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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 14  |  Issue : 1  |  Page : 6-10

To assess the utility of proliferative marker Ki-67 in surface epithelial ovarian tumor


Department of Pathology, Jawaharlal Nehru Medical College, Wardha, Maharashtra, India

Date of Web Publication21-May-2019

Correspondence Address:
Dr. Sheronica Laishram
Department of Pathology, Jawaharlal Nehru Medical College, Wardha, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdmimsu.jdmimsu_71_18

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  Abstract 


Background: Surface epithelial ovarian tumor (SEOT) accounts for more than 90% of all the ovarian tumors and are the most lethal one. Cellular proliferation plays a significant role in the clinical behavior and aggressiveness of ovarian tumor. Proliferative activity of the tumor can be assessed using the proliferative marker Ki-67, which has both diagnostic and prognostic values. Aim and Objective: The aim and objective of this study was to assess the expression of proliferative marker Ki-67 in various SEOT and correlate its level of expression with clinicopathological parameters including the International Federation of Gynecology and Obstetrics (FIGO) staging and preoperative CA-125 level. Materials and Methods: The study was a cross-sectional and observational study carried out in the Department of Pathology, JNMC, Sawangi, Wardha, over 2 years. It included 74 patients with surgically resected specimen of SEOT. Ki-67 immunohistochemistry was performed in all the 74 cases, and the percentage of immunopositive cells was expressed as Ki-67 labeling index (Ki-67 LI). Results: Out of 74 cases, 54 were benign and 20 were malignant which comprised serous and mucinous histological subtypes. Ki-67 expression was found to be positive only in malignant tumors (Ki-67 LI >1%). High Ki-67 LI was associated with high-grade serous cystadenocarcinoma (48.5%), advanced FIGO staging (40.5%), and high CA-125 levels. However, there was no association between Ki-67 LI and histological subtype. Conclusion: Ki-67 is a cost-effective proliferative marker. Therefore, immunohistochemical assessment of Ki-67 expression can be included in routine histopathological report of SEOT for diagnosis and prognostication which will help in better understanding of the biologic behavior of the tumor and modifying treatment strategies.

Keywords: Immunohistochemistry, Ki-67, proliferative index, surface epithelial ovarian tumor


How to cite this article:
Laishram S, Gupta V, Bhake A, Wankhede A, Agrawal D. To assess the utility of proliferative marker Ki-67 in surface epithelial ovarian tumor. J Datta Meghe Inst Med Sci Univ 2019;14:6-10

How to cite this URL:
Laishram S, Gupta V, Bhake A, Wankhede A, Agrawal D. To assess the utility of proliferative marker Ki-67 in surface epithelial ovarian tumor. J Datta Meghe Inst Med Sci Univ [serial online] 2019 [cited 2019 Jun 26];14:6-10. Available from: http://www.journaldmims.com/text.asp?2019/14/1/6/258659




  Introduction Top


Ovarian cancer represents one of the most common gynecological malignancies accounting for 30% of all cancers of female genital tract. In woman of reproductive age and elderly woman, it stands as the seventh most commonly diagnosed cancer and the fifth leading cause of cancer deaths.[1],[2]

Despite development of new diagnostic and newer chemotherapeutic modalities, the overall 5-year survival is still poor which is about 40%. At the time of diagnosis, more than 70% of the women diagnosed with ovarian carcinoma have advanced disease due to its asymptomatic nature and lack of reliable markers for early diagnosis.[3] Several prognostic factors which are known to influence survival of ovarian cancer include age at diagnosis, histological type and grade, ploidy, International Federation of Gynecology and Obstetrics (FIGO) stage, CA-125 levels, and the amount of residual tumor after primary surgery.[4],[5]

Cellular proliferation plays a significant role in the clinical behavior and aggressiveness of ovarian tumor. This can be assessed by determining the proliferative activity of the tumor which is reported to be of both diagnostic and prognostic values.

