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ORIGINAL ARTICLE  
Year : 2014  |  Volume : 57  |  Issue : 4  |  Page : 558-563
Overexpression and amplification of Murine double minute 2 as a diagnostic tool in large lipomatous tumor and its correlation with Ki67 proliferation index: An institutional experience


Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

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Date of Web Publication11-Oct-2014
 

   Abstract 

Context: Well-differentiated liposarcoma (WDLPS) is the most common type of liposarcoma and sometimes can be difficult to distinguish from large lipoma due to the similar morphology. Aims: This study proposed to evaluate the expression and amplification of Murine double minute 2 (MDM2) gene and determine its correlation with Ki67 proliferation index. Settings and Design: This study used cross-sectional design. Materials and Methods: This study enrolled 37 cases of lipomatous tumors with >5 cm in size. Eighteen cases of WDLPS and 19 cases of lipoma were stained for MDM2 and Ki67 immunohistochemistry, followed by MDM2 in situ hybridization in 12 selected cases. Statistical Analysis Used: MDM2 overexpression and amplification status for both groups were compared using Chi-square test, with the alternative of Fisher's exact test. Correlation test between MDM2 overexpression and clinical characteristics with the Ki67 proliferation index were performed using Pearson's test with the alternative of Spearman's rho test. Results: MDM2 overexpression was detected in all WDLPS cases and in 3 (16%) of lipoma cases with significance difference (P = 0.000), whereas MDM2 amplification was found in all WDLPS and in 1 of lipoma cases (P = 0.200). There was a strong correlation between MDM2 overexpression and higher Ki67 proliferation index (r = 0.645, P = 0.000). Conclusion: Evaluation of MDM2 overexpression can be used as a useful adjunct to differentiate WDLPS from large lipoma and seems to be related with Ki67 proliferation index.

Keywords: Ki67, lipoma, Murine double minute 2 (MDM2) gene, MDM2 protein, well-differentiated liposarcoma

How to cite this article:
Putri RI, Siregar NC, Siregar B. Overexpression and amplification of Murine double minute 2 as a diagnostic tool in large lipomatous tumor and its correlation with Ki67 proliferation index: An institutional experience . Indian J Pathol Microbiol 2014;57:558-63

How to cite this URL:
Putri RI, Siregar NC, Siregar B. Overexpression and amplification of Murine double minute 2 as a diagnostic tool in large lipomatous tumor and its correlation with Ki67 proliferation index: An institutional experience . Indian J Pathol Microbiol [serial online] 2014 [cited 2021 Nov 28];57:558-63. Available from: https://www.ijpmonline.org/text.asp?2014/57/4/558/142663



   Introduction Top


Liposarcoma is a unique soft tissue tumor with the histological diversity and biological characteristics related to different molecular changes in each subtype. Well-differentiated liposarcoma (WDLPS) is the most common subtype of liposarcoma and sometimes is challenging to be discriminated from lipoma due to the similar histological features. [1],[2],[3] However, these two entities have different prognosis and management due to the recurrence risk and the ability of WDLPS to dedifferentiate into more aggressive tumor. Lipoma has a lower recurrence rate (<5%) compared to WDLPS (43-91%), with the tumor located in the retroperitoneum reached the highest risk due to the difficulty in performing wide excision in this region. [1],[4],[5],[6],[7]

Recent use of cytogenetic and molecular analysis has successfully found the genomic profile in WDLPS. WDLPS has specific molecular changes called supernumerary ring and giant chromosomes that resulting in the amplification of 12q13-15 regions. Murine double minute 2 (MDM2), as a proto oncogene that regulating cell growth is consistently amplified among other genes in this chromosomes region, therefore, it is frequently used as a marker of WDLPS. On the contrary, this genetic amplification was not found in lipoma, a more common benign lipomatous tumor. [7],[8],[9]

Some techniques can be used to detect the amplification and overexpression of MDM2 such as immunohistochemistry (IHC), in situ hybridization (ISH), or polymerase chain reaction. Sirvent et al. in his study, revealed that ISH of MDM2 in WDLPS has higher sensitivity and specificity than other techniques, that is, 95% and 100%, respectively. [8] Weaver et al. and Tanas et al. also concluded that identification of MDM2 amplification using ISH is an accurate method with 100% sensitivity and specificity. [10],[11] However, IHC of MDM2 is a more simple detection method with high reproducibility so it can be used as an additional examination to distinguish WDLPS from lipoma. [12] Elmoneim and Sherbiny compared IHC and ISH MDM2 for diagnosing lipomatous tumors and they concluded that IHC examination is accurate enough and thus, further molecular examination like ISH is not required unless there were some significant difficulties. [13]

In addition to be a diagnostic tool, overexpression/amplification of MDM2 can also be used as a predicting factor of poor prognosis and low-survival rate in some cases of soft tissue sarcoma specially liposarcoma. There are some markers to predict the tumor prognosis, like Ki67, the proliferation index that synthesized through cellular cycles and correlated to tumor cell progressivity. [14]

This study will identify the profile of MDM2 overexpression and amplification in WDLPS compared to lipoma and its correlation with proliferation index. It is expected that there was a significant difference so that the examination of MDM2 can be used as an adjunct tool for diagnosing lipomatous tumor and has predictive value for malignancy. In addition, this study also identifies the correlation between MDM2 overexpression as well as the clinical characteristics with the Ki67 proliferation index.


