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Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins.

Kanthan R, Senger JL, Diudea D - World J Surg Oncol (2010)

Bottom Line: Overexpression of p16 and Mcl-1 were observed in patients with longer survival outcomes (>2 years).P16 and p21 were overexpressed in the carcinomatous and sarcomatous elements respectively.Cyclin-D1 was focally expressed only in the carcinomatous elements.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada. rani.kanthan@saskatoonhealthregion.ca

ABSTRACT

Aim: The aim of our study was to evaluate survival outcomes in malignant mixed Mullerian tumors (MMMT) of the uterus with respect to the role of cell cycle and apoptotic regulatory proteins in the carcinomatous and sarcomatous components.

Methods: 23 cases of uterine MMMT identified from the Saskatchewan Cancer Agency (1970-1999) were evaluated. Immunohistochemical expression of Bad, Mcl-1, bcl-x, bak, mdm2, bax, p16, p21, p53, p27, EMA, Bcl-2, Ki67 and PCNA was correlated with clinico-pathological data including survival outcomes.

Results: Histopathological examination confirmed malignant epithelial component with homologous (12 cases) and heterologous (11 cases) sarcomatous elements. P53 was strongly expressed (70-95%) in 15 cases and negative in 5 cases. The average survival in the p53+ve cases was 3.56 years as opposed to 8.94 years in p53-ve cases. Overexpression of p16 and Mcl-1 were observed in patients with longer survival outcomes (>2 years). P16 and p21 were overexpressed in the carcinomatous and sarcomatous elements respectively. Cyclin-D1 was focally expressed only in the carcinomatous elements.

Conclusions: Our study supports that a) cell cycle and apoptotic regulatory protein dysregulation is an important pathway for tumorigenesis and b) p53 is an important immunoprognostic marker in MMMT of the uterus.

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Histopathological Evaluation with Immunohistochemical Staining. A: Hematoxylin-eosin stain (original magnification ×250). The star (*) indicates the malignant heterologous component of uterine MMMT. B: Hematoxylin-eosin stain (original magnification ×250). The arrows indicate the malignant epithelial component of uterine MMMT. C: Staining with Bax antibody (original magnification ×250). The expression of Bax antibody is diffuse with the thin arrowhead indicating weak staining, the thick arrowhead indicating medium staining, and the tailed arrow indicating strong staining. D: Staining with p53 antibody(original magnification ×250). The star (*) indicates the negatively stained heterologous sarcomatous element, and the arrow indicates positive staining in the epithelial component. E: Staining with p16 antibody (original magnification ×250). The star (*) indicates the negatively stained region, and the arrow indicates the strong positive staining in the malignant epithelial glands. F: Staining with Cyclin D1 antibody (original magnification ×250). The star (*) indicates the negatively stained heterologous sarcomatous element, while the arrow indicates a focus positive staining in the adjacent epithelial component.
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Figure 1: Histopathological Evaluation with Immunohistochemical Staining. A: Hematoxylin-eosin stain (original magnification ×250). The star (*) indicates the malignant heterologous component of uterine MMMT. B: Hematoxylin-eosin stain (original magnification ×250). The arrows indicate the malignant epithelial component of uterine MMMT. C: Staining with Bax antibody (original magnification ×250). The expression of Bax antibody is diffuse with the thin arrowhead indicating weak staining, the thick arrowhead indicating medium staining, and the tailed arrow indicating strong staining. D: Staining with p53 antibody(original magnification ×250). The star (*) indicates the negatively stained heterologous sarcomatous element, and the arrow indicates positive staining in the epithelial component. E: Staining with p16 antibody (original magnification ×250). The star (*) indicates the negatively stained region, and the arrow indicates the strong positive staining in the malignant epithelial glands. F: Staining with Cyclin D1 antibody (original magnification ×250). The star (*) indicates the negatively stained heterologous sarcomatous element, while the arrow indicates a focus positive staining in the adjacent epithelial component.

Mentions: Twenty-three cases of uterine MMMT were identified from the records of the Saskatchewan Cancer Agency (1970-99). The original slides and paraffin blocks were retrieved and reviewed to confirm the diagnosis as seen in Figures 1A and 1B. A representative block was chosen for detailed histological and immunohistochemical study with the antibodies as listed in Table 1. EMA, Bcl-2, Ki67, PCNA, Bad, Mcl-1; bcl-x, bak, mdm2, bax, p16, p21, p27, p53 and Cyclin D1 expression were evaluated by the standard avidin-biotin complex method with positive and negative controls as per standard laboratory protocol. Immunostaining results were scored on a semi-quantitative scale including staining intensity and percentage of positive cells. The extent of immunostaining was divided into four categories according to the percentage of immunostained neoplastic cells: < 25% (1+), 25-50% (2+), 50-75% (3+), and > 75% (4+). In addition, the qualitative intensity of immunostaining of the tumor cells was quantitatively scored into three categories: weak (1+), moderate (2+), and strong (3+) as seen in Figure 1C. The intensity of the endothelial cell staining served as an internal control. A combined immunoreactivity score was calculated by multiplying the score for the percentage x the score of intensity, resulting in a combined score that ranged from 0 to 12. Scores 4 and above were considered positive for the purposes of this study.


Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins.

