비소세포폐암 환자에시 Ki-67 단백질 발현증가의 임상적 의의

Clinical Significance of Increased Ki-67 Protein Expression in Non-small Cell Lung Cancers

  • 이건 (포천중문의과대학교 흉부외과학교실) ;
  • 임창영 (포천중문의과대학교 흉부외과학교실) ;
  • 김광일 (포천중문의과대학교 병리학교실) ;
  • 이헌재 (포천중문의과대학교 흉부외과학교실)
  • Lee Gun (Department of Thoracic and Cardiovascular Surgery, Pochon CHA Medical University) ;
  • Lim Chang-Young (Department of Thoracic and Cardiovascular Surgery, Pochon CHA Medical University) ;
  • Kim Kwang-Il (Department of Pathology, Pochon CHA Medical University) ;
  • Lee Hyeon-Jae (Department of Thoracic and Cardiovascular Surgery, Pochon CHA Medical University)
  • 발행 : 2006.05.01

초록

배경: Ki-67 단백질은 세포의 증식활성도를 나타내는 생물표식자로, 비소세포폐암 환자에서 Ki-67 단백질의 증가는 예후에 나쁜 영향을 미치는 것으로 알려져 있다. 이 연구는 비소세포폐암으로 폐절제술을 실시한 환자에서 Ki-67 단백질의 발현정도를 조사하여, 단백질의 발현증가가 환자의 임상적 병리적 양상과 술 후 재발과 생존기간에 미치는 영향을 알아보기 위해 시행되었다. 대상 및 방법: 근치적 폐절제술을 실시한 38명의 비소세포폐암 조직에서 단클론항체 Ki-67로 면역조직화학염색을 실시하여 Ki-67 Labeling Index (LI)를 구하였다. 환자를 Ki-67 증가군$(LI{\ge}20%)$과 Ki-67 비증가군(LI<20%)으로 분류하여, 두 군의 술 전 임상적 병리적 특성, 술 후 생존기간 및 무병생존기간을 비교하였다. 결과: Ki-67 LI는 불균질한 분포를 보였고 평균 LI는 $20.0{\pm}20.1%$였다. Ki-67 증가군과 비증가군 간에나이, 성별, 흡연, TNM 병기, 혈관침윤은 유의한 차이가 없었다. 그러나 증가군은 비증가군에 비해 편평상피암이 많고, 분화도가 나쁘며, 임파침윤이 많았다$(p{\le}0.05)$. 증가군은 중앙 생존기간(47.2 vs. 96.5개월)과 중앙 무병생존기간(18.2 vs. 72.3개월)이 비증가군보다 짧았으나 통계적 유의성은 없었다(각각 p=0.312, p=0.327). 결론: 이상의 연구를 통해 비소세로폐암 환자에서의 Ki-67 단백질 발현증가는 수술 후 환자의 예후에 나쁜 인자로 작용하여 생존기간과 무병생존기간이 짧아지는 경향을 보였으나 통계적 유의성이 부족하여 향후 지속적인 연구가 필요할 것이다.

Background: The Ki-67 protein is a biomarker associated with cell proliferation and a valuable negative prognostic factor in non-small cell lung cancer. We investigated the Ki-67 protein expression in resected non-small cell lung cancer to evaluate the impact on clinicopathological characteristics and postoperative prognosis. Material and Method: Using monoclonal antibody Ki-67, we immunohistochemically examined 38 surgically resected non-small ceil lung cancers to determine Ki-67 Labeling Index (LI). We analysed the differences of clinicopathological characteristics and postoperative recurrence and survival between High Ki-67 Group $(LI{\ge}20%)$ and Low Ki-67 Group (LI<20%). Result: The Ki-67 LIs were heterogenous and a mean values was $20.0{\pm}20.05%$. There were no significant differences in age, sex, smoking, TNM stage, and vascular invasion between High Ki-67 Group and Low Ki-67 Group. A High Ki-67 Group was significantly associated with squamous cell type, poor differentiation, and lymphatic invasion $(p{\le}0.05)$. High Ki-67 Group showed a trend of lower survival (median 47.2 vs. 90.5 months, p=0.312) and lower disease-free survival (median 18.2 vs. 72.3 months, p=0.327) than Low Ki-67 Group. Conclusion: These results indicate that increased Ki-67 protein expression may be a negative prognostic factor and showed a trend of shortened survival and disease-free survival. To evaluate the pivotal role of Ki-67 protein expression, a long-term follow-up and further study are required.

