| Abstract|| |
Background: Ovarian cancers remain the most lethal of all gynecological malignancies despite major developments in their treatment. Objectives: To study the rate of expression and staining patterns of p53 in various histological types and grades of epithelial ovarian tumors (EOT). Materials and Methods: Sixty EOTs received in a tertiary care center were studied for gross, microscopy, and p53 immunohistochemistry (IHC) expression patterns. Parameters such as age, laterality of tumor, ascites, capsule rupture, tumor size, stage at presentation, metastasis, tumor grade, and number of mitosis were correlated. Results: Of the sixty cases studied, 23 (38.3%) were malignant. Serous carcinomas were the largest group with 17 cases (74%) followed by mucinous with 4 cases (17%) and 2 clear cell carcinomas (9%). All benign and borderline EOT were p53 negative. 65.2% of the malignancies were p53 positive and all of them were serous malignancies. 15 out of 16 high-grade serous carcinomas were p53 positive (94%), while one case was negative (6%). 10 cases (63%) showed intense diffuse positivity of more than 60% of the nucleus, while 5 cases (31%) showed aberrant null staining <5% staining of the nucleus. All mucinous, clear cell carcinomas, and the only low-grade serous carcinoma in the study were p53 negative. P53 staining had positive correlations with variables like capsule rupture, ascites, laterality, and CA 125. Conclusions: The study highlights the different rates of expression and staining patterns of p53 and the need for correct interpretation of p53 IHC for the diagnosis of various EOT.
Keywords: Epithelial ovarian tumors, high-grade serous carcinoma, IHC, p53
|How to cite this article:|
Razak Amanullah NA, Poothiode U, Vilasiniamma L. Expression of p53 in epithelial ovarian tumors. Indian J Pathol Microbiol 2020;63:235-40
| Introduction|| |
Ovarian tumors represent 3% of female malignancies, with over 140,000 worldwide annual associated deaths., Epithelial tumors constitute over 90% of all the ovarian cancers. The incidence is either steady or slowly increasing in the western nations and rapidly increasing in the Asian subcontinent.
Ovarian tumors are a heterogeneous group of tumors with multiple, poorly understood etiopathogenesis and dismal prognosis which is partly due to the lacunae in the understanding of their pathogenesis., Screening for ovarian cancer has been based on strategies using serum tumor markers or ultrasound imaging of the ovaries. However, serum CA125 is elevated in only about 50% of patients with clinically detectable early-stage ovarian carcinomas. Insight into their pathogenesis requires an understanding of the genetic mutations, tumor suppressor/oncogenes, and cell cycle regulators of ovarian cancers to develop new technologies to identify other biomarkers that can be used for early detection.
TP53 is the most frequently altered gene in human cancers and loss of functional p53 protein occurs in most epithelial ovarian cancers. Association between p53 IHC positivity and histological subtype in the literature has been controversial. Hence, the need to study p53 IHC in an Indian cohort considering all the technical factors that could potentially affect the staining (the antibody clone, IHC technique, interpretation of staining, etc.).
This study aims to evaluate the expression of p53 by immunohistochemistry (IHC) in the different histological types and grades of epithelial ovarian tumors (EOT) and attempts to compare it with various clinicopathological prognostic factors, namely, age, clinical presentation, stage, gross morphology, histopathology, grade, serum CA-125, etc.
| Materials and Methods|| |
Sixty EOT specimens received in the Department of Pathology of a tertiary care hospital from February 2014 to October 2015 were studied. Ethics committee permission was obtained, and ethical practices were followed. All specimens obtained were subjected to detailed gross and histopathological examinations. Relevant clinical details were collected by reviewing the medical records using a structured pro forma. After examining the hematoxylin and eosin stained slides, the tumors were classified according to WHO 2014 classification. IHC was performed according to heat-induced epitope retrieval method and IHC of the marker p53 (DAKO- DO 7, ready to use mouse monoclonal antibody against p53-wild and mutant staining) was done in all 60 cases. Bloom Richardson grade-II breast carcinoma and colon carcinoma were used as positive controls as recommended in the product datasheet of DAKO DO-7 mouse monoclonal antibody against p53 in the initial run. In subsequent runs, cases that were found to be positive were also kept as positive controls. Negative controls (sections in which p53 antibody omitted and IHC done) were also kept.
P53 expression and staining patterns of all tumors were studied. Clinical and histomorphological parameters like age, laterality of tumor, ascites, capsule rupture, tumor size, stage at presentation, metastasis, histological differentiation of tumor, tumor grade, and number of mitosis were studied. Special stains like mucicarmine, PAS was done when indicated. SerumCA-125 levels and clinical details were collected from the case records. Ovarian tumors treated with neo-adjuvant chemotherapy or radiotherapy were excluded as it could potentially interfere with IHC staining.
