Open Access

Management of Diagnosis and Treatment in a Case of Fibrolamellar Carcinoma

BACINSCHI XENIA 1
ZGURA ANCA FLORINA 1
MERCAN-STANCIU ADRIANA 2
GRASU MUGUR 3
HERLEA VLAD 4
TOMA LETITIA 2
DODOT MIHAI 2
MARTINIUC ALEXANDRU 5
ANGHEL RODICA 1
  &  
HAINEALA BOGDAN 2

1Department of Oncology-Radiotherapy, Prof. Dr. Alexandru Trestioreanu Institute of Oncology,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

2Department of Internal Medicine II, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

3Department of Interventional Radiology, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

4Department of Pathology, Fundeni Clinical Institute, Bucharest, Romania

5Department of General Surgery, Fundeni Clinical Institute,Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Cancer Diagnosis & Prognosis Mar-Apr; 1(1): 23-28 DOI: 10.21873/cdp.10004
Received 05 February 2021 | Revised 21 July 2024 | Accepted 05 March 2021
Corresponding author
Anca Zgura, Department of Oncology- Radiotherapy, Prof. Dr. Alexandru Trestioreanu Institute of Oncology, Carol Davila University of Medicine and Pharmacy, 37 Dionisie Lupu Street, District 2, 020021 Bucharest, Romania. Tel.: +40 751110005 medicanca@gmail.com

Abstract

Background/Aim: Fibrolamellar carcinoma is a rare primary hepatic malignancy that has recently been recognized as a distinct clinical entity, highly different from the well-known hepatocellular carcinoma. This report describes the clinical and paraclinical aspects of the fibrolamellar carcinoma, emphasizing its particularities. Case Report: A 30-year-old patient presented to the hospital with nonspecific symptoms and weight loss, with imaging findings showing abdominal and mediastinal masses. Multiple biopsies were performed, leading to a diagnosis of metastatic fibrolamellar carcinoma. Given the extent of the disease, systemic drug treatment was administered, although prognosis was poor with tumor growth, resulting in biliary duct invasion. Conclusion: Fibrolamellar carcinoma is a rare type of malignancy, with a difficult differential diagnosis in which imaging techniques are important but for which biopsy remains the gold standard. The prognosis depends on tumor extent and may include surgical methods or chemotherapy.
Keywords: Liver cancer, fibrolamellar carcinoma, hepatocellular carcinoma, sorafenib

Fibrolamellar carcinoma (FLC) is a rare pathological entity that was first described by Edmondson in 1956 as a histological variant of hepatocellular carcinoma (HCC) (1). The term itself was introduced later, in 1980, by Craig et al., who highlighted the clinical and paraclinical features, recognizing FLC as a distinct type of hepatic malignancy (2,3). Considering its unique clinical, biological and histological characteristics, FLC was recently given its own World Health Organization classification number (4).

Differences between HCC and FLC start with the etiology of the disease, with no established risk factors for FLC. This particular tumor type appears to be more frequent in young patients, discovered either incidentally or with non-specific symptoms. No serological marker has been found specifically linked to FLC and imaging investigations reveal no particularities. Ultimately, the differential diagnosis is based on the histological aspect of the tumor; thus, a positive diagnosis requires either fine-needle aspiration (FNA) biopsy or specimens obtained intraoperatively.

Literature data show that patients diagnosed with FLC can benefit from aggressive surgical treatment, such as liver transplantation or liver resection. Trans-arterial chemo-embolization may also be a useful option in some cases (5).

Case Report

We present the case of a 30-year-old man, with no prior medical history, who was admitted to our hospital with ongoing lumbar pain, important weight loss (approximately 10 kg), nausea and malaise – symptoms that were persistent over the previous two months. Patient consent was obtained prior to the publication of this article.

Physical examination was normal, with no palpable abdominal mass or hepatomegaly, no palpable peripheral lymphadenopathy and no ascites. The alpha-fetoprotein (AFP) level was highly elevated (451.90 ng/ml), the peripheral blood tests were otherwise within normal limits. The patient had abdominal ultrasonography performed at another facility which had described intrahepatic masses.

