|Year : 2013 | Volume
| Issue : 3 | Page : 164-169
Immunohistochemical detection of p53 and MDM2 expressions in liposarcoma with World health organization classification
A Arici1, T Ozgur2, N Ugras3, U Yalcinkaya3
1 Tokat State Hospital, Pathology Laboratory, Tokat, Turkey
2 Department of Pathology, Mustafa Kemal University, School of Medicine, Antakya/ Hatay, Turkey
3 Department of Pathology, Uludag University, School of Medicine, Gorukle/Bursa, Turkey
|Date of Web Publication||23-Sep-2013|
Department of Pathology, Mustafa Kemal University, School of Medicine, Antakya/ Hatay
Source of Support: None, Conflict of Interest: None
Background: Liposarcomas are among the most common soft tissue sarcomas in adulthood. Aim: The purpose of the study is to perform a histopathologic typing according to World Health Organization (WHO) classification of cases diagnosed with liposarcoma and to examine the difference of p53 and MDM2 expressions. Materials and Methods: The haematoxylin-eosin stained sections of 48 subjects enrolled in the study have been evaluated on the basis of the WHO classification for liposarcoma and sections stained using p53 and MDM2. Statistical Analysis Used: Chi-Square test was applied. Results: 20 subjects were diagnosed with well-differentiated liposarcoma (WLS), 16 myxoid liposarcoma (ML), 7 pleomorphic liposarcoma (PL), and 5 de-differentiated liposarcoma (DLS). The number of cases stained positive with MDM2 and p53 were positive correlated in all subjects (P = 0.02). p53 and MDM2 positivity increased in high grade tumors (P = 0.01). Conclusion: p53 and MDM2 immuno-reactivity was found to be potentially useful in liposarcoma diagnosis but a definitive implication would be rather unhealthy due to the small number of cases in our study.
Keywords: Liposarcoma, MDM2, p53, World health organization classification
|How to cite this article:|
Arici A, Ozgur T, Ugras N, Yalcinkaya U. Immunohistochemical detection of p53 and MDM2 expressions in liposarcoma with World health organization classification. Indian J Cancer 2013;50:164-9
|How to cite this URL:|
Arici A, Ozgur T, Ugras N, Yalcinkaya U. Immunohistochemical detection of p53 and MDM2 expressions in liposarcoma with World health organization classification. Indian J Cancer [serial online] 2013 [cited 2019 Jun 17];50:164-9. Available from: http://www.indianjcancer.com/text.asp?2013/50/3/164/118717
| » Introduction|| |
Liposarcomas are among the most common soft tissue sarcomas in adulthood. It corresponds to 10 to 16% of soft tissue sarcomas. Liposarcomas develop through immature fat tissue cells called lipoblasts or more often from primitive mesenchymal cells. ,, Although they settle in the deep tissues such as thigh and retroperitone in particular, they can occur in many parts of the body including head and neck. ,,
Liposarcomas have a wide variety of histological, biologic and cytogenetic subcategories. The new classification of soft tissue tumors has been published by the World Health Organization (WHO) in 2002. Categories of liposarcoma according this classification are shown in [Table 1]. 
Despite the investigations on the prognostic importance of various factors in soft tissue sarcoma, there seems to be two most important parameters. These are staging and histological typing.
p53 as the most commonly mutating tumor suppressive gene in human carcinoma, assuming an important role in the prevention of cancer development is localized on chromosome 17p13.1. ,,,,
While p53 mutations occur more often as 50% and above in the cancers of organs such as colon, breast and lungs, they are also common in sarcomas, leukemia, lymphoma and the tumors of the nervous system.  The presence of p53 mutations in many human tumors (~50%) is an indicator that the protein (Tp53) produced by this gene assumes an important protective role in the development of cancer. , The major functional activity of the p53 protein is to stop the cell cycle and initiate apoptosis in response to DNA damage. 
