Fibrolamellar carcinoma of the liver: An immunohistochemical study of nineteen cases and a review of the literature

doi:10.1016/S0046-8177(88)80261-2

Human Pathology

Volume 19, Issue 7, July 1988, Pages 784-794

https://doi.org/10.1016/S0046-8177(88)80261-2 Get rights and content

Hepatocellular carcinoma (HCC) is a rapidly fatal neoplasm ofhigh worldwide prevalence. Fibrolamellar carcinoma (FLC), a variant of HCC, lacks the dismal prognosis of “ordinary” HCC (O-HCC) and is characterized by a diagnostic histologic appearance. The current study analyzes the clinical characteristics, immunohistochemistry, and treatment of nineteen cases of FLC. These data, together with a detailed review of the literature, further characterize this unique variant. FLC affects younger patients and lacks the male predominance of O-HCC. Also, FLC lacks specific association with cirrhosis, hepatitis B virus infection, use of oral contraceptives, and alcohol abuse, all of which are implicated in other hepatic tumors. This, along with differences in serum tumor marker prevalence (AFP, B₁₂ binding protein) suggests that its pathogenesis differs from that of O-HCC. Despite these differences, FLC shares a common differentiation with O-HCC. The increased, amounts in FLC of stainable α-1-antitrypsin, fibrinogen, and C-reactive protein, all of which are acute phase reactants and normal hepatocyte products, implies better differentiation of FLC cells. Finally, the better prognosis of FLC is supported by this study, since only two of the 19 patients died because of tumor. This contrasts with the reported survival of patients with O-HCC, usually measured in weeks. Hepatic transplantation may hold promise for future patients with “surgically unresectable” FLC as procedure-related complications are overcome.

References (125)

InouyeAA et al.
Primary liver cancer: A review of 205 cases in Hawaii
Am J Surg
(1979)
IhdeDC et al.
Clinical manifestations of hepatoma, review of 6 years' experience at a cancer hospital
Am J Med
(1974)
StengerRJ
Liver disease
Hum Pathol
(1977)
SoreideO et al.
Characteristics of fibrolamellar hepatocellular carcinoma, a study of nine cases and a review of the literature
Am J Surg
(1986)
NagorneyDM et al.
Fibrolamellar hepatoma
Am J Surg
(1985)
CollierNA et al.
Neurotensin secretion by fibrolamellar carcinoma of the liver
Lancet
(1984)
SlavutinLJ et al.
Case report: Hepatocellular carcinoma with lamellar fibrosis: an important histological variant
Pathology
(1981)
KeeleyAF et al.
Ultrastructure of hyaline cytoplasmic inclusions in a human hepatoma: relationship to Mallory's alcoholic hyalin
Gastroenterol
(1972)
ChlebowskiRT et al.
Hepatocellular carcinoma, diagnostic and prognostic features in North American patients
Cancer
(1984)
MaltzC et al.
Hepatocellular carcinoma: New directions in etiology
Am J Gastroenterol
(1980)

OonCJ et al.

Primary hepatocellular carcinoma: Present state of the disease and propects for the future

Cancer Chemother Pharmacol

(1982)

LaiCL et al.

Histologic prognostic indicators in hepatocellular carcinoma

Cancer

(1979)

LaiCL et al.

Clinical features of hepatocellular carcinoma: Review of 211 patients in Hong Kong

Cancer

(1981)

Al-SarrafM et al.

Primary liver cancer: A review of the clinical features, blood groups, serum enzymes, therapy, and survival of 65 cases

Cancer

(1974)

BengmarkS et al.

The natural history of primary carcinoma of the liver

Scand J Gastroenterol

(1971)

MacSweenRNM

A clinicopathological review of 100 cases of primary malignant tumours of the liver

J Clin Pathol

(1974)

El-DomeiriAA et al.

Primary malignant tumors of the liver

Cancer

(1971)

KewMC

Clinical, pathologic, and etiologic heterogeneity in hepatocellular carcinoma: Evidence from Southern Africa

Hepatology

(1981)

ZhaoyouT et al.

