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Fibrolamellar Hepatocellular Carcinoma
Introduction
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare cancer of the liver. It displays features that make it very different in its behavior and clinical findings from conventional hepatocellular carcinoma (HCC).[1] FL-HCC accounts for a negligible percentage of primary liver cancers (1%). Patients affected by FL-HCC are usually in a lower age group than HCC. The presenting complaints, blood tests, radiological evaluation, and treatment strategies differ from HCC. Prompt diagnosis and initiation of appropriate care plans play an important role in this disease entity, eventually affecting the outcome. This article aims at reviewing the salient features of FL-HCC, comparing it to HCC.[2]
Etiology
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Etiology
No certain underlying trigger is detected in FL-HCC. These patients do not have a history of cirrhosis or chronic liver disease. Less than 10% of patients with a diagnosis of FL-HCC have cirrhotic liver morphology.[3] This is very different from underlying cirrhosis/liver fibrosis seen in patients diagnosed with conventional HCC.[2]
Epidemiology
Patients affected by FL-HCC most commonly are in the second or the third decade.[4][5] In contrast, the patients with HCC are most commonly in an older age group, usually around the sixth decade. A very small percentage of primary liver cancer is attributed to Fl-HCC (1%). Although HCC appears to be more common in men, FL-HCC does not demonstrate any gender preference. More than half of the patients affected by FL-HCC are white, while greater than 80% of patients with HCC are white.[4]
Pathophysiology
At diagnosis, most FL-HCC masses are approximately slightly greater than 10cm. At the time of the histopathological examination, four-tenths of the patients have a positive margin and vascular invasion after resection. Metastasis to locoregional lymph nodes has been demonstrated in about half the patients. On examination, these tumors are usually large, single, yellow, with well-defined margins, and demonstrate features of rapid growth, outgrowing the blood supply, and having a central scar.
Histopathology
Under microscopic examination, these tumors have big cells with eosinophilic cytoplasm, large central nuclei, and a central lamellated scar surrounding these large cells.[6]
History and Physical
Patients usually present with symptoms and signs ranging from pain to a liver mass detected while evaluating some other clinical condition.[7][8] The most common symptoms seem to be abdominal pain or a palpable mass. Symptoms commonly seen with a malignant process such as conventional HCC are not seen in FL-HCC.[9][10] Serum tumor markers do not have an important role in the evaluation or diagnosis of FL-HCC and are elevated in less than one-tenth of the patient population.[11][7]
Evaluation
Radiological evaluation appears to be the most useful evaluation tool. The most commonly used techniques include ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI).
Sonographic features include a lobulated mass with varied echotexture. These findings are non-specific and may not help differentiate them from other hepatic neoplasms. The central scar is not easily discernible and, if present, can be seen as an area of increased echogenicity.[12]
Computed Tomography usually shows a single tumor with well-demarcated margins, with most of these tumors showing decreased attenuation. Greater than 70% of the patients demonstrate a calcified central scar. Liver mass CT protocol commonly involves different intravenously acquisitions at different time points following contrast administration to highlight features in the arterial, portal venous, and delayed phases. Greater than 80% of the patients demonstrate masses that have increased contrast avidity in the arterial phase, reflecting the high blood supply of these tumors. Almost half of these masses enhance similarly to the background liver in the venous phase, and about one-third of the tumors have higher contrast avidity. Almost two-thirds of these masses enhance similar to the background liver on the delayed phase and can be difficult to differentiate. The central fibrous scar in these masses can show contrast avidity in this later phase.[5]
Magnetic resonance imaging shows a decreased signal on T1-weighted sequences in about two-thirds of the patients. The fibrous nature of the scar often demonstrates decreased signals on both T1 and T2 weighted sequences. The enhancement characteristics of the tumor and the central scar are similar to those described above on CT imaging.[13] Like many other malignant tumors, these also can show restricted diffusion with increased signal on diffusion-weighted imaging sequences (DWI).[14] In addition to the above findings, radiological evaluation plays an important role in detecting additional distant diseases that are not apparent otherwise.[5]
Treatment / Management