   Materials and Methods Top


This study was approved by the Institutional Review Board. A total of 37 cases of WDLPS and lipoma from our hospital, in time of January 2009 to December 2012 were selected for this study. All tumors were >5 cm in size and treated by complete excision or resection. All specimens were reviewed and sub-classified according to the 2013 World Health Organization criteria.

For MDM2 and Ki67 immunostainings, 4-mm-thick paraffin sections were cut and mounted on poly-L-lysine glass slides. The slides were deparaffinized in xylene and rehydrated with ethanol. Endogenous peroxidase was blocked using 95 ml of methanol plus 5 ml of 3% hydrogen peroxide solution. Heat-based antigen retrieval was carried out for 10 min. Both primary antibodies used were from Biocare Medical for MDM2 (dilution 1:300) and Ki67 (dilution 1:200). Slides were incubated for 1 h with the primary antibodies followed by staining with streptavidin-biotin peroxidase. Slides were then revealed in a diaminobenzidine solution for 3 min and stained with hematoxylin for 2 min. A well-characterized WDLPS case and a tonsil tissue were used as positive controls for MDM2 and Ki67, respectively. Negative controls were obtained by omitting the primary antibodies. A cutoff point of >20% moderate to strong nuclear immunoreactivity on the tumor cells was defined as a positive overexpression of MDM2. For Ki67, total of immunoreactive nuclei in 10 high-power fields were counted as a continuous variable. [14]

Twelve cases consist of 8 WDLPS and 4 extraordinary lipomas were examined for MDM2 amplification on chromosome 12q13-15 region using ZytoDot 2C SPEC MDM2/CEN12 Probe (Zytovision). The average number of MDM2 and CEN12 signals in 10 high-power field was then determined, and an MDM2/CEN12 ratio was calculated for each case. A well-characterized WDLPS was used as a positive control. Negative controls were internal controls. A ratio of ΃2.0 was considered amplified for the MDM2 gene, while the ratio of <2.0 was considered nonamplified. A ratio of <2.0 with >2 signals of both probes was considered polysomic for CEP12. [15]

Descriptive data are presented in the frequency table. Categorical variables were compared using Chi-square test, with the alternative of Fisher's exact test. Correlation test between MDM2 overexpression and clinical characteristics with the Ki67 proliferation index were performed using Pearson's test with the alternative of Spearman's rho test. P < 0.05 was considered statistically significant. The power of correlation (r) was scored by Colton classification. Statistical analysis was performed using SPSS Statistics for Windows, Version 17.0 (SPSS Inc., 2008, Chicago, USA).


   Results Top


Based on our archives, using the search code of M885, there were 455 lipomatous tumors, consist of 390 (86%) lipoma, and 65 (14%) liposarcoma in different levels of malignancy. About 33 (51%) cases of all liposarcoma were WDLPS.

The ratio of male and female patients in lipoma group was 1:1.2, and 1:1 for liposarcoma. The median age of lipoma group was 44 (1-84) years, and 52 (16-69) in WDLPS group.

A total of 37 cases was included in the final analysis with reclassification done in three cases. About 18 (49%) cases were diagnosed as WDLPS while the remaining 19 (51%) were lipoma. Normality test was carried out for all continuous variables (age, tumor size, and Ki67 index) using Saphiro-Wilk. Data were normally distributed when P > 0.05.

[Table 1] shows the baseline characteristics of both WDLPS and lipoma groups in this study.
Table 1: Baseline characteristics

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The IHC examination showed MDM2 overexpression in all cases of WDLPS. On the other hand, 3 (16%) cases in lipoma group also showed MDM2 overexpression, consist of 1 angiolipoma and 2 cases of pleomorphic/spindle cell lipoma. Meanwhile in the remaining 16 (84%) cases, no nuclear positivity was found. [Figure 1] shows some expressions of MDM2 in WDLPS and lipoma.
Figure 1: Sclerosing type of well-differentiated liposarcoma (a). Immunohistochemistry (IHC) showed Murine double minute 2 (MDM2) overexpression in stromal atypical nuclei and lipoblast (arrow) (b). Lipoma-like liposarcoma with mature adipocytes and scattered atypical nuclei (c), which showed immunoreactvity on MDM2 staining (d). Lipoma with numerous fibrous tissue (e), MDM2 IHC revealed negative result (f). True magnification ×100 (a, c, e), ×200 (f), and ×400 (b, d)

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Chi-square test has been done to compare the MDM2 overexpression in WDLPS and lipoma and there was statistically significance difference (P = 0.000).