Ki-67 is an excellent immunohistochemical marker to determine proliferating cells of the tumor. It is expressed in all active phases of the cell cycle (G1, S, G2, and M phase) except in resting cells (quiescent cells – G0 phase). The monoclonal Ki-67/MIB-1 antibody reacts with the nuclear Ki-67 antigen expressed in proliferating cells.[6] Its expression reflects tumor proliferation and has been found to indicate tumor aggression, tumor metastasis, and known to predict disease outcome in many human malignancies such as central nervous system tumors (meningioma), lymphoproliferative diseases, connective tissue tumors, and breast tumors.[7]

In the present study, we evaluated the diagnostic and prognostic significances of Ki-67 antigen expression in surface epithelial ovarian tumor (SEOT) by correlating its expression with histological subtype, grade of serous ovarian carcinoma, FIGO staging of surface epithelial ovarian carcinoma, and preoperative CA-125 level.


  Materials and Methods Top


The study was a cross-sectional and observational study carried out in the Department of Pathology, Jawaharlal Nehru Medical College, Sawangi, Wardha, over 2 years from August 1, 2016 to July 31, 2018 comprising of 74 patients with surgically resected specimen of SEOT. The patients were admitted in the Department of Surgery and Obstetrics and Gynaecology and underwent total hysterectomy with bilateral/unilateral salpingo-oophorectomy or unilateral/bilateral salpingo-oophorectomy or oophorectomy as indicated. The study was approved by the Institutional Ethics Committee. An informed consent was obtained from all the patients who were included in the study.

All the specimen of 74 cases were received in labeled jar containing 10% formalin solution along with histopathological requisition forms with relevant clinical information. The relevant clinical information was reviewed and recorded in the pro forma. The type of surgery and the type of specimen received were reviewed. The values of CA-125 level of malignant cases were documented retrospectively from medical record.

After fixation in 10% formalin solution overnight (12 h), the specimens were subjected to grossing with proper gross examination and in detail documentation of gross findings. Tissue sections were carefully dissected from representative areas following the guidelines of grossing technique given by standard books and processed in the automated tissue. Using rotatory microtome, 3–5 μ thick sections were cut from the representative paraffin-embedded blocks. The sections were then stained with hematoxylin and eosin (H and E) staining and Ki-67 immunohistochemical staining for histopathological examination and immunohistochemistry (IHC) study, respectively.

The sections stained with routine H and E were viewed under light microscope, and histopathological diagnosis was made based on the WHO classification of SEOT. First, the tumors were broadly categorized as benign and malignant; thereafter, it was further classified based on histological subtypes. The serous ovarian carcinoma was further classified into low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC) based on two-tier grading system. This system is primarily based on the assessment of nuclear atypia and using the mitotic index as a secondary feature. The mitotic figure in LGSC is <12/high-power filed (HPF), while in HGSC, it is more than or equal to 12/HPF.[8] Staging of the malignant SEOT was done according to the FIGO staging. It was done at the time of diagnosis based on preoperative radiological, operative, and histopathological findings.[9]

Ki-67 antigen immunostaining was carried out by standard IHC method and peroxidase-antiperoxidase method using monoclonal mouse antihuman Ki-67/MIB-1 antibody kit, code IS626, DAKO™ (Glostrup, Denmark). Reactive lymph node was taken as a positive control whereas adipose tissue was used as negative control.

Ki-67 immunopositivity was observed as brown granular nuclear staining. For Ki-67 scoring, the most immunopositive area of the tumor was selected avoiding foci of inflammation. The number of immunopositive nuclei is counted in 1000 tumor cells in at least 10 HPF(×40).[9],[10] The percentage of immunopositive cells is referred to as labeling index (LI)/proliferative index. The average of three counts of Ki-67 immunopositive cells over the same slide was taken and expressed as the percentage of Ki-67 immunopositive cells in the tumor.[11] Ki-67 expression was quantitatively assessed and regarded as negative (if Ki-67 LI <1%) and positive (if Ki-67 LI ≥1%).[12]

Statistical methods

All the data obtained were entered into Microsoft Excel Worksheets after which it was analyzed using the software, IBM Corp., Armonk, New York and GraphPad Software INC, California Corporation. Chi-square test, Student's unpaired t-test, and F-test (one-way ANOVA test) were used to calculate the association between different parameters involved in the study. P < 0.05 was considered statistically significant. Pearson's correlation coefficient was used to calculate the correlation between Ki-67 and CA-125 levels.


