Fibrolamellar Hepatocellular Carcinoma

 

Abstract (less than 150 words)

Fibrolamellar carcinoma is a rare primary hepatocellular malignancy arising in non-cirrhotic livers of young individuals. Large solitary liver mass with non-specific symptoms are commonly noted at presentation. Characteristic histological features include large polygonal cells with abundant oncocytic cytoplasm and prominent nucleoli in the background of fibrolamellar collagenous stroma. Important differential diagnosis includes hepatocellular carcinoma and intrahepatic cholangiocarcinoma, which may be distinguished by a judicious panel of immunohistochemical studies, including CK7, CD68, Hep-par and -fetoprotein. Prognosis of fibrolamellar carcinoma is similar to the subset of classical hepatocellular carcinoma that occursin the absence of liver cirrhosisand is strongly correlated with tumor  resectability. Treatment options other than surgical resection include liver transplantation, chemotherapy and hepatic artery embolization. In this article, we review the clinical features, gross and microscopic pathology, differential diagnosis, treatment, and prognosis of this rare and interesting tumor.

Fibrolamellar carcinoma (FLC) is a unique primary hepatocellular malignancy, encompassing  patient demographics, risk factors and tumor markers distinct from that  of the classical hepatocellular carcinoma (HCC). Although the exact pathogenesis of FLCs remains to be elucidated, they lack oncogenic drivers (TP53 and CTNNB1 mutations) commonly found in hepatocellular carcinoma.(references: Kannangai R, Wang J, Liu QZ, Sahin F, Torbenson M. Survivin overexpression in hepatocellular carcinoma is associated with p53 dysregulation. International Journal of Gastrointestinal Cancer. 2005;35(1):53-60.

And Terris B, Pineau P, Bregeaud L, et al. Close correlation between β-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. Oncogene. 1999;18(47):6583-6588. ) While the distinct features of FLC were recognized from the first description by Edmondson in 1956¹, it was not until the 2010 edition of WHO classification of Tumors that FLC was assigned its own WHO classification code².

Clinical features

FLC comprises approximately 5% of all liver carcinomas³. FLC shows no gender predilection and typically presents as a large solitary mass(>10 cm in approximately 70% of patients) whereas classical HCC occurs with a male preponderancece and presents with smaller tumor sizes (< 10 cm in approximately 70% of patients)⁴. One of the most distinctive features of FLC is the unimodal age distribution between the teens and twenties⁵. More than 85% of the FLC occurs in individuals younger than 35 years of age^{5, 6}. This is in contrast to classical HCC, which typically presents in patients in their fifties and sixties (reference 8. Craig). However, it is worth noting that the most common liver cancer in children and young adults remains classical HCC (60-80 % of hepatic carcinomas in this age group)⁷.

Patients with FLC generally present with nonspecific symptoms, such as nausea, vomiting, abdominal discomfort and weight loss⁸. Major physical examination findings include palpable abdominal mass and/or hepatomegaly; however, a variety of unusual presentations have been reported, such as biliary obstruction, recurrent deep vein thrombosis and gynecomastia⁵. Imaging studies show solitary mass in the liver (Figure 1A). Lymphadenopathy is detected in 70% of the patients at presentation and nearly 50% of the patients eventually develop distant metastasis to various sites, including mediastinum, ovary, pericardium and ovary⁴. Serum levels of transaminases (ASL, ALT) and alkaline phosphatase can be elevated⁸, and reference 5. Serum -fetoprotein level is typically normal except for 5-10% of the reported cases in which the -fetoprotein level is greater than 200 ng/ ml^{9, 10}. Other serum findings include elevated Vitamin B12 binding capacity (transcobalamin I and II), increased fibrinogen, neurotensin and Des-gamma carboxyprothrombin (DCP)⁵.

Pathological features

Macroscopically, FLC typically presents as a heterogenous and well-circumscribed mass in a noncirrhotic background. The mass is pale tan or yellow  in color and has variable firmness (Figure 1B). Central scar and calcification are found in approximately 70 % of the cases¹¹. At the time of resection, the tumor is generally large (9-14 cm in greatest dimension) and vascular invasion is frequently detected (25% for gross vascular invasion and 50% for microscopic vascular invasion)¹².

Microscopically, the tumor is composed oflarge polygonal cells with prominent nucleolus, well-delineated cell borders,  and abundant granular eosinophilic cytoplasm, arranged in nests, cords, and trabeculae surrounded by thin parallel bands of fibrosis (lamellar fibrosis) (Figure 1C). The bands of layered collagen can coalesced to formed thick septa and scars.(reference 8:  craig paper).  The oncocytic appearance to the cytoplasm reflects the abundance of mitochondria at the ultrastructural level (reference 8:  craig paper).  Occasional neuroendocrine features, including positivity for chromogranin which could account for neuroendocrine differentiation in some cases¹³.  Bile production is frequently noted, confirming the tumor’s hepatocellular origin.  Copper accumulation secondary to the cholestasis is well described in this tumor. (reference: Lefkowitch JH, Muschel R, Price JB, Marboe C, Braunhut S. Copper and copper-binding protein in fibrolamellar liver cell carcinoma. Cancer. 1983;51(1):97-100. Have to Quote Jay L in our paper :).  The malignant cells are generally moderately differentiated with an average size 3 times that of normal hepatocytes and 1.6 times that of malignant cells in a well-differentiated HCC^{5, 8}.

