Am J Surg Pathol Volume 31, Number 5, May 2007
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Transcript of Am J Surg Pathol Volume 31, Number 5, May 2007
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Matthew M. Yeh, MD, PhD, Anne M. Larson, MD,w Jean S. Campbell, PhD,
Nelson Fausto, MD, Stephen J. Rulyak, MD,w and Paul E. Swanson, MD
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Many risk factors for development of HCC are well known ,Ex: chronic hepatitis and cirrhosis.
Underlying molecular mechanisms leading to hepatocarcinogenesis
remain largely unclear.
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Transforming growth factor-a (TGF-a) is a mitogen
1)synthesized as a transmembrane polypeptide
2)cleaved to a 50 amino acid diffusible form
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TGF-a---EGFR
bind the EGFR (epidermal growth factor receptor) and activate the signaling cascade from this receptor.
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TGF-a---transgenic mice
Overexpression of TGF-a in the liver of transgenic mice induces increased proliferation, dysplasia, adenoma, and carcinoma.
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TGF-a---HCC and adjacent liver
Previous studies have also confirmed the presence of TGF-a in a significant portion of HCC and adjacent liver.
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DNA topoisomerase II-a (Topo II-a) is a nuclear protein
targeted by several chemotherapeutic agents and has been shown to be overexpressed in HCC.
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Ki-67 is a nuclear protein that is detected in proliferating cells (late G1, S, G2, and M phase), but absent in resting cells (G0 phase).
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The expression of TGF-a or Topo II-a in dysplastic nodules has not been investigated.
most previous studies investigating the expression of TGF-a in HCC were performed in cirrhotic livers.
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examined the patterns of Ki-67, TGF-a, and Topo II-a expression in liver cirrhosis, low-grade dysplastic nodules (LGDN), HGDN, and HCC, using an immunohistochemical approach
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to define the possible relationships of these markers to tumor progression.
evaluated the difference in expression of TGF-a in HCC between cirrhotic and noncirrhotic livers.
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Explanted liver specimens from patients with cirrhosis who underwent liver transplantation surgery at the University of Washington Medical Center from 1989 to 2002 were retrospectively reviewed.
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Resected liver specimens in patients who underwent surgery for HCC at the University of Washington Medical Center from 1989 to 1992 were also retrospectively reviewed.
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The morphologic diagnoses of the liver lesions were confirmed by the consensus opinion of 2 pathologists (M.M.Y. and P.E.S.)
using the criteria published by the International Working Party(IWP).
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Monoclonal anti-TGF-a Monoclonal anti-Topo II-a monoclonal anti-Ki-67
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Immunohistochemical analyses were performed on representative sections of HCC, HGDN, LGDN, cirrhosis, and noncirrhotic liver parenchyma.
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The intensity of TGF-a immunostaining: graded by the 2 pathologists (M.M.Y.
and P.E.S.) from 0 to 4.
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0-no staining; 1-focal weak staining in the
hepatocytic cytoplasm; 2-diffuse weak staining in the
hepatocytic cytoplasm; 3-diffuse weak and focal strong
staining in the hepatocyticcytoplasm; 4-diffuse strong staining in the
hepatocytic cytoplasm,
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The percentage of nuclei positive for Topo II-a and Ki-67
was obtained by manually counting 500 hepatocytes in the most intensively stained regions.
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in 52 cirrhotic livers from explanted or resected specimens: 46 HCC, 17 HGDN, and 12 low-grade dysplastic nodules were identified.
18 surgically resected cases of noncirrhoticliver with HCC were identified.
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TGF-a-- HCC arising in the noncirrhotic and cirrhotic
The mean intensity score for TGF-a staining was 0.8 and 1.8 in HCC arising in the noncirrhotic and cirrhotic background, respectively (P=0.003).
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Most previously reported genomic and molecular studies have focused on fully developed HCC.
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postulated that the expression patterns of TGF-a,Ki-67, and Topo II-a should differ in the progression from cirrhosis through LGDN, HGDN to HCC.
Also compared the expression of TGF-a in HCC arising in cirrhotic livers with that of HCC arising in noncirrhotic livers.
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Ki-67--- index of proliferation
Ki-67’s expression has been considered a reliable index of proliferation.
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Increased proliferation--- stomach and esophagus
Increased proliferation has been observed in premalignant and malignant conditions of other organs, such as the stomach and esophagus.
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Proliferation index---HCC
proliferation indices have been well-described in HCC.
Watanuki et al ---have reported a mean Topo II-a index
of 14.1% in HCC, with a mean Ki-67 index of 25.6% in the same lesion.
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Proliferation index---HCC
In the current study, ---Topo II-a and Ki-67 proliferative indices
in HCC were similar to those of Watanuki and colleagues (18.9±10.4 and 26.1±13.6, respectively)
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Topo II-a and Ki-67--- decreased survival and earlier cancer-related death
Increased Topo II-a and Ki-67 protein expression in HCC correlates with decreased recurrence-free survival and earlier cancer-related death.
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Ki-67 and Topo II-a--- poor v.s. well or
moderately differentiated HCC
Previous studies have shown that poorly differentiated HCC has more immunoreactivity to Ki-67 and Topo II-a than well or moderately differentiated HCC.
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the place of LGDN
In the current study, there was no significant difference in Ki-67 and Topo II-a staining between LGDN and the adjacent cirrhotic nodules.
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the place of LGDN
further study with expanded numbers will be necessary to better define the place of LGDN within the concept of stepwise progression.
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TGF-a--- mice, human HCC
Overexpression of TGF-a in the livers of transgenic mice leads to the development of HCC.
Previous studies have demonstrated that human HCC expresses TGF-a as well
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TGF-a—cirrhotic v.s. nocirrhotic
The current study demonstrates that cirrhotic livers exhibit stronger expression of TGF-a when compared with noncirrhotic hepatic parenchyma.
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TGF-a--- cirrhosis-associated HCC v.s. HCC in noncirrhotic livers
the intensity of TGF-a immunoreactivity in cirrhosis-associated HCC was stronger than that of HCC in noncirrhotic livers.
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TGF-a--- decline expression
there was also a decline in TGF-a expression from cirrhosis, through LGDN and HGDN to HCC.
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TGF-a---etiology-dependent
Kiss and colleagues: HBV-positive, higher proportion of HCC
overexpressing TGF-a was observed compared with the HBV-negative group (21% and 6%, respectively).
suggesting that TGF-a as a role in human hepatocarcinogenesis may be etiology-dependent.
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the decrease in TGF-a expression from cirrhosis, through LGDN and HGDN to HCC supports the premise that TGF-a is more important to the early events in hepatocarcinogenesis.
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Although the relatively lower expression of TGF-a in HGDN and HCC seems counterintuitive (because overexpression of TGF-a in transgenic mice results in the development of dysplasia and HCC)
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we might plausibly argue that TGF-a is actively produced in cirrhotic liver and is gradually consumed in the process of hepatocarcinogenesis,
whereas other growth factors involved in the later stages of hepatocarcinogenesis may continue to be produced.
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TGF-a – less v.s. well differentiated HCC
Morimitsu et al ---have observed decreased expression
of TGF-a in less differentiated HCC compared with well-differentiated HCC.
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Proliferative activity increases from cirrhosis to HCC, with HGDN showing an intermediate proliferative index.
---This finding provides another compelling line of evidence that HGDN is an advanced premalignant lesion in hepatocarcinogenesis.
TGF-a plays an early role in cirrhosis associated hepatocarcinogenesis and that this process may be etiology-dependent.