  Results Top


In the present study, out of 74 cases of SEOT, 54 (72.97%) were benign and 20 (27.03%) were malignant. The histological subtypes of SEOT observed in the study were serous and mucinous. Serous tumor was more common in both benign and malignant groups. The maximum number of cases were of serous cystadenoma (29, 39.19%) and the least number of cases were of mucinous cystadenocarcinoma (6, 8.11%).

The number of high-grade serous cystadenocarcinoma cases (8, 57.14%) was slightly higher than the low-grade serous cystadenocarcinoma cases (6, 42.85%). Maximum number of the cases of both benign tumor (18/54, 33.33%) as well as malignant tumor (8/20, 40%) was observed in the age group of 41–50 years. The median age of patients with malignant tumor was higher (55 years) than the median age of patients with benign tumor (42 years). No case of malignant tumor was observed before the age of 40 years. There was statistically significant difference between the age of presentation in benign and malignant tumors (P< 0.05).

Regarding clinical presentation, maximum number of patients presented with a single symptom at the time of diagnosis. Pain abdomen was the most common clinical presentation, followed by abdominal mass which were presented by 24 (32.43%) cases and 20 (27.03%) cases, respectively, as the only symptom. Out of 20 (27.03%) cases presenting with two symptoms, abdominal mass was associated with pain abdomen in 8 (10.81%) cases and abdominal distension in 12 (16.22%) cases. Ten (13.51%) cases were associated with multiple presentations.

All the 54 benign tumors were unilateral. Out of 20 malignant tumors, 15 (75%) were unilateral and 5 (25%) were bilateral; all the bilateral tumors were of serous cystadenocarcinoma. The association of laterality of involvement with histopathological grade of SEOT was found to be statistically significant (P< 0.05), which signifies that bilateral involvement is associated with serous cystadenocarcinoma. On cut section, the most common morphological feature found was mixed solid and cystic in 34 (45.95%) cases while the least common morphological feature was solid which was found in only 9 (12.16%) cases.

In this study, we observed that Ki-67 expression was found to be negative in all the benign tumors (Ki-67 LI <1%). However, all the malignant tumors were found positive for Ki-67 expression (Ki-67 LI ≥1%). [Table 1] shows the association of Ki-67 LI with various clinicopathological variables of malignant SEOT.
Table 1: Association of Ki.67 labeling index with various clinicopathological variables of malignant surface epithelial ovarian tumor

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The median Ki-67 LI was higher in serous cystadenocarcinoma (39%) than mucinous cystadenocarcinoma (36%) signifying that Ki-67 expression is higher in malignant serous ovarian tumor. However, Ki-67 LI did not show any significant association with the histological subtypes (P > 0.05). The difference between the median Ki-67 LI of high-grade (48.5%) and low-grade serous cystadenocarcinoma (27.5%) was found to be statistically significant with P < 0.05 which signifies that there is higher Ki-67 expression in HGSC as compared to LGSC.

Out of 20 malignant SEOTs which were staged according to the FIGO staging, highest number of cases were of Stage III, that is, 12 (60%) and lowest were of Stage II, that is, 3 (15%). No Stage IV ovarian tumor was diagnosed during the study period. The highest Ki-67 LI was observed in Stage III tumor which was 62%, and the lowest Ki-67 LI was observed in Stage I which was 20%. The median Ki-67 LI for Stage III was 40.5% which was the highest, followed by Stage II (30%) and Stage I (25%). The Ki-67 expression was found to be higher with the increasing stage of tumor. This association was found to be statistically significant (P< 0.05).

The median value of CA-125 level of 20 malignant cases observed was 117.55 U/ml. The highest value of CA-125 level which was 969.2 U/ml had a Ki-67 LI of 51%, and the lowest value of CA-125 level of 5.2U/ml had a Ki-67 LI of 20%. It was observed that higher values of CA-125 level were found in malignant tumor with higher Ki-67 expression.

