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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 2  |  Page : 116-122

Relevance and interrelationship of progesterone receptor, Ki67, and p53 in meningiomas: An immunohistochemical analysis in 273 cases


1 Department of Pathology, Institute of Human Behaviour and Allied Sciences, Delhi, India
2 Department of Biostatistics, Institute of Human Behaviour and Allied Sciences, Delhi, India
3 Department of Neurosurgery, Guru Teg Bahadur Hospital, University College of Medical Sciences, Delhi, India

Date of Web Publication14-May-2019

Correspondence Address:
Dr. Ishita Pant
Department of Pathology, Institute of Human Behaviour and Allied Sciences, Dilshad Garden, Delhi - 110 095
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijhas.IJHAS_82_18

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  Abstract 


BACKGROUND: Meningiomas are among the most common of central nervous system neoplasms. These are classified into meningiomas with low risk of recurrence and aggressive behavior (World Health Organization [WHO] Grade I) and meningiomas with greater likelihood of recurrence and aggressive behavior (WHO Grade II and Grade III) according to the WHO 2016 criteria. A host of markers are implicated in the genesis, progression, and recurrence of meningiomas. This study was undertaken with the aim to analyze the sociodemographic profile of various grades of meningiomas and to assess the relevance and correlation between progesterone receptor (PR), Ki67, and p53 among these.
MATERIALS AND METHODS: Retrospective analysis was performed for 273 cases of intracranial and intraspinal meningiomas. All intracranial and intraspinal meningiomas were graded according to the WHO 2016 criteria. Immunohistochemistry was performed using PR, Ki67, and p53 in 273 cases. Statistical analysis was performed.
RESULTS: According to the WHO 2016 grading system, 254 were Grade I (93.04%), 14 were Grade II (5.13%), and 5 were Grade III (1.83%) meningiomas. According to the histological type, among Grade I, 207 meningiomas were transitional (75.82%), 11 meningothelial (4.03%), 11 angiomatous (4.03%), 8 psammomatous (2.93%), 6 fibroblastic (2.19%), 5 microcystic (1.83%), 4 metaplastic (1.47%), and 2 secretory (0.73%). Among Grade II, there were 13 cases of atypical meningiomas (4.76%) and 1 case of clear-cell meningioma (0.37%). Among Grade III, 3 meningiomas were rhabdoid variant (1.09%) and 2 cases were anaplastic meningiomas (0.37%). In all the cases, correlation with PR, p53, and Ki67 was assessed.
CONCLUSION: Immunohistochemical evaluation of PR status, p53 expression, and Ki67 labeling index do add information to the routine histopathological evaluation of meningiomas. In addition, these markers do help in assessing the biological behavior of meningiomas.

Keywords: Immunohistochemistry, Ki67, meningioma, p53, progesterone receptor


How to cite this article:
Pant I, Chaturvedi S, Tripathi CB, Singh G. Relevance and interrelationship of progesterone receptor, Ki67, and p53 in meningiomas: An immunohistochemical analysis in 273 cases. Int J Health Allied Sci 2019;8:116-22

How to cite this URL:
Pant I, Chaturvedi S, Tripathi CB, Singh G. Relevance and interrelationship of progesterone receptor, Ki67, and p53 in meningiomas: An immunohistochemical analysis in 273 cases. Int J Health Allied Sci [serial online] 2019 [cited 2019 Jul 21];8:116-22. Available from: http://www.ijhas.in/text.asp?2019/8/2/116/258189




  Introduction Top


Meningiomas are the most common primary central nervous system neoplasms, mostly benign, slow-growing neoplasms, constituting between 13% and 26% of all brain tumors overall.[1] They occur most commonly in middle-aged patients, with a peak during the sixth and seventh decades. The male-to-female ratio is approximately 1:1.7. These are classified into meningiomas with low risk of recurrence and aggressive behavior (World Health Organization [WHO] Grade I) and meningiomas with greater likelihood of recurrence and aggressive behavior (WHO Grade II and Grade III) according to the WHO 2016 criteria. Grade II and III meningiomas occur at a higher rate in males.[2]

The major prognostic factor of relevance in meningiomas is the prediction of recurrence and this depends on the extent of resection, its histopathological type, grading, proliferation indices, and progesterone receptor (PR) status. The WHO grading based on the histopathological features alone has certain limitations in predicting the exact behavior of meningiomas. Hence, the use of certain immunohistochemical markers such as Ki67, p53, and PR aids in determining the aggressive nature of the tumor and its recurrence potential. In this purview, this study was conducted with the aim to investigate the correlation between various grades of meningiomas with the proliferation index Ki67, p53, and hormonal (PR) markers.