The MDM2 gene is localized in the 12q 13-14 chromosome. MDM2 amplification was observed in 30% of the sarcomas. MDM2 binds to the amino-terminal transcription region of p53 and inhibits transcription. MDM2 also induces the destruction of p53. ,
MDM2 over expression was shown to cause immortalization in rat embryonic fibroblasts and to be tumorigenic in neonatal rat astrocytes. Moreover, MDM2 over expression causing tumor development in breast epithelium in transgenic rats in vivo supports MDM2's oncogenic function in cell transformation. 
The purpose of the study is to perform a histopathologic typing in accordance with the WHO classification of cases diagnosed with liposarcoma, and examine the difference of p53 and MDM2 expressions in terms of the type, grade and localization of liposarcoma to detect their relationship with relapse and tumor diameter.
| » Materials and Methods|| |
48 subjects diagnosed with liposarcoma through the excisional biopsy material submitted to the Uludag University Faculty of Medicine Pathology Department Laboratory for histopathology analysis between 2002 and 2009 were enrolled in this study (the study was approved by the decision no. 2009 - 6 / 12 dated April 8, 2009 of the Medical Research Ethics Board of the Uludag University).
Patient information regarding age, gender and tumor localization was obtained from pathology reports.
The haematoxylin-eosin (HE) stained cross sections of the subjects have been re-evaluated for histopathology typology on the basis of the classification for liposarcoma and the preparation representing the tumor in the best manner was selected. Section of 3-4 mm thickness was cut from the paraffin blocks of these preparations and then were de-paraffinized and rehydrated through a graded series of alcohol microwave antigen retrieval method was used, followed by incubation with p53 (Monoclonal Mouse Anti-Human p53 protein, Clone: DO-7) ve MDM2 (Leica / Novocastra NCL-MDM2, Mouse Monoclonal, Lot:114318) Immuno-histologic staining (IHS) was applied.
Tissues of colon carcinoma were used for p53 and breast carcinoma for MDM2 as positive control. Sections of these positive controls were stained by the preparations of the study subjects on simultaneous basis.
Immuno-histochemical evaluation was performed collectively by to pathologists. Nuclear staining of the tumor cells above 10% was considered sufficient for p53 and MDM2 positivity. 
Statistical analysis of the results was performed by the Department Biostatistics of the Uludag University, Faculty of Medicine. Data was analyzed using SPSS for Windows 13.0 statistical software package. Categorical data were presented in the form of frequency and percentage. Other data were specified as median and minimum-maximum. Pearson Chi-Square test was used for statistical comparison. The level of significance was admitted as P ≤ 0.05.
| » Results|| |
Of the 48 subjects enrolled in the study, 20 were found WDL (41.7%), 16 ML (33.3%), 7 PL (14.6%) and 5 DL (10.4%) according to the liposarcoma classification by WHO. This categorization is shown in [Figure 1].
The average tumor diameter of the subjects was found as 17 ± 1 cm. Average tumor diameters in subjects with WDL, ML, PL and DL were 15.5 ± 1.4 cm, 15.7 ± 1.9 cm, 19.2 ± 2.3 cm, and 24.4 ± 3.5 cm, respectively. No difference of statistical significance was found between the diameters of the four tumor categories (P = 0.077).
The subjects were rated on the basis of the FNLCC criteria (5). Consequently, 20 subjects (41.7%) were classified as grade 1, 8 (16.7%) as grade 2 and 20 (41.7%) as grade 3. All of tumors in the grade 1 category were WDL, and those in grade 2 were ML. The group of grade 3 tumors contained 8 ML, 7 PL and 5 DL.