Kanthan R, Senger JL, Diudea D - World J Surg Oncol (2010)

Histopathological Evaluation with Immunohistochemical Staining. A: Hematoxylin-eosin stain (original magnification ×250). The star (*) indicates the malignant heterologous component of uterine MMMT. B: Hematoxylin-eosin stain (original magnification ×250). The arrows indicate the malignant epithelial component of uterine MMMT. C: Staining with Bax antibody (original magnification ×250). The expression of Bax antibody is diffuse with the thin arrowhead indicating weak staining, the thick arrowhead indicating medium staining, and the tailed arrow indicating strong staining. D: Staining with p53 antibody(original magnification ×250). The star (*) indicates the negatively stained heterologous sarcomatous element, and the arrow indicates positive staining in the epithelial component. E: Staining with p16 antibody (original magnification ×250). The star (*) indicates the negatively stained region, and the arrow indicates the strong positive staining in the malignant epithelial glands. F: Staining with Cyclin D1 antibody (original magnification ×250). The star (*) indicates the negatively stained heterologous sarcomatous element, while the arrow indicates a focus positive staining in the adjacent epithelial component.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2913917&req=5

Figure 1: Histopathological Evaluation with Immunohistochemical Staining. A: Hematoxylin-eosin stain (original magnification ×250). The star (*) indicates the malignant heterologous component of uterine MMMT. B: Hematoxylin-eosin stain (original magnification ×250). The arrows indicate the malignant epithelial component of uterine MMMT. C: Staining with Bax antibody (original magnification ×250). The expression of Bax antibody is diffuse with the thin arrowhead indicating weak staining, the thick arrowhead indicating medium staining, and the tailed arrow indicating strong staining. D: Staining with p53 antibody(original magnification ×250). The star (*) indicates the negatively stained heterologous sarcomatous element, and the arrow indicates positive staining in the epithelial component. E: Staining with p16 antibody (original magnification ×250). The star (*) indicates the negatively stained region, and the arrow indicates the strong positive staining in the malignant epithelial glands. F: Staining with Cyclin D1 antibody (original magnification ×250). The star (*) indicates the negatively stained heterologous sarcomatous element, while the arrow indicates a focus positive staining in the adjacent epithelial component.
Mentions: Twenty-three cases of uterine MMMT were identified from the records of the Saskatchewan Cancer Agency (1970-99). The original slides and paraffin blocks were retrieved and reviewed to confirm the diagnosis as seen in Figures 1A and 1B. A representative block was chosen for detailed histological and immunohistochemical study with the antibodies as listed in Table 1. EMA, Bcl-2, Ki67, PCNA, Bad, Mcl-1; bcl-x, bak, mdm2, bax, p16, p21, p27, p53 and Cyclin D1 expression were evaluated by the standard avidin-biotin complex method with positive and negative controls as per standard laboratory protocol. Immunostaining results were scored on a semi-quantitative scale including staining intensity and percentage of positive cells. The extent of immunostaining was divided into four categories according to the percentage of immunostained neoplastic cells: < 25% (1+), 25-50% (2+), 50-75% (3+), and > 75% (4+). In addition, the qualitative intensity of immunostaining of the tumor cells was quantitatively scored into three categories: weak (1+), moderate (2+), and strong (3+) as seen in Figure 1C. The intensity of the endothelial cell staining served as an internal control. A combined immunoreactivity score was calculated by multiplying the score for the percentage x the score of intensity, resulting in a combined score that ranged from 0 to 12. Scores 4 and above were considered positive for the purposes of this study.

Bottom Line: Overexpression of p16 and Mcl-1 were observed in patients with longer survival outcomes (>2 years).P16 and p21 were overexpressed in the carcinomatous and sarcomatous elements respectively.Cyclin-D1 was focally expressed only in the carcinomatous elements.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada. rani.kanthan@saskatoonhealthregion.ca

ABSTRACT

Aim: The aim of our study was to evaluate survival outcomes in malignant mixed Mullerian tumors (MMMT) of the uterus with respect to the role of cell cycle and apoptotic regulatory proteins in the carcinomatous and sarcomatous components.

Methods: 23 cases of uterine MMMT identified from the Saskatchewan Cancer Agency (1970-1999) were evaluated. Immunohistochemical expression of Bad, Mcl-1, bcl-x, bak, mdm2, bax, p16, p21, p53, p27, EMA, Bcl-2, Ki67 and PCNA was correlated with clinico-pathological data including survival outcomes.

Results: Histopathological examination confirmed malignant epithelial component with homologous (12 cases) and heterologous (11 cases) sarcomatous elements. P53 was strongly expressed (70-95%) in 15 cases and negative in 5 cases. The average survival in the p53+ve cases was 3.56 years as opposed to 8.94 years in p53-ve cases. Overexpression of p16 and Mcl-1 were observed in patients with longer survival outcomes (>2 years). P16 and p21 were overexpressed in the carcinomatous and sarcomatous elements respectively. Cyclin-D1 was focally expressed only in the carcinomatous elements.

Conclusions: Our study supports that a) cell cycle and apoptotic regulatory protein dysregulation is an important pathway for tumorigenesis and b) p53 is an important immunoprognostic marker in MMMT of the uterus.

Show MeSH
Related in: MedlinePlus