The scatter [Graph 1] depicts a significant positive correlation between Ki-67 and CA-125 (r = 0.505, P = 0.008) which signifies that higher values of CA-125 level in malignant SEOT are associated with higher Ki-67 expression.




  Discussion Top


Ovarian cancer is an extremely heterogeneous disease which poses a challenge to its early diagnosis.[13] The heterogeneity of the ovarian tumor is indicated by differences in genetic and epidemiological risk factors, precursor lesions, molecular changes in oncogenesis, pattern of spread, response to chemotherapy, prognosis, and survival. Most of the ovarian tumors are diagnosed at an advanced stage because of asymptomatic nature and ineffective screening tools resulting in poor prognosis. The 10-year survival is estimated to be 90% survival rate for early stage as compared to 15%–30% at later stages of ovarian cancer.[3],[14] Hence, an early diagnosis and a better understanding of the disease are necessary to aid the management and bring about a better prognosis.

In the present study, we have observed that only malignant tumors were positive for Ki-67 expression (Ki-67 LI >1%). Similarly, in the study conducted by Verma et al., positive Ki-67 expression was observed only in the malignant tumors.[15] The higher expression of Ki-67 in malignant tumor could be explained by the fact that it is a nuclear protein present in proliferating cells, and its expression is indicative of high proliferation rate and aggressiveness of malignant tumor cell as compared to benign tumor.

Ki-67 expression was correlated with prognostic factors such as histologic subtype, tumor grade, FIGO stage, and CA-125 level in many studies to evaluate its significance in diagnostic and prognosis. In the present study, the mean Ki-67 LI was higher in serous cystadenocarcinoma (39.42 ± 13.91%) than mucinous cystadenocarcinoma (35.16 ± 7.19%) signifying that Ki-67 expression is higher in malignant serous ovarian tumor. Similarly, in the study of Mahadevappa et al., the mean Ki-67 LI of serous carcinoma was 65.03 ± 21.67, which was higher than that of mucinous carcinoma (60.24 ± 21.91).[16] Other studies conducted by Gursan et al., Sylvia et al., and Köbel et al. have also shown similar findings. Similar to the present study, no significant association (P > 0.05) was found between Ki-67 expression and histological subtypes of malignant SEOT in the above-mentioned studies.[7],[17],[18]

Among serous cystadenocarcinoma, the difference between the median Ki-67 LI of HGSC (48%) and LGSC (28%) was found to be statistically significant with P < 0.05, which signifies that there is higher Ki-67 expression in HGSC as compared to LGSC. Similar statistically significant association (P< 0.05) was also found in the studies of Köbel et al., Mahadevappa et al., Verma et al., and Chen et al.[7],[15],[16],[19] In Köbel et al., the median Ki-67 LI of LGSC was 2.5% and that of HGSC was 22.4%. In Mahadevappa et al., the median Ki-67 LI of LGSC was 37.96% and that of HGSC was 65.34%. Ki-67 expression is higher in HGSC than LGSC because HGSC owing to its grade has more cellular proliferative activity and nuclear atypia along with higher mitotic activity than LGSC. Mitotic index ≥12/10 HPF is seen in HGSC, and mitotic index <12/10 HPF is seen in LGSC.[8]

CA-125 levels in ovarian carcinoma are being used as a marker for screening and diagnosis, monitoring response to therapy, and relapse or recurrence. It has been considered as an important independent prognostic factor which reflects a larger tumor burden and more advanced stage.[15] In the present study, the median value of preoperative CA-125 levels of 20 malignant cases was 117.55 U/ml. The case having the highest value of CA-125 of 969.2 U/ml had a Ki-67 LI of 51% and the lowest value of CA-125 of 5.2U/ml had a Ki-67 LI of 20%. A significant correlation between Ki-67 LI and CA-125 levels (r = 0.578, P = 0.008) which signifies that higher values of CA-125 level in malignant SEOT is associated with higher Ki-67 expression. While in the study conducted by Mahadevappa et al., no significant correlation was found between Ki-67 LI and CA-125 levels.[16] The studies conducted by Jha and Karki and Sylvia et al. reported CA-125 levels to be significantly higher in higher grades of ovarian tumor with adverse prognostic factors.[17],[20] While in the study of Verma et al., with increasing histopathological grade, an increase in serum CA-125 levels was observed, but it was not statistically significant (P > 0.05) as few number of cases were there for each grade.[15]