Tumor localizations of the subjects were evaluated as lower extremity, upper extremity, head-neck region and trunk. Tumors localized in the retroperitoneum and back were included in the trunk group. The collective evaluation of all subjects yielded 21 (43.8%) tumor localizations in the trunk (18 in the retroperitoneum, and 3 in the back), 18 in the lower extremity (37.5%), 5 in the upper extremity (10.4%) and 4 in the head-neck region (8.3%). 8 lower extremity, 2 upper extremity, 2 head-neck region, 8 trunk (6 retro peritoneum, 2 back) localizations were observed in WDL subjects; 9 lower extremity, 3 upper extremity, 2 head-neck region, 2 torso (2 retro peritoneum) in ML; 1 lower extremity, 6 trunk (5 retroperitoneum, 1 back) in PL and 5 torso (5 retroperitoneum) in DL. The categorization is shown in [Table 2].
Relapse was found in 5 (10.4%) of the 48 subjects enrolled in the study. 2 of the subjects which were found with relapse were ML, 2 PL, and 1 DL. A subject diagnosed with PL was found to have two relapses. No relapse was observed in the subjects with WDL. Average relapse was observed in 23.8 months as the earliest in month 16, and the latest in 36.
Metastasis was observed in 2 subjects. One of the metastases was a right thigh localized ML diagnosis, and was found in the anterior abdominal wall simultaneously with the primary tumor. The other was diagnosed as a ML localized in the spermatic cord and metastasis was detected in the right inguinal region 3 years after the primary tumor.
The evaluation of the subjects in terms of p53 and MDM2 immunoreactivity as shown in [Table 3] resulted in p53 in 7 WDL cases out of 20 (35%), MDM2 positive in 6 (30%), and both p53 and MDM2 in 3 (15%) collectively. 8 out of sixteen cases with ML (50%) had p53, 8 (50%) MDM2 positive, and 6 (37.5%) had both p53 and MDM2 collectively. 2 out of seven PL cases (28.6%) were found positive for p53, 3 (42.9%) MDM2 positive, 2 (28.6%) had both p53 and MDM2. All of the 5 cases with DL (100%) were positive in p53 and MDM2. A collective evaluation of all subjects resulted in 22 positive cases for p53 in 48 subjects (45.8%) [Figure 2], and 22 MDM2 (45.8%) [Figure 3], while the number of subjects that were positive in both p53 and MDM2 was 16 (33.3%). A statistically significant relationship in terms of p53 and MDM2 positivity was found in all subjects (P = 0, 02).
p53 positivity was found in 7 (35%) out of 20, and MDM2 in 6 (30%) grade 1 tumors. The number of subjects where p53 and MDM2 were collectively positive was 3 (15%). Of 8 grade 2 tumors, 4 (50%) were found to have p53, and 5 (62.5%) to have MDM2 positivity. The total number of subjects that were p53 and MDM2 positive was 3 (37.5%). 11 (55%) out of 20 grade 3 tumors (55%) were with p53, and 11 (55%) with MDM2 positivity. The number of subjects where p53 and MDM2 were collectively positive was 10 (50%). The p53 and MDM2 immunoreactivity of the cases depending on their tumor grade is shown in [Table 4]. A statistically significant relationship was found between the subjects with collective positive reaction in p53 and MDM2 in the grade 3 tumors (P = 0, 01). Accordingly, the positivity of p53 and MDM2 increases in direct proportion with the increasing tumor grade.
8 out of the 18 tumors (44.4%) localized in the lower extremity were found positive in p53, 7 (38.9%) in MDM2 and 5 (27.8%) in both, p53 and MDM2 collectively. None of the 5 tumors localized in the upper extremity had p53 and MDM2 positivity. 2 (50%) of 4 tumors localized in the head-neck region were found to positive in p53, 2 (50%) in MDM2, and 2 (50%) in both p53 and MDM2. 12 (57.1%) of 21 tumors localized in the trunk were positive in p53, 13 (61.9%) in MDM2, and 9 (42.9%) in both p53 and MDM2 on collective basis. The p53 and MDM2 immunoreactivity of the cases based on their tumor localization is shown in [Table 5].
Considering the tumor diameters, no statistically significant difference was found between the liposarcoma in terms of p53 and MDM2 positivity (P = 1.00).
No significant difference was observed in terms of p53 and MDM2 positivity between the relapsed cases (P > 0.05).
