Ki-67 labeling index as a prognostic marker in advanced stomach cancer

Sang Hyuk Seo,Kwang Hee Kim,Sang Hoon Oh,Yunseon Choi,Ki Jung Ahn,Ji Young Lee,Sang Min Lee,박지선,Woo Gyeong Kim 대한외과학회 2019 Annals of Surgical Treatment and Research(ASRT) Vol.96 No.1

Purpose: Proliferation marker Ki-67 is widely used in cancer prognosis prediction. We tried to investigate the role of Ki-67 as a prognostic factor in stomach cancer after surgery in this study. Methods: We retrospectively evaluated 251 patients who underwent curative resection for gastric cancer from 2010 to 2015. In pathologic examination, Ki-67 labeling index was defined as the percentage of Ki-67 antigen positive cells. Prognostic significance of Ki-67 for gastric cancer was evaluated. Disease-free survival (DFS) was assessed as a primary end-point. Results: The median follow-up period was 28.0 months. Thirty-one patients (12.4%) showed Ki-67 labeling index (LI) lower than 25%. Sixty-eight patients (26.6%) showed recurrence during follow-up period. Recurrence was associated with Ki- 67 LI level (≤25%, P = 0.016), and lymph node metastasis status (P = 0.002). High Ki-67 LI level (>25%) was also related to p53 positivity (P < 0.001) and poorly cohesive type (P = 0.002). The 3-year DFS was 69.4%. Low Ki-67 LI level (≤25%) was related with low DFS (47.6% vs. 72.6%, P = 0.016). T stage (P < 0.001), N stage (P = 0.006), lymphovascular invasion (P = 0.010), and neuronal invasion (P = 0.001) also affected the DFS. In addition, T stage (P = 0.03) and Ki-67 LI (P = 0.035) were independent prognostic factors for DFS. In patients treated with adjuvant chemotherapy (n = 239, 93.4%), low Ki-67 (≤25%) was a poor prognostic factor for DFS (P = 0.013). Conclusion: Low Ki-67 LI predicts high rate of progression and low DFS of stomach cancer. Ki-67 LI can be a predictive marker in resected stomach cancer treated with surgery and adjuvant chemotherapy.

두경부 편평세포암종과 종양주변 점막에서의 Ki-67 표지지수

최건,유강목,유동희,채성원,정광윤,최종욱 대한이비인후과학회 1998 대한이비인후과학회지 두경부외과학 Vol.41 No.6

Ki67 Index in Breast Cancer: Correlation with Other Prognostic Markers and Potential in Pakistani Patients

Haroon, Saroona,Hashmi, Atif Ali,Khurshid, Amna,Kanpurwala, Muhammad Adnan,Mujtuba, Shafaq,Malik, Babar,Faridi, Naveen Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.7

Introduction: Breast cancer aggressiveness can be correlated with proliferation status of tumor cells, which can be ascertained with tumor grade and Ki67 indexing. However due to lack of reproducibility, the ASCO do not recommend routine use of Ki67 in determining prognosis in newly diagnosed breast cancers. We therefore aimed to determine associations of the Ki67 index with other prognostic markers like tumor size, grade, lymph node metastasis, ER, PR and HER2neu status. Methods: A total of 194 cases of newly diagnosed breast cancer were included in the study. Immunohistochemical staining for ER, PR, HER2neu and Ki67 was performed by the DAKO envision method. Associations of the Ki67 index with other prognostic factors were evaluated both as continuous and categorical variables. Results: Mean age of the patients was 51.7 years (24-90). Mean Ki67 index was 26.9% (1-90). ER, PR, HER2neu positivity was noted in 90/194 cases (46.4%), 74/194 cases (38.1%) and 110/194 cases (56.70%) respectively. Significant association was found between Ki67 and tumor grade, PR, HER2neu positivity and lymph node status, but no link was apparent with ER positivity and tumor size. There wasan inverse relation between Ki67 index and PR positivity, whereas a direct correlation was seen with HER2neu positivity. However, high Ki67 (>30%) was associated with decreased HER2neu positivity as compared to intermediate Ki67 (16-30%). The same trend was established with lymph node metastasis. Conclusion: Our study indicates that with high grade tumors, clinical utility of ki67 is greater in combination with other prognostic markers because we found that tumors with Ki67 higher than 30% have better prognostic profile compared to tumors with intermediate Ki67 level, as reflected by slightly lower frequency of lymph node metastasis and HER2neu expression. Therefore we suggest that Ki67 index should be categorized into high, intermediate and low groups when considering adjuvant chemotherapy and prognostic stratification.