In approximately half of the cases, the tumor cells can contain discrete round to oval, pale, amphophilic cytoplasmic inclusions, so called “pale bodies”)⁸, which stain positive for for fibrinogen. Smaller eosinophilic inclusions, termed hyaline bodies are also found in approximately half of the cases (Figure 1D)⁸. Despite their distinct histologic appearance,  pale bodies and hyaline bodies are not specific for FLC and should not be used as diagnostic criteria⁵. Emphasis is placed on on cytology and lamellar fibrosis for the diagnosis of this tumor.  Of note, FLC could present with other pathological variants, such as clear cell carcinoma and pseudoglandular-like tumor with mucin production¹⁴.

Differential diagnosis

Despite major clinical and histologic differences between FLC and classical HCC, a fair number of FLC cases could be misdiagnosed as HCC especially when serum -fetoprotein is elevated. Conversely, a significant number of HCCs may show focal areas with features of FLC^{3, 5}. Immunohistochemical studies may be helpful in differentiating FLC from classical HCC in these scenarios (see below for discussion). Importantly, any FLC with poorly-differentiated histology should prompt careful re-examination as most FLC are well to moderately differentiated⁵. In young female patients with a history of estrogen-progesterone use, focal nodular hyperplasia (FNH) should be considered because central stellate scar could exist in both FLC and FNH⁴. However, FNH exhibits prominent ductular reaction at the interface between fibrous septa and normal parenchyma. In children with suspected FLC, hepatoblastoma and mesenchymal harmatoma should be considered in the differential diagnosis³.

Immunophenotypic features

A small panel of immunohistochemical studies comprised of CK7, CD68, HepPar and -fetoprotein immunohistochemical stains are helpful in confirming the diagnosis of FLC.

CK7 staining is highly sensitive (100%) for FLC; however, CK7 positivity is seen could express in approximately 30% of HCC cases. EMA showed similar sensitivity profiles for FLC and HCC but it is expressed non-specifically in 43 % of the adjacent normal tissue in FLC cases⁹. CD68, a transmembrane protein expressed in lysosomal and endosomal organelles prominent in macrophages is expressed uniquely in FLC. CD68 positivity is highly sensitive (96%) and specific (80%) for FLC; the negative predictive value is 98%¹⁵. Of note, CD68 staining in sinusoidal Kupffer cells in background non-neoplastic liver parenchyma can serve as an internal control for this immunohistochemical stain. Given the high sensitivity of the these markers, double negative CK7 and CD68 immunohistochemical stains would likely exclude a diagnosis of FLC.

FLCs are reported in literature to be negative for -fetoprotein^{4, 9}. In our experience, -fetoprotein often exhibits high background staining; however, a true positive stain in the lesional cells should prompt re-consideration of the FLC diagnosis. HepPar, an antigen discovered on hepatoid and hepatocellular neoplasms, is expressed in both FLC and classical HCC. HepPar staining is useful in differentiating FLC with pseudoglandular pattern from intrahepatic cholangiocarcinoma, both of which are CK7 positive. In our experience, arginase is another immunohistochemical stain that serves similar purpose as HepPar in our arsenal of immunohistochemical studies. Of note, occasional positivity for chromogranin is reported in FLC. Overall, it is recommended that potential FLC cases should be confirmed with CK7 and CD68 immunostaining^{5, 9, 15}.

Treatment and prognosis

The key to successful management of FLC is early diagnosis followed by surgical resection. Statistics comparing 5-year survival of unresected and resected FLC varies (0-39% and 63-76% respectively) but show convincingly that resected patients have significantly better prognosis than non-resected patients^{10, 16}. With more than 50% of recurrent liver and metastatic diseases, aggressive surgical resection and lymphadectomy should be considered. Furthermore, resection of metastatic disease may be beneficial ¹⁷. When partial hepatectomy is not feasible due to deep invasion and adhesion, orthotopic liver transplant may be considered¹⁸.

Chemotherapy may be beneficial in cases of inoperable FLC. Commonly used chemotherapy agents include cisplatium, epirubicin, 5-fluorouracil and recombinant interferon alpha-2b ^{3, 19, 20}. FLC does not respond to chemotherapy as well as classical HCC²¹. For patients who are not candidates for surgical resection or liver transplantation and not responsive to chemotherapy, hepatic artery embolization could be an alternative treatment option²².

Metastasis status is an important prognostic factor because it would affect surgical options. 5-year survival rates for patients with and without metastasis at presentation are 39% and 86% respectively⁴. Whereas gender, tumor sizes, atypia and cellular proliferation do not appear to correlate with survival, liver cirrhosis is a well-recognized adverse prognostic factor³. FLC patients and HCC patients without underlying cirrhosis exhibit similar 5-year (45 vs 56%) and overall (40 vs 56.3%) survival but better than those with cirrhosis (5-year and overall survival are 27% and 23.3%). When no metastatic disease is noted at presentation, 5-year survival is similar in FLC and non-cirrhotic HCC patients (62 vs 57%) and significantly better than cirrhotic HCC patients (27%)⁴.

Conclusion

FLC is a rare but aggressive liver neoplasm and it should be considered in the differential diagnosis in young individuals without liver cirrhosis. Clinical symptoms are generally non-specific. Characteristic histological and immunological features should establish the diagnosis. An early accurate diagnosis allows appropriate therapy and surgical resection remains one of the most important prognostic factors.

Figures and table (no more than 8)

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