Author Affiliations: Digestive Surgery Division, Department of Gastroenterology (Herman P, Chagas AL, Perini MV, Coelho FF, Fonseca GM, Carrilho FJ and Cecconello I) and Department of Pathology (Alves VAF), University of São Paulo School of Medicine, Avenida Doutor Enéas de Carvalho Aguiar, 255, Instituto Central, 9° andar, Sala 9074, CEP: 05403-900, Cerqueira Cesar-São Paulo, SP, Brazil

Corresponding Author: Paulo Herman, MD, PhD, Digestive Surgery Division, Department of Gastroenterology, University of São Paulo School of Medicine, Avenida Doutor Enéas de Carvalho Aguiar, 255, Instituto Central, 9° andar, Sala 9074, CEP: 05403-900, Cerqueira Cesar-São Paulo, SP, Brazil (Tel/Fax: +55-11-26617560; Email: pherman@uol.com.br)

 

© 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(14)60294-0

Published online August 21, 2014.

 

 

Acknowledgements: The authors thank Marcio Augusto Diniz for the statistical analysis.

Contributors: HP designed the study. CAL reviewed all cases. PMV performed the statistical analysis. HP, CFF and FGM wrote the paper. AVAF reviewed all pathologic specimens. PMV, CFJ and CI reviewed the paper. HP is the guarantor.

Funding: None.

Ethical approval: The study was approved by Institutional Ethics Committee of our university.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare disease with an indolent behavior. Its prognosis is better than that of patients with hepatocellular carcinoma. The authors present their experience with resection of FLHCC.

 

METHODS: Twenty-one patients with FLHCC were treated at our institution between 1990 and 2012. Of these patients, 14 were subjected to resection of the tumor. Patient demographics, medical history, results of imaging studies and laboratory tests, surgical data, and pathologic findings were evaluated.

 

RESULTS: The median age of the patients at the diagnosis of the tumor was 20 years and 14 patients were female. None of the patients had tumor-associated chronic liver disease or cirrhosis. The mean tumor size was 12.8 cm (range 6-19) and 18 patients had a single liver nodule. Fourteen patients were subjected to hepatectomy and six of them had lymph node metastases resected. Pathologic evaluation revealed that 5 (35.7%) patients had major vascular invasion. Tumor recurrence was seen in 8 patients (66.7%), during a follow-up. The median survival time for patients who were subjected to resection was 36 months. The 5-year overall survival rate and disease free survival rate were 28.0% and 8.5%, respectively. Univariate analysis showed that vascular invasion was the only variable associated with the disease free survival rate.

 

CONCLUSIONS: Despite an aggressive treatment, patients with FLHCC presented unexpected low survival rates. It seems that an underestimated malignant behavior is attributed to this disease, and that the forms of adjuvant treatment should be urgently evaluated.

 

(Hepatobiliary Pancreat Dis Int 2014;13:618-621)

 

KEY WORDS: fibrolamellar hepatocellular carcinoma; hepatectomy; hepatocellular carcinoma; lymph node excision; survival

Fbrolamellar hepatocellular carcinoma (FLHCC) is a variant and rare form of hepatocellular carcinoma (HCC) initially described in 1956 by Edmondson.^[1] It usually affects young patients with equal frequency between genders and, distinctly from conventional HCC, without an underlying liver disease.^{[2, 3]} The incidence rate is estimated at 0.02/100 000 inhabitants, representing 1%-2% of all HCC cases in the United States. The etiology of the disease is still unknown.^{[2, 4, 5]}

 

Patients usually present vague symptoms as weight loss, abdominal pain or discomfort and, in most cases, an abdominal mass.^[6] Due to an apparent indolent behavior and absence of symptoms, diagnosis is done usually in an advanced form of the disease where large liver masses and metastatic lymph nodes are observed in up to 70% of the cases.^{[6, 7]}

 

Liver function tests are usually normal with normal or slightly raised levels of aminotransferases and alpha-fetoprotein.^{[2, 3, 6, 8]} An elevated serum vitamin B₁₂ and vitamin B₁₂ binding capacity has been reported.^{[6, 8-10]} At radiological evaluation FLHCC appears as a hyper-vascular heterogeneous mass, with a central scar in a non-cirrhotic liver. Small calcifications within the tumor can also be observed.^[11-13]

 

When compared to conventional HCC, FLHCC appears to have a better prognosis.^{[3, 6, 8, 14, 15]} The reported 5-year overall survival for patients submitted to curative treatment as resection or liver transplantation ranges from 58% to 82%. For those patients with unresectable disease, mean survival time is about 12 months.^{[4-6, 14, 16-18]}

 

The authors present their experience with resection of FLHCC and discuss that this indolent disease despite an aggressive treatment, did not present the expected good results. It seems that an underestimated malignant behavior is attributed to this rare disease.

