Fibrolamellar Hepatocellular Carcinoma

Article Author:
Melinda Smith
Article Author:
Charles Marcus
Article Editor:
Brian Markovich
Updated:
7/12/2020 12:55:11 PM
PubMed Link:
Fibrolamellar Hepatocellular Carcinoma

Introduction

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a liver cancer that is different in its clinical features from conventional hepatocellular carcinoma (HCC).[1] A nearly negligible amount of liver cancers are attributed to FL-HCC. FL-HCC affects patients from a different and lower demographic age than HCC. Prompt initiation of treatment is of utmost importance since it can have a positive impact on patient outcomes. This article aims at reviewing the salient clinical and imaging features of FL-HCC, in contrast to HCC.

Etiology

No specific etiological factor has been recognized for fibrolamellar hepatocellular carcinoma. Less than 10% of patients with FL-HCC have underlying liver disease.[2] This is different from patients with HCC who often demonstrate an underlying cirrhotic liver morphology.[3]

Epidemiology

Patients most commonly present in their second or third decade.[4][5] In contrast, patients with HCC are often in their sixth decade. Fibrolamellar hepatocellular carcinoma is approximately 100 times less common than conventional HCC and demonstrates no gender preference like HCC, which is more common in men. More than 80% of patients affected by FL-HCC are White.[4]

Pathophysiology

These tumors are often large at presentation, measuring greater than 10 cm. On histopathological examination, these tumors demonstrate vascular invasion and have a positive surgical margin in about one-third of patients. Almost half of these patients demonstrate locoregional disease in the abdomen outside the liver. These tumors are usually large and single, with well-demarcated borders and features of rapid growth outgrowing their blood supply. These masses can also have a central scar.

Histopathology

On microscopic examination, these tumors have large cells with eosinophilic cytoplasm, large nuclei and features of lamellated fibrous tissue distributed between sheets of malignant cells.[6]

History and Physical

Patients with fibrolamellar hepatocellular carcinoma present with nonspecific signs and symptoms. These may vary from a patient with no symptoms with an abdominal mass detected during the evaluation of some other clinical condition to a patient who presents with abdominal discomfort or a palpable mass. Cachectic symptoms seen with other liver malignancies are not seen often.[7][8][9][10]

Serum tumor markers are not commonly elevated in these patients when evaluating patients with FL-HCC. In contrast to conventional HCC, serum alpha-fetoprotein is elevated in less than one-tenth of the patients.[11][7]

Evaluation

Due to the uncommon nature of fibrolamellar hepatocellular carcinoma and varied presentation, radiological evaluation plays an important role in the management of these patients and can include ultrasonography (US), Computed Tomography (CT) and magnetic resonance imaging (MRI).

Sonographic features include a single, large, lobulated tumor of varied echogenicity. The central scar described above is not readily demonstrated on ultrasound but, if seen, can demonstrate increased echogenicity.[12] 

On CT, these masses are seen as a single, large tumor with well-demarcated margins in more than two-thirds of the patients. These tumors, more often than not, demonstrate decreased attenuation characteristics in reference to the surrounding liver parenchyma, with more than two-thirds of patients showing a calcified central stellate scar. Liver protocol CT examinations are usually acquired in 3 distinct phases performed in specific time intervals to highlight tumor and liver parenchymal characteristics in the early arterial, portal venous, and delayed phases. In the arterial phase, most of these tumors enhance more than the surrounding liver with attenuation characteristics similar to the liver on portal venous and delayed phases reflecting the vascular nature of this tumor. If present, the central scar shows delayed enhancement secondary to the fibrous nature of the tissue.[5]

On magnetic resonance imaging, these masses demonstrate decreased signal on T1 weighted sequences more commonly in contrast to the surrounding liver parenchymal signal characteristics with increased T2-signal and restricted diffusion. The central scar of these tumors demonstrates a signal in keeping with the fibrous tissue described above with hypointense T1 and T2 signal and delayed enhancement.[13] The enhancement characteristics following contrast administration follow the pattern described above with increased arterial enhancement.[14]