For better characterization, computerized tomography of the thoracic, abdominal and pelvic regions was carried out. The exploration revealed an adenopathic tumoral mass, with inter-hepato-gastro-pancreatic development and iodophilic nature, with small necrotic areas within, involving the celiac trunk and its branches and creating a mass effect on the hepatic pedicle. A hepatic tumoral mass of about 55/40 mm was also described within segment IVB.

In the thoracic region, the computed tomography scan revealed the presence of a tumoral lymphadenopathy of about 75×55 mm, located in the right cardio-phrenic angle, with similar characteristics to those of the hepatic mass. Upper endoscopy, colonoscopy and echocardiographic examination were normal.

Given the presence of mediastinal lymphadenopathy, the patient was referred for an endoscopic ultrasound examination, during which a trans-esophageal endoscopic ultrasound-guided FNA was performed. The microscopic analysis showed enlarged cells with eosinophilic cytoplasm and large nuclei with prominent nucleoli, thus leading to the hypothesis of metastatic hepatic malignancy.

The patient was transferred to the General Surgery Clinic, where a laparotomy was performed, revealing a hemorrhagic tumoral mass, with inter-hepato-gastro-pancreatic localization, for which the chosen surgical management on site included partial resection with hemostasis. The lesion was considered not to be completely resectable because of its extensive vascular involvement. Multiple lymphadenopathies were also assessed, as well as the hepatic segment IV mass – most probably the primary tumor, as revealed by computed tomography shown in Figure 1 and Figure 2.

Macroscopically, the histopathological examination described an encapsulated grey nodal mass of about 10×6×5.5 cm, with necrotic areas at the section surface. Microscopically, it showed malignant epithelial proliferation, with polygonal-shaped cells, with eosinophilic cytoplasm and voluminous hyperchromatic nuclei, having intranuclear inclusions and atypical mitoses shown in Figure 3A. The aforementioned tumoral proliferation was also characterized by trabecular and alveolar nature, as well as by important intracellular lamellar collagenous fibrosis shown in Figure 3B and C, being compatible with the histopathological diagnosis of FLC.

Immunohistochemical tests were positive in the cytoplasm for cytokeratin 8/18 (CK8/18), CD68 antibody, deletions in glypican 3, CK7 and CK19 (Figure 3D-H, respectively); positive in the blood vessels for CD34, negative for CD10 and weakly positive in the cytoplasm for epidermal growth factor receptor (Figure 4). The immunohistochemical pattern, therefore, confirmed the histopathological diagnosis.

The result of the biopsy was analyzed in the context of the extent of disease by a multidisciplinary team that included an internist, a surgeon and a specialist in medical oncology, who recommended the administration of sorafenib.

After about 2 months of taking sorafenib with good tolerance and apparently good response, the patient presented at the hospital with jaundice, most probably due to tumoral growth and tumoral biliary obstruction. The laboratory findings showed elevated levels of alanine transaminase and aspartate transaminase, at about five times the normal values. Total bilirubin was 13.91 mg/dl, with direct bilirubin of 13 mg/dl. Alkaline phosphatase and gamma-glutamyl-transpeptidase were also significantly increased (550 U/l and respectively 905 U/l). The patient also had moderate anemia (with hemoglobin of 8.8 g/dl). An external-internal biliary drainage was performed, thus leading to the reduction of the bilirubin level and the remission of jaundice. Treatment with sorafenib was interrupted, considering the progression of the tumor under therapy, and subsequent episodes of cholangitis after biliary drainage. The patient was lost to follow-up 7 months after diagnosis.

Discussion

In this article, we report the case of a FLC, diagnosed in a young patient with no comorbidities – a pattern that is consistent with the literature description of this type of tumor.

While the development of HCC is based on active hepatic inflammation, viral infection, alcohol-related alterations, non-alcoholic fatty disease, cirrhosis or dietary aflatoxin B1, the mechanisms that lead to FLC remain unclear, as it usually occurs in the absence of liver injuries (such as inflammation or fibrosis), with no histological findings of precursor lesions (6). Although no etiological relationship has been demonstrated, it has been noted that FLC resembles focal nodular hyperplasia with a central scar, both affecting young individuals and sharing several imaging and histological features, such as a stellate central scar in imaging findings, and copper accumulation in histological examinations (7,8). Genetic mutations involved in the development of FLC may include a deletion on chromosome 19, as a recent study showed (9). Advances in gene sequencing have determined the detection of a recurrent DNAJ heat shock protein family (Hsp40) member B1–protein kinase cAMP-activated catalytic subunit alpha chimeric transcript fusion protein (DNAJB1–PRKACA) to be the driver mutation for FLC, thus opening the way for new targeted therapeutic approaches (10).

