Fibrolamellar Carcinoma: A Multimodal Approach

Abstract

Fibrolamellar carcinoma is a rare variant of hepatocellular carcinoma not associated with cirrhosis or viral hepatitis. Serum alpha-fetoprotein levels are usually normal; the histology is of a well-differentiated tumor, and the staging is the same as for hepatocellular carcinoma. We describe the case of a female patient in her 4th decade of life with a diagnosis of fibrolamellar hepatocellular carcinoma with a multimodal approach. The rare incidence of this cancer and its unusual clinical presentation justifies reporting this case and highlights the importance of multidisciplinary teams in the treatment of cancer patients.

Introduction

Fibrolamellar carcinoma is a rare and distinct form of liver cancer, which differs from hepatocellular carcinoma in several peculiarities, including demography, risk factors, tumor markers, and possibly prognosis. It occurs equally in males and females, being more common in children and young adults. Inaugural symptoms are usually nonspecific. Diagnosis is typically made based on clinical and imaging presentation; negative alpha-fetoprotein may support the diagnosis in a patient with suggestive radiological findings. The histological result is considered the gold standard to confirm the diagnosis. The most important prognostic factors are disease stage and resectability. Surgical resection with complete lymphadenectomy represents the best long-term survival hypothesis. Approximately 20–25% of the patients have categorically unresectable disease, which is associated with a 5-year survival rate of 0–5% and an average 12-month survival [1]. The best therapeutic sequence in these patients is not established, and there are no guidelines [2]. The role of liver transplantation is controversial and can be considered in selected patients without extrahepatic metastases. Systemic therapy is an appropriate option for patients with unresectable tumors, but the choice of regimen is empirical. There is a case report of a sustained complete response with gemcitabine and oxaliplatin (GEMOX) [3]. Locoregional techniques, such as hepatic artery chemoembolization or microwave ablation, have been used as an alternative approach for non-resection and/or transplant patients or those who do not respond or do not tolerate systemic therapy.

Historically classified as a subtype of hepatocellular carcinoma, fibrolamellar carcinoma has a unique molecular presentation. At the genomic level, it contains a single 400-kb deletion in chromosome 19, leading to a functional DNAJB1-PRKACA fusion protein. Honeyman et al. [4] identified this chimeric transcript that is expressed uniquely in fibrolamellar carcinoma. Some patients lack the classical histological features or display a “mixed” histology, a rare liver tumor defined by the presence of features from both hepatocellular carcinoma and fibrolamellar carcinoma. In these rare tumors, the DNAJB1-PRKACA fusion transcript is expressed at high levels, therefore indicating that mixed fibrolamellar hepatocellular carcinoma is similar to pure fibrolamellar carcinoma at the genomic level [5]. Despite its high penetrance and apparent specificity, the oncogenic role of this fusion event remains unclear.

Case Presentation

The authors describe a case with unusual presentation in a peculiar clinical context: a female patient in her 4th decade of life with no comorbidities who resorted to the emergency department for a condition of epigastric and left thoracalgia in June 2013, with negative physical examination. Of the complementary examinations, we highlight abdominal ultrasound with a 5-cm hyperechogenic nodule in the left lobe, to be clarified. The analytical assessment proved innocent. On the follow-up assessment in December 2016, the lesion was increased to 6.5 cm (Fig. 1). At the multidisciplinary evaluation, she was proposed for biopsy; however, the pre-biopsy ultrasound revealed an important arterial component, and the examination was canceled. The patient underwent hepatic lobectomy and left hepatic gastric artery and lymphadenectomy after performing a positron emission tomography-computed tomography (PET-CT) scan that showed no distant sign of disease. The histopathological report revealed fibrolamellar hepatocellular carcinoma pT1N1 (Fig. 2). In September 2017, the patient showed hepatic and small epiploon adenopathies on MRI (Fig. 3). After performing a PET-CT scan (Fig. 4) that showed no distant sign of disease, the patient underwent extensive surgical lymphadenectomy. This revealed multiple ganglion metastases (7/14). In February 2018, after a new TC scan, the patient presented a peritoneal nodule, suggestive of carcinomatosis. At this time, the team opted for systemic treatment with a platinum doublet chemotherapy (GEMOX). After 6 cycles (July 2018), the patient presented without target organ complaints, and imagologically with disappearance (complete response) of the peritoneal nodule and a de novo liver lesion in segment V with 1 cm of diameter. Complete MRI study (September 2018) confirmed the presence of the single infracentimetric liver injury in segment V. In December 2018, she underwent microwave ablation of the aforementioned lesion (Fig. 5). Follow-up at 2 months (February 2019) revealed appearance of two new segment VII lesions (Fig. 6). Accordingly, the patient underwent percutaneous microwave ablation of the metastatic lesions in May 2019. On a control CT scan (June 2019), the ablation sites showed no signs of viability, which made us assume complete response (Fig. 7). The patient currently maintains follow-up with imaging, analytical, and clinical evaluation every 3 months, being asymptomatic (ECOG PS 0), and with no evidence of active oncologic disease.

Fig. 1.

MRI showing dimensional increase to more than the double (December 2016).

Fig. 2.

a Left lobectomy surgery with la­paroscopic hepatic and left gastric artery lymphadenectomy. b Histological finding compatible with pT1 N1 fibrolamellar hepatocellular carcinoma (3/5). HE. ×100.

Fig. 3.

MRI showing hilar adenopathy and small epiploon (September 2017).

Fig. 4.

PET-CT FDG with no evidence of distant disease (October 2017).

Fig. 5.

MRI confirming the presence of the single infracentimetric liver lesion in segment V. Status after locoregional treatment (September 2018).

Fig. 6.

MRI showing the appearance of two new segment VII lesions (February 2019).

Fig. 7.

CT scan where the ablation sites show no signs of viability, indicating complete response (June 2019).

Discussion and Conclusion

Fibrolamellar carcinoma accounts for 1% of all liver carcinomas and typically presents in young patients with no history of liver disease and normal alpha-fetoprotein levels. Treatment differs from conventional hepatocellular carcinoma, with surgery playing a central role in this entity. There are no clinical trials supporting the benefit of one systemic therapy over another, so the choice of regimen is empirical. Despite the rapid progress in the past years, there are still many critical unresolved questions in fibrolamellar carcinoma. It has immerged as a distinct molecular entity driven by a novel DNAJB1-PRKACA fusion protein that now serves as the main focus of therapeutic outcomes that can be translated to the clinic.

Statement of Ethics

The authors confirm that written patient consent and permission to publish have been obtained.

Disclosure Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors did not receive a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contributions

J.V.B., N.S., and A.P. conceived the idea, developed, and took the lead in writing the manuscript. M.R. provided critical feedback and helped shape the manuscript. J.S.C.; H.P.M; R.L. supervised the work. All authors discussed the results and contributed to the final manuscript.