Small hepatocellular carcinoma, clinical analysis of 30 cases

Chin Med J

(1979)

ChanSH et al.

HLA antigen in Chinese patients with hepatocellular carcinomas

J Nat Cancer Inst

(1980)

AnthonyPP

Primary carcinoma of the liver: A study of 282 cases in Ugandan Africans

J Pathol

(1973)

DavidsonAR et al.

The variable course of primary hepatocellular carcinoma

Br J Surg

(1974)

PrimackA et al.

A staging system for hepatocellular carcinoma: Prognostic factors in Ugandan patients

Cancer

(1975)

EdmondsonHA

Differential diagnosis of tumors and tumorlike lesions of liver in infancy and childhood

Am J Dis Child

(1956)

BermanMM et al.

Hepatocellular carcinoma, polygonal cell, type with fibrous stroma: an atypical variant with a favorable prognosis

Cancer

(1980)

CraigJR et al.

Fibrolamellar carcinoma of the liver, a tumor of adolescents and young adults with distinctive clinicopathologic features

Cancer

(1980)

TeitelbaumDH et al.

Fibrolamellar carcinoma of the liver: Review of three cases and the presentation of a characteristic set of tumor markers defining this tumor

Ann Surg

(1985)

CaballeroT et al.

Fibrolamellar hepatocellular carcinoma-an immunohistochemical and ultrastructural study

Histopathology

(1985)

ParadinasFJ et al.

High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma

Br Med J

(1982)

StromeyerFW et al.

Ground-glass cells in hepatocellular carcinoma

Am J Clin Pathol

(1980)

LackEE et al.

Hepatocellular carcinoma review of 32 cases in childhood and adolescence

Cancer

(1983)

LefkowitchJH et al.

Copper and copper-binding protein in fibrolamellar liver cell carcinoma

Cancer

(1983)

FarhiDC et al.

Hepatocellular carcinoma in young people

Cancer

(1983)

VecchioFM et al.

Fibrolamellar carcinoma of the liver: The malignant counterpart of focal nodular hyperplasia with oncocytic change

Am J Clin Pathol

(1984)

WetzelWJ et al.

Fibrolamellar carcinoma: Distinctive clinical and morphologic variant of hepatoma

South Med J

(1983)

AlbaughJS et al.

Recurrent obstructive jaundice caused by fibrolamellar hepatocellular carcinoma

Dig Dis Sci

(1984)

BaithunSI et al.

Oncocytic hepatocellular tumour

Histopathology

(1983)

AlbukerkJ

Hepatocellular carcinoma in young adults

NY State J Med

(1981)

AnT et al.

Hyaline globules and intracellular lumina in a hepatocellular carcinoma

Am J Clin Pathol

(1983)

WongLK et al.

Fibrolamellar hepatocarcinoma: Radiology, management, and pathology

Am J Roentgenol

(1982)

GoodmanZD et al.

Hepatocellular carcinoma in women: Probable lack of etiologic association with oral contraceptive steroids

Hepatology

(1982)

ChuongJJH et al.

The histopathologic and clinical indicators of prognosis in hepatoma

J Clin Gastroenterol

(1982)

PayneCM et al.

Fibrolamellar carcinoma of liver: A primary malignant oncocytic carcinoid?

Ultrastruct Pathol

(1986)

OrdóñegNG et al.

Comparison of α-1-antitrypsin and α-1-antichymotrypsin in hepatocellular carcinoma: An immunoperoxidase study

Am J Gastroenterol

(1984)

FarhiDC et al.

Ultrastructure of fibrolamellar oncocytic hepatoma

Cancer

(1982)

Guix PericásM et al.

Hepatocarcinoma fibrolamelar

Gastroenterol Hepatol

(1983)

BorelB et al.

Le carcinome fibrolamellaire du foie, a propos d'une observation

Arch Anat Cytol Pathol

(1982)

ChouxR et al.