FLC typically affects young individuals. The clinical signs and symptoms may include abdominal pain, weight loss, fatigue, malaise (2). However, in some cases, the disease remains clinically silent and the carcinomatous nodule is discovered incidentally. There have also been reported signs of biliary obstruction due to tumoral invasion of the biliary tree, or even due to metastatic compression (3,11-13). Gynecomastia may also appear in some cases (14). A recent study has shown that the majority of patients complain of abdominal pain, abdominal distension, anorexia, fever and jaundice as main symptoms (15).

Biological markers are equally as non-specific as the clinical presentation. Usual blood biochemistry and cell counts are within normal limits (11). The serum level of AFP is usually within the normal range, although there might be situations of increased blood AFP level associated with FLC. However, there is a high possibility that the few reported cases of FLC with high levels of AFP are in fact misdiagnosed HCCs as the differential diagnosis between the two types of tumors remains a significant problem (6). Some authors have also described a close association between elevated serum vitamin B12 level and the presence of FLC (15,16).

Imaging studies in FLC mostly describe a large, well-defined tumor, possibly with a central scar or calcification (17). The mass is heterogeneously enhanced and the typical HCC aspect of arterial enhancement with portal wash-out is not visible. Fewer than 10% of cases present with portal vein thrombosis or biliary obstruction. Medical literature reports only a few cases of metastatic FLC, distant metastatic disease being described mostly of the lungs, peritoneum and adrenal glands (15-18). There are even fewer literature cases where metastases are characterized using FNA, since this method may result in the aspiration of malignant hepatocytes, without fibrotic lamellae (thus leading to a false diagnosis of HCC and not FLC) (18,19). The most objective and effective means of differentiating between the two types of hepatic masses remains, therefore, the histopathological analysis (20).

Among the particularities of our case, we note the association of a high AFP levels at diagnosis, as FLCs often do not produce AFP (fewer than 10% of the patients diagnosed with FLC have an AFP level higher than 200 ng/ml) (21). Furthermore, we noted that the patient had lymph node metastases, both mediastinal and abdominal, at admission. Although the FNA of the mediastinal lymphadenopathy result was not suggestive of the diagnosis of FLC, it undoubtedly testified to the hepatic origin of the lymph node metastasis. However, a final diagnosis was not possible until an exploratory laparotomy with biopsy was performed, confirming the presence of FLC.

Once diagnosed, the prognosis of FLC remains unclear. It is reported to be associated with a higher survival rate than HCC, as FLC is not associated with chronic liver disease (22). Whenever possible, the main therapeutic approach should be liver resection or transplantation, taking into account the fact that these patients are usually young, without comorbidities (5). Nevertheless, there is a high rate of recurrence as late as 5 years after resection, mainly due to the presence of nodal metastases at the time of the first intervention (12). More than 50% of patients undergoing liver transplantation present disease recurrence (23). This may be due to the fact that current indications for transplantation in patients with FLC include advanced disease. Recent reviews suggest that after surgical resection, FLC has a better prognosis than HCC but survival rates after transplantation do not differ significantly (24,25). In our patient’s case, despite the absence of cirrhosis, the poor prognosis was suggested by the presence of metastatic disease and, therefore, by the contraindication of aggressive surgical treatment, such as liver transplantation or tumor resection.

It is considered that if the tumor is unresectable, median survival is 14 months (26). Treatment options in this case include systemic therapy or transarterial chemoembolization, until the development of new molecule-targeted drugs. The only approved treatment is sorafenib, as ‘orphan product’, given the lack of statistically supporting evidence or alternative therapy. Small studies on therapy with 5-fluorouracil and recombinant interferon α-2b (27) or platinum salts (28) have shown their higher efficacy in FLC than HCC, however, without statistical significance or major improvement in overall survival. Due to the rarity of this disease, especially when associated with the presence of metastasis, there is not enough data concerning the use and efficacy of sorafenib in patients with metastatic FLC. However, since the drug targets both tumor growth and neo-angiogenesis, it can be considered as a choice in treating patients with FLC. In the presented case, the patient had very good tolerability to the chemotherapy agent (one of the reasons being the fact that he had no associated comorbidities) but the disease seemed to be progressive despite its use, leading to tumor growth and biliary duct obstruction, with jaundice.

