Ultrastructure of fibrolamellar oncocytic hepatoma

Farhi, Diane C.; Shikes, Robert H.; Silverberg, Steven G.

doi:10.1002/1097-0142(19820815)50:4<702::aid-cncr2820500414>3.0.co;2-f

Cited by 67 publications

(17 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ultrastructural features, such as numerous mitochondria with small electron-dense deposits, dense bodies, whether membrane-bound or not, and others, correspond with previous studies (Craig et al 1980, Farhi et al 1982, An et al 1983) and explain the oncocytic, eosinophilic appearance at light microscopy.…”

Section: Discussionsupporting

confidence: 90%

Fibrolamellár hepatocellular carcinoma. An immunohistochemical and ultrastructural study

et al. 1985

View full text Add to dashboard Cite

Two cases of fibrolamellar carcinoma of the liver are reported in young female patients of 12 and 21 years of age. Small amounts of perinuclear alpha-fetoprotein were found, unrelated to hyaline globules, as well as alpha 1-antitrypsin in a periglobular fashion in isolated cells. Ferritin was present in a large number of cells. Ultrastructurally, the well differentiated nature of the neoplasm was substantiated by previously unreported findings such as intercellular lumina analogous to bile canaliculi and peroxisome-like bodies containing a central crystalloid. Filamentous material resembling Mallory's type of hyaline was also found. We conclude that both immunohistochemical and ultrastructural features reflect a high degree of differentiation.

show abstract

Section: Discussionsupporting

confidence: 90%

Fibrolamellár hepatocellular carcinoma. An immunohistochemical and ultrastructural study

et al. 1985

View full text Add to dashboard Cite

show abstract

“…Furthermore, tumor cells contained large nuclei with coarse chromatin and one or more prominent nucleoli (Figure 2 B and 2 C ) 19,20 , and their abundant cytoplasm was characteristically granular and eosinophilic in analogy with the “oncocyte-like” aspects of the mitochondria-rich cytoplasm in cells of human FL-HCC 21 . Indeed, ultrastructural analysis obtained by transmission electron microscopy confirmed the presence of tightly packed mitochondria in cells from mouse FL-HCC and also evidenced the characteristic nuclear morphology of these oncocytic hepatocytes 22,23 (Figure 2 D and Supplementary Figure 2 A ). Additionally, tumor cells contained inclusions resembling the intracellular “pale bodies” as well as the hyaline globules often observed in human FL-HCC (Figure 2 C , Supplementary Figure 2 B ), and accordingly, these globules contained material that was positive for the periodic acid-Schiff (PAS) stain and sensitive to diastase enzymatic digestion (Figure 2 E , and data not shown) 1 .…”

Section: Resultsmentioning

confidence: 65%

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

et al. 2017

View full text Add to dashboard Cite

Background & Aims Fibrolamellar hepatocellular carcinoma (FL-HCC) is a primary liver cancer that predominantly affects 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. Methods 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. Results 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. Conclusions 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.

show abstract

“…15 In the liver, the fibrolamellar oncocytic hepatoma, a variant of hepatocellular carcinoma, also shows densely packed, abnormal mitochondria. 16,19 These tumors need to be disassociated from the oncocytic change observed in the mitochondrial DNA depletion syndrome and in other conditions as well, such as toxicity from insecticides and valproic acid. 16 In an attempt to explain the oncocytic change, it has been suggested that such cells express high levels of oxidative and enzymatic activities.…”

Section: Discussionmentioning

confidence: 99%

The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies

et al. 2001

View full text Add to dashboard Cite

Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood. In some patients, the levels of mitochondrial DNA are markedly reduced, a condition referred to as mtDNA depletion syndrome (MDS). We report here on the ultrastructural changes in the livers of 10 infants with the hepatic form of this syndrome. All patients displayed progressive liver failure, neurological abnormalities, hypoglycemia, and lactic acidosis that warranted investigation of respiratory chain disorder in liver tissue, specifically expressing the disease. Decreased activity of respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, IV) was shown in 5 patients. Mitochondrial DNA depletion was confirmed by Southern blot analysis in the livers of 6 patients. We found hepatocytes filled with mitochondria having aspects of "oncocytic transformation," associated with numerous changes in shape, size, cristae, and matrix. The changes were virtually identical in all specimens. In many hepatocytes, microvesicular steatosis was the salient feature. Additional findings included cholestasis and focal cytoplasmic biliary necrosis (CBN), as well as cytosiderosis in hepatocytes and sinusoidal cells. In some hepatocytes the damage appeared extreme, but fibrosis was identified only in the few patients who died beyond 6 months of age. Although individual ultrastructural findings are not specific, when taken together, they show a diagnostic pattern highly suggestive of a respiratory chain disorder. In the appropriate clinical context, these findings can direct the clinician towards the diagnosis of hepatic MDS. (HEPATOLOGY 2001;34:776-784.)The mitochondrial respiratory chain is a highly organized system involved in the ATP-generating, oxidative phosphorylation (OXPHOS) process. It is composed of 5 enzymatic complexes, which include more than 100 proteins. Thirteen of the polypeptides are encoded by mitochondrial DNA (mtDNA) whereas the remaining subunits by the nuclear genome.

show abstract

Ultrastructure of fibrolamellar oncocytic hepatoma

Cited by 67 publications

References 10 publications

Fibrolamellár hepatocellular carcinoma. An immunohistochemical and ultrastructural study

Fibrolamellár hepatocellular carcinoma. An immunohistochemical and ultrastructural study

CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1–Prkaca Gene Fusion Is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma

The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies

Contact Info

Product

Resources

About