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Regional Differences in Gallbladder Cancer Pathogenesis: Insights from a Comparison of Cell Cycle-Regulatory, PI3K, and Pro-Angiogenic Protein Expression

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The variable incidence of gallbladder cancer (GBCA) suggests regional pathogenetic differences. This study compares cell cycle-regulatory, angiogenesis-related, and PI3K pathway protein expression in GBCAs from three continents.

Methods

Immunohistochemical expression of several proteins was assessed, correlated with clinicopathologic variables, and compared among centers from Chile (Fundación Arturo López Pérez [FALP]), Japan (Yokohama City University [YCU]), and the United States (Memorial Sloan-Kettering Cancer Center [MSKCC]). Hierarchical clustering was used to partition the data based on protein-expression and treatment center.

Results

Tissue from 117 patients (MSKCC = 76; FALP = 22; YCU = 19) was analyzed. Mdm2 overexpression was seen only at MSKCC (p < 0.0001). Absence of p21 (p = 0.03) and VEGFR2 (p = 0.018) were more common and p27 expression was less frequent (p = 0.047) in tumors from YCU. Ki-67 labeling index in YCU tumors (median = 10) was two-thirds lower than at other centers. On hierarchical clustering analysis, all YCU patients (p = 0.017) and those with early tumors (p = 0.017) clustered separately from MSKCC. Median disease-specific survival after curative intent (R0) resection was 27 months and was similar among centers (p = 0.9). Median disease-specific survival of patients with early tumors was 28.4 months and was higher at YCU (not reached, p = 0.06).

Conclusions

Cell cycle-regulatory protein expression patterns of YCU tumors differed from those treated at FALP and MSKCC. The differential clustering of protein expression and survival in patients with early tumors suggest regional differences in pathogenesis and disease biology.

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Authors and Affiliations

  1. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Jean M. Butte MD, Kenichi Matsuo MD, Michael I. D’Angelica MD, Yuman Fong MD, Ronald P. DeMatteo MD & William R. Jarnagin MD

  2. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Javiera Torres MD, Emanuela F. Veras MD & David S. Klimstra MD

  3. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Mithat Gönen PhD

  4. Department of Surgery, Yokohama City University, Yokohama, Japan

    Kenichi Matsuo MD & Itaru Endo MD

  5. Department of Pathology, Yokohama City University, Yokohama, Japan

    Yoshiyaki Inayama MD

  6. Department of Surgery, Instituto Oncológico Fundación Arturo López Pérez, Santiago, Chile

    Jean M. Butte MD, Enrique Waugh MD & Hernan De La Fuente MD

  7. Department of Pathology, Instituto Oncológico Fundación Arturo López Pérez, Santiago, Chile

    Manuel Meneses MD

  8. Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile

    Javiera Torres MD

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  1. Jean M. Butte MD
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  9. Yoshiyaki Inayama MD
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  13. Itaru Endo MD
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  15. William R. Jarnagin MD
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Correspondence to William R. Jarnagin MD.

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Butte, J.M., Torres, J., Veras, E.F. et al. Regional Differences in Gallbladder Cancer Pathogenesis: Insights from a Comparison of Cell Cycle-Regulatory, PI3K, and Pro-Angiogenic Protein Expression. Ann Surg Oncol 20, 1470–1481 (2013). https://doi.org/10.1245/s10434-012-2761-0

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  • DOI: https://doi.org/10.1245/s10434-012-2761-0

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