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Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar Hepatocellular Carcinoma of Liver

Fibrolamellar hepatocellular carcinoma (FHC) is one of many types of hepatocellular carcinoma. It is usually diagnosed in adolescents or young adults without a history of chronic liver disease. Its etiology remains elusive, but the DNAJB1-PRKACA fusion gene has been identified as a constant genetic feature of FHC that may be involved in the pathogenesis of the tumor. Affected individuals may be cured by means of tumor resection or liver transplantation.


Presentation

Most patients remain asymptomatic for prolonged periods of time. Those who do develop symptoms may present with non-specific upper abdominal pain, loss of appetite and weight. Early satiety, nausea, and vomiting may result from space-occupying tumors that interfere with the gastrointestinal transit. Furthermore, FHC patients may describe malaise and weakness [1]. Liver-specific symptoms such as jaundice may be observed in advanced stages of the disease but are reported in <5% of all cases [2] [3].

Fatigue
  • This hypervascular tumor is radiographically characterized by a central scar. 1 Most patients experience vague abdominal pain, weight loss, and fatigue.[mdedge.com]
  • FLC generally present with a nonspecific clinical signs and symptoms, which include abdominal pain, fatigue, malaise and weight loss. Overall the most common physical finding is an abdominal mass or hepatomegaly.[medresearch.in]
  • Side effects can include: fatigue, rash, decreased appetite, diarrhea, pain, bleeding, blistering of hands and feet, and holes in the stomach or intestine. Immunotherapy.[webmd.com]
  • Many patients complain of abdominal pain and fatigue, which can be caused by a multitude of things in the pediatric and adolescent population including the flu and a gastrointestinal virus.[fibroregistry.org]
Constitutional Symptom
  • Presentation is non-specific, with constitutional symptoms and occasionally gynecomastia due to elevated estrone levels 1. Hepatomegaly is usually evident as these masses are typically large.[radiopaedia.org]
Abdominal Pain
  • A 6-year-old Malay boy presented with fever and abdominal pain for 2 months. Computerised tomography showed a nodular mass in the left lobe of the liver. There was also portal vein thrombosis on the left side.[ncbi.nlm.nih.gov]
  • Common symptoms included a palpable mass, abdominal pain and weight loss; two patients presented jaundice. In two patients the tumor had been removed eight and three years previously, and they were readmitted when FLHCC recurred.[ncbi.nlm.nih.gov]
  • In this case, the patient presented with a common complaint of abdominal pain but was found to have this rare diagnosis.[shmabstracts.com]
  • FLC typically presents with vague abdominal pain, nausea, abdominal fullness, malaise, and weight loss.[cancertherapyadvisor.com]
Abdominal Tenderness
  • An 18-year-old female patient was admitted with ascites, right upper abdominal tenderness and peripheral edema. Angiography showed complete occlusion of the vena cava inferior up to the level of the right atrium.[ncbi.nlm.nih.gov]
Arthritis
  • The spectrum of diseases, in which dysregulation of epigenetic processes occurs is equally wide: it includes, apart from cancer, autoimmunological diseases (e.g. rheumatoid arthritis, multiple sclerosis, diabetes type 1), neurodegenerative disorders,[omicsonline.org]
Forgetful
  • Portmann, Not to Forget the Unusual Tumour, Clinical Dilemmas in Primary Liver Cancer, (53-59), (2011).[doi.org]

Workup

Most FHC patients are adolescents or adults younger than 40 years, and they don't have a history of chronic liver disease like viral hepatitis and liver cirrhosis [1] [4]. The absence of a medical history of liver disease and the lack of symptoms during early stages of FHC development mean that the majority of FHC have grown to a considerable size before being detected [1]. In a recent study comprising about 20 primary FHC, the mean diameter of tumors at the time of diagnosis was 11 cm [5]. Nevertheless, >40% of FHC patients present with localized disease [6].