Of all samples in this study, 12 cases were eligible for further examination using chromogenic ISH (CISH), that is, 5 lipoma-like WDLPS, 3 sclerosing WDLPS, 2 pleomorphic/spindle cell lipoma, 1 angiolipoma, and 1 ordinary lipoma. The results were assessed blinding to histopathological and IHC features. Two cases cannot be interpreted due to inadequate results of staining. Eight (100%) cases of WDLPS revealed MDM2 gene amplification, however, one case of lipoma showed the amplification as well. The alternative statistical test, Fisher's exact failed to prove the difference amplification status for both groups (P = 0.200). [Figure 2] shows the results of CISH MDM2 positive control and some examples of cases.

Tumor cell proliferation index was assessed using Ki67 index [Figure 3]. Statistical test, Spearman's rho between MDM2 overexpression and Ki67 index showed strong correlation (r = 0.645, P = 0.000). Results of MDM2 IHC staining, CISH MDM2, and Ki67 index were compiled in [Table 2].
Table 2: MDM2 IHC staining, CISH MDM2, and Ki67 proliferation index based on histological subtype

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Figure 2: Chromogenic in situ hybridization Murine double minute 2 showed amplification in (a) positive control, (b) Lipoma-like liposarcoma, and a case of pleomorphic/spindle cell lipoma (c) (arrow). (d) No amplification was found in angiolipom (arrowhead). True magnification ×1000 (a-d)

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Figure 3: Immunohistochemistry Ki67 staining on (a) well-differentiated liposarcoma, with 63 nuclei strongly stained in 10 high-power fields, (b) angilipoma, with four positive nuclei and (c) spindle cell/ pleomorphic lipoma with six positive nuclei (arrows). (d) Ordinary lipoma, with no nuclei stained by Ki67. True magnification ×400 (a-d)

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As an additional analysis, correlation test was also performed between some clinical characteristics and Ki67 index. Pearson's correlation test between tumor size and Ki67 index showed strong correlation (r = 0.550, P = 0.000), while Spearman's rho correlation test between histological subtype of WDLPS and location of tumor with Ki67 index revealed significant correlation as at the rate of 0.481 and 0.477, respectively (P = 0.003). Gender and age did not show significant correlation with Ki67 index.

Data of Ki67 proliferation index based on the histological subtype, size, and location of the tumor in WDLPS group were summarized in [Table 3].
Table 3: Ki67 index in WDLPS based on histological subtype, size, and location

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   Discussion Top


Compared to worldwide data, our hospital archive shows the similar data of gender ratio as well as the proportion of WDLPS, which presenting 51% of all liposarcomas. The median of age in lipoma group is 47 years, almost a decade earlier than in WDLPS group. [5],[16]

Most WDLPS are located in lower extremities, in accordance with the references that stating, 75% WDLPS occurred at the lower extremities, 20% at retroperitoneum and the remaining at mediastinum and paratesticle. [17] In lipoma group, location in the trunk is dominating the samples. Although trunk is the predilection area of lipoma, however, this region is the second most frequent location in WDLPS group. Therefore, when facing lipomatous tumors located in the trunk, we recommend to done the section carefully and to collect the clinical information as well.

As in the other soft tissue sarcoma, tumor location contributes to the WDLPS prognosis. [18] In this study, 23% tumors are located in retroperitoneum and all of them are larger than 18 cm in size. Tumor inside the body cavity such as in retroperitoneum is likely to be late detected so that the tumor is getting larger and make it impossible to undergo wide excision. Although rarely metastasize, local recurrence frequently occurs in WDLPS when the excision in the first surgery was not free margin. [14],[16] Weiss et al. revealed that of all cases of WDLPS located at retroperitoneum, 91% had local recurrence, 17% underwent de-differentiation, and 33% of patients died during the 10-year followup. [19]

Tumor size also has an important role to suspect a malignancy in soft tissue tumor. This study found a significant difference of tumor size in WDLPS and lipoma groups, support the references statement that tumor smaller than 5 cm is more likely to be considered benign and vice versa. [1],[4]

In line with the other study, lipoma-like liposarcoma is the most commonly found histological subtype followed by sclerosing liposarcoma. [1],[7],[17] On the other hand, some variants of lipoma such as angiolipoma, fibrolipoma, and pleomorphic/spindle cell lipoma have different histological presentation from the ordinary lipoma. These subtypes show increased cellularity composing of spindle cells that can be either stromal or endothelial cells, as well as the proliferation of fibrous tissue. [20]