The proportion of tumors showing p53 positivity is expressed as percentage. Statistical analysis is done using SPSS version 16. Chi-square test and Fisher's exact test were used to find if there is any statistically significant association between p53 expression and the parameters studied. The kept P value for level of significance is P < 0.05 and high significance is P < 0.001.
Interpretation of Staining: Nuclear staining for the marker was considered and expressed in percentage. Positive: two types of positive staining patterns are seen: (a) If >% of cells positive, diffuse positive due to missense mutation of p53. (b) If <5% of the cells positive, null positive staining due to non-sense mutation of p53. Cases are considered negative when 5–60% cells show patchy staining due to wild/normal type of p53 mutation.
Results and analysis
Among the 60 cases of EOT, 30 (50%) were benign, 7 (11.7%) were borderline, and 23 (38.3%) were malignant. Serous tumors formed the majority with 29 cases (48.3%) [Table 1] and [Figure 1]. Malignancies accounted for 32.3% of the cases in the age group 20–49 but increased to 48.1% in the age group more than 49 years. Serous malignancies were the largest group with 17 cases (74%) followed by mucinous with 4 cases (17%) and 2 clear cell carcinomas (9%) [Figure 2] and [Figure 3].
|Figure 1: Distribution of tumors based on the relative proportion of benign, borderline, and malignant tumors among the various histological types|
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|Figure 2: Proportion of cases among the different histological types of malignant ovarian tumors|
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|Figure 3: Gross photographs of some epithelial ovarian tumors: (a and b) serous carcinomas, (c) borderline serous tumor, (d) clear cell carcinoma with a mural nodule formation, (e) serous cystadenoma, and (f) mucinous cystadenoma|
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Expression of p53
All benign and borderline EOT were p53 negative. Among the 23 malignant tumors, 15 (65.2%) were p53 positive and all of them were serous malignancies. All mucinous carcinomas and clear cell carcinomas were p53 negative. Two (9%) out of the 17 serous carcinomas were also p53 negative [Figure 4]. Sixty-three percentage of HGSC showed diffuse p53 staining, while 31% showed aberrant null staining. A case of the HGSC and the only LGSC was p53 negative [Table 2].
|Table 2: Distribution of p53 positivity among the low-grade and high-grade serous malignancies|
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Association of p53 staining with tumor stage
p53 was positive in 36% of the cases in stage 1 tumors, all the tumors in stage 2, and 88.5% of the cases in stage 3 and above. This result was statistically significant by Chi-square test with Chi-square value of 45.0 and a P value of <0.001. Hence, p53 positivity increased with higher stage.
Association of p53 staining with independent variables like capsule rupture, laterality, ascites, and serum CA 125 values
Among the p53 positive serous tumors, 11 cases (73%) had capsule rupture, while 4 cases (27%) had an intact capsule. This was found to be statistically significant with a Chi-square value of 11.481 and a P value of 0.003. P53 was found to be positive in 8 (89%) out of the 9 tumors with bilateral ovarian masses. This showed statistically significant association with a Chi-square value of 24.69 and a P value of <0.001. Among all tumors with ascites, 50% were p53 positive and 50% were p53 negative. Fifty percentage of the tumors with ascites were p53 positive with 33% being intensely staining and 17% being null staining. All the p53 positive cases had ascites. The association was found to be statistically significant by Chi-square test with a Chi-square value of 20 and a 2-sided P value of <0.001.
CA 125 levels of only 40 cases were available for analysis. The mean serum CA 125 was 413.02 u/ml for p53 positive (aberrant >% diffuse staining), 1577.16 u/ml for p53 positive (null staining), and 58 u/ml for p53 negative tumors. This was found to be statistically significant by one-way ANOVA with an F value of 9.670 and a P value of <0.001.88% of the tumors with metastasis was p53 positive. This was also found to be statistically significant by Chi-square test with a Chi-square value of 32 and a P value of <0.001.
Eighty-nine percentage of the tumors with high mitosis (mitosis >) are p53 positive. This is statistically significant by Chi-square test with a Chi-square value of 29.59 and a P value < 0.001. Mean mitosis among the diffuse positive staining was 20/10 hpf while the mean for null staining was 8/10 hpf. This was also found to be statistically significant by one-way ANOVAs with an F value of 31.168 and P value of <0.001.