Un nouveau cas de carcinome fibrolamellaire du foie avec ultrastructure

Arch Anat Cytol Pathol

(1983)

MinarVE et al.

Sonderform eines hepatozellularen Karzinoms mit günstigem Verlauf

Z Gastroenterologie

(1982)

HsuSM et al.

The use of avidinbiotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures

J Histochem Cytochem

(1981)

Cited by (139)

Exploring the molecular pathogenesis, diagnosis and treatment of fibrolamellar hepatocellular carcinoma: A state of art review of the current literature
2023, Pathology Research and Practice
This paper aims to present a detailed overview of fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC) that accounts for approximately 1–9% of all cases a. according to the SEER database. Despite ongoing research, the aetiology of FLC tumours remains unclear. Nevertheless, FLC is believed to have a better overall prognosis than other primary liver tumours, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. This study aims to present a comprehensive overview of fibrolamellar carcinoma (FLC), with a focus on its epidemiology, pathogenesis, diagnosis, treatment, and prognosis. FLC frequently incorporate features of stomach pain, weight loss, and malaise in their clinical signs and symptoms, which are generally nonspecific Ultimately, the most common physical finding is an abdominal mass or hepatomegaly. With this said, several unusual presentations have been documented such as Budd Chiari syndrome, severe anaemia, non-bacterial thrombotic endocarditis and many more. In regards to this tumour’s genetic analysis, it is characterised by a 400 kb deletion on chromosome 19 leading to a functional DNAJB1-PRKACA chimeric transcript in addition to tetraploidy in 50% of cases. FLC is chromosomally stable as compared to typical HCC. mTOR pathway activation has also been found to play a critical role in 47% of these tumours and EFGR over-expression is also evident. Fibrolamellar carcinomas (FLCs) exhibit a distinctive gross appearance, characterized by a yellow to pale tan colour, with a consistency that can vary from soft to firm and hard. In addition, a central scar is observed in 60–70% of FLC cases. The central scar is typically white or grey in colour and has a fibrous appearance, which is often surrounded by nodular, tumour-like tissue. Its histologic appearance is characterized by large polygonal cells with abundant eosinophilic cytoplasm, large vesiculated nuclei, large nucleoli, and arranged in lamellar bands of collagen fibres. Lamellar bands of fibrosis, consisting of collagen type I, III and IV, have also been identified as a distinctive histologic feature that is observed under low power magnification. Ultrasound, CT and MRI along with image guided biopsy are the primary modalities in diagnosis. Current management options include systemic therapy which has thus far been unremarkable with platinum-based therapies as well combination therapy with interferon alpha-2b being the most successful options. Surgical resection remains the primary treatment modality and there have been no advances in targeted therapies. Although the prognosis for FLC is favourable as compared to other hepatic cancer subtypes such as intrahepatic cholangiocarcinoma, there is a high rate of recurrence ranging from 33% to 100% with a median recurrence-free survival of 20–48 months. As a result of this there is a low overall cure rate associated with this tumour type and much more research is required to gain an in-depth understanding of the molecular mechanisms occurring in order to provide more adequate treatment to patients who suffer from this condition
Tumours and Tumour-Like Lesions
2023, MacSween's Pathology of the Liver, Eighth Edition
This chapter presents a comprehensive approach to primary liver tumours as per the World Health Organization Classification of Liver Tumours 2019. The discussions include clinical features, aetiology and treatment summaries, as well as detailed gross pathology, histopathology and the use of up-to-date immunohistochemistry and molecular pathology in the diagnosis. Cytopathologic features, emphasizing fine-needle aspiration diagnosis, are also included. Numerous detailed tables and photographs of liver lesions highlight important diagnostic features. The immunohistochemical approach to aid in the identification of metastatic versus primary liver tumours is also discussed.