Ki-67이 Luminal B형 유방암 환자의 예후에 미치는 영향

류동원,최우식,이충한 고신대학교 의과대학 2010 고신대학교 의과대학 학술지 Vol.25 No.1

배경: Ki-67는 세포의 분열지수로서 특히 세포분열초기 나타나는 것으로 알려져 있다. 그래서 Ki-67의 분열지수가 높은 경우 조기 재발 및 예후와 관련되어 있다는 보고가 있다. 본 연구에서는 본원의 자료를 토대로 Ki-67의 분열지수가 예후에 영향을 미치는지를 알아보고자 한다 방법: 2001년 1월부터 2005년 12월까지 본원에서 유방암으로 수술을 받은 679명의 환자를 대상으로 후향적으로 조사를 하였다. 술후 조직병리학적 보고서를 토대로 조사하였다. Ki-67의 수치를 기준으로 10%이하군, 10%에서 20%군, 20%이상군으로 나누었다. 세군사이의 임상병리학적 요소의 분포를 비교하였으며 Kaplan-Meier를 이용하여서 생존율을 분석하였다. 결과: 환자들의 평균나이는 46세였으며, 평균종양의 크기는 3.2cm였다. 20%이상군에서 진행성 유방암환자의 비율이 높았다.(p=0.007) 특히 림프절의 전이정도와도 관련이 있었다.( p=0.003) 그러나 Ki-67과 생존율과는 의미있는 관련성을 없었다.( p=0.6112). 결론: 본원의 조사에 따르면 Ki-67은 진행성 유방암과 호르몬 수용체 음성과는 밀접한 관계를 가지고 있었으나 생존율에는 영향을 미치지 않았다. 그러나 본조사는 추적기간이 짧고 조사 규모가 크지 않아서 향후 계속적으로 추적 관찰한다면 더 의미있는 결과과 나올것이다. Background: Ki-67 expression has been considered to be a reliable marker for assessing tumor cell proliferation. The aims of the ourstudy were to assess the correlationbetween Ki-67 expression and clinocopathologic factors and to analyze the effect of Ki-67 expression on survival rate. Methods:The study subjects, 679 women with breast cancer, were a subset of patients operated at OOO hospital from Jun 2001 to Dec 2005.Patients are grouped into 3 categories according to Ki-67 determined in surgical specimens. Clincopathologic factors were compared with 3 categories of Ki-67. Chi-squared tests were used for statistical analysis. Kaplan–Meier estimates are presented for thesurvival function, and differences in survival were analyzed usingthe log rank test. Results: The median age was 46yrs, and median tumor size was 3.2cm. The strong correlation was observed between tumor staging and Ki-67 staining(p=0.007) and Group III(more than 20% staing) showed more advanced N-staging(p=0.003). The number of patients with estrogen receptor negative was higher in Group III(p=0.001) and that with HER-2 receptor positive was also higher in Group III(p =0.001) comparing with other groups. The univariate analysis for prognostic factors associated with DFS revealed that both the tumor groupas T1, T2, T3 or T4 and lymph node as N0, N1, N2 or N3 were statistically significant(p=0.0003 and p=0.0015 respectively) but the Ki-67 staining as <10%, 10~20%, >20% was statistically not significant(p=0.6112). The univariate analysis for prognostic factors associated with OS revealed that Tumor staging and N-staging was statically significant(p=0.003 and p=0.0015 respectively). Conclusions: According to our study, Ki-67 positive groups was associated with more advanced staging, ER-negative, PR-negative and HER-positive respectively. But there is no significant association between Ki-67 staining and 5-year disease free survival rate including overall survival rate.