Primary treatment of this tumor involves a treatment strategy that aims at a cure. When possible, complete resection is the preferred treatment, which appears to favor the outcome.[15] However, a high percentage of patients (greater than two-thirds) eventually show recurrent disease.[15] A good portion of these patients have locoregional diagnosis during the surgical treatment, and these additional sites of disease are also treated along with the primary tumor resection, which has shown to have a better prognostic value.[16] These tumors are often very aggressive in their behavior, and a failed surgical attempt at resection, the necessity of second surgical intervention, and finally, hepatic transplantation are often encountered. These additional interventions can hurt the outcome.[17]
Chemotherapy has served as a treatment tool before and following surgical resection. Due to the limited incidence of FL-HCC, no RCT has elucidated the most efficacious chemotherapeutic regimen. Of note is that no neoadjuvant/adjuvant systemic therapies have yet been reported, showing an improved survival benefit in patients with resectable FL-HCC.[15] Chemotherapy with agents such as gemcitabine, cisplatin, 5-fluorouracil, interferon, and oxaliplatin have to be utilized and have shown varying degrees of response.[18][19] Combined treatment strategies, including surgery, chemotherapy, and radiation, have shown better outcomes.[20] Decreasing the mass size before surgical resection with percutaneous radioembolization has been studied.[21] A novel targeted therapy that has demonstrated efficacy in treating HCC, sorafenib, was evaluated retrospectively in FL-HCC, showing limited effectiveness.[19] Potential targets in the mTOR pathway and/or Aurora A kinase were recently identified. Currently, no controlled trials have evaluated these targets. There has been a favorable outcome in utilizing rapamycin (mTOR inhibitor) in an unresectable patient.[22] Checkpoint inhibition has shown reasonable efficacy in a Phase II study of advanced HCC.[23] Controlled trials evaluating checkpoint inhibitors in FL-HCC are lacking, and case reports to date are limited and unequivocal.[15][19](B2)
Differential Diagnosis
The differential diagnosis of this disease includes:
- Focal nodular hyperplasia
- Giant cavernous hemangioma
- Hepatocellular carcinoma (HCC)
Imaging plays a crucial role in differentiating these lesions. Focal nodular hyperplasia demonstrates characteristics that follow the normal surrounding liver parenchyma on the portal venous and later delayed phase imaging. In the early arterial phase, it can show hyperenhancement which is usually uniform.[24] Calcification is not a common feature. The Hyperintense signal on T2-weighted is seen in the central scar that can be seen in these masses and is attributed to biliary ductules as opposed to the scar related to FL-HCC described above.[25]
Cavernous hemangiomas follow the enhancement characteristics of blood vessels in all 3 phases. The classic pattern seen is a discontinuous and nodular enhancement pattern in the periphery of these masses in the early phases with subsequent contrast filling of the center.[26]
Conventional HCC includes prompt enhancement in the arterial phase with a contrast washout in the delayed phases. These patients often have a cirrhotic liver, which is reflected in the imaging.
Medical Oncology
Identifying a recurrent DNAJB1-PRKACA chimeric transcript in FLC by Honeyman et al initiated the growth in our ability to differentiate FL-HCC from conventional HCC. It may lead to insight into FL-HCC’s pathogenesis.[27] DNAJB1-PRKACA rearrangements are absent in conventional HCC and cholangiocellular tumors. DNAJB1-PRKACA and PRKACA rearrangement detection by break-apart fluorescence in situ hybridization (FISH) probe or polymerase chain reaction (PCR) provides both sensitive and specific elucidation in the context of primary hepatocellular neoplastic processes.[28] Engelholm et al found that introducing the DNAJB1-PRKACA fusion gene into wild-type mice was sufficient to initiate hepatic tumors in mice with features consistent with human FLC.[29]
Prognosis
Successful surgical treatment is associated with a better overall outcome. However, if there is a locoregional or distant disease, there is a negative impact on outcomes[30][31]. As expected, survival decreases as the number of disease site involvement increases.[32] If patients have findings of conventional HCC along with FL-HCC, which can rarely occur, there is a negative impact on prognosis.[6] The overall prognosis is superior to conventional HCC in the setting of underlying cirrhosis when compared to patients with a non-cirrhotic liver.[33] There is a statistically significant difference in the survival of patients diagnosed with FL-HCC compared to those with conventional HCC. Factors correlated with improved outcomes include disease confined to the liver, completed removal of the tumor at surgery, and treatment with different modalities as described above.[1][34][20]
Complications
Surgical complications are often encountered in these patients, especially those requiring complicated surgical treatment. Most patients affected with this disease are in a younger age group with a disease extent that is often higher than other liver malignancies. This necessitates a complex and aggressive approach to treatment, resulting in a higher rate of surgical complications.