  Materials and Methods Top


A retrospective analysis of the histopathology records and clinical case files was done in 273 cases of histopathologically diagnosed cases of intracranial and intraspinal meningioma (WHO Grade I, II, and III) received over a period of 10 years in our department. All intracranial and intraspinal meningiomas were included in the study. Hematoxylin and eosin staining was done for histological typing and grading of the tumors, and the cases were analyzed for histopathological typing and grading as per the WHO 2016 criterion.

Immunohistochemical staining for Ki67, p53, and PR was done in all cases. Ki67 and p53 expressions were defined as the percentage of positive cells, determined by counting 1000 tumor cells in fields with the largest number of positive cells. For PR, the immunostained sections were graded semi quantitatively for intensity and extent of staining. This semi-quantitative scoring scale included as follows: (a) staining intensity (graded as; 0: absent, 1: weak, 2: moderate, and 3: strong) and (b) percentage of positive tumor cells (0: indicating the absence of positive nuclei; 1: The presence of a few positive tumor nuclei (<10% in the entire section); 2: An estimated 10%–50% of positive nuclei; 3: 51%–80% of positive tumor nuclei; and 4: >80% of positive tumor nuclei). An immunoreactive score (IRS, previously designed by Roser et al. in 2004) was calculated for each tumor by multiplying the staining intensity by the indicator for positive tumor cells, producing an IRS range from 0 to 12. Tumors with an IRS of 2 or more were considered receptor positive.[2]

Statistical analysis

The significance of age among the three grades of meningiomas was assessed using the one-way ANOVA test. Comparison of Ki67, p53 expression between Grade I, Grade II, and Grade III meningiomas was determined using the Chi-square test. The significance of gender and location among the various grades of meningiomas was also assessed using the Chi-square test. The average PR score among the different histological grades was calculated using nonparametric test (Kruskal–Wallis test). A value of P < 0.05 was considered statistically significant.


  Results Top


Among the 273 meningioma cases, based on the WHO 2016 grading criteria, Grade I meningiomas (254 cases) were the most common representing 93.04% of cases followed by 14 cases of Grade II (5.13%) and 5 cases (1.83%) of Grade III meningiomas [Figure 1]. According to histological type, among the Grade I, 207 meningiomas were transitional (75.82%), 11 meningothelial (4.03%), 11 angiomatous (4.03%), 8 psammomatous (2.93%), 6 fibroblastic (2.19%), 5 microcystic (1.83%), 4 metaplastic (1.47%), and 2 secretory (0.73%) [Figure 2]. Among Grade II, there were 13 cases of atypical meningiomas (4.76%) and 1 case of clear-cell variant (0.37%) [Figure 3]. Among Grade III, three cases were of rhabdoid meningioma (1.09%) and two were anaplastic meningioma (0.73%) [Figure 4] and [Table 1].
Figure 1: Grading pattern among the 273 cases of meningiomas

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Figure 2: Histopathology showing (a) Transitional meningioma (H and E, ×200). (b) Meningothelial meningioma (H and E, ×200). (c) Angiomatous meningioma (H and E, ×200). (d) Psammomatous meningioma (H and E, ×200). (e) Fibroblastic meningioma (H and E, ×200). (f) Microcystic meningioma (H and E, ×200). (g) Metaplastic meningioma (H and E, ×200). (h) Secretory meningioma (H and E, ×200)

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Figure 3: Histopathology showing (a) Atypical meningioma (H and E, ×200). (b) Clear-cell meningioma (H and E, ×200)

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Figure 4: Histopathology showing (a) Rhabdoid meningioma (H and E, ×200). (b) Anaplastic meningioma (H and E, ×200)

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Table 1: The histopathological types and grades as per World Health Organization 2016 criteria

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Overall, the mean age was 44.03 years (range: 9–78 years) [Box 1]. The mean age (± standard deviation) among Grade I meningiomas was 44.65 ± 13.63 years, among Grade II, it was 39.14 ± 15.89 years, while among Grade III, it was 21.80 ± years. A statistically significant difference was seen in relation to the age with different grades of meningiomas (one-way ANOVA test P < 0.05) [Table 2]. There were 78 male (28.6%) and 195 female patients (71.4%). In all cases, including aggressive variants, there was a female predominance, the male-to-female ratio was 1:2.5. Among 254 cases of Grade I meningiomas, male-to-female ratio was 1:3, among 14 cases of Grade II meningiomas, it was 1:1 while among 5 cases of Grade III meningiomas, it was 1:1.5 [Box 1]. No significant association (Chi-square test P > 0.05) was found in relation to gender with different grades of meningiomas [Table 2]. Overall, 226 cases (82.8%) were found at the intracranial location, followed by 41 cases (15%) found at the intraspinal location, and 6 cases (2.2%) were found at the intraventricular location. Among the intracranial meningiomas, 150 cases (54.9%) were at the cerebral convexities followed by 43 cases at posterior fossa (15.6%). Regarding the intraspinal location, maximal 30 cases (10.9%) were found in the thoracic region [Box 1]. Among the three grades, the most common locations found were as follows: cerebral convexities, posterior fossa, and sphenoid ridges; reported as 76.4% in Grade I, 78.6% in Grade II, and 100% in Grade III meningiomas. No significant association (Chi-square test P > 0.05) was found in relation to location with different grades of meningiomas [Table 2].