The localization, number, and size of liver tumors are assessed with distinct imaging techniques. Sonography is widely available and easy to use, so it is generally employed to clarify whether there are mass lesions in the liver [2]. Any suspicious finding requires further characterization by means of high-resolution computer tomography or magnetic resonance imaging. The latter techniques are also employed to assess for the presence of lymph node and distant metastases. Positron emission tomography has little sensitivity for the detection of FHC [1]. In general, FHC appear as heterogenous mass lesions that may surround a central stellate scar and include calcifications. Radiating fibrotic bands may be recognized [3]. Contrast enhancement is frequently described [2].

Still, the diagnosis of FHC requires the histological examination of tissue samples. FHC consist of large, polygonal tumor cells with abundant granular, eosinophilic cytoplasm. These cells have round nuclei with prominent nucleoli. Pale bodies and hyaline bodies may be observed in the cytoplasm [3]. Bile canaliculi may be dilated and filled with bile, justifying the diagnosis of intratumoral cholestasis. Pseudoglands are also common. Abundant collagen deposits forming parallel bands give the tumor a lamellar appearance and are the cause of its denomination as a fibrolamellar carcinoma. It should be noted, though, that collagen fibers in FHC may also be arranged in a disordered manner. While the total absence of intratumoral fibrosis suggests another type of hepatocellular carcinoma, FHC may contain areas with little or no fibrosis [7].

Immunostaining is recommended to support the histological diagnosis of FHC. This type of hepatocellular carcinoma stains positive for cytokeratin 7 and CD68 [5]. Furthermore, FHC samples should test positive for markers of hepatic differentiation like Hep Par-1, arginase-1, and albumin [3] [7]. Staining for glypican-3 yields positive results in about 50% of all cases. FHC don't usually express α-fetoprotein, which is reflected in normal or slightly elevated serum levels of this marker. In FHC patients, serum concentrations of α-fetoprotein don't exceed 200 ng/ml [7]. Similarly, the concentrations of hepatic transaminases and other liver enzymes are within reference ranges or slightly increased [1].

Because the DNAJB1-PRKACA fusion gene is specific for FHC, molecular biological studies may be realized to confirm the tentative diagnosis of FHC. They are particularly useful to clear doubts arising from uncertain histological results. In this context, real-time polymerase chain reaction and fluorescent in situ hybridization may be carried out on tissue samples obtained by biopsy, during tumor resection or transplantation [5].

Right Pleural Effusion
  • Imaging Findings CT images of the chest demonstrated mild dependent edema and a small, right pleural effusion. There was no evidence of a pulmonary embolus or of nodules, which would suggest metastatic disease.[pubs.rsna.org]
Brain Edema
  • Timely diagnosis and pathophysiology-guided treatment can prevent not only serious neurological complications, such as brain edema, seizures, and permanent neurological damage, but also allow continuation of potentially life-saving cancer treatment.[ncbi.nlm.nih.gov]

Treatment

FHC is a potentially curable disease [8]. The complete resection of the tumor and liver transplantation may result in cure, but FHC doesn't usually respond to chemotherapy [4]. About half of FHC patients have lymph node metastases at the time of diagnosis, so lymph node dissection should be part of the surgical intervention. Most commonly, FHC metastasize to the hilar lymph nodes and to the lymph nodes in the hepatoduodenal ligament, but mediastinal, retroperitoneal, and pelvic nodes may also be affected. Despite all efforts, recurrence is common: It affects more than half of FHC patients. Those diagnosed with recurrent FHC are recommended surgical resection again, although the complete resection of the tumor may be difficult to achieve depending on the site of recurrence. FHC are frequently reported to recur at extrahepatic sites. Distant metastases are most commonly detected in the lungs, peritoneum, adrenal glands, and bones [1] [3].

Protein kinase A may constitute a therapeutic target in FHC patients [4] [9]. Clinical trials are currently carried out to assess the efficacy of known and novel kinase inhibitors like sorafenib and ENMD-2076 [10] [11]. Furthermore, inhibitors of mammalian target of rapamycin like everolimus are tested in patients with advanced FHC [10].

Prognosis

The presence of lymph node metastases at the time of diagnosis has been identified as an important prognostic factor: Five-year survival rates approximate 100% in node-negative FHC patients but are significantly lower in node-positive individuals [3]. In sum, patients diagnosed with FHC have a better prognosis than those suffering from non-fibrolamellar hepatocellular carcinoma: 30-40% of affected individuals remain alive five years after the initial diagnosis and regardless of the presence of lymph node metastases [3] [6]. The median overall survival time of FHC patients has been reported to be 39 months [8].