29 (60.4%) of 48 patients enrolled in the study were accessed and checked for their status of survival. 19 (39.5%) patients were inaccessible. 23 (79.3%) of the subjects were alive while 6 (20.6%) had died. 3 subjects died for tumor associated reasons, while 3 for reasons other than the tumor. One of the subjects died due to the tumor was diagnosed with oral cavity, and the other one with retroperitoneal localized ML. In addition to ML, the third subject was also diagnosed with a primary tumor localized in the right thigh and simultaneous metastasis in the anterior abdominal wall. The earliest death occurred in 2 months, and the latest in the 55 th month. 11 (55%) out of 20 IDK cases was accessed. All of these subjects were alive. 11 (68.7%) of the subjects with 16 ML were accessed. While 7 were alive, 4 had died. Of the 7 cases with PL, 5 (71.4%) were accessed. While 4 out of these patients were alive, 1 had died. 2 (40%) of 5 cases with DL were accessed. 1 was alive and 1 had died.
| » Discussion|| |
Liposarcomas among the soft tissue sarcomas are the second most common cases after pleomorphic cell sarcoma (malignant fibrous histiocytoma).  They compose 0.1 to 0.2% of the malignant tumors in adults. 
The types of liposarcoma according to the WHO latest soft tissue tumor classification are shown in [Table 1]. With 40 to 45%, WDL is the most common subcategory among all types of liposarcoma. ML with 30-35% is the second most common type. ,, While according to a study by Kim et al.,  the most common subtype is WDL with 50 (53.2%) of 94 liposarcoma cases, ML was found in 22 (23.4%); DL in 15 (16%), round cell liposarcoma (RCL) in 5 (5.3%) and PL in 2 (2.1%). Similar to these results, our study found 20 (41.7%) out of 48 liposarcoma cases were WDL and 16 (33.3%) were ML.
The most common areas of liposarcoma localization are the thighs and retroperitoneal region. Often times, localization in the extremity is notable in all types of liposarcoma except DL. DL, on the other hand, is localized in the retro peritoneum at 75%.  47.9% of the cases in our study were found localized in the extremities, 43.8% in the trunk and 8.3% in the head-neck area, and that these results were consistent with the literature. All of our DL cases were found to be localized in the retroperitoneal region.
In their study conducted with the examination of data of 1266 patients, Smith et al. found that the WDL located in the retroperitoneal region had bad prognosis regardless of tumor diameter and clinical properties.  Our study did not result in a relationship between tumor diameters and liposarcoma subtypes.
Clinical behavior of liposarcoma demonstrates a close relationship with histopathological properties. Local relapse is more frequent in low-grade and well-differentiated lesions. These generally do not tend to distant metastases. High grade lesions however, are often poorly differentiated and act aggressive. Their course commonly involves metastatic spread. ,
Liposarcomas are the most common mesenchymal tumors of the retroperitoneal region and typically tend to local invasion. Frequency of local relapse is relatively high in 3 years during the post diagnostic term.  Nearly all relapse are observed in such regions and organs that are anatomically close to the original tumor. Our study found a relapse ratio of 10.4%. All of the cases with relapse were grade 3 tumors, which 2 were ML, 2 PL and 1 DL. 3 of these cases were localized in retroperitoneum and 2 in the extremity. Relapse was seen in 23.8 months at average.
While the most frequent ML metastases occurred in the lungs and bone, metastases in all other liposarcomas occur in other soft tissues.  Evans et al.  found that 12 out of 16 metastatic ML's occurred in soft tissue regions, 7 in the lungs, and 8 in the bone. In our study, metastasis was found in 2 cases with ML as the primary.
Kim et al.  found that 72 (76.6%) of 94 subjects diagnosed with liposarcoma with an average follow up period of 48 months were alive, and 22 (23.4%) had died associated with the disease. The 5-yearly survey was found as 78.1% and 10-yearly survey as 67.5%. 5-yearly survey was found 93.3% for WDL, 75.7% for ML, 54.5% for DL, 40% for RCL and 0% for PL. Since not all the subjects could be accessed during our study, no comment was made on the prognosis and survey.