Table 2: Sociodemographic details, histopathological variables, and their correlation with World Health Organization grade in 273 cases of meningiomas

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Immunohistochemical expression of Ki67, p53, and PR showed varied results among Grade I, II, and III meningiomas [Figure 5]. Among 273 cases, Ki67 labeling index was maximal in Grade II and Grade III meningiomas and minimal in Grade I meningiomas [Figure 6]. Ki67 labeling index was <1% in 93.3% cases and >1% in 6.70% cases of Grade I meningiomas (range <1% to 18%), in Grade II meningiomas, it was <1% in 57.10% cases and >1% in 42.90% of cases (range <1% to 20%), whereas in Grade III meningiomas, Ki67 labeling index was <1% in 40% of cases and >1% in 60% of cases (range <1% to 25%). Ki67 labeling index in this study showed a statistically significant association (Chi-square test P < 0.05) among the three grades of meningiomas. Regarding p53 expression, it was minimal in Grade I meningiomas, followed by Grade II meningiomas, and maximal in Grade III meningiomas [Figure 7]. p53 expression was <1% in 70.9% cases and >1% in 29.10% cases of Grade I meningiomas (range <1% to 80%), in Grade II meningiomas, it was <1% in 21.40% cases and >1% in 78.60% of cases (range <1% to 55%), while in Grade III meningiomas, all the cases showed >1% p53 expression (range 12%–50%). p53 expression in this study showed a statistically significant association (Chi-square test P < 0.05) among the three grades of meningiomas. In contrast, PR expression was maximal in Grade I meningiomas (range 0–12), followed by Grade II meningiomas (range 0–9), and it was negative in all Grade III meningiomas [Figure 8]. Mean PR score (± standard deviation) was 5.57 ± 4.51 in Grade I meningiomas; it was 3.00 ± 3.37 in Grade II meningiomas, and in Grade III meningiomas, it was 0.00 ± 0.00. A statistically significant difference ((Kruskal–Wallis test P < 0.05) was found in relation to PR expression among the three grades of meningiomas [Table 2].
Figure 5: Histopathology showing (a) Ki67 showing <1% immunopositivity (Ki67, ×200). (b) Ki67 showing >1% nuclear immunopositivity (Ki67, ×200). (c) p53 showing <1% immunopositivity (p53, ×200). (d) p53 showing >1% nuclear immunopositivity (p53, ×200). (e) Progesterone receptor showing nuclear immunonegativity (progesterone receptor, ×200). (f) Progesterone receptor showing nuclear immunopositivity (progesterone receptor, ×200)

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Figure 6: Distribution pattern of Ki67 among various grades of meningiomas

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Figure 7: Distribution pattern of p53 among various grades of meningiomas

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Figure 8: Distribution pattern of progesterone receptor among various grades of meningiomas

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  Discussion Top


Meningiomas are mostly benign, slow-growing neoplasms that most likely derive from the meningothelial cells of the arachnoid layer. There are three major groups of meningiomas, which differ in grade and biological behavior. Most meningiomas are benign and correspond histologically to Grade I; however, certain histological subtypes are associated with less favorable clinical outcomes and correspond histologically to Grades II and III.[3]

Meningiomas most commonly occur in middle-aged and elderly patients, with a female predominance, however, Grade II and III meningiomas occur at higher rates in males.[4] In concordance with the existing literature, in this study, the majority of meningiomas manifested in middle age, with a statistically significant difference among Grade I, II, and III meningiomas, similarly an overall female predominance was found in this study, in concordance to the studies reported by Babu et al., Backer-Grøndahl et al., and Shrilakshmi;[4],[5],[6] however, we did not find any statistically significant association among the various grades of meningiomas, and the gender which was contrary to the study of Veeramani and Maheshwari published in 2017.[7]

As far as the location is concerned, in this study, the most common site was intracranial and among the intracranial meningiomas, 54.9% were at the cerebral convexities. Our results regarding location were in agreement to the existing literature. The most common histopathological variant in this study was transitional meningioma (76.2%), similar to the results published by Babu et al.(35.3%), Backer-Grøndahl et al.(40%), Veeramani and Maheshwari (48%), and Shanthi et al.(50%).[4],[5],[7],[8] All these authors had reported transitional meningioma as the most common variant in their studies. Contrary to our results, meningothelial meningioma had been reported as the most common variant by Gursan et al.(50%), Mukherjee et al. (36.7%), Shrilakshmi (23.4%), Telugu et al.(26.3%), Mukhopadhyay et al. (38.8%), and Madabhushi et al.(25%).[1],[3],[6],[9],[10],[11] In this study, 93.04% of cases were Grade I, totally in concordance to the existing literature.