Etiology

In 2014, Honeyman et al. examined a series of tissue samples derived from primary FHC, recurrences, and metastases, and identified a chimeric transcript that is expressed by tumor cells but not by adjacent hepatocytes [4]. This transcript has been found to be the result of a specific deletion on chromosome 19 that encompasses about 400 kb. The transcript consists of the N-terminal domain of DnaJ family member B1 and the C-terminal domain of cAMP-activated catalytic subunit α of protein kinase A. They are encoded by exon 1 of the DNAJB1 gene and by exons 2-10 of the PRKACA gene, respectively. The chimeric protein retains kinase activity but is missing the regulatory subunits of protein kinase A: Due to the deletion of exon 1 of the PRKACA gene, they are unable to bind to the respective catalytic subunit [4]. In 2015, it has been stated that the 400-kb deletion on chromosome 19 that results in the DNAJB1-PRKACA gene fusion is specific for FHC [5].

ARG2 overexpression is another feature of FHC [3]. Otherwise, FHC is a chromosomally stable and homogenous tumor. By contrast, conventional hepatocellular carcinoma is characterized by chromosomal and epigenetic instability. Mutations in genes AFP, BIRC5, CTNNB1, and TP53, which are frequently found in non-fibrolamellar types of hepatocellular carcinoma, have not been detected in FHC [3].

Epidemiology

The annual incidence of FHC has been estimated to be 1 in 5,000,000 inhabitants, rendering this type of hepatocellular carcinoma a rare disease. FHC accounts for <1% of hepatic malignancies, but for about 13% of cases of primary liver cancer diagnosed in patients aged <40 years. The patients' mean age at the time of diagnosis is 39 years, and the disease affects women and men equally [6].

Sex distribution
Age distribution

Pathophysiology

Little is known about the pathophysiological events leading to FHC development, but the deletion of part of chromosome 19, as explained above, is assumed to play a major role in this process. Under physiological conditions, protein kinase A is a heterotetramer consisting of regulatory and catalytic subunits. The catalytic subunits remain inactive until cAMP causes their dissociation from the regulatory subunits. To begin with, this regulatory mechanism requires that the regulatory subunits bind to the catalytic subunits. The respective domain of the catalytic subunit α is encoded by exon 1 of the PRKACA, which is not part of the DNAJB1-PRKACA fusion gene [4]. Thus, the regulatory mechanism is canceled in FHC patients and increased activity of protein kinase A can be measured in FHC tumor cells. Since protein kinase A is involved in the regulation of cell growth and differentiation as well as apoptosis, it seems feasible that its constitutive activity may lead to tumor development.

However, the experimental overexpression of wild-type PRKACA didn't result in cancerogenesis [9]. This finding suggests that the fusion of genes DNAJB1 and PRKACA is not the only requisite for the development of FHC. In this context, a possible dysregulation of the Wnt/β-Catenin pathway has been discussed, but mutations in the CTNNB1 gene are not characteristic of FHC [3].

Prevention

Since etiology and pathogenesis of FHC remain largely unknown, no recommendations can be given to prevent the development of this type of hepatocellular carcinoma.

Summary

Hepatocellular carcinoma is the most common malignancy of the liver. It originates from degenerated hepatocytes and is often developed by patients suffering from chronic liver diseases such as hepatitis b, hepatitis c, alcoholic and non-alcoholic steatohepatitis, and liver cirrhosis. There are distinct triggers of hepatic cancerogenesis and the pathophysiological events preceding the development of hepatocellular carcinoma may vary from patient to patient. Accordingly, several types of hepatocellular carcinoma have been described, and they differ with regards to their morphological and genetic features. Current research focusses on identifying the molecular background of certain types of hepatocellular carcinoma and designing molecular targeted therapies. Furthermore, the specific type of hepatocellular carcinoma may be associated with better or worse responsiveness to determined therapies and may imply a more or less favorable prognosis for the affected individual [7].