Association of p53 with Nuclear atypia was not done as nuclear atypia was found to be highly subjective with high inter-observer variability. There was no association between p53 positivity and size of the tumor (One-way ANOVA F value = 0.049, P = 0.953).
| Discussion|| |
Ovarian tumors are a heterogeneous group of tumors with poorly defined etiopathogenesis. p53 mutation is one of the most frequent mutations among ovarian tumors. Recent WHO grouping of ovarian tumors into type 1 and type 2 based on studies done by Kurman et al. highlights the importance of p53 mutations in ovarian tumors., Earlier studies had proved that immunohistochemical staining patterns of p53 (>60%, <5%) can serve as a surrogate marker for TP53 mutations in ovarian carcinoma., The more recent concept of classification of ovarian carcinomas into 5 main histological types is: high-grade serous carcinoma (HGSC), clear-cell carcinoma, endometrioid carcinoma, mucinous carcinoma, and low-grade serous carcinoma (LGSC), which differs with respect to their biology, clinical presentation, and response to chemotherapy., Hence, IHC can be used as a robust adjunct tool for the subclassification of ovarian carcinomas.
Among the 23 malignant tumors, 15 (65.2%) were p53 positive. All benign and borderline EOT were p53 negative. This is in concordance with the previous studies which showed mutation or inactivation of p53 in average 50% (range 13.7–82%) of invasive ovarian tumors, rarely in borderline tumors and virtually nonexistent in benign tumors or normal ovarian epithelium [Table 3].,,
|Table 3: Comparison of p53 poitivity in epithelial ovarian tumors with other studies|
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In the present study, all the p53 positive tumors were serous malignancies. Malignant mucinous tumors and clear cell tumors were p53 negative [Figure 3]. These results correlated well with older studies. Conversely, p53 positivity was seen in 94% of serous carcinomas only. Two of the serous tumors (a HGSC and a LGSC) were p53 negative. The results were comparable to studies by Havrilesky et al., Leitao et al., and Chiesa et al. but relatively lower positivity rates were seen in Lassus et al. and Sylvia et al. [Table 4].,,,, This may be due to (1) small sample size, (2) the method of counting p53 positivity, and (3) the inter-observer variability in interpretation of slides.
|Table 4: Comparison of p53 positivity in serous malignancies with other studies|
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p53 expression in high-grade serous carcinomas (HGSC)
When serous carcinomas are graded by the two-tier system, 94% were high-grade serous carcinomas (HGSC), while 6% (one case) was low-grade serous carcinoma. It was also observed that 15 out of 16 HGSC were p53 positive (94%), while one case was negative (6%). There was only one LGSC in the study and it was also p53 negative, which reflects the current IHC expression profile by WHO. Studies by Chiesa-Vottero et al. in 2007 and Bilyk et al. in 2011 indicate p53 positivity in 80% of serous ovarian carcinomas and protein expression differences depending on the degree of differentiation, high-grade tumors being diffusely p53 positive.,
The 2014 WHO recommends the use of aberrant p53 staining pattern to distinguish between high grade and LGSC. Even though the pathogenic ways in the ovarian carcinogenesis are thought to be independent for type 1 (low grade) and type 2 (high grade) tumors, studies have proven the occurrence of high-grade serous ovarian carcinomas from low-grade lesions.,, There are also reports of borderline synchronous tumors or recurrent borderline tumors recurring as high-grade carcinomas. In the present study, one case of high-grade carcinoma presented areas with variable tumor differentiation and p53 negative reaction, which could be explained by this theory. But further testing with larger sample size and a panel including other antibodies is warranted.
Staining patterns of p53
It is also important to recognize the two positive patterns of p53 IHC. In this study, among the positive cases, 10 cases (63%) showed intense diffuse positivity of more than 60% of the nucleus, while 5 cases (31%) showed aberrant null staining <5% staining of the nucleus [Figure 5]. The study by Lassus et al. showed excessive staining in 43% of cases and completely negative in 16% of cases. Aberrant (excessive or completely negative) p53 expression was found to be a strong and independent prognostic factor for overall survival in serous ovarian carcinoma.
