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CASE REPORT Table of Contents  
Ahead of print publication
Fibrolamellar hepatocellular carcinoma presenting as cholestatic jaundice: An unusual presentation of a rare disease


1 Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Radiology, Dayanand Medical College and Hospital, Ludhiana, Ludhiana, India
3 Department of Pathology, Dayanand Medical College, Ludhiana, Punjab, India

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Date of Submission26-Mar-2021
Date of Decision06-May-2021
Date of Acceptance20-May-2021
Date of Web Publication24-May-2022
 

   Abstract 


Fibrolamellar hepatocellular carcinoma is a rare primary hepatic tumor that usually occurs in youth. The common presenting features are vague abdominal pain, nausea, vomiting and weight loss. We present a case report of a young male who presented with cholestatic jaundice and on evaluation was diagnosed to have fibrolamellar hepatocellular carcinoma. He underwent successful surgical resection of the tumor. In young individuals presenting with unexplained cholestasis, fibrolamellar hepatocellular carcinoma should be considered.

Keywords: Fibrolamellar hepatocellular carcinoma, immunohistochemistry, obstructive jaundice


How to cite this URL:
Singh A, Goyal S, Mehta V, Kakkar C, Narang V, Sood A. Fibrolamellar hepatocellular carcinoma presenting as cholestatic jaundice: An unusual presentation of a rare disease. Indian J Pathol Microbiol [Epub ahead of print] [cited 2022 Dec 9]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=345866





   Introduction Top


Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of primary hepatocellular carcinoma (HCC) and accounts for 1-9% of all HCC.[1] While historically FL-HCC has been considered to be derived from hepatocytes, the histopathology (HPE) and immunohistochemistry (IHC) studies have demonstrated markers of both hepatocyte and biliary differentiation.[2] FL-HCC usually presents with vague abdominal pain, nausea, malaise and weight loss. We describe a case of FL-HCC in a young male presenting with features of cholestatic jaundice.


   Case Report Top


A 22-year-old previously healthy male presented with complaints of jaundice, pruritus, anorexia and weight loss for one month. His physical examination revealed deep icterus, cutaneous scratch marks from pruritus, ecchymosis and mild hepatomegaly. His admission laboratory tests were notable for total serum bilirubin 11.4 mg/dL (direct fraction 9.5 mg/dL), aspartate aminotransferase (AST) 80 IU/L (normal <40 IU/L), alanine aminotransferase (ALT) 67 IU/L (normal <40 IU/L), alkaline phosphatase (ALP) 310 IU/L (normal 50-130 IU/L) and serum albumin 4.3 g/dL (normal 3.5-5.5 g/dL). The international normalized ratio was 2.9. Serology for hepatitis B and hepatitis C was negative.

Ultrasound abdomen revealed a well-defined rounded hypoechoic mass involving the left lobe of the liver. The patient underwent non contrast magnetic resonance cholangiopancreatography (MRCP) which revealed an ill-defined mass in the left lobe of liver which was isointense on T1 and T2 weighted images [Figure 1], the lesion had dark scar on T2 weighted images with frank extension of the tumour into the left duct till the hilum causing upstream biliary dilatation in both lobes [Figure 2] Alpha-fetoprotein, carcinoembryonic antigen and cancer antigen 19-9 were normal. Fine needle biopsy from the lesion revealed a cellular tumor with abundant eosinophilic vacuolated cytoplasm and intracytoplasmic pigments. The tumor cells were arranged in trabecular and acinar pattern surrounded by lamellate collagen fibers. [Figure 3] Surrounding hepatic parenchyma was normal. The IHC stains were positive for CK-7, hepatocyte paraffin-1, CD-68 and epithelial membrane antigen (EMA). [Figure 4] Staining for CDX-2, CK-20 and HMB-45 were negative. The histology and IHC findings were consistent with the diagnosis of FL-HCC. The patient underwent complete surgical resection of the tumor with negative margins along with an adequate lymph node dissection and is asymptomatic on one year follow up.
Figure 1: Axial T2 weighted image reveals an ill-defined infiltrative mass in the left lobe with central dark scar (arrow), extension into the left duct causing its expansion (thick short arrow) with dilatation of the right duct (dotted arrow)

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Figure 2: MRCP thick slab image reveals dilatation of the left (thick arrow) and right ductal system (thin arrow)

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Figure 3: (a) Hematoxylin and Eosin stain showing sheets and glandular pattern of large polygonal tumor cells having prominent eosinophilic nucleoli and abundant eosinophilic cytoplasm. Intracytoplasmic bile also seen. (b) Masson Trichome Stain showing separation of the tumour lobules by thick bundles of hyalinized keratin

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Figure 4: Immunohistochemistry staining of the tumor positive for CK-7 and hepatocyte paraffin-1

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   Discussion Top


FL-HCC is a rare malignant primary hepatic tumor. The pathogenesis of FL-HCC is poorly understood with origin from both hepatocytic and cholangiocytic cell lines reported. An association between hepatitis B and FL-HCC has also been described. A unique fusion gene between DNAJB1 (DnaJ/HSP40 homolog, subfamily B, member 1) and PRKACA (protein kinase, cAMP-dependent, catalytic, alpha) called DNAJB1-PRKACA has been described in the literature.[3] However, the diagnostic, therapeutic and prognostic role of this fusion gene is yet to be established.