수술로 절제한 위장관기질종양에서 Ki-67 발현의 예후적 중요성

정성연 ( Seong Yeon Jeong ),박원우 ( Won Wo Park ),김유선 ( You Sun Kim ),박영일 ( Young Il Park ),김승협 ( Seung Hyup Kim ),윤원재 ( Won Jae Yoon ),문정섭 ( Jeong Seop Moon ),이병모 ( Byung Mo Lee ),홍성우 ( Seong Woo Hong ),강 대한소화기학회 2014 대한소화기학회지 Vol.64 No.2

목적: 현재까지 위장관기질종양(GIST)을 양성과 악성으로 분류할 수 있는 명확한 조직학적 기준은 없지만, 전이나 재발을 일으킬 수 있는 위험도를 종양세포의 유사분열 수와 종양의 크기를 기준으로 나누고 있다. Ki-67은 세포 증식의 표지자로 사용되는 단백질로, GIST의 예후 인자로의 가능성이 주목되고 있다. 이에 저자들은 수술 치료를 시행한 GIST 환자 중 Ki-67 면역조직화학염색을 시행한 32예의 Ki-67 지수와 유사 분열 지수와의 관련성, GIST의 재발률 및 무병 생존율에 대하여 분석 검토하여 보았다. 대상 및 방법: 인제대학교 서울백병원에서 수술 치료를 통하여 GIST를 제거한 32명의 환자를 대상으로 연구를 시행하였고 환자들의 의무기록을 통하여 성별, 연령, 증상 등의 임상적 특징과, 종양의 크기, 위치 등의 조직학적 특징 및 재발률에 대하여 조사하였다. 결과: NIH 진단기준으로 very low risk는 4예, low risk는 9예, intermediate risk는 14예, high risk는 5예였다. Ki-67 지수는 1-18%의 범위 내에 있었고, 평균은 5.56±4.48%였다. 평균 추적관찰 기간은 35.72±29.04개월이었고 관찰 도중 6 예(18.7%)에서 재발 혹은 전이가 발견되었다. Ki-67 지수가 5% 이하인 군의 누적 무병 생존율은 12개월, 24개월, 60개월에 각각 100%, 100%, 86%였다. 반면 Ki-67 지수가 5% 초과인 군의 누적 무병 생존율은 12개월, 24개월, 60개월에 각각 82.1%, 70.3%, 46.9%로 Ki-67 지수가 5% 이하인 환자에 비하여 무병 생존율에 유의한 차이를 보였다(p=0.007) 결론: Ki-67 지수가 5% 초과할 경우 GIST 재발의 고위험성을 시사한다. 향후 Ki-67 지수의 표준화와 치료 방향의 결정에 미치는 Ki-67 지수의 역할에 대한 연구가 필요하다. Background/Aims: Assessment of malignant potential in gastrointestinal stromal tumor (GIST) is still problematic. The maximum tumor diameter and the mitotic index are generally used as an index of malignancy of GISTs. The Ki-67 labeling index has recently been used as an index of cell growth. The aim of this study was to investigate the prognostic value of K -67 in GIST. Methods: We retrospectively reviewed the medical records of 32 patients with GIST who underwent surgical resection at Inje University Seoul Paik Hospital. We analyzed their Ki-67 expression, histologic finding, and prognosis. Results: According to the tumor size and mitotic count, 4 patients were classified as very low risk, 9 patients as low risk, 14 patients as intermediate risk and 5 patients as high risk. The average Ki-67 index was 5.56±4.48%. The median follow-up duration was 35.72±29.04 months, and local/distant recurrences were observed in 6 (18.7%) patients. The overall cumulative disease free survival rates in patients with Ki-67 index ≤5% at 1 year, 2 years, and 5 years were 100%, 100%, and 86%, respectively. The overall cumulative disease free survival rates in patients with Ki-67 index >5% were at 1 year, 2 years, and 5 years were 82.1%, 70.3%, and 46.9%, respectively. There was significant relationship between elevated Ki-67 and disease free survival rate (p=0.007). Conclusions: Our study suggests that Ki-67 index >5% confers a higher risk of relapse in patients with GIST. Future work should focus on standardization of Ki-67 assessment and specification of its role in making treatment decisions.(Korean J Gastroenterol 2014,64:87-92)