Radiological evaluation is crucial in detecting additional locoregional and distant disease, which is not apparent clinically.[5]

Treatment / Management

The goal of primary treatment in fibrolamellar hepatocellular carcinoma is a cure, which can significantly impact the outcome, especially in patients who have surgical treatment with complete removal of the tumor.[15] A good portion of these patients have locoregional disease at diagnosis, and surgical treatment of these disease sites is often undertaken along with primary tumor resection, which has been shown to improve the outcome in these patients.[16] Since these tumors grow rapidly and tend to spread to adjacent disease sites, the chances of incomplete resection, second surgical intervention, and liver transplant are high, which in turn increases the associated mortality and morbidity.[17] 

Chemotherapy before and/or after definitive treatment improves outcomes.[14] Treatment with agents like gemcitabine, cisplatin, fluorouracil, and oxaliplatin can be utilized with good treatment response.[18] There is an improved overall prognosis and outcome with a combined treatment approach involving surgery, chemotherapy, and radiation.[19] Decreasing the size of the tumor prior to surgical resection through radioembolization has been achieved.[20]

Differential Diagnosis

Focal nodular hyperplasia, large cavernous hemangioma, and conventional HCC are diagnoses that have to be considered when evaluating a tumor with characteristics described above. Focal nodular hyperplasia follows attenuation characteristics of the surrounding liver on portal venous and delayed phase imaging with increased contrast enhancement on the arterial phase.[21] The central scar in these tumors do not show calcification and have hyperintense T2-signal attributed to biliary ductules when imaged with MRI.[22]

Although cavernous hemangiomas can have similar imaging features, they have distinctive enhancement features, which are early peripheral and nodular enhancement with subsequent central filling.[23]

Conventional HCC, on the other hand, demonstrates early arterial phase enhancement with subsequent washout. Background liver fibrotic changes are often demonstrated.

Surgical Oncology

The surgical treatment of this condition includes preoperative radioembolization, wedge resection, anatomic liver resection, or total hepatectomy with orthotopic liver transplantation.

Prognosis

Complete surgical removal of fibrolamellar hepatocellular carcinoma is associated with a higher survival rate. As expected, microvascular invasion and positive locoregional or distant disease have a negative impact on the outcome.[24][25][26] Rarely patients can have a combined FL-HCC and conventional HCC pattern of disease, which has a poor outcome.[6] Overall, patients with FL-HCC do better than those with conventional HCC. There is a statistically significant better prognosis in patients with FL-HCC than patients with conventional HCC in cirrhotic patients as opposed to patients with noncirrhotic livers and conventional HCC.[27] Patients with localized disease did better than patients with extrahepatic disease.[1] Surgical resection of metastases and combined treatment using different modalities have a positive impact on treatment.[28][19]

Complications

Considering the patient demographics, the aggressive behavior of the disease and technically difficult surgical management of these patients, complications and associated comorbidities are very common and should be anticipated for prompt care.

Deterrence and Patient Education

Patient education on the risks of this disease is essential as there is a high rate of recurrence.

Enhancing Healthcare Team Outcomes

Studies have shown a statistically significant better outcome if patients are managed by an interprofessional team well versed in managing complicated oncology patients with an evidence-based approach in a higher level care center with facilities and resources that can handle prompt and timely management of these patients.[29][30]


