10.1186/1471-2407-5-142.
http://dx.doi.org/10.1186/1471-2407-5-14...
). The influence of hormonal stimulation in the development of
FLHCC remains unclear. Thus, future studies should address the hypothesis raised
herein that estrogens might play a role in the pathophysiology of this tumor.
The data described in the present series highlight relevant epidemiological
differences between FLHCC and conventional HCC. In contrast with our study on FLHCC,
a multicenter Brazilian study conducted by Carrilho et al. reported that 1,405
patients who were diagnosed with conventional HCC had a median age at diagnosis of
59 years old and were mostly male (78%); additionally, the vast majority of these
patients (98%) had liver cirrhosis (2727 Carrilho FJ, Kikuchi L, Branco F, Gonçalves CS, Mattos AA.
Clinical and epidemiological aspects of hepatocellular carcinoma in Brazil.
Clinics. 2010;65(12):1285-90,
http://dx.doi.org/10.1590/S1807-59322010001200010.
http://dx.doi.org/10.1590/S1807-59322010...
). More
clinical and epidemiological differences between FLHCC and HCC have been described
previously (1010 El-Serag HB, Davila JA. Is fibrolamellar carcinoma different
from hepatocellular carcinoma? A US population-based study.
Hepatology. 2004;39(3):798-803,
http://dx.doi.org/10.1002/hep.20096.
http://dx.doi.org/10.1002/hep.20096...
,1212 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR,
D′Angelica M, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer. 2006;106(6):1331-8,
http://dx.doi.org/10.1002/cncr.21703.
http://dx.doi.org/10.1002/cncr.21703...
).
In the present study, all patients were symptomatic at diagnosis, and the most common
symptoms were abdominal pain, weight loss, and nausea, as described in other series
(66 Arista-Nasr J, Gutierrez-Villalobos L, Nuncio J, Maldonaldo H,
Bornstein-Quevedo L. Fibrolamellar hepatocellular carcinoma in Mexican patients.
Pathol Oncol Res. 2002;8(2):133-7,
http://dx.doi.org/10.1007/BF03033723.
http://dx.doi.org/10.1007/BF03033723...
,88 Moreno-Luna LE, Arrieta O, García-Leiva J, Martinez B, Torre
A, Uribe M, et al. Clinical and pathologic factors associated with survival in
young adult patients with fibrolamelar hepatocarcinoma. BMC Cancer. 2005;5:142,
http://dx.doi.org/10.1186/1471-2407-5-142.
http://dx.doi.org/10.1186/1471-2407-5-14...
,2323 Maniaci V, Davidson BR, Rolles K, Dhillon AP, Hackshaw A, Begent
RH, et al. Fibrolamellar hepatocellular carcinoma - prolonged survival with
multimodality therapy. Eur J Surg Oncol.
2009;35(7):617-621.), which likely reflects an
advanced stage of disease at diagnosis (60% had a pTNM stage IV). Most patients
presented a large hepatic mass; the median tumor size was 12 cm. More than half of
the patients presented with extra-hepatic disease, including remarkable lymph node
involvement. Vascular invasion was also present in 42% of the patients, as evaluated
by radiological and pathological findings.
Among the 20 patients who underwent surgery, six tumors were considered unresectable
due either to extensive liver involvement or to the presence of unresectable
extra-hepatic disease. This was similar to the 13 unresectable cases found by Stipa
et al. (1212 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR,
D′Angelica M, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer. 2006;106(6):1331-8,
http://dx.doi.org/10.1002/cncr.21703.
http://dx.doi.org/10.1002/cncr.21703...
) in a series of 41 patients with
FLHCC. Out of the 13 patients resected in our series with pathological staging, the
median tumor size was 12 cm, 38% had vascular invasion, and 46% had lymph node
metastases. Maniaci et al. (2323 Maniaci V, Davidson BR, Rolles K, Dhillon AP, Hackshaw A, Begent
RH, et al. Fibrolamellar hepatocellular carcinoma - prolonged survival with
multimodality therapy. Eur J Surg Oncol.
2009;35(7):617-621.), reported a
series of 10 FLHCC cases with a mean tumor diameter of 13.4 cm, and 7/10 resected
patients had lymph node metastases. In another series reported by Pinna et al.
(2828 Pinna AD, Iwatsuki S, Lee RG, Todo S, Madariaga JR, Marsh JW, et
al. Treatment of fibrollamelar hepatoma with subtotal hepatectomy or
transplantation. Hepatology. 1997;26(4):877-83,
http://dx.doi.org/10.1002/hep.510260412.
http://dx.doi.org/10.1002/hep.510260412...