 

 

After the approval by the Institutional Ethics Committee, the medical records of twenty-one patients with diagnosis of FLHCC who had been treated at our institution between 1990 and 2012 were reviewed. Clinical information was collected from a prospective database, and data included patient demographics, medical history, results of imaging studies, laboratory tests and surgical outcomes. The data from the pathologic evaluation of micro or macro vascular invasion and the presence of satellite nodules were also collected. All cases were reviewed by one experienced pathologist.

 

The median age of the patients at diagnosis was 20 years (range 13-49) and 14 patients were female. None of the patients had tumor-associated chronic liver disease or cirrhosis; all patients had normal liver function tests and alpha-fetoprotein levels within normal limits. All patients had such symptoms at the time of presentation as abdominal pain (61.9%), weight loss (57.1%), and presence of an abdominal mass (47.6%).

 

Thirteen patients had been previously subjected to percutaneous biopsy. All patients were staged with thoracic and abdominal computed tomography. All patients were evaluated by a multidisciplinary team at a weekly meeting.

 

The overall survival of the patients was defined as the interval between diagnosis and last follow-up or death. The survival was calculated with the Kaplan-Meier method and compared by simple and multiple Cox regression. A P value <0.05 was considered statistically significant.

 

 

The characteristics of the patients are shown in Table 1. Mean tumor size was 12.8 cm (range 6-19) and eighteen patients had a single liver nodule. One patient was referred to systemic treatment because of metastasis of the disease. In 20 patients who underwent surgery, 6 were considered as unresectable because of the extensive involvement of the liver or the presence of extrahepatic disease. In 14 patients who had been subjected to hepatectomy, 6 had lymph nodes metastases resected (in 3 patients the metastatic tumor located on the liver hilum and in the other 3 on the liver hilum plus other sites). Six patients were subjected to right hepatectomy, two to left hepatectomy, two to right extended hepatectomy, two to bisegmentectomies, and two to a wedge resection. At pathologic evaluation, major vascular invasion was present in 5 (35.7%) patients and one (7.1%) patient had satellite nodules. Three patients (21.4%) had microscopic coincident margins (R1 resection).

 

Two patients were lost to follow-up, with a mean follow-up period of 42 months (range 12-240). In 12 patients who had had resection and follow-up, 8 (66.7%) patients presented recurrent disease in the liver (n=3), abdominal lymph nodes (3), both liver and lymph nodes (1), and peritoneal disease (1). Two patients with liver recurrence were subjected to re-resection, and five received adjuvant chemotherapy.

 

The median overall survival time for patients who had had resection was 36 months, whereas that for those who had had palliative treatment only presented a median overall survival of 10 months. None of the patients who had received a palliative treatment presented a long-term survival. Five-year overall survival and disease-free survival rates for the patients who underwent resection were 28.0% and 8.5%, respectively (Fig.).

 

Univariate analysis revealed that vascular invasion was the only variable associated with 5-year disease free survival (Table 2).

 

 

FLHCC is a slow-growing indolent tumor that affects young patients without an underlying liver disease and, whenever possible, should be treated by resection that is considered the treatment of choice, leading to 58% to 82% of 5-year overall survival rates.^{[2, 3, 5, 6, 14, 19, 20]}

 

For patients with only unresectable liver disease, liver transplantation has been employed with a 5-year overall survival rate of 29% to 55%. Other forms of treatment like chemotherapy and intraarterial treatment have been rarely reported.^{[5, 14, 20-23]}

 

Despite relatively indolent tumor biology, FLHCC usually recurs after resection. The sites of recurrence include the liver, regional lymph nodes, peritoneum and lungs.^{[24, 25]} Lymph nodes remain the most frequent site of metastatic spread, observed in 24% to 57% of the patients.^{[17, 18, 26]} In our series, in 6 of 14 patients, positive lymph nodes were resected and in one third of the patients, lymph nodes were the site of recurrence. These observations favor the routine resection of hilar lymph nodes during hepatectomy in order to minimize the risk of recurrence.