Deterrence and Patient Education
Patient education on the risks of this disease is essential as there is a high recurrence rate.
Enhancing Healthcare Team Outcomes
These patients benefit from a treatment approach integrating different clinical teams familiar with treating complex malignancies with an evidence-based approach in a higher-level care center with the resources necessary to manage these patients.[35][36]
References
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:218(2):196-205. doi: 10.1016/j.jamcollsurg.2013.10.011. Epub 2013 Oct 24 [PubMed PMID: 24315886]
Level 2 (mid-level) evidenceRamakrishna 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:2(3-4):367-83. doi: 10.1159/000343852. Epub [PubMed PMID: 24400224]
Sobel ME. Metastasis suppressor genes. Journal of the National Cancer Institute. 1990 Feb 21:82(4):267-76 [PubMed PMID: 2405170]
El-Serag HB, Davila JA. Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology (Baltimore, Md.). 2004 Mar:39(3):798-803 [PubMed PMID: 14999699]
Level 2 (mid-level) evidenceGaneshan 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:43(12):3340-3348. doi: 10.1007/s00261-018-1657-2. Epub [PubMed PMID: 29948061]
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:70(3):207-13. doi: 10.6061/clinics/2015(03)10. Epub 2015 Mar 1 [PubMed PMID: 26017653]
Level 3 (low-level) evidenceWahab 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 27:9(2):61-67. doi: 10.4240/wjgs.v9.i2.61. Epub [PubMed PMID: 28289511]
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:137(3):394-400 [PubMed PMID: 19621182]
Level 3 (low-level) evidenceYen JB, Chang KW. Fibrolamellar hepatocellular carcinoma- report of a case. Chang Gung medical journal. 2009 May-Jun:32(3):336-9 [PubMed PMID: 19527614]
Level 3 (low-level) evidenceTerzis I, Haritanti A, Economou I. Fibrolamellar hepatocellular carcinoma: a case report with distinct radiological features. Journal of gastrointestinal cancer. 2010 Mar:41(1):2-5. doi: 10.1007/s12029-009-9094-7. Epub [PubMed PMID: 19960280]
Level 3 (low-level) evidenceAbdel-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:395(6):625-32. doi: 10.1007/s00423-010-0643-0. Epub 2010 Apr 2 [PubMed PMID: 20358380]
Friedman AC, Lichtenstein JE, Goodman Z, Fishman EK, Siegelman SS, Dachman AH. Fibrolamellar hepatocellular carcinoma. Radiology. 1985 Dec:157(3):583-7 [PubMed PMID: 2997835]
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:213(2):352-61 [PubMed PMID: 10551212]
Level 2 (mid-level) evidenceDo 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:87(1040):20140024. doi: 10.1259/bjr.20140024. Epub 2014 Jun 4 [PubMed PMID: 24896196]
Level 2 (mid-level) evidenceChakrabarti 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:10(3):554-561. doi: 10.21037/jgo.2019.01.35. Epub [PubMed PMID: 31183207]
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 & pancreatic diseases international : HBPD INT. 2014 Dec:13(6):618-21 [PubMed PMID: 25475864]
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:1(4):342-6 [PubMed PMID: 9834368]
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:5(1):169-72. doi: 10.1159/000338242. Epub 2012 Apr 3 [PubMed PMID: 22666208]
Level 3 (low-level) evidenceBauer U, Mogler C, Braren RF, Algül H, Schmid RM, Ehmer U. Progression after Immunotherapy for Fibrolamellar Carcinoma. Visceral medicine. 2019 Mar:35(1):39-42. doi: 10.1159/000497464. Epub 2019 Feb 12 [PubMed PMID: 31312648]
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:35(6):617-21. doi: 10.1016/j.ejso.2008.12.009. Epub 2009 Jan 13 [PubMed PMID: 19144491]