키워드

참고문헌

  1. Lad T, Rubistein L, Sadeghi A. The benefit of adjuvant treatment for resectable locally advanced non-small cell lung cancer. J Clin Oncol 1988;6:9-17 https://doi.org/10.1200/JCO.1988.6.1.9
  2. Ginsberg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In: DeVita VT Jr, Hellman S, Steven A. Cancer principles & practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers. 1997;858-910
  3. Socinski MA. Adjuvant therapy of resected non-small cell lung cancer. Clin Lung Cancer 2004;6:162-9 https://doi.org/10.3816/CLC.2004.n.029
  4. Hunter T, Pines J. Cyclins and cancer.II. Cyclin D and CDK inhibitors come of age. Cell 1994;79:573-82 https://doi.org/10.1016/0092-8674(94)90543-6
  5. Sherr CJ. Cancer cell cycles. Science 1996;274:1672-7 https://doi.org/10.1126/science.274.5293.1672
  6. Minna, JD, Sekido Y, Fong KM, Gazdar AF. Molecular biology of lung cancer. In: DeVita VT Jr, Hellman S, Steven A. Cancer: principles & practice of oncology. 5th ed. Philadelpha: Lippincott-Raven Publishers. 1997;849-57
  7. Gupta AK, Harris EER, BArnhard EJ, et al. Overview of cell cycle and apoptosis. In: Pass HI, Mitchell JB, Johnson DH, Turris AT, Minna JD. Lung cancer. Principle and practice. Philadelphia: Lippincott Williams & Wilkins. 2000;5-67
  8. Forgacs E, Zochbauer-Muller S, Olan E, Minna JD. Molecular genetic abnormalities of human lung cancer. Pathol Oncol Res 2001;7:6-13 https://doi.org/10.1007/BF03032598
  9. Dobash Y, Shoji M, Jiang SX, Kobayashi M, Kawakubo Y, Kameya T. Active cyclinA-CDK2 complex, a possible critical factor for cell proliferation in human primary lung carcinomaas. Am J Pathol 1998;84:49-53
  10. Kawabuchi B, Moriyama S, Hirinaka M, et al. p16 inactivation in small-sized lung adenocarcinoma; its association with poor prognosis. Int J Cancer 1999;84:49-53 https://doi.org/10.1002/(SICI)1097-0215(19990219)84:1<49::AID-IJC10>3.0.CO;2-Y
  11. Gerdes J, Lemke H, Baisch H, Wacker H-H, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunology 1984;133:1710-5
  12. Scott RJ, Hall PA, Haldane JS, et al. A comparison of immunohistochemical markers of cell proliferation with experimentally determined growth fraction. J Pathol 1991;165: 173-8 https://doi.org/10.1002/path.1711650213
  13. Gerdes J, Stein H, Pilen S, et al. Prognostic relevance of tumor-cell growth fraction in malignant non-Hodgkin's lymphomas. Lancet 1987;2:448-9
  14. Hall PA, Gregory W, Richards MA, d'Ardenne AJ, Lister TA, Stansfield AG. The prognostic significance of Ki67 immunostaining in non-Hodgkin's lymphoma. J Pathol 1988; 54:223-35
  15. Hall PA, Levison DA. Assessment of cellular proliferation in histological material. J Clin Pathol 1990;43:184-92 https://doi.org/10.1136/jcp.43.3.184
  16. Hommura F, Dosaka-Akita H, Mishina T, et al. Prognostic significance of p27KIP1 protein and Ki-67 growth fraction in non-small cell lung cancers. Clin Cancer Research 2000; 6:4073-81
  17. Niemiec J, Kolodziejski L, Dyczek S. EGFR LI and Ki-67 LI are independent prognostic parameters influencing survivals of surgically treated squamous cell lung cancer patients. Neoplasma 2005;52:231-7
  18. Viberti L, Papotti M, Abbona GC, Celano A, Filosso PL, Bussolati G. Value of Ki-67 immunostaining in preoperative biopsies of carcinomas of lung. Hum Pathol 1997;28:189-92 https://doi.org/10.1016/S0046-8177(97)90105-2
  19. Mehdi SA, Etzell JE, Newman NB, Kohman LJ, Graziano SL. Prognostic significance of Ki-67 immunostaining and symptoms in resected stage I and II non-small cell lung cancer. Lung cancer 1998;20:99-108 https://doi.org/10.1016/S0169-5002(98)00027-0
  20. Kawama H, Tamaru J, Tanaka T, et al. Role of p27kip1 and cyclin dependent kinase 2 in the proloferation of non-small cell lung cancer. Am J Pathol 1998;153:505-13 https://doi.org/10.1016/S0002-9440(10)65593-9