The diagnosis of FL-HCC is based on clinical features and cross-sectional imaging. Clinically, FL-HCC presents with abdominal pain, nausea, anorexia and weight loss in young adults of any sex. Uncommonly gynaecomastia, paraneoplastic secretion of beta-human chorionic gonadotropin or thyroid hormones, hypoglycemia and hyper-ammonemia have been reported.[4],[5] The liver is healthy without any evidence of cirrhosis. Chronic viral infections such as hepatitis B and hepatitis C are negative and alpha fetoprotein levels are normal. Therefore, high index of suspicion is required. FL-HCC presenting as cholestatic jaundice, as seen in our case is rare.[6],[7] It is therefore important that apart from other causes of intrahepatic cholestasis such as viral hepatitis, drug toxicity, primary biliary cholangitis, sclerosing cholangitis, cholestasis of pregnancy, infiltrative diseases, and total parenteral nutrition; FL-HCC should also be kept as a differential in young patients. In patients with unexplained cholestasis and/or atypical disease course, early cross-sectional imaging using MRCP or computed tomography should be contemplated.

On imaging, the presence of solitary lesion, with calcification (40-68%) and/or central stellate scar (65-70%) are seen commonly in patients with FL-HCC. The enhancement pattern of FL-HCC is heterogeneous, most of the lesions are hypervascular on arterial phase with variable appearance on venous and delayed phases. Conventional HCC on the contrary is hypervascular on arterial phase with washout on venous and delayed phases. Presence of intra-lesional fat strongly favours conventional HCC over fibrolamellar variant.[8] However, the gold standard remains biopsy from the lesion that demonstrates tumor cells arranged in cords separated by lamellated collagen fibers. The dense collagen bundles arranged in parallel lamellae are not seen in conventional HCC. Also, FL-HCC has greater differentiation than HCC. The histological differences between conventional HCC and FL-HCC are the most objective criteria for differentiating between the two disease entities. IHC staining is positive for CK-7 and EMA. The tumor cells may be positive for copper and copper binding protein.

FL-HCC has unique clinical, radiological, histological and prognostic features compared to HCC and therefore differentiating the two is important. Also, it is essential to differentiate FL-HCC from benign tumors like focal nodular hyperplasia, hemangioma and adenoma. Fibrotic metastatic tumors are other important differentials of FL-HCC.

The prognosis of FL-HCC depends on the staging and resectability of the disease. In the absence of metastatic disease, complete surgical resection with lymphadenectomy is the preferred approach. For patients with unresectable disease, liver transplant may offer an alternative. FL-HCC is poorly responsive to systemic chemotherapy through clinical trials targeting mechanistic target of rapamycin (mTOR), epithelial growth factor receptor, transforming growth factor-beta and DNAJB1-PRKACA encoded protein Aurora kinase A (AURKA) have suggested a potential therapeutic role.[9],[10],[11] Repeat surgical resection may be carried out in patients with recurrent disease.

In conclusion, FL-HCC should be considered as a differential in young patients presenting with cholestatic jaundice. Early diagnosis and treatment are essential for long term survival.

Declaration of patient consent

Informed patient consent was obtained for publication of the case details.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Lafaro KJ, Pawlik TM. Fibrolamellar hepatocellular carcinoma: Current clinical perspectives. J Hepatocell Carcinoma 2015;2:151-7.  Back to cited text no. 1
    
2.
Paradis V. Histopathology of hepatocellular carcinoma. Recent Results Cancer Res 2013;190:21-32.  Back to cited text no. 2
    
3.
El Dika I, Bowman AS, Berger MF, Capanu M, Chou JF, Benayed R, et al. Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver. Cancer 2020;126:4126-35.  Back to cited text no. 3
    
4.
McCloskey JJ, Germain-Lee EL, Perman JA, Plotnick LP, Janoski AH. Gynecomastia as a presenting sign of fibrolamellar carcinoma of the liver. Pediatrics 1988;82:379-82.  Back to cited text no. 4
    
5.
Soreide O, Czerniak A, Bradpiece H, Bloom S, Blumgart L. Characteristics of fibrolamellar hepatocellular carcinoma. A study of nine cases and a review of the literature. Am J Surg 1986;151:518-23.  Back to cited text no. 5
    
6.
Soyer P, Roche A, Levesque M. Fibrolamellar hepatocellular carcinoma presenting with obstructive jaundice. A report of two cases. Eur J Radiol 1991;13:196-8.  Back to cited text no. 6
    
7.
Eckstein RP, Bambach CP, Stiel D, Roche J, Goodman BN. Fibrolamellar carcinoma as a cause of bile duct obstruction. Pathology (Phila) 1988;20:326-31.  Back to cited text no. 7
    
8.
Ganeshan D, Szklaruk J, Kundra V, Kaseb A, Rashid A, Elsayes KM. Imaging features of fibrolamellar hepatocellular carcinoma. AJR Am J Roentgenol 2014;202:544-52.  Back to cited text no. 8
    
9.
Riehle KJ, Yeh MM, Yu JJ, Kenerson HL, Harris WP, Park JO, et al. mTORC1 and FGFR1 signaling in fibrolamellar hepatocellular carcinoma. Mod Pathol 2015;28:103-10.  Back to cited text no. 9
    
10.
Buckley AF, Burgart LJ, Kakar S. Epidermal growth factor receptor expression and gene copy number in fibrolamellar hepatocellular carcinoma. Hum Pathol 2006;37:410-4.  Back to cited text no. 10
    
11.
Abou-Alfa GK, Mayer R, Venook AP, O'Neill AF, Beg MS, LaQuaglia M, et al. Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma. Oncologist. 2020;25:e1837-45.  Back to cited text no. 11
    

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Correspondence Address:
Varun Mehta,
Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana - 141 001, Punjab
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_316_21



    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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