Knowing the oncogenes that play a role in the pathogenesis of tumors is important in determining the treatment methods to be applied for such tumors. Mutation of the p53 gene accountable for tumor suppression results in the gene to become unable to suppress the tumor and also leads to the growth and spread of the tumor. The presence of this protein is also an indicator of the tumor's aggression. MDM2 binds to the amino-terminal transcription region of p53 and inhibits transcription. In addition, MDM2 leads to the destruction of p53. p53 is stable in the cells where MDM2 mutation is observed in MDM2 where p53 is unable to bind. MDM2 functions like an oncogene in cell transformation. 
p53 and MDM2 expression is not observed in the lipomas. , While they observed no p53 and MDM2 positivity in the lipoms, Pilotti et al.  Identified the p53 positivity as 74% in the WDL's and MDM2 positivity as 93%. In our study, p53 positivity in the WDL's was found as 35%, and MDM2 was 30%. These findings support the idea that p53 and MDM2 could be used in the separation of lipoma like liposarcoma from lipomas.
The results obtained with p53 and MDM2 using the IHC method at ML and RCL in the literature are controversial. While Pilotti et al.  found p53 positivity in 2 of 33 cases of ML and RCL, no MDM2 positivity was identified. Hisaoka et al.  reported positivity for p53 in 5 out of 10 ML and RCL, and MDM2 in 6. In our study, 8 out of 16 cases of ML were p53, and 8 were MDM2 positive. These findings are parallel to those of Hisaoka et al.
In a study conducted by Pilotti et al.,  12 of 14 DLS cases were found p53, and 9 were MDM2 positive. Hasegawa et al.  found that p53 and MDM2 expression was associated with tumor progression in DLS. Similarly, Oda et al. defined that in ML p53 mutation were related to poor prognosis  . In our study, positive stains of both p53 and MDM2 were observed in all 5 DLS.
The p53 positivity of 45.8% found in our subject is parallel to the 43% found by Taubert et al. 
While in a study by Schneider et al.,  the MDM2 positivity was 42.2%, it was found to be 53.8% by Ladanyi et al.  Our study resulted in 45.8%.
Taubert et al.  found a relationship between p53 positive tumors in liposarcoma, malign fibrous histiocytomas and increased tumor grade. The study conducted by Dei Tos et al.  resulted in positive correlation between MDM2 over expression and tumor grade in ML and RCL. A study performed by Schneider et al.  found that the p53 and MDM2 positivity in grade 3 tumors was higher than those in tumors of the grade 1 and 2. Our study found that grade 2 and 3 tumors had higher p53 and MDM2 positivity than grade 1 tumors.
Retroperitoneal liposarcoma is known for a worse prognosis compared to other localizations. A study performed by Pilotti et al. showed that the rate of expression of p53 and MDM2 in retroperitoneal liposarcoma, compared to those localized in the extremity was higher.  The higher rate of p53 and MDM2 positivity compared to those with localization in the extremity in retroperitoneal liposarcoma suggests that p53 inhibition associated to MDM2 plays a role in the retroperitoneal liposarcoma pathogenesis in particular. Similar to the study performed by Pilotti et al., our study resulted in a higher rate of p53 and MDM2 positivity in tumors with retroperitoneal localization higher than those localized in the extremity.
Consequently, as a result of the evaluation of all findings as a whole, both the histopathologic typing and other pathological properties of our subjects are consistent with the literature based on the WHO classification of liposarcoma. The relationship between p53 and MDM2 expression and liposarcoma pathogenesis is unknown. Despite the findings which support the opinion that p53 and MDM2 are two useful markers for liposarcoma in terms of diagnostics, we think that due to the small number of subjects in our study, final conclusions would require more elaborate studies with a broader scope.
The study was performed at Uludag University Pathology.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]