 

The diagnosis, almost always established in an advanced stage of the disease, may be related to the fact that FLHCC has an indolent behavior, does not lead to symptoms, and occurs in young patients without chronic liver disease. Unlike patients with liver cirrhosis, these patients are not subjected to a screening program. Confirmed by late diagnosis of an advanced disease, patients in our series presented large tumors (mean 12.8 cm) and 6 patients were subjected to hepatectomy associated with resection of lymph node metastasis. Stipa et al^[26] reported in a group of 41 patients with FLHCC, 28 underwent resection of a mean tumor size of 9 cm and, 50% had lymph node metastasis.

 

In patients with advanced stage or a preserved liver function, resection is the best option for them to control the disease.^{[20, 27, 28]} In our experience, the 5-year overall survival rate was 28.0% and the 5-year disease free survival rate, 8.5%. Although the results were worse than expected, resection remains the first-line treatment as recently shown by Kaseb and colleagues^[20] and confirmed by our data.

 

The prognosis of the disease mainly depends on the size and number of lesions, vascular invasion, and positive lymph nodes.^{[4, 17, 18]} In our series, only the presence of vascular invasion influenced the 5-year disease-free survival rate; because of the small number of cases, however, data of our study should be evaluated with care.

 

Regional spread of lymph nodes should not be considered as a limitation for curative resection.^{[27, 28]} Maniaci et al^[29] have reported an aggressive approach with resection and, for the treatment of recurrence, resection associated with radio- or chemotherapy with good results.

 

In a recent review,^[14] the 5-year overall survival rate for the entire group of patients was 44% which is better than that in our series. In patients who were subjected to hepatectomy the overall survival rate was 70% and in those who were subjected to liver transplantation, 34%. Mavros et al^[14] stated that most of studies considered that patients with FLHCC have a better prognosis than those with HCC. However, these data are not consensual and remain controversial. The same group, using SEER data, analyzed 7225 patients with surgically treated FLHCC or HCC in the United States and found a marked difference in overall survival, i.e. patients with FLHCC surviving a median of 75 months vs 43 months for those with HCC.^[15] In our series, patients had resection of large tumors with extrahepatic disease, which might influence the survival rate. However, in patients with disease limited to the liver, their results still remain disappointing. The small number of patients in our series and in the majority of reported series do not permit to draw significant conclusions but, when dealing with such a rare disease, even a small sample of reports is important to lead to a discussion.

 

Because of high recurrence rates, multimodality approach including adjuvant therapy should be considered. Adjuvant chemotherapy seems to affect patient survival,^[20] but it has been rarely reported.

 

Despite an aggressive treatment, patients with FLHCC do not present a significantly better prognosis compared to those with HCC. An underestimated malignant behavior is attributed to this rare disease, showing an urgent need for systemic multicenter trials.

 

 

1 Edmondson HA. Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. AMA J Dis Child 1956;91:168-186. PMID: 13282629

2 El-Serag HB, Davila JA. Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology 2004;39:798-803. PMID: 14999699

3 Torbenson M. Review of the clinicopathologic features of fibrolamellar carcinoma. Adv Anat Pathol 2007;14:217-223. PMID: 17452818

4 Craig JR, Peters RL, Edmondson HA, Omata M. Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 1980;46:372-379. PMID: 6248194

5 Ang CS, Kelley RK, Choti MA, Cosgrove DP, Chou JF, Klimstra D, et al. Clinicopathologic characteristics and survival outcomes of patients with fibrolamellar carcinoma: data from the fibrolamellar carcinoma consortium. Gastrointest Cancer Res 2013;6:3-9. PMID: 23505572

6 Liu S, Chan KW, Wang B, Qiao L. Fibrolamellar hepatocellular carcinoma. Am J Gastroenterol 2009;104:2617-2624. PMID: 19638962

7 Stevens WR, Johnson CD, Stephens DH, Nagorney DM. Fibrolamellar hepatocellular carcinoma: stage at presentation and results of aggressive surgical management. AJR Am J Roentgenol 1995;164:1153-1158. PMID: 7717223

8 Ward SC, Waxman S. Fibrolamellar carcinoma: a review with focus on genetics and comparison to other malignant primary liver tumors. Semin Liver Dis 2011;31:61-70. PMID: 21344351

9 Kanai T, Takabayashi T, Kawano Y, Kuramochi S, Miyazawa N. A case of postoperative recurrence of fibrolamellar hepatocellular carcinoma with increased vitamin B12 binding capacity in a young Japanese female. Jpn J Clin Oncol 2004;34:346-351. PMID: 15333688