), 41 patients with FLHCC underwent
surgical treatment; these cases had a median tumor size of 13 cm, microvascular
invasion (51.2%), and macrovascular invasion (24.4%); 90% were pTNM stage IV.
Diagnosis at an advanced stage of disease may be related to the fact that FLHCC
occurs in young patients without chronic liver disease who are thus not subjected to
a screening program. In our institution, cirrhotic patients are evaluated through an
HCC screening program, which allows for diagnosis in the early and asymptomatic
stages of disease (2626 Paranaguá-Vezozzo DC, Ono SK, Alvarado-Mora MV, Farias AQ,
Cunha-Silva M, França JI, et al. Epidemiology of HCC in Brazil: Incidence
and risk factors in a ten-year cohort. Ann Hepatol.
2014;13(4):386-93.). In a Brazilian
multicenter study, most patients were asymptomatic, and the majority of conventional
HCC cases were diagnosed in the early or intermediate stage (2727 Carrilho FJ, Kikuchi L, Branco F, Gonçalves CS, Mattos AA.
Clinical and epidemiological aspects of hepatocellular carcinoma in Brazil.
Clinics. 2010;65(12):1285-90,
http://dx.doi.org/10.1590/S1807-59322010001200010.
http://dx.doi.org/10.1590/S1807-59322010...
).
Although FLHCC is commonly diagnosed in the advanced stage, resection remains the
best option to achieve disease control (2323 Maniaci V, Davidson BR, Rolles K, Dhillon AP, Hackshaw A, Begent
RH, et al. Fibrolamellar hepatocellular carcinoma - prolonged survival with
multimodality therapy. Eur J Surg Oncol.
2009;35(7):617-621.,2828 Pinna AD, Iwatsuki S, Lee RG, Todo S, Madariaga JR, Marsh JW, et
al. Treatment of fibrollamelar hepatoma with subtotal hepatectomy or
transplantation. Hepatology. 1997;26(4):877-83,
http://dx.doi.org/10.1002/hep.510260412.
http://dx.doi.org/10.1002/hep.510260412...
,2929 Stevens WR, Johnson CD, Stephens DH, Nagorney DM. Fibrolamellar
hepatocellular carcinoma:stage at presentation and results of agressive surgical
management. AJR Am J Roentgenol. 1995;164(5):1153-8,
http://dx.doi.org/10.2214/ajr.164.5.7717223.
http://dx.doi.org/10.2214/ajr.164.5.7717...
). In our series, 17/21 (81%) patients were treated. Fourteen
patients underwent surgery as the first-line therapy, and liver resection was
associated with lymphadenectomy in six. Nine patients (43%) underwent only
resection, and five also received adjuvant chemotherapy. The other three patients
(14%) received chemotherapy alone. In the present study, patients who underwent
surgical treatment alone showed a strong tendency towards a better survival when
compared with those who underwent other forms of treatment, such as chemotherapy,
surgery plus chemotherapy, or palliative care (p = 0.05). This finding
is likely related to an early tumor stage at diagnosis, allowing these patients to
undergo surgery without adjuvant chemotherapy. Other studies also reported a better
survival in patients who underwent surgical treatment compared with unresectable
patients (88 Moreno-Luna LE, Arrieta O, García-Leiva J, Martinez B, Torre
A, Uribe M, et al. Clinical and pathologic factors associated with survival in
young adult patients with fibrolamelar hepatocarcinoma. BMC Cancer. 2005;5:142,
http://dx.doi.org/10.1186/1471-2407-5-142.
http://dx.doi.org/10.1186/1471-2407-5-14...
,1111 El-Gazzaz G, Wong W, El-Hadary MK, Gunson BK, Mirza DF, Mayer
AD, et al. Outcome of liver resection and transplantation for fibrolamellar
hepatocellular carcinoma. Transpl Int. 2000;13(Suppl 1):S406-9.,1212 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR,
D′Angelica M, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer. 2006;106(6):1331-8,
http://dx.doi.org/10.1002/cncr.21703.
http://dx.doi.org/10.1002/cncr.21703...
).
The follow-up of the 10 patients who were surgically treated showed tumor recurrence
in eight cases. The median time to recurrence was 12 months, and vascular invasion
was associated with an increased risk of tumor recurrence. Previous studies have
also reported a high recurrence rate, ranging from 36 - 100%, with a median time to
relapse between 10 and 33 months (1111 El-Gazzaz G, Wong W, El-Hadary MK, Gunson BK, Mirza DF, Mayer
AD, et al. Outcome of liver resection and transplantation for fibrolamellar
hepatocellular carcinoma. Transpl Int. 2000;13(Suppl 1):S406-9.,2828 Pinna AD, Iwatsuki S, Lee RG, Todo S, Madariaga JR, Marsh JW, et
al. Treatment of fibrollamelar hepatoma with subtotal hepatectomy or
transplantation. Hepatology. 1997;26(4):877-83,
http://dx.doi.org/10.1002/hep.510260412.
http://dx.doi.org/10.1002/hep.510260412...
