Authors: Chun-Chieh Lin, MD, PhD; Hui-Min Yang, MD
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY
Abstract (significantly less than 150 words)
Fibrolamellar carcinoma is a rare primary hepatocellular malignancy arising in non-cirrhotic livers of little individuals. Significant solitary liver mass with non-specific symptoms are commonly noted at demonstration. Characteristic histological features contain large polygonal cells with abundant oncocytic cytoplasm and prominent nucleoli in the background of fibrolamellar collagenous stroma. Important differential analysis includes hepatocellular carcinoma and intrahepatic cholangiocarcinoma, which might be distinguished by a judicious panel of immunohistochemical studies, including CK7, CD68, Hep-par and ï¡-fetoprotein. Prognosis of fibrolamellar carcinoma is similar to the subset of classical hepatocellular carcinoma that occursin the lack of liver cirrhosisand is strongly correlated with tumorÂ resectability. Treatment plans other than medical resection involve liver transplantation, chemotherapy and hepatic artery embolization. On this page, we review the scientific features, gross and microscopic pathology, differential analysis, treatment, and prognosis of this exceptional and interesting tumor.
Fibrolamellar carcinoma (FLC) is definitely a unique main hepatocellular malignancy, encompassingÂ affected individual demographics, risk elements and tumor markers distinct from thatÂ of the classical hepatocellular carcinoma (HCC). Although the specific pathogenesis of FLCs remains to come to be elucidated, they lack oncogenic motorists (TP53 and CTNNB1 mutations) commonly within 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 Malignancy. 2005;35(1):53-60.
And Terris B, Pineau P, Bregeaud L, et al. Close correlation between Î²-catenin gene alterations and nuclear accumulation of the necessary protein in human being hepatocellular carcinomas. Oncogene. 1999;18(47):6583-6588. ) While the distinct features of FLC were acknowledged from the first information by Edmondson in 19561, it had been not until the 2010 edition of WHO classification of Tumors that FLC was designated its own WHO classification code2.
FLC comprises approximately 5% of most liver carcinomas3. FLC displays no gender predilection and commonly presents as a sizable solitary mass(>10 cm in around 70% of sufferers) whereas classical HCC comes about with a male preponderancece and presents with smaller sized tumor sizes (< 10 cm in about 70% of sufferers)4. One of the most distinctive top features of FLC may be the unimodal age distribution between your teens and twenties5. A lot more than 85% of the FLC occurs in individuals young than 35 years of age5, 6. That is in contrast to classical HCC, which typically presents in patients within their fifties and sixties (reference 8. Craig). However, it is worth noting that the most typical liver cancer in kids and young adults remains classical HCC (60-80 % of hepatic carcinomas in this generation)7.
Patients with FLC generally present with nonspecific symptoms, such as for example nausea, vomiting, abs discomfort and weight loss8. Major physical examination results include palpable stomach mass and/or hepatomegaly; however, a number of unusual presentations have already been reported, such as biliary how to write an opinion essay obstruction, recurrent deep vein thrombosis and gynecomastia5. Imaging studies show solitary mass in the liver (Figure 1A). Lymphadenopathy is usually detected in 70% of the patients at presentation and almost 50% of the patients ultimately develop distant metastasis to several sites, incorporating mediastinum, ovary, pericardium and ovary4. Serum degrees of transaminases (ASL, ALT) and alkaline phosphatase could be elevated8, and reference 5. Serum ï¡-fetoprotein level is typically normal except for 5-10% of the reported cases in which the ï¡-fetoprotein level is higher than 200 ng/ ml9, 10. Other serum findings include elevated Supplement B12 binding ability (transcobalamin I and II), elevated fibrinogen, neurotensin and Des-gamma carboxyprothrombin (DCP)5.
Macroscopically, FLC commonly presents as a heterogenous and well-circumscribed mass in a noncirrhotic history. The mass can be pale tan or yellowÂ in color and has variable firmness (Number 1B). Central scar and calcification are located in approximately 70 %70 % of the cases11. At the time of resection, the tumor is normally large (9-14 cm in biggest dimension) and vascular invasion is generally detected (25% for gross vascular invasion and 50% for microscopic vascular invasion)12.
Microscopically, the tumor is made up oflarge polygonal cells with prominent nucleolus, well-delineated cell borders,Â and abundant granular eosinophilic cytoplasm, arranged in nests, cords, and trabeculae surrounded by slim parallel bands of fibrosis (lamellar fibrosis) (Figure 1C). The bands of layered collagen can coalesced to formed heavy septa and scars.(reference 8:Â craig paper).Â The oncocytic appearance to the cytoplasm displays the abundance of mitochondria at the ultrastructural level (reference 8:Â craig paper).Â Occasional neuroendocrine features, incorporating positivity for chromogranin which could take into account neuroendocrine differentiation in a few cases13.Â Bile production is generally noted, confirming the tumor’s hepatocellular origin.Â Copper accumulation secondary to the cholestasis is definitely well explained in this tumor. (reference: Lefkowitch JH, Muschel R, Cost 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 inside our paper :).Â The malignant cells are usually moderately differentiated with an average size 3 times that of typical hepatocytes and 1.6 occasions that of malignant cells in a well-differentiated HCC5, 8.