10 Paradinas FJ, Melia WM, Wilkinson ML, Portmann B, Johnson PJ, Murray-Lyon IM, et al. High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma. Br Med J (Clin Res Ed) 1982;285:840-842. PMID: 6288165

11 Kane RA, Curatolo P, Khettry U. "Scar sign" on computed tomography and sonography in fibrolamellar hepatocellular carcinoma. J Comput Tomogr 1987;11:27-30. PMID: 3026731

12 Ichikawa T, Federle MP, Grazioli L, Madariaga J, Nalesnik M, Marsh W. Fibrolamellar hepatocellular carcinoma: imaging and pathologic findings in 31 recent cases. Radiology 1999;213:352-361. PMID: 10551212

13 McLarney JK, Rucker PT, Bender GN, Goodman ZD, Kashitani N, Ros PR. Fibrolamellar carcinoma of the liver: radiologic-pathologic correlation. Radiographics 1999;19:453-471. PMID: 10194790

14 Mavros MN, Mayo SC, Hyder O, Pawlik TM. A systematic review: treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma. J Am Coll Surg 2012;215:820-830. PMID: 22981432

15 Mayo SC, Mavros MN, Nathan H, Cosgrove D, Herman JM, Kamel I, et al. Treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma: a national perspective. J Am Coll Surg 2014;218:196-205. PMID: 24315886

16 Berman MM, Libbey NP, Foster JH. Hepatocellular carcinoma. Polygonal cell type with fibrous stroma--an atypical variant with a favorable prognosis. Cancer 1980;46:1448-1455. PMID: 6251961

17 Ringe B, Wittekind C, Weimann A, Tusch G, Pichlmayr R. Results of hepatic resection and transplantation for fibrolamellar carcinoma. Surg Gynecol Obstet 1992;175:299-305. PMID: 1329242

18 Pinna AD, Iwatsuki S, Lee RG, Todo S, Madariaga JR, Marsh JW, et al. Treatment of fibrolamellar hepatoma with subtotal hepatectomy or transplantation. Hepatology 1997;26:877-883. PMID: 9328308

19 Martínez Isla A, Ferrara A, Badia JM, Holloway I, Tanaka H, Riaz A, et al. Fibrolamellar hepatocellular carcinoma: results of partial liver resection. Rev Esp Enferm Dig 1997;89:699-705. PMID: 9421556

20 Kaseb AO, Shama M, Sahin IH, Nooka A, Hassabo HM, Vauthey JN, et al. Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma. Oncology 2013;85:197-203. PMID: 24051705

21 McPeake JR, O'Grady JG, Zaman S, Portmann B, Wight DG, Tan KC, et al. Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome. J Hepatol 1993;18:226-234. PMID: 24051705

22 Penn I. Hepatic transplantation for primary and metastatic cancers of the liver. Surgery 1991;110:726-735. PMID: 1656538

23 O'Grady JG, Polson RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg 1988;207:373-379. PMID: 2451484

24 Kakar S, Burgart LJ, Batts KP, Garcia J, Jain D, Ferrell LD. Clinicopathologic features and survival in fibrolamellar carcinoma: comparison with conventional hepatocellular carcinoma with and without cirrhosis. Mod Pathol 2005;18:1417-1423. PMID: 15920538

25 Wojcicki M, Lubikowski J, Post M, Chmurowicz T, Wiechowska-Kozlowska A, Krawczyk M. Aggressive surgical management of recurrent lymph node and pancreatic head metastases of resected fibrolamellar hepatocellular carcinoma: a case report. JOP 2012;13:529-532. PMID: 22964960

26 Stipa F, Yoon SS, Liau KH, Fong Y, Jarnagin WR, D'Angelica M, et al. Outcome of patients with fibrolamellar hepatocellular carcinoma. Cancer 2006;106:1331-1338. PMID: 16475212

27 Meriggi F, Forni E. Surgical therapy of hepatic fibrolamellar carcinoma. Ann Ital Chir 2007;78:53-58. PMID: 17518332

28 Ichikawa T, Federle MP, Grazioli L, Marsh W. Fibrolamellar hepatocellular carcinoma: pre- and posttherapy evaluation with CT and MR imaging. Radiology 2000;217:145-151. PMID: 11012437

29 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;35:617-621. PMID: 19144491