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:41(5):816-820. doi: 10.1007/s00270-018-1903-6. Epub 2018 Feb 21 [PubMed PMID: 29468286]
Ang CS, Kelley RK, Choti MA, Cosgrove DP, Chou JF, Klimstra D, Torbenson MS, Ferrell L, Pawlik TM, Fong Y, O'Reilly EM, Ma J, McGuire J, Vallarapu GP, Griffin A, Stipa F, Capanu M, Dematteo RP, Venook AP, Abou-Alfa GK. Clinicopathologic characteristics and survival outcomes of patients with fibrolamellar carcinoma: data from the fibrolamellar carcinoma consortium. Gastrointestinal cancer research : GCR. 2013 Jan:6(1):3-9 [PubMed PMID: 23505572]
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M, KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. The Lancet. Oncology. 2018 Jul:19(7):940-952. doi: 10.1016/S1470-2045(18)30351-6. Epub 2018 Jun 3 [PubMed PMID: 29875066]
Level 2 (mid-level) evidenceMathieu D, Bruneton JN, Drouillard J, Pointreau CC, Vasile N. Hepatic adenomas and focal nodular hyperplasia: dynamic CT study. Radiology. 1986 Jul:160(1):53-8 [PubMed PMID: 3520655]
Level 2 (mid-level) evidenceRummeny 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:171(2):323-6 [PubMed PMID: 2539605]
Level 2 (mid-level) evidencePrasanna 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:30(4):1139-44. doi: 10.1148/rg.304095198. Epub [PubMed PMID: 20631374]
Level 3 (low-level) evidenceHoneyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG, Lim II, Gleason CE, Murphy JM, Rosenberg BR, Teegan L, Takacs CN, Botero S, Belote R, Germer S, Emde AK, Vacic V, Bhanot U, LaQuaglia MP, Simon SM. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science (New York, N.Y.). 2014 Feb 28:343(6174):1010-4. doi: 10.1126/science.1249484. Epub [PubMed PMID: 24578576]
Dinh TA, Vitucci EC, Wauthier E, Graham RP, Pitman WA, Oikawa T, Chen M, Silva GO, Greene KG, Torbenson MS, Reid LM, Sethupathy P. Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma. Scientific reports. 2017 Mar 17:7():44653. doi: 10.1038/srep44653. Epub 2017 Mar 17 [PubMed PMID: 28304380]
Engelholm LH, Riaz A, Serra D, Dagnæs-Hansen F, Johansen JV, Santoni-Rugiu E, Hansen SH, Niola F, Frödin M. CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma. Gastroenterology. 2017 Dec:153(6):1662-1673.e10. doi: 10.1053/j.gastro.2017.09.008. Epub 2017 Sep 18 [PubMed PMID: 28923495]
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:50(1):153-6. doi: 10.1016/j.jpedsurg.2014.10.039. Epub 2014 Dec 10 [PubMed PMID: 25598114]
Level 2 (mid-level) evidenceMavros 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:215(6):820-30. doi: 10.1016/j.jamcollsurg.2012.08.001. Epub 2012 Sep 13 [PubMed PMID: 22981432]
Level 1 (high-level) evidenceYamashita 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:20(10):1725-31. doi: 10.1007/s11605-016-3216-x. Epub 2016 Jul 25 [PubMed PMID: 27456016]
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:7(2):49-54 [PubMed PMID: 24799971]
Level 1 (high-level) evidenceKaseb 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. 2013:85(4):197-203. doi: 10.1159/000354698. Epub 2013 Sep 19 [PubMed PMID: 24051705]
Level 2 (mid-level) evidenceTanaka 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 15:57(24):3537-3543. doi: 10.2169/internalmedicine.1243-18. Epub 2018 Aug 10 [PubMed PMID: 30101933]
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:36(5):e328-32. doi: 10.1097/MPH.0000000000000137. Epub [PubMed PMID: 24608073]
Level 3 (low-level) evidence