|Figure 5: H and E and corresponding p53 staining in some of the cases. The three types of p53 patterns in ovarian tumors: Diffuse positive staining, null-positive staining, and negative staining (wild). The smaller insets beside the H&E staining indicate corresponding TP53 staining. P53 stains the nuclei of the cells. (a- c) are high-grade serous carcinomas. p53 showed diffuse positive nuclear staining in most of the malignant cells. (d) A case of high-grade serous carcinoma with endometrioid areas showing p53 positive staining in more than 60% cells—p53 positive. (e and f) are high-grade serous carcinomas with p53 staining<5% of cells or null positive staining. Faint positivity of the stromal cell nucleus proves that the stain has worked. g) A case of high-grade serous carcinoma showing wild type of p53 staining. p53 staining 5-60% (wild type). h)n Serous cystadenofibroma lined by benign flattened cells- p53 negative|
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In this context, it is important to note that only when both patterns of immunolabelling commonly associated with TP53 mutation (60–100% of tumor cells positive and tumors completely negative for p53) were combined, immunohistochemical analysis would give 95% correlation with nucleotide sequencing of the mutations. Study by Anna Yemelyanova et al. reports that p53 immunohistochemical scoring systems should not interpret the complete absence of expression as consistent with wild-type TP53. Moreover, intensity of staining has been graded in some of the older studies which do not improve the scoring system when compared with the nuclear sequencing. Hence, grading of intensity and determination of the positivity index is not relevant in case of p53 mutations in ovarian carcinomas.
Association of p53 with clinicopathologic variables
Among the p53 positive serous tumors, 11 cases (73%) had capsule rupture, while 4 cases (4%) had an intact capsule. Studies correlating the hypothesis of serous tubal in situ carcinoma with capsule rupture in HGSC show p53 positivity.,
P53 was found to be positive in 8 (89%) out of the 9 tumors with bilateral ovarian masses. This association was statistically significant and is comparable to studies done by Skirnisdottir et al. All the p53 positive cases had ascites with 33% being intensely staining and 17% being null staining. Study by Sylvia et al. showed 84.21% positivity in tumors with ascites.
From the 40 available serum CA 125 values, the mean was significantly higher for positive staining (diffuse and null positive) as compared to normal values for benign tumors. This was in concordance with the results obtained by Sylvia et al. and Angelopoulou et al. Study by Hafner et al. reports that p53 could be more sensitive than CA 125 in detecting residual disease.
P53 positivity was associated with higher grade and stage. 88.5% of stage 3 and 4 cases and 100% of the stage 2 cases were associated with p53 positivity as compared to 36% of the stage 1 cases. Eighty-eight percentage of the cases with metastasis were p53 positive. Higher stage and advanced disease have been found to be associated with p53 positivity by Sylvia et al. This is in contrary to a study by Kadkhodayan et al. in 2004 which reported no correlation between p53 and tumor type, grade, and stage.
Eighty-nine percentage of the tumors with high mitosis (mitosis >) are p53 positive. 93.3% of the tumors with severe nuclear atypia were p53 positive. Nuclear atypia and mitosis are the two features in grading serous tumors as per the two-tier system. Independent association of nuclear atypia and mitosis with p53 positivity was also seen in this study. Similar studies by Kmet et al. in 2003 and Skirnisdottir et al. in 2002 reports that p53 positivity correlated to tumor grade., There was no association seen between the tumor size and p53 staining among the malignant serous tumors.
A recent study by Koebel et al. on 1626 ovarian carcinoma samples from the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type showed that histotype prediction by 4-marker IHC marker panel (WT1, TP53, NAPSA, and PGR) can classify EOT with 87% accuracy while an 8 panel IHC marker (WT1, TP53, CDKN2A, NAPSA, PGR, TFF3, ARID1A, VIM) is more feasible in cohort reclassification for research purposes and claims to provide statistically validated, inexpensive IHC algorithms, which have versatile applications in research, clinical practice, and clinical trials. These recent advances make it necessary for not only correctly interpreting p53 IHC of the ovary in routine pathology practice but also for further validation of this data in a bigger cohort of Asian population and further research.
| Conclusions|| |
P53 IHC is a surrogate marker for p53 gene mutation in clinical practice. p53 positivity is seen in serous EOT, the expression being higher in high-grade serous carcinomas and in the advanced stage. It helps to differentiate between borderline and malignant tumors and high-grade from low-grade serous carcinomas. It can also assist in differentiating the endometrioid carcinomas from the serous types. Both staining patterns—diffuse staining and null positive patterns—are to be analyzed in routine practice. Null staining pattern deserves further studies for the association with its poorer prognosis. Hence, choosing an antibody clone which detects both wild and mutant staining is mandatory for p53 IHC. Understanding of p53 staining patterns is mandatory to use it along with a panel of other antibodies for the correct classification and further research of morphologically confusing EOT.
We are grateful to Dr Sankar S, Dr Laila Raji N, Dr Lillykutty Pothen, Dr Sheeja S for the support; Dr Siva and Dr Austoria for the statistical help and Smt. Kala Kumari for the technical support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Nihad Abdul Razak Amanullah
College of Applied Medical Sciences in Jubail, Imam Abdulrahman Bin Faisal University, P O Box 3856, Jubail Industrial City, Al Jubail 35816, Eastern Province
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]