Tumours and Tumour-like Lesions of the Liver
2018, MacSween's Pathology of the Liver
CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma
2017, Gastroenterology
Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects children and young adults with no underlying liver disease. A somatic, 400 Kb deletion on chromosome 19 that fuses part of the DnaJ heat shock protein family (Hsp40) member B1 gene (DNAJB1) to the protein kinase cAMP-activated catalytic subunit alpha gene (PRKACA) has been repeatedly identified in patients with FL-HCC. However, the DNAJB1–PRKACA gene fusion has not been shown to induce liver tumorigenesis. We used the CRISPR/Cas9 technique to delete in mice the syntenic region on chromosome 8 to create a Dnajb1–Prkaca fusion and monitored the mice for liver tumor development.
We delivered CRISPR/Cas9 vectors designed to juxtapose exon 1 of Dnajb1 with exon 2 of Prkaca to create the Dnajb1–Prkaca gene fusion associated with FL-HCC, or control Cas9 vector, via hydrodynamic tail vein injection to livers of 8-week-old female FVB/N mice. These mice did not have any other engineered genetic alterations and were not exposed to liver toxins or carcinogens. Liver tissues were collected 14 months after delivery; genomic DNA was analyzed by PCR to detect the Dnajb1–Prkaca fusion, and tissues were characterized by histology, immunohistochemistry, RNA sequencing, and whole-exome sequencing.
Livers from 12 of the 15 mice given the vectors to induce the Dnajb1–Prkaca gene fusion, but none of the 11 mice given the control vector, developed neoplasms. The tumors contained the Dnajb1–Prkaca gene fusion and had histologic and cytologic features of human FL-HCCs: large polygonal cells with granular, eosinophilic, and mitochondria-rich cytoplasm, prominent nucleoli, and markers of hepatocytes and cholangiocytes. In comparing expression levels of genes between the mouse tumor and non-tumor liver cells, we identified changes similar to those detected in human FL-HCC, which included genes that affect cell cycle and mitosis regulation. Genomic analysis of mouse neoplasms induced by the Dnajb1–Prkaca fusion revealed a lack of mutations in genes commonly associated with liver cancers, as observed in human FL-HCC.
Using CRISPR/Cas9 technology, we found generation of the Dnajb1–Prkaca fusion gene in wild-type mice to be sufficient to initiate formation of tumors that have many features of human FL-HCC. Strategies to block DNAJB1–PRKACA might be developed as therapeutics for this form of liver cancer.
Fibrolamellar carcinoma: A histologically unique tumor with unique molecular findings
2017, Seminars in Diagnostic Pathology
Citation Excerpt :
However, neither of these cytoplasmic inclusions are specific to fibrolamellar carcinoma and their presence should not be equated with the diagnosis. Pale bodies are amphophilic, round cytoplasmic inclusions and are believed to be a mixture of acute phase reactants including fibringoen.14 Based on electron microscopy, the pale bodies appear to begin as intracellular lumina that fill up with these unsecreted acute phase reactant proteins, dilating and expanding to fill the cytoplasm as pale bodies.
Fibrolamellar carcinoma is a unique type of hepatocellular carcinoma with a distinctive predilection for young patients without underlying liver disease, characteristic large neoplastic cells with intervening, dense fibrosis, co-expression of keratin 7 and CD68 and activation of protein kinase A (most often by formation of DNAJB1-PRKACA). Fibrolamellar carcinoma has a similar prognosis to conventional hepatocellular carcinomas arising in non-cirrhotic livers. The current American Joint Cancer Committee staging system does not provide optimal stratification of patients with fibrolamellar carcinoma and an alternate systems should be considered in the future. The only effective treatment for fibrolamellar carcinoma is complete resection. Novel therapies may be on the horizon as investigation into the molecular biology of fibrolamellar carcinoma continues.
Scheuer’s Liver Biopsy Interpretation
2015, Scheuer's Liver Biopsy Interpretation

View all citing articles on Scopus

^a: Department of Pathology, Presbyterian-University Hospital

^b: University of Pittsburgh School of Medicine, Pittsburgh, Pa.

