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MIB-1 (Ki-67), p53, estrogen receptor, and progesterone receptor expression in uterine smooth muscle tumors
MIB-1 (Ki-67), p53, Estrogen Receptor, and Progesterone Receptor Expression in Uterine Smooth Muscle Tumors KHUSH MITTAL, MD, AND RITA IOVINE DEMOPOULOS, MD The diagnosis of benign, uncertain malignant potential, and malignant uterine smooth muscle tumors depends on mitotic counts, nuclear atypia, and other morphologic features. This study was undertaken to evaluate the utility of selected immunohistochemical markers in differentiating these tumors. Fifteen cases of cellular leiomyoma, 7 cases of smooth muscle tumor of uncertain malignant potential (STUMP), and 12 cases of leiomyosarcoma were immunostained for MIB-1 (Ki-67), p53, estrogen receptor and progesterone receptor (PR) using monoclonal antibodies and the avidin-biotinperoxidase method. The percentage of cells stained was subjectively assessed to the nearest 5%. One percent was used for rare positive cells. MIB-1 expression of >15% was seen in 11 and expression of p53 in >15% cells was present in 5 of 12 leiomyosarcomas. MIB-1 and/or p53 expression of >15% was seen in all 12 leiomyosarcomas but in none of the 7 STUMP or 15 cellular leiomyomas. PR was
absent in 10 of 12 leiomyosarcomas but present in 7 of 7 STUMP and 14 of 15 cellular leiomyomas. MIB-1 of 5% to 10% was seen in 6 of 7 STUMP but in only 1 of 15 cellular leiomyomas. MIB-1, p53, and PR are useful in differentiating leiomyosarcoma from STUMP and cellular leiomyoma. MIB-1 is useful in distinguishing STUMP from cellular leiomyomas. HUM PATHOL 32:984-987. Copyright © 2001 by W.B. Saunders Company Key words: leiomyosarcoma, leiomyoma, smooth muscle tumor of uncertain malignant potential, smooth muscle tumor of uncertain malignant potential, MIB-1, Ki-67, p53, estrogen receptors, progesterone receptors, immunostaining. Abbreviations: STUMP, smooth muscle tumor of uncertain malignant potential; HPF, high-power fields; ER, estrogen receptor; PR, progesterone receptor.
The diagnosis of benign, uncertain malignant potential, and malignant uterine smooth muscle tumors depends on mitotic counts, nuclear atypia, and other morphologic features.1 The distinction between leiomyoma, smooth muscle tumor of low malignant potential, and leiomyosarcoma may at times be problematic because of difficulty in recognizing mitotic figures. At other times, clumped or degenerative nuclei may be misinterpreted as mitotic figures. It would be useful to have additional markers to distinguish among these tumors. This study was undertaken to evaluate the utility of selected immunohistochemical markers in differentiating among these tumors.
they had ⱖ10 mitoses/10 HPF and as STUMP if they had 5 to 9 mitoses/10 HPF. Tumors with mild nuclear atypia and ⱖ5 mitoses/10 HPF were classified as STUMP. A myxoid smooth muscle tumor with 2 mitoses/10 HPF and invasive growth pattern was diagnosed as leiomyosarcoma. Tumors without nuclear atypia or with fewer mitoses than outlined above were diagnosed as leiomyomas. Leiomyomas with markedly crowded nuclei and scant cytoplasm were diagnosed as cellular leiomyomas. A representative block was selected from each case. Blank slides were obtained from this block and immunostained using mouse monoclonal antibodies for MIB-1 (Immunotech, Cedex, France), p53 (Ventana, Tucson, AZ), estrogen receptor (ER; Ventana), progesterone receptor (PR; Ventana), and the avidin-biotin-peroxidase method. Antibodies were from clone6F11 for ER and from clone 1A6 for PR. The antibody for ER recognizes the classical ER or ER-␣. The final reaction product was developed with diaminobenzidine. Antigens were retrieved by microwaving in citrate buffer for 20 minutes for ER, PR, and p53 and 30 minutes for MIB-1. The immunostaining was carried out in automated Ventana ES immunostainer. The percentage of cells stained was subjectively assessed to the nearest 5% by the 2 authors. One percent was used for rare positive cells. Clinical follow-up was obtained for patients with diagnoses of STUMP or leiomyosarcoma. Results of follow-up were correlated with findings on immunostaining. The data were analyzed statistically using the Kruskal-Wallis test (nonparametric analysis of variance). All P values are 2 tailed.
MATERIALS AND METHODS Fifteen cases of cellular leiomyomata, 7 cases of smooth muscle tumor of uncertain malignant potential (STUMP), and 12 cases of leiomyosarcoma were retrieved from the files of the division of gynecologic pathology at New York University Medical Center. The diagnosis of leiomyosarcoma and STUMP was based on previously published criteria.2 Tumors with marked nuclear atypia were classified as leiomyosarcoma if they had ⱖ5 mitoses/10 high-power fields (HPF) and as STUMP if they had 1 to 4 mitoses/10 HPF. Tumors with moderate nuclear atypia were classified as leiomyosarcoma if
From the