Results of this study showed that IHC MDM2 is useful in distinguishing WDLPS from lipoma, as shown by higher positivity in WDLPS group (100%) than lipoma group (16%). This finding is in line with Binh et al.'s study, revealing that IHC MDM2 has high sensitivity and specificity in diagnosing WDLPS, that is, 100% and 96%, respectively. [21]

Three of 19 lipoma cases showed positive results in IHC MDM2 examination. Two cases are pleomorphic/spindle cell lipoma, and 1 is angiolipoma. All of these tumors are smaller than 10 cm in size and located in trunk and upper extremities which are the predilection area of lipoma. Although in relatively small percentage, Binh et al. and Aleixo et al. also found the same results, which in their study, 2 pleomorphic lipoma and 1 case of angiomyolipoma showed positive results. In such cases, examination should be continued to the gene level, and when amplification is found, it is more likely to be WDLPS. [21],[22]

Amplification of MDM2 is also found in all cases of WDLPS. It implies that in this study amplification is the only cause of MDM2 overexpression. In their study, Pilotti et al. revealed MDM2 amplification in all cases of WDLPS with MDM2 overexpression. [23]

In lipoma group, MDM2 gene amplification was found in one case of pleomorphic/spindle cell lipoma which also showed MDM2 overexpression. Therefore, in this case, careful reevaluation should be taken. Another case of pleomorphic/spindle cell, which also showed of MDM2 overexpression, results in failure to evaluate CISH staining due to the over digested nuclei.

Statistical analysis of MDM2 amplification in this study does not show a significant difference between WDLPS and lipoma group (P = 0.200), but this result has to be confirmed by larger sample size and more representative population in order to have valid results. A multivariate study by Zhang et al. showed that reclassification of histopathological diagnosis using the status MDM2 amplification is significant in determining the risk of tumor recurrence. [24]

In addition to its diagnostic role, some studies have found a correlation between MDM2 overexpression and tumor progression to a higher grade of malignancy. Other studies revealed that MDM2 overexpression is correlated to the risk of dedifferentiation in WDLPS although with unknown mechanism. [14]

As a negative regulator of p53, amplification and overexpression of MDM2 are known to be correlated with a worse prognosis. [25] This study showed that MDM2 overexpression has a strong correlation with higher tumor cell proliferation index. The significant difference of Ki67 index between lipoma and WDLPS group in this study proved the role of Ki67 in distinguishing proliferation activity in lipomatous tumor.

All histological subtypes of WDLPS show MDM2 overexpression and amplification of MDM2 gene. However, higher Ki67 index was found in sclerosing the subtype, which is in line with the literature implying that sclerosing liposarcoma is more likely found in large tumors. Therefore, it can be said that this subtype has more aggressive biological characteristics. [5]

Additional analysis in this study also shows a significant correlation between tumor size and proliferation activity. In their study, Kim et al. concluded that tumor smaller than 10 cm has higher survival rate (100%) while tumor larger than 10 cm show decrease of approximately 32%. This finding is in line with the nomogram made by Memorial Sloan-Kettering Cancer Centre, which concluded that tumor size, grade, depth, margin status, recurrence, and tumor location are the prognostic factors in liposarcoma. [16],[26]

Tumor located in lower extremities is more likely to have higher cellular proliferation index, and in the contrary, for tumor located in the trunk, the proliferation index is lower because these two locations are the predilection areas of WDLPS and lipoma which in this study also showed a significant difference of Ki67 index.


   Conclusion Top


Our study revealed that MDM2 overexpression is higher in WDLPS than in lipoma and thus, has a significant correlation with higher Ki67 proliferation index. Even though, further examination of CISH MDM2 with larger sample is needed to observe the accordance between histopathological features, MDM2 overexpression, and amplification of MDM2 gene in lipomatous tumor. Moreover, there is a significance difference of Ki67 index between WDLPS and lipoma group and also positive correlations between larger tumor size, sclerosing subtype of WDLPS, as well as tumor location in lower extremity with the higher index of Ki67.

As suggestions, clinical information such as tumor depth and margin status is important to be explored in further study, and multivariate analysis is needed to identify the independent prognostic factors for WDLPS. In addition, when facing a lipoma more than 5 cm in size or lipoma located at lower extremities, additional examination of IHC, and ISH MDM2, as well as Ki67, is useful to avoid misdiagnosis. Periodically monitoring also needed to collect the data about recurrence, metastasis, and disease-related death, to have more valid prognosis parameter.



 
   References Top

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Correspondence Address:
Rizky Ifandriani Putri
Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia, Salemba Raya 6, Jakarta - 10430
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.142663

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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