Conclusion

FLC is a peculiar entity at both histological and molecular levels. It affects young individuals, in the absence of liver cirrhosis, therefore leading to a good prognosis when it is limited to hepatic localization. When metastatic, it is associated with a poor outcome. Differential diagnosis is difficult, and, although imaging findings are crucial, biopsy remains the gold diagnostic standard. The use of chemotherapy in metastatic FLC is considered controversial, as there are not enough literature data to support its efficacy.

Conflicts of Interest

None declared.

Author’s Contributions

BH and RA analyzed and interpreted the patient data and performed critical review of the article. AFZ, XB, AMS and LT analyzed the data and made major contributions in writing the article. MG interpreted the imaging findings of the patient. MD performed the critical review of the literature. AM were involved in the surgical management of the patient and performed the literature review. VH performed the histological examination of the tumor and was a major contributor in writing the article. All Authors read and approved the final article.

References

1 Edmondson HA Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. AMA J Dis Child. 91(2) 168 - 186 1956. PMID: 13282629. DOI: 10.1001/archpedi.1956.02060020170015
2 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. 46(2) 372 - 379 1980. PMID: 6248194. DOI: 10.1002/1097-0142(19800715)46:2<372::aid-cncr2820460227>3.0.co;2-s
3 Torbenson M Fibrolamellar carcinoma: 2012 update. Scientifica (Cairo). 2012 743790 2012. PMID: 24278737. DOI: 10.6064/2012/743790
4 Bosman FT World Health Organization, and International Agency for Research on Cancer, WHO Classification of Tumours of the Digestive System. International Agency for Research on Cancer, Lyon, France, Fourth Edition.
5 Groeschl RT Miura JT Wong RK Bloomston M Lidsky ML Clary BM Martin RC Belli G Buell JF & Gamblin TC Multi-institutional analysis of recurrence and survival after hepatectomy for fibrolamellar carcinoma. J Surg Oncol. 110(4) 412 - 415 2014. PMID: 24844420. DOI: 10.1002/jso.23658
6 Torbenson M Review of the clinicopathologic features of fibrolamellar carcinoma. Adv Anat Pathol. 14(3) 217 - 223 2007. PMID: 17452818. DOI: 10.1097/PAP.0b013e3180504913
7 Vecchio FM Fabiano A Ghirlanda G Manna R & Massi G Fibrolamellar carcinoma of the liver: The malignant counterpart of focal nodular hyperplasia with oncocytic change. Am J Clin Pathol. 81(4) 521 - 526 1984. PMID: 6322571. DOI: 10.1093/ajcp/81.4.521
8 Imkie M Myers SA Li Y Fan F Bennett TL Forster J & Tawfik O Fibrolamellar hepatocellular carcinoma arising in a background of focal nodular hyperplasia: A report of 2 cases. J Reprod Med. 50(8) 633 - 637 2005. PMID: 16220774.
Pubmed |
9 Honeyman 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. 343(6174) 1010 - 1014 2014. PMID: 24578576. DOI: 10.1126/science.1249484
10 Lalazar G & Simon SM Fibrolamellar carcinoma: Recent advances and unresolved questions on the molecular mechanisms. Semin Liver Dis. 38(1) 51 - 59 2018. PMID: 29471565. DOI: 10.1055/s-0037-1621710
11 Ringe B Wittekind C Weimann A Tusch G & Pichlmayr R Results of hepatic resection and transplantation for fibrolamellar carcinoma. Surg Gynecol Obstet. 175(4) 299 - 305 1992. PMID: 1329242.
Pubmed |
12 Maniaci V Davidson BR Rolles K Dhillon AP Hackshaw A Begent RH & Meyer T Fibrolamellar hepatocellular carcinoma: Prolonged survival with multimodality therapy. Eur J Surg Oncol. 35(6) 617 - 621 2009. PMID: 19144491. DOI: 10.1016/j.ejso.2008.12.009