Although the majority of meningiomas are considered benign (Grade I) and slow-growing tumors, still about 20% of them may show a more aggressive course manifesting usually as local recurrences.[12] A variety of clinical, radiological, and histological prognosticators has been defined in the literature. Of these, the extent of surgical resection plays the most important role, as tumors that are incompletely resected often recur regardless of other considerations.[12] In addition, certain ancillary techniques have always aided in improving the diagnostic and prognostic accuracy. In the past, several studies have attempted to correlate the role of Ki67, p53, and PR in cases of meningioma and also to assess their importance as prognostic markers in predicting the behavior of meningioma. The results have been varied. In 2006, Kasuya et al. had reported that in their study 18.9% of Grade I tumors, 96.4% of Grade II tumors, and 94.5% of Grade III tumors had Ki67 proliferation index ≥3.[13] Later, Ildan et al. stated that in their study, Grade II meningiomas were heterogeneous and had two groups, namely tumors with low proliferative grade and tumors with the high proliferative grade.[14] Carvalho et al. in 2007 reported that higher Ki67 labeling indices were associated with an increased risk of recurrence and emphasized that it can be used as an adjunct to grading of meningiomas.[15] Afterward, Louis et al., Ragel and Jensen, and Abry et al. demonstrated that Ki67 proliferation index had increased with the grades of meningiomas with a statistically significant difference of mean Ki67-labelling index between Grade I, II and I and III meningiomas.[16],[17],[18] Amatya et al. in their study reported that generally, higher the Ki67 index, higher is the grade of meningiomas and its tendency for recurrence.[19] Ki67 in this study showed a statistically significant association among the three grades of meningiomas, showing <1% proliferative activity in 93.3% Grade I meningiomas, and >1% proliferative activity in 42.9% of Grade II, and 60% Grade III meningiomas establishing a strong correlation with the grade, highlighting the role of Ki67 as a prognostic marker. Our results were in consonance with the earlier quoted studies.

p53 protein association with histological grade of meningioma has been extensively studied. Results showed wide range of p53 immunoreactivity in meningiomas that varied from 10% to 88%.[20],[21],[22] Perry et al. had reported a tendency for higher p53 values in higher grades of meningiomas.[23] In the study by Cho et al., p53 immunoreactivity demonstrated in Grade I, Grade II, and Grade III meningiomas were 9.5%, 72.7%, and 88.9%, demonstrating that immunoreactivity of p53 was significantly higher as the histological grade increased.[24]

In concordance with the earlier quoted studies, in this study, p53 was mostly positive in Grade III meningiomas (100%), followed by Grade II (78.6%), and Grade I meningiomas (29.1%). This study also showed a statistically significant association between p53 levels and meningioma grade.

Assessment of PR is important in meningiomas because of the usual female preponderance. Earlier studies had suggested that the expression of PR is roughly inversely proportional to the WHO histological grade and in addition, PR scoring also helps in assessing the Grade I meningiomas that are likely to recur.[25] Hilbig et al. in earlier years had reported that among Grade 1 meningiomas, 58.3% were positive for PR while 48.2% Grade II meningiomas were positive for PR.[26] Roser et al. later reported that there was significantly lower PR expression in the WHO Grade II (atypical) and III (anaplastic) meningiomas compared with WHO Grade I meningiomas.[27] Shayanfar et al. also demonstrated positive nuclear immunostaining for PR in 96.8% of Grade I, 20% in Grade II, and total immunonegativity (0%) in Grade III meningiomas.[28] Similarly, Brandis et al. and Wolfsberger et al. in their studies reported that malignant meningiomas (Grade III) were completely immunonegative for PR.[29],[30] The difference between the three grades was statistically significant in their studies.[28]

Our results were in accordance with these earlier quoted studies, showing the highest PR score of 5.57 in Grade I meningiomas compared to a score of 3.0 in Grade II meningiomas and complete immunonegativity in Grade III meningiomas with a PR score of 0.


  Conclusion Top


Immunohistochemical evaluation of PR status, p53 expression, and Ki67 labeling index do add information to the routine histopathological evaluation of meningiomas. In addition, these markers help in assessing the biological behavior of meningiomas and in formulating the suitable treatment plan for various grades of meningiomas as early as possible.

Acknowledgment

The authors would like to thank Ms. Meetu Raj Behal, Ms. Kavita Dhaiya, and Ms. Kirtika for their untiring technical assistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1], [Table 2]



 

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