In approximately half of the situations, the tumor cells can contain discrete round to oval, pale, amphophilic cytoplasmic inclusions, hence known as "pale bodies")8, which stain great for for fibrinogen. Small eosinophilic inclusions, termed hyaline bodies will be also found in approximately half of the cases (Number 1D)8. Despite their specific histologic appearance,Â 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 the tumor.Â Of notice, FLC could present with other pathological variants, such as apparent cell carcinoma and pseudoglandular-like tumor with mucin production14.
Despite major medical and histologic distinctions between FLC and classical HCC, a fair number of FLC instances could possibly be misdiagnosed as HCC especially when serum ï¡-fetoprotein can be elevated. Conversely, a significant amount of HCCs may show focal areas with features of FLC3, 5. Immunohistochemical studies could be beneficial in differentiating FLC from classical HCC in these scenarios (see below for conversation). Significantly, any FLC with poorly-differentiated histology should prompt very careful re-examination as most FLC are well to moderately differentiated5. In young female people with a brief history of estrogen-progesterone employ, focal nodular hyperplasia (FNH) is highly recommended because central stellate scar could exist in both FLC and FNH4. However, FNH exhibits prominent ductular reaction at the user interface between fibrous septa and common parenchyma. In kids with suspected FLC, hepatoblastoma and mesenchymal harmatoma should be considered in the differential diagnosis3.
A small panel of immunohistochemical analyses made up of CK7, CD68, HepPar and ï¡-fetoprotein immunohistochemical staining are helpful in confirming the analysis of FLC.
CK7 staining is extremely delicate (100%) for FLC;
however, CK7 positivity is seen could express in roughly 30% of HCC conditions. EMA showed similar sensitivity profiles for FLC and HCC nonetheless it is expressed non-especially in 43 % of the adjacent normal cells in FLC cases9. CD68, a transmembrane proteins expressed in lysosomal and endosomal organelles prominent in macrophages is certainly expressed uniquely in FLC. CD68 positivity is highly very sensitive (96%) and specific (80%) for FLC; the unfavorable predictive value is 98%15. Of note, CD68 staining in sinusoidal Kupffer cells in backdrop non-neoplastic liver parenchyma can serve as an internal control for this immunohistochemical stain. Given the great sensitivity of the these markers, double adverse CK7 and CD68 immunohistochemical stains would likely exclude a analysis of FLC.
FLCs will be reported in literature to come to be detrimental for ï¡-fetoprotein4, 9. Inside our experience, ï¡-fetoprotein sometimes exhibits high background staining; however, a genuine great stain in the lesional cells should prompt re-account of the FLC analysis. HepPar, an antigen discovered on hepatoid and hepatocellular neoplasms, can be expressed in both FLC and classical HCC. HepPar staining is useful in differentiating FLC with pseudoglandular routine from intrahepatic cholangiocarcinoma, both of which are CK7 positive. In our experience, arginase can be another immunohistochemical stain that serves similar purpose as HepPar in our arsenal of immunohistochemical studies. Of note, occasional positivity for chromogranin is normally reported in FLC. Overall, it is strongly recommended that potential FLC conditions should be confirmed with CK7 and CD68 immunostaining5, 9, 15.
Treatment and prognosis
The key to effective administration of FLC is early diagnosis accompanied by surgical resection. Statistics comparing 5-yr survival of unresected and resected FLC differs (0-39% and 63-76% respectively) but show convincingly that resected clients have substantially better prognosis than non-resected patients10, 16. With an increase of than 50% of recurrent liver and metastatic diseases, aggressive surgical resection and lymphadectomy is highly recommended. Furthermore, resection of metastatic disease may be useful 17. When partial hepatectomy is not feasible because of deep invasion and adhesion, orthotopic liver transplant may be considered18.
Chemotherapy may be beneficial in conditions testmyprep of inoperable FLC. Typically used chemotherapy agents include cisplatium, epirubicin, 5-fluorouracil and recombinant interferon alpha-2b 3, 19, 20. FLC does not respond to chemotherapy together with classical HCC21. For patients who aren’t candidates for medical resection or liver transplantation rather than responsive to chemotherapy, hepatic artery embolization could be an alternative treatment option22.
Metastasis status is an important prognostic factor since it would affect surgical options. 5-year survival rates for individuals with and without metastasis at presentation are 39% and 86% respectively4. Whereas gender, tumor sizes, atypia and cellular proliferation do not may actually correlate with survival, liver cirrhosis can be a well-accepted adverse prognostic factor3. FLC sufferers and HCC people without underlying cirrhosis exhibit comparable 5-12 months (45 vs 56%) and overall (40 vs 56.3%) survival but much better than those with cirrhosis (5-year and overall survival happen to be 27% and 23.3%). When no metastatic disease is usually noted at demonstration, 5-year survival is comparable in FLC and non-cirrhotic HCC patients (62 vs 57%) and drastically better than cirrhotic HCC patients (27%)4.
FLC is a exceptional but aggressive liver neoplasm and it must be regarded in the differential diagnosis in young persons without liver cirrhosis. Clinical symptoms are usually non-particular. Characteristic histological and immunological features should build the diagnosis. An early accurate diagnosis allows ideal therapy and medical resection remains among the most crucial prognostic factors.
Figures and table (no more than 8)
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