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Int J Clin Exp Pathol 2010;3(8):792-797
Original Article
Cell cycle biology of fibrolamellar hepatocellular carcinoma
Sadhna Dhingra, Wei Li, Dongfeng Tan, Maryam Zenali, Haizeng Zhang, Robert E. Brown
Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center-Medical School at Houston; Department of
Pathology and Laboratory Medicine, M.D. Anderson Cancer Center, Houston, Texas, USA
Received October 15, 2010; accepted October 31, 2010; available online November 2, 2010
Abstract: Fibrolamellar hepatocellular carcinoma (FLHCC) has a better prognosis than conventional hepatocellular carcinoma. Nevertheless,
FLHCC has a propensity to recur with limited responsiveness to chemotherapy. Objective: The purpose of this study was to provide insight into
the cell cycle biology of FLHCC, as it relates to FLHCC’s relatively indolent nature and lack of chemoresponsiveness. Design: In seven cases
of FLHCC, we assessed: 1. immunoexpression of protein analytes indicating cell cycle progression including Ki-67 (G1, S, G2 and M phases)
and S-phase kinase-associated protein (Skp) 2 along with the mitotic index (MI); 2.immunoreactivity for cyclin-dependent kinase inhibitors of
cell cycle progression from G1 to S phase, p27Kip1 and p16INK4. Results: The mean percentage of Ki-67 nuclear positivity in neoplastic
hepatocytes ranged from 1.0% to 29.7%. Nuclear Skp2 immunoexpression was not observed in any of the cases. The mitotic index was very
low (0-1 mitotic figure / 10 high-power fields). All cases showed moderate to strong nuclear p16INK4 positivity (diffuse in five and focal in two).
Contrastively, the adjacent non-neoplastic hepatocytes expressed only mild (2 cases) to no (3 cases) p16INK4. Conclusion: Our analysis has
revealed that cell cycle arrest in FLHCC occurs in G0G1 phase and is associated with overexpression of the cell cycle regulator, p16INK4 in
tumoral cell nuclei compared with non-neoplastic hepatocytes. In conjunction with our previous immunohistochemical demonstration of a
constitutively activated nuclear factor (NF)-kappaB pathway and stemness characteristics of FLHCC with limited differentiation, this cell cycle
arrest elucidates the biology of FLHCC’s indolent nature and relative chemoresistance. (IJCEP1010004).
Keywords: Cell cycle, liver, fibrolamellar hepatocellular carcinoma, immunohistochemistry, p16INK4, chemoresistance
Full text PDF
Address all correspondence to:
Robert E. Brown, MD
Department of Pathology and Laboratory Medicine
University of Texas Health Science Center Medical School at Houston
6431 Fannin Street, MSB 2.286
Houston, TX 77030, USA.
Tel: 713-500-5332
Fax: 713-500-0695
Email: Robert.Brown@uth.tmc.edu
Original Article
Cell cycle biology of fibrolamellar hepatocellular carcinoma
Sadhna Dhingra, Wei Li, Dongfeng Tan, Maryam Zenali, Haizeng Zhang, Robert E. Brown
Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center-Medical School at Houston; Department of
Pathology and Laboratory Medicine, M.D. Anderson Cancer Center, Houston, Texas, USA
Received October 15, 2010; accepted October 31, 2010; available online November 2, 2010
Abstract: Fibrolamellar hepatocellular carcinoma (FLHCC) has a better prognosis than conventional hepatocellular carcinoma. Nevertheless,
FLHCC has a propensity to recur with limited responsiveness to chemotherapy. Objective: The purpose of this study was to provide insight into
the cell cycle biology of FLHCC, as it relates to FLHCC’s relatively indolent nature and lack of chemoresponsiveness. Design: In seven cases
of FLHCC, we assessed: 1. immunoexpression of protein analytes indicating cell cycle progression including Ki-67 (G1, S, G2 and M phases)
and S-phase kinase-associated protein (Skp) 2 along with the mitotic index (MI); 2.immunoreactivity for cyclin-dependent kinase inhibitors of
cell cycle progression from G1 to S phase, p27Kip1 and p16INK4. Results: The mean percentage of Ki-67 nuclear positivity in neoplastic
hepatocytes ranged from 1.0% to 29.7%. Nuclear Skp2 immunoexpression was not observed in any of the cases. The mitotic index was very
low (0-1 mitotic figure / 10 high-power fields). All cases showed moderate to strong nuclear p16INK4 positivity (diffuse in five and focal in two).
Contrastively, the adjacent non-neoplastic hepatocytes expressed only mild (2 cases) to no (3 cases) p16INK4. Conclusion: Our analysis has
revealed that cell cycle arrest in FLHCC occurs in G0G1 phase and is associated with overexpression of the cell cycle regulator, p16INK4 in
tumoral cell nuclei compared with non-neoplastic hepatocytes. In conjunction with our previous immunohistochemical demonstration of a
constitutively activated nuclear factor (NF)-kappaB pathway and stemness characteristics of FLHCC with limited differentiation, this cell cycle
arrest elucidates the biology of FLHCC’s indolent nature and relative chemoresistance. (IJCEP1010004).
Keywords: Cell cycle, liver, fibrolamellar hepatocellular carcinoma, immunohistochemistry, p16INK4, chemoresistance
Full text PDF
Address all correspondence to:
Robert E. Brown, MD
Department of Pathology and Laboratory Medicine
University of Texas Health Science Center Medical School at Houston
6431 Fannin Street, MSB 2.286
Houston, TX 77030, USA.
Tel: 713-500-5332
Fax: 713-500-0695
Email: Robert.Brown@uth.tmc.edu
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