후두와 하인두 편평세포암종에서 Ki-67표지지수와 Cyclin D1 발현의 예후적 의미

소상훈,송병철,정인교,노영수,임현준,김덕환 대한이비인후과학회 1999 대한이비인후과학회지 두경부외과학 Vol.42 No.5

Expression of the p16INK4a and Ki-67 in relation to the grade of cervical intraepithelial neoplasia and high-risk human papillomavirus infection

남은지,김재욱,홍종욱,장형선,이상엽,장시영,이대우,김상운,김재훈,김영태,김성훈,김종욱 대한부인종양학회 2008 Journal of Gynecologic Oncology Vol.19 No.3

Objective: The purposes of this study were to evaluate the expression of p16INK4a (referred as to p16) and Ki-67 in cervical intraepithelial neoplasia (CIN), and the correlation between high-risk human papillomavirus (HPV) infection and the above biomarkers. Methods: We analyzed 31 patients who were diagnosed with CIN at Kwandong University Myongji Hospital from October 2006 to September 2007. CIN specimens (CIN1, 12; CIN2, 6; CIN3, 13) were obtained by colposcopydirected biopsy (CDB) or loop electrical excision procedure (LEEP). The expressions of p16 and Ki-67 were evaluated by immunohistochemical methods with antibodies to p16 and Ki67. The immunohistochemical staining results were classified into four grades: 0, 1, 2 and 3. HPV genotyping or Hybrid Capture-II test was used to detect high-risk HPV. Results: The expression of p16 (p<0.001) and Ki-67 (p=0.003) were positively associated with CIN grade. p16 expressions increased significantly with high-risk HPV infection (p=0.014), especially HPV type 16 and 58. Ki-67 expression was not related with high-risk HPV. There was positive correlation between the expression of the p16 and Ki-67 (p=0.007). Conclusion: CIN grade were positively related to the expression of p16 and Ki-67. p16 expressions of high-risk HPV specimens significantly increased more than Ki-67. Therefore, in the diagnosis of CIN and high-risk HPV infection, p16 can be a useful biomarker. Objective: The purposes of this study were to evaluate the expression of p16INK4a (referred as to p16) and Ki-67 in cervical intraepithelial neoplasia (CIN), and the correlation between high-risk human papillomavirus (HPV) infection and the above biomarkers. Methods: We analyzed 31 patients who were diagnosed with CIN at Kwandong University Myongji Hospital from October 2006 to September 2007. CIN specimens (CIN1, 12; CIN2, 6; CIN3, 13) were obtained by colposcopydirected biopsy (CDB) or loop electrical excision procedure (LEEP). The expressions of p16 and Ki-67 were evaluated by immunohistochemical methods with antibodies to p16 and Ki67. The immunohistochemical staining results were classified into four grades: 0, 1, 2 and 3. HPV genotyping or Hybrid Capture-II test was used to detect high-risk HPV. Results: The expression of p16 (p<0.001) and Ki-67 (p=0.003) were positively associated with CIN grade. p16 expressions increased significantly with high-risk HPV infection (p=0.014), especially HPV type 16 and 58. Ki-67 expression was not related with high-risk HPV. There was positive correlation between the expression of the p16 and Ki-67 (p=0.007). Conclusion: CIN grade were positively related to the expression of p16 and Ki-67. p16 expressions of high-risk HPV specimens significantly increased more than Ki-67. Therefore, in the diagnosis of CIN and high-risk HPV infection, p16 can be a useful biomarker.