¹: Dr. Berman is the recipient of American Cancer Society Fellowship CF No. 86-232.

View full text

Fibrolamellar carcinoma of the liver: An immunohistochemical study of nineteen cases and a review of the literature

Am J Surg

Am J Med

Hum Pathol

Am J Surg

Am J Surg

Lancet

Pathology

Gastroenterol

Hepatocellular carcinoma, diagnostic and prognostic features in North American patients

Cancer

Hepatocellular carcinoma: New directions in etiology

Am J Gastroenterol

Primary hepatocellular carcinoma: Present state of the disease and propects for the future

Cancer Chemother Pharmacol

Histologic prognostic indicators in hepatocellular carcinoma

Cancer

Clinical features of hepatocellular carcinoma: Review of 211 patients in Hong Kong

Cancer

Primary liver cancer: A review of the clinical features, blood groups, serum enzymes, therapy, and survival of 65 cases

Cancer

The natural history of primary carcinoma of the liver

Scand J Gastroenterol

A clinicopathological review of 100 cases of primary malignant tumours of the liver

J Clin Pathol

Primary malignant tumors of the liver

Cancer

Clinical, pathologic, and etiologic heterogeneity in hepatocellular carcinoma: Evidence from Southern Africa

Hepatology

Small hepatocellular carcinoma, clinical analysis of 30 cases

Chin Med J

HLA antigen in Chinese patients with hepatocellular carcinomas

J Nat Cancer Inst

Primary carcinoma of the liver: A study of 282 cases in Ugandan Africans

J Pathol

The variable course of primary hepatocellular carcinoma

Br J Surg

A staging system for hepatocellular carcinoma: Prognostic factors in Ugandan patients

Cancer

Differential diagnosis of tumors and tumorlike lesions of liver in infancy and childhood

Am J Dis Child

Hepatocellular carcinoma, polygonal cell, type with fibrous stroma: an atypical variant with a favorable prognosis

Cancer

Fibrolamellar carcinoma of the liver, a tumor of adolescents and young adults with distinctive clinicopathologic features

Cancer

Fibrolamellar carcinoma of the liver: Review of three cases and the presentation of a characteristic set of tumor markers defining this tumor

Ann Surg

Fibrolamellar hepatocellular carcinoma-an immunohistochemical and ultrastructural study

Histopathology

High serum vitamin B12 binding capacity as a marker of the fibrolamellar variant of hepatocellular carcinoma

Br Med J

Ground-glass cells in hepatocellular carcinoma

Am J Clin Pathol

Hepatocellular carcinoma review of 32 cases in childhood and adolescence

Cancer

Copper and copper-binding protein in fibrolamellar liver cell carcinoma

Cancer

Hepatocellular carcinoma in young people

Cancer

Fibrolamellar carcinoma of the liver: The malignant counterpart of focal nodular hyperplasia with oncocytic change

Am J Clin Pathol

Fibrolamellar carcinoma: Distinctive clinical and morphologic variant of hepatoma

South Med J

Recurrent obstructive jaundice caused by fibrolamellar hepatocellular carcinoma

Dig Dis Sci

Oncocytic hepatocellular tumour

Histopathology

Hepatocellular carcinoma in young adults

NY State J Med

Hyaline globules and intracellular lumina in a hepatocellular carcinoma

Am J Clin Pathol

Fibrolamellar hepatocarcinoma: Radiology, management, and pathology

Am J Roentgenol

Hepatocellular carcinoma in women: Probable lack of etiologic association with oral contraceptive steroids

Hepatology

The histopathologic and clinical indicators of prognosis in hepatoma

J Clin Gastroenterol

Fibrolamellar carcinoma of liver: A primary malignant oncocytic carcinoid?

Ultrastruct Pathol

Comparison of α-1-antitrypsin and α-1-antichymotrypsin in hepatocellular carcinoma: An immunoperoxidase study