There are more than a dozen types of hepatocellular carcinoma, one of them being FHC. FHC is different from other types of hepatocellular carcinoma in that it only develops in non-cirrhotic livers [7]. It is mainly diagnosed in adolescents and young adults without a history of chronic liver disease, and it is associated with a better prognosis than conventional hepatocellular carcinoma [4] [6]. The etiology of FHC remains elusive, but a putative driver mutation on chromosome 19 has recently been identified as a specific feature of this type of hepatocellular carcinoma [5]. In detail, the deletion of 400 kb on the short arm of chromosome 19 results in the in the DNAJB1-PRKACA gene fusion [4].

Patient Information

Hepatocellular carcinoma is the most common form of liver cancer. More than a dozen types of hepatocellular carcinoma are distinguished, one of them being fibrolamellar hepatocellular carcinoma (FHC). FHC is usually diagnosed in adolescents and young adults who don't have a history of chronic liver disease or alcohol abuse, which are the main triggers of the development of other types of hepatocellular carcinoma. The causes of FHC are the subject of intense research but remain largely unclear. A deletion of a determined part of the DNA sequence composing chromosome 19 has recently been described as a specific feature of FHC tumor cells, but it is not yet clear how this mutation is caused.

Affected individuals may suffer from early satiety, nausea, and vomiting, may describe malaise and weakness. FHC patients often lose their appetite and weight. All these symptoms are non-specific and don't allow for the diagnosis of liver cancer. Diagnostic imaging has to be carried out to visualize mass lesions in the liver and to check whether the tumor has already metastasized to the regional lymph nodes or distant organs. For the diagnosis of FHC, tissue samples have to be obtained by means of biopsy or surgery, and they have to be examined under the microscope.

Surgery is the mainstay of treatment. If the tumor can be removed entirely, FHC patients have a favorable prognosis. The outcome is worse if the tumor can't be removed. Liver transplantation may be required and constitutes another chance for cure. Due to the rarity of the disease, information regarding the efficacy of chemotherapy or molecular targeted therapy is scarce. Patients who are diagnosed with advanced-stage FHC may be included in clinical trials to augment their chances of survival, but the prognosis of individuals suffering from non-resectable, metastatic liver cancer is poor.

References

Article

  1. Lim, II, Farber BA, LaQuaglia MP. Advances in fibrolamellar hepatocellular carcinoma: a review. Eur J Pediatr Surg. 2014; 24(6):461-466.
  2. Estrella Diez E, Álvarez Higueras FJ, Marín Zafra G, et al. Fibrolamellar hepatocellular carcinoma: a rare entity diagnosed by abdominal ultrasound. Rev Esp Enferm Dig. 2016; 108(8):494-495.
  3. Ganeshan D, Szklaruk J, Kundra V, Kaseb A, Rashid A, Elsayes KM. Imaging features of fibrolamellar hepatocellular carcinoma. AJR Am J Roentgenol. 2014; 202(3):544-552.
  4. Honeyman JN, Simon EP, Robine N, et al. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014; 343(6174):1010-1014.
  5. Graham RP, Jin L, Knutson DL, et al. DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 2015; 28(6):822-829.
  6. El-Serag HB, Davila JA. Is fibrolamellar carcinoma different from hepatocellular carcinoma? A US population-based study. Hepatology. 2004; 39(3):798-803.
  7. Torbenson MS. Morphologic Subtypes of Hepatocellular Carcinoma. Gastroenterol Clin North Am. 2017; 46(2):365-391.
  8. Mavros MN, Mayo SC, Hyder O, Pawlik TM. A systematic review: treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma. J Am Coll Surg. 2012; 215(6):820-830.
  9. Kastenhuber ER, Lalazar G, Houlihan SL, et al. DNAJB1-PRKACA fusion kinase interacts with beta-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2017; 114(50):13076-13084.
  10. Bill R, Montani M, Blum B, Dufour JF, Escher R, Buhlmann M. Favorable response to mTOR inhibition in a young patient with unresectable fibrolamellar carcinoma of the liver. Hepatology. 2018.
  11. Borisa AC, Bhatt HG. A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies. Eur J Med Chem. 2017; 140:1-19.

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Last updated: 2019-07-11 19:58