자궁경부 이형성증과 암의 진단을 위한 액상세포 검체에서 p16^INK4a/Ki-67 이중면역염색의 평가

성미희,이훈택,신민식,오서영,김욱연,Sung, Mi Hee,Lee, Hoon Taek,Shin, Min Shik,Oh, Seo Young,Kim, Wook Youn 대한임상검사과학회 2015 대한임상검사과학회지(KJCLS) Vol.47 No.3

Recently, $p16^{INK4a}$/Ki-67 dual immunostaining has been introduced as a new biomarker protocol for early detection of uterine cervical dysplasia and cancer in liquid-based cytology (LBC). We performed the $p16^{INK4a}$/Ki-67 dual immunostaining using a CINtec$^{(R)}$ PLUS kit in a total of 109 LBC cases of cervicovaginal smear and compared its results with those from LBC, HPV hybrid capture II (HC II) test and histological diagnosis. Expression of $p16^{INK4a}$ and Ki-67 was significantly associated with cases of LSIL or higher in cytological diagnosis and cases of cervical intraepithelial neoplasia (CIN) 1 or higher in histological diagnosis (p<0.001 and p<0.001, respectively). Among forty-six cases of atypical squamous cells of undetermined significance (ASCUS) in LBC, $p16^{INK4a}$ and Ki-67 was expressed in 31 (67.4%), which were positively associated with cases of CIN I lesion or higher in histology. The sensitivity of $p16^{INK4a}$/Ki-67 dual immunostaining for finding lesions of CIN 1 or higher was 89.0%, which was higher than LBC. The specificity was 73.5%, which was higher than that of the HC II test. Based on these results, the $p16^{INK4a}$/Ki-67 dual immunostaining method can be a useful diagnostic marker for improving the sensitivity of LBC and the specificity of HC II test. 최근 $p16^{INK4a}$/Ki-67 이중면역염색은 액상세포검사에서 자궁경부 이형성증과 암을 조기에 발견하기 위한 새로운 생체 표지자로 대두되고 있다. 저자들은 자궁경부질도말의 액상세포검체 총 109례에서 CINtec$^{(R)}$ PLUS kit를 사용하여 $p16^{INK4a}$/Ki-67 이중면역염색을 시행하였고, 그 결과를 액상세포검사, HPV hybrid capture II (HC II) 검사 그리고 조직학적 진단과 서로 비교하였다. $p16^{INK4a}$/Ki-67 양성 발현은 세포학적 진단에서 저등급 편평상피내병변 이상의 증례 그리고 조직학적 진단에서 자궁경부 상피내종양 1등급 이상의 증례에서 유의미하게 높았다. 액상세포검사상 비정형 편평 상피세포 소견을 보이는 46례 중, 31례 (67.4%)가 $p16^{INK4a}$과 Ki-67 양성 소견을 보였고, 이러한 양성 증례들은 조직검사에서도 대부분 자궁경부 상피내종양 1등급 이상의 병변에 해당하였다. 자궁경부 상피내종양 1등급 이상의 병변을 발견하기 위한 $p16^{INK4a}$/Ki-67 이중면역염색의 민감도는 액상세포검사보다 높은 89.0%였고, 특이도는 73.5%로 HC II 검사보다 높게 분석되었다. 따라서, $p16^{INK4a}$/Ki-67 이중면역염색 방법은 액상세포검사법의 민감도와 HC II 검사법의 특이도를 보완하기 위한 진단적 검사로 유용하다고 할 수 있다.

급성골수성백혈병에서 Ki-67 단클론항체를 이용한 세포주기 분석

안진석,김은실,김흥태,박선양,김병국 大韓血液學會 2002 大韓血液學會誌 Vol.37 No.3

악성림프종에서 Argyrophilic Nucleolar Orgnizer Region과 Ki-67의 발현

이희정,이안희,이교영,강창석,심상인,김병기 대한병리학회 2000 Journal of Pathology and Translational Medicine Vol.34 No.4