References

[1] Mayo SC,Mavros MN,Nathan H,Cosgrove D,Herman JM,Kamel I,Anders RA,Pawlik TM, Treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma: a national perspective. Journal of the American College of Surgeons. 2014 Feb;     [PubMed PMID: 24315886]
[2] Sobel ME, Metastasis suppressor genes. Journal of the National Cancer Institute. 1990 Feb 21;     [PubMed PMID: 2405170]
[3] Ramakrishna G,Rastogi A,Trehanpati N,Sen B,Khosla R,Sarin SK, From cirrhosis to hepatocellular carcinoma: new molecular insights on inflammation and cellular senescence. Liver cancer. 2013 Aug;     [PubMed PMID: 24400224]
[4] El-Serag HB,Davila JA, Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology (Baltimore, Md.). 2004 Mar;     [PubMed PMID: 14999699]
[5] Ganeshan D,Szklaruk J,Kaseb A,Kattan A,Elsayes KM, Fibrolamellar hepatocellular carcinoma: multiphasic CT features of the primary tumor on pre-therapy CT and pattern of distant metastases. Abdominal radiology (New York). 2018 Dec;     [PubMed PMID: 29948061]
[6] Chagas AL,Kikuchi L,Herman P,Alencar RS,Tani CM,Diniz MA,Pugliese V,Rocha Mde S,D'Albuquerque LA,Carrilho FJ,Alves VA, Clinical and pathological evaluation of fibrolamellar hepatocellular carcinoma: a single center study of 21 cases. Clinics (Sao Paulo, Brazil). 2015 Mar;     [PubMed PMID: 26017653]
[7] Wahab MA,El Hanafy E,El Nakeeb A,Ali MA, Clinicopathological features and surgical outcome of patients with fibrolamellar hepatocellular carcinoma (experience with 22 patients over a 15-year period). World journal of gastrointestinal surgery. 2017 Feb 27;     [PubMed PMID: 28289511]
[8] Butte JM,Waugh E,Meneses M,Pruzzo R,Carvallo C,Redondo F,Suárez C,Parada H,Amaral H,de La Fuente H, [Fibrolamellar liver carcinoma: report of two cases and review of the literature]. Revista medica de Chile. 2009 Mar;     [PubMed PMID: 19621182]
[9] Yen JB,Chang KW, Fibrolamellar hepatocellular carcinoma- report of a case. Chang Gung medical journal. 2009 May-Jun;     [PubMed PMID: 19527614]
[10] Terzis I,Haritanti A,Economou I, Fibrolamellar hepatocellular carcinoma: a case report with distinct radiological features. Journal of gastrointestinal cancer. 2010 Mar;     [PubMed PMID: 19960280]
[11] Abdel-Wahab M,El-Husseiny TS,El Hanafy E,El Shobary M,Hamdy E, Prognostic factors affecting survival and recurrence after hepatic resection for hepatocellular carcinoma in cirrhotic liver. Langenbeck's archives of surgery. 2010 Aug;     [PubMed PMID: 20358380]
[12] Friedman AC,Lichtenstein JE,Goodman Z,Fishman EK,Siegelman SS,Dachman AH, Fibrolamellar hepatocellular carcinoma. Radiology. 1985 Dec;     [PubMed PMID: 2997835]
[13] 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 Nov;     [PubMed PMID: 10551212]
[14] Do RK,McErlean A,Ang CS,DeMatteo RP,Abou-Alfa GK, CT and MRI of primary and metastatic fibrolamellar carcinoma: a case series of 37 patients. The British journal of radiology. 2014 Aug;     [PubMed PMID: 24896196]
[15] Chakrabarti S,Tella SH,Kommalapati A,Huffman BM,Yadav S,Riaz IB,Goyal G,Mody K,Borad M,Cleary S,Smoot RL,Mahipal A, Clinicopathological features and outcomes of fibrolamellar hepatocellular carcinoma. Journal of gastrointestinal oncology. 2019 Jun;     [PubMed PMID: 31183207]
[16] Herman P,Chagas AL,Perini MV,Coelho FF,Fonseca GM,Alves VA,Carrilho FJ,Cecconello I, Surgical treatment of fibrolamellar hepatocellular carcinoma: an underestimated malignant tumor? Hepatobiliary     [PubMed PMID: 25475864]