,2929 Stevens WR, Johnson CD, Stephens DH, Nagorney DM. Fibrolamellar
hepatocellular carcinoma:stage at presentation and results of agressive surgical
management. AJR Am J Roentgenol. 1995;164(5):1153-8,
http://dx.doi.org/10.2214/ajr.164.5.7717223.
http://dx.doi.org/10.2214/ajr.164.5.7717...
).
In a series of 28 patients who underwent resection, Stipa et al. (1212 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR,
D′Angelica M, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer. 2006;106(6):1331-8,
http://dx.doi.org/10.1002/cncr.21703.
http://dx.doi.org/10.1002/cncr.21703...
) reported that the five-year recurrence-free
survival rate was 18%, and the only significant negative prognostic factor for
recurrence was the presence of lymph node metastases. Pinna et al. (2828 Pinna AD, Iwatsuki S, Lee RG, Todo S, Madariaga JR, Marsh JW, et
al. Treatment of fibrollamelar hepatoma with subtotal hepatectomy or
transplantation. Hepatology. 1997;26(4):877-83,
http://dx.doi.org/10.1002/hep.510260412.
http://dx.doi.org/10.1002/hep.510260412...
) reported that the pTNM stage was
significantly associated with tumor-free survival. All patients without tumor
recurrence were still alive at the end of our study, suggesting that postsurgical
tumor recurrence is likely a major prognostic factor in patients with FLHCC.
In contrast to adenocarcinomas from almost all other organs, for which the
identification of histological subtypes has led to the search for specific molecular
profiles and, in many instances, to the classification of entirely different
clinical-pathological entities, most studies report “hepatocellular
carcinoma” as a generic tumor type, and thus do not acknowledge the potential
for different origins and biological behaviors. In this regard, Malouf et al. (3030 Malouf G, Falissard B, Azoulay D, Callea F, Ferrell LD, Goodman
ZD, et al. Is histological diagnosis of primary liver carcinomas with fibrous
stroma reproducible among experts? J Clin Pathol. 2009;62(6):519-24,
http://dx.doi.org/10.1136/jcp.2008.062620.
http://dx.doi.org/10.1136/jcp.2008.06262...
) have recently reported the relevance of the
identification of stromal-rich HCCs, which are subtyped with poor reproducibility
even among experts. This fact could at least partially explain the under-reporting
of FLHCC even in regions such as Latin America where it does not appear to be so
rare. Indeed, this is one of the major motivations for the present report, with an
emphasis on updating the clinical and histopathological criteria for the definition
of FLHCC as an important subtype of HCC. In the present series, pure FLHCC was
associated with a significantly higher overall survival, whereas mixed FLHCC was
associated with an increased risk of death. This finding is consistent with recent
data from Malouf et al., who reported a longer median overall survival in patients
with pure FLHCC compared with patients with mixed FLHCC (9 years vs. 3 years;
p<0.02) (1919 Malouf GG, Brugieres L, Le Deley MC, Faivre S, Fabre M, Paradis
V, et al. Pure and mixed fibrolamellar hepatocellular carcinoma differ in
natural history and prognosis after complete surgical resection. Cancer.
2012;118(20):4981-9, http://dx.doi.org/10.1002/cncr.27520
http://dx.doi.org/10.1002/cncr.27520...
). Mixed FLHCC was reported
for 10% to 25% of tumors in some series (1212 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR,
D′Angelica M, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer. 2006;106(6):1331-8,
http://dx.doi.org/10.1002/cncr.21703.
http://dx.doi.org/10.1002/cncr.21703...
,1919 Malouf GG, Brugieres L, Le Deley MC, Faivre S, Fabre M, Paradis
V, et al. Pure and mixed fibrolamellar hepatocellular carcinoma differ in
natural history and prognosis after complete surgical resection. Cancer.
2012;118(20):4981-9, http://dx.doi.org/10.1002/cncr.27520
http://dx.doi.org/10.1002/cncr.27520...
).
Other factors that were associated with a worse prognosis in other studies include
vascular invasion, lymph node metastasis, positive surgical margins, and old age
(44 Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular
carcinoma. Am J Gastroenterol. 2009;104(10):2617-24.,1212 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR,
D′Angelica M, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer. 2006;106(6):1331-8,
http://dx.doi.org/10.1002/cncr.21703.
http://dx.doi.org/10.1002/cncr.21703...