13 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. 85(4) 197 - 203 2013. PMID: 24051705. DOI: 10.1159/000354698
14 Meriggi F & Forni E Surgical therapy of hepatic fibrolamellar carcinoma. Ann Ital Chir. 78(1) 53 - 58 2007. PMID: 17518332.
Pubmed |
15 Assi HA Mukherjee S Machiorlatti M Vesely S Pareek V & Hatoum H Predictors of outcome in patients with fibrolamellar carcinoma: Analysis of the national cancer database. Anticancer Res. 40(2) 847 - 855 2020. PMID: 32014928. DOI: 10.21873/anticanres.14017
16 Ward SC & Waxman S Fibrolamellar carcinoma: A review with focus on genetics and comparison to other malignant primary liver tumors. Semin Liver Dis. 31(1) 61 - 70 2011. PMID: 21344351. DOI: 10.1055/s-0031-1272835
17 Ichikawa T Federle MP Grazioli L & Marsh W Fibrolamellar hepatocellular carcinoma: Pre- and posttherapy evaluation with CT and MR imaging. Radiology. 217(1) 145 - 151 2000. PMID: 11012437. DOI: 10.1148/radiology.217.1.r00se46145
18 Kassahun WT Contemporary management of fibrolamellar hepatocellular carcinoma: diagnosis, treatment, outcome, prognostic factors, and recent developments. World J Surg Oncol. 14(1) 151 2016. PMID: 27215576. DOI: 10.1186/s12957-016-0903-8
19 Altavilla G & Guariso G Focal nodular hyperplasia of the liver associated with portal vein agenesis: a morphological and immunohistochemical study of one case and review of the literature. Adv Clin Path. 3(4) 139 - 145 1999. PMID: 10936892.
Pubmed |
20 Iliescu L Mercan-Stanciu A Ioanitescu ES & Toma L Hepatitis C-associated B-cell non-hodgkin lymphoma: A pictorial review. Ultrasound Q. 34(3) 156 - 166 2018. PMID: 30020272. DOI: 10.1097/RUQ.0000000000000369
21 Yoon G Koh CW Yoon N Kim JY & Kim HS Stromal p16 expression is significantly increased in endometrial carcinoma. Oncotarget. 8(3) 4826 - 4836 2017. PMID: 27902476. DOI: 10.18632/oncotarget.13594
22 Stipa F Yoon SS Liau KH Fong Y Jarnagin WR D’Angelica M Abou-Alfa G Blumgart LH & DeMatteo RP Outcome of patients with fibrolamellar hepatocellular carcinoma. Cancer. 106(6) 1331 - 1338 2006. PMID: 16475212. DOI: 10.1002/cncr.21703
23 El-Serag HB & Davila JA Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology. 39(3) 798 - 803 2004. PMID: 14999699. DOI: 10.1002/hep.20096
24 Mavros MN Mayo SC Hyder O & Pawlik TM A systematic review: Treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma. J Am Coll Surg. 215(6) 820 - 830 2012. PMID: 22981432. DOI: 10.1016/j.jamcollsurg.2012.08.001
25 Njei B Konjeti VR & Ditah I Prognosis of patients with fibrolamellar hepatocellular carcinoma versus conventional hepatocellular carcinoma: A systematic review and meta-analysis. Gastrointest Cancer Res. 7(2) 49 - 54 2014. PMID: 24799971.
Pubmed |
26 Bartlett D Di Bisceglie A & Dawson L Cancer of the Liver. In: De Vita VT, Lawrence TS and Rosenberg S: Cancer: Principles & Practice of Oncology, Eighth edition.. Philadelphia, PA: Lippincott, Williams and Wilkins. pp.1129 2008.
27 Patt YZ Hassan MM Lozano RD Brown TD Vauthey JN Curley SA & Ellis LM Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol. 21(3) 421 - 427 2003. PMID: 12560429. DOI: 10.1200/JCO.2003.10.103
28 Weeda VB Murawski M McCabe AJ Maibach R Brugières L Roebuck D Fabre M Zimmermann A Otte JB Sullivan M Perilongo G Childs M Brock P Zsíros J Plaschkes J Czauderna P & Aronson DC Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma—results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer. 49(12) 2698 - 2704 2013. PMID: 23683550. DOI: 10.1016/j.ejca.2013.04.012