The FIGO system has been identified as an important independent prognostic factor with higher stage reflecting more aggressive tumor biology. Women with advanced stage cancers (FIGO Stages III and IV) had significantly higher tumor expression of Ki-67 compared to patients with early-stage cancers (FIGO Stages I and II). In advanced disease, women with complete chemotherapy response had higher Ki-67/MIB-1 expression than women without complete chemotherapy response. Patients with Stage I disease have better survival rate (>95%, 5-year survival) than patients with Stage IV disease (10%, 5-year survival).[21],[22]

Findings observed in the study of Mahadevappa et al. showed statistically significant association (P< 0.001) between Ki-67 expression and FIGO staging; the median Ki-67 LI in FIGO Stage I–IV were 39.7%, 69.5%, 70.6%, and 59.6%, respectively.[16] Khouja et al. found a correlation between high Ki-67 expression with higher grade, ascites, advanced FIGO stage, and the presence of residual disease after primary surgery.[23] In the study of Choudhury et al., the mean Ki-67 LI was higher in advanced tumor with higher FIGO stage. The mean Ki-67 LI in Stage III/IV was 39.5 ± 17.2% as compared to 25.7 ± 14.0% in Stage I/II cancers.[11] In the present study, high median Ki-67 LI was noted with advanced FIGO stage (Stage III – 40.5%), which was statistically significant (P< 0.001). In the study of Khandakar et al. and Garzetti et al., higher expression of Ki-67 was significantly correlated with poor survival.[2],[24]

All the above findings indicate that Ki-67 expression is more in malignant tumors which are of high histological grade and advanced FIGO stage pointing towards the aggressive clinical behavior and poor prognosis.

Different studies, which have evaluated the relationship between Ki-67 expression and long-term survival, have reported that the proliferative index is a good predictor of patient outcome in epithelial ovarian cancer. The median survival of patients with high Ki-67 expression in ovarian carcinoma was lower compared to patients with low Ki-67 expression in ovarian carcinoma.[15],[16],[23]

The assessment of the proliferative index by Ki-67 LI determines the proliferative potential of malignant SEOT and helps in assessing the aggressiveness of the tumors, thereby correlating with prognosis. The high Ki-67 expression in tumors is more sensitive to chemotherapy, thereby giving better response to chemotherapy and longer survival rate. The 5-year survival rate is considerably better in early stages (around 90%) and relatively dismal (10%–30%) in advanced stage.[2] Patients with early-stage ovarian carcinomas with high Ki-67 LI are likely to benefit from adjuvant chemotherapy despite the tumor grade and type. Studies by Khandakar et al. and Miller et al. found a significant lower Ki-67 LI subsequent to neoadjuvant chemotherapy and significant differences in the tumor histomorphology after neoadjuvant chemotherapy with better survival outcome.[2],[24]

Several recent studies suggested that Ki-67 is a potential therapeutic target in cancer due to its expression in all proliferating cells. Inactivation of the proliferation marker Ki-67 will lead to cell death specifically in proliferating cells and thus could be a potential strategy for the treatment not only of ovarian cancer but also of numerous other malignancies.[2],[25],[26]


  Conclusion Top


Ki-67 expression of SEOT when studied along with the tumor grade and FIGO stage aids in the diagnosis and prognostication as well as predicting the tumor response to chemotherapy and patient's overall survival. Recently, it has also become a potential therapeutic target in several malignancies.

Moreover, Ki-67 antibody (MIB-1antibody) is a cost-effective and easily accessible immunohistochemical marker. Therefore, immunohistochemical assessment of Ki-67 expression (labeling index) can be included in routine histopathological report of SEOT for diagnosis and prognostication which will help in better understanding of the biologic behavior of the tumor and modifying treatment strategies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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