[17] Hemming AW,Langer B,Sheiner P,Greig PD,Taylor BR, Aggressive surgical management of fibrolamellar hepatocellular carcinoma. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 1997 Jul-Aug;     [PubMed PMID: 9834368]
[18] Gras P,Truant S,Boige V,Ladrat L,Rougier P,Pruvot FR,Hebbar M, Prolonged Complete Response after GEMOX Chemotherapy in a Patient with Advanced Fibrolamellar Hepatocellular Carcinoma. Case reports in oncology. 2012 Jan;     [PubMed PMID: 22666208]
[19] Maniaci V,Davidson BR,Rolles K,Dhillon AP,Hackshaw A,Begent RH,Meyer T, Fibrolamellar hepatocellular carcinoma: prolonged survival with multimodality therapy. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2009 Jun;     [PubMed PMID: 19144491]
[20] Mafeld S,French J,Tiniakos D,Haugk B,Manas D,Littler P, Fibrolamellar Hepatocellular Carcinoma: Treatment with Yttrium-90 and Subsequent Surgical Resection. Cardiovascular and interventional radiology. 2018 May;     [PubMed PMID: 29468286]
[21] Mathieu D,Bruneton JN,Drouillard J,Pointreau CC,Vasile N, Hepatic adenomas and focal nodular hyperplasia: dynamic CT study. Radiology. 1986 Jul;     [PubMed PMID: 3520655]
[22] Rummeny E,Weissleder R,Sironi S,Stark DD,Comptom CC,Hahn PF,Saini S,Wittenberg J,Ferrucci JT, Central scars in primary liver tumors: MR features, specificity, and pathologic correlation. Radiology. 1989 May;     [PubMed PMID: 2539605]
[23] Prasanna PM,Fredericks SE,Winn SS,Christman RA, Best cases from the AFIP: giant cavernous hemangioma. Radiographics : a review publication of the Radiological Society of North America, Inc. 2010 Jul-Aug;     [PubMed PMID: 20631374]
[24] Darcy DG,Malek MM,Kobos R,Klimstra DS,DeMatteo R,La Quaglia MP, Prognostic factors in fibrolamellar hepatocellular carcinoma in young people. Journal of pediatric surgery. 2015 Jan;     [PubMed PMID: 25598114]
[25] Mavros MN,Mayo SC,Hyder O,Pawlik TM, A systematic review: treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma. Journal of the American College of Surgeons. 2012 Dec;     [PubMed PMID: 22981432]
[26] Yamashita S,Vauthey JN,Kaseb AO,Aloia TA,Conrad C,Hassan MM,Passot G,Raghav KP,Shama MA,Chun YS, Prognosis of Fibrolamellar Carcinoma Compared to Non-cirrhotic Conventional Hepatocellular Carcinoma. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2016 Oct;     [PubMed PMID: 27456016]
[27] Njei B,Konjeti VR,Ditah I, Prognosis of Patients With Fibrolamellar Hepatocellular Carcinoma Versus Conventional Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. Gastrointestinal cancer research : GCR. 2014 Mar;     [PubMed PMID: 24799971]
[28] Kaseb AO,Shama M,Sahin IH,Nooka A,Hassabo HM,Vauthey JN,Aloia T,Abbruzzese JL,Subbiah IM,Janku F,Curley S,Hassan MM, Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma. Oncology. 2013;     [PubMed PMID: 24051705]
[29] Tanaka H,Hijioka S,Iwaya H,Mizuno N,Kuwahara T,Okuno N,Ito A,Kuraoka N,Matsumoto S,Obata M,Kurita Y,Yasuda M,Shimizu Y,Kuroda H,Sato Y,Haneda M,Sasaki E,Yatabe Y,Hara K, Fibrolamellar Hepatocellular Carcinoma with Multiple Lung Metastases Treated with Multidisciplinary Therapy. Internal medicine (Tokyo, Japan). 2018 Dec 15;     [PubMed PMID: 30101933]
[30] Okur A,Eser EP,Yilmaz G,Dalgiç A,Akdemir ÜÖ,Oğuz A,Karadeniz C,Akyol G,Demiroğullari B,Boyunağa Ö,Pinarli FG, Successful multimodal treatment for aggressive metastatic and recurrent fibrolamellar hepatocellular carcinoma in a child. Journal of pediatric hematology/oncology. 2014 Jul;     [PubMed PMID: 24608073]