). In our study, the presence of macrovascular invasion, according to
radiological and pathological findings, was associated with poor survival. The
presence of microvascular invasion, however, was not shown to be associated with
worse survival; this is likely because only 3 cases presented microvascular
invasion. Pinna et al. (2828 Pinna AD, Iwatsuki S, Lee RG, Todo S, Madariaga JR, Marsh JW, et
al. Treatment of fibrollamelar hepatoma with subtotal hepatectomy or
transplantation. Hepatology. 1997;26(4):877-83,
http://dx.doi.org/10.1002/hep.510260412.
http://dx.doi.org/10.1002/hep.510260412...
) reported vascular
invasion as the most important negative prognostic factor for survival in their
series. Lymph node metastasis was the only significant negative prognostic factor in
the series reported by Stipa et al. (1212 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR,
D′Angelica M, et al. Outcome of patients with fibrolamellar
hepatocellular carcinoma. Cancer. 2006;106(6):1331-8,
http://dx.doi.org/10.1002/cncr.21703.
http://dx.doi.org/10.1002/cncr.21703...
). In
a series of 15 patients with FLHCC, Moreno-Luna reported that the factors associated
with higher survival were age over 23 years, resectability, the absence of major
vascular invasion, and free surgical borders (88 Moreno-Luna LE, Arrieta O, García-Leiva J, Martinez B, Torre
A, Uribe M, et al. Clinical and pathologic factors associated with survival in
young adult patients with fibrolamelar hepatocarcinoma. BMC Cancer. 2005;5:142,
http://dx.doi.org/10.1186/1471-2407-5-142.
http://dx.doi.org/10.1186/1471-2407-5-14...
). In our series, other poor prognostic factors, such as extra-hepatic
metastasis and positive margins, were associated with worse survival, but these
associations were not statistically significant, likely because of the small number
of patients.
An important finding from morphological studies is the growing necessity for extensive histological sampling to search for tumor heterogeneity because the presence of areas of conventional HCC in FLHCC was related to poor survival. Our recommendation is that in addition to the selection of all areas presenting gross features of possible markers of worse prognosis, such as intra-hepatic satellite nodules, vascular invasion, and extra-hepatic invasion, including lymph node and organ metastases, at least one paraffin block should be prepared for each centimeter of the largest extension of the primary tumor.
The results from the multivariate analysis should be interpreted with caution because
the small sample size and small number of events by covariate analysis can introduce
estimation bias for the hazard ratios (3131 Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of
events per independent variable in proportional hazards regression analysis. II.
Accuracy and precision of regression estimates. J Clin Epidemiol.
1995;48(12):1503-10,
http://dx.doi.org/10.1016/0895-4356(95)00048-8.
http://dx.doi.org/10.1016/0895-4356(95)0...
).
However, as FLHCC is considered a rare type of cancer, the number of cases presented
herein is among the largest published series from a single institution.
In conclusion, in the present series of 21 cases from a single academic center, fibrolamellar hepatocellular carcinoma was more common in young female patients, none of whom had evidence of chronic liver disease. The majority of patients were diagnosed at an advanced stage and had large tumors; additionally, most already had extra-hepatic metastases, especially to lymph nodes. Whenever feasible, surgery is the best therapeutic option to achieve disease control, even in advanced cases. Vascular invasion was related to a significantly higher risk of recurrence in patients who underwent surgical resection, and the presence of macrovascular invasion in imaging or pathology studies was a predictor of poor survival. Our findings suggest that extensive histological sampling must be performed to search for tumor heterogeneity because the presence of areas of conventional HCC in FLHCC was directly related to poor survival.
ACKNOWLEDGMENTS
The authors would like to thank the Alves de Queiroz Family Fund for Research for the support of our continued work and the Laboratory of Epidemiology and Statistics of Department of Gastroenterology, School of Medicine - University of São Paulo, SP, Brazil for their permanent assistance.
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» http://dx.doi.org/10.1002/hep.510260412 -
29Stevens WR, Johnson CD, Stephens DH, Nagorney DM. Fibrolamellar hepatocellular carcinoma:stage at presentation and results of agressive surgical management. AJR Am J Roentgenol. 1995;164(5):1153-8, http://dx.doi.org/10.2214/ajr.164.5.7717223.
» http://dx.doi.org/10.2214/ajr.164.5.7717223 -
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» http://dx.doi.org/10.1136/jcp.2008.062620 -
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» http://dx.doi.org/10.1016/0895-4356(95)00048-8
Publication Dates
-
Publication in this collection
Mar 2015
History
-
Received
30 Oct 2014 -
Reviewed
3 Dec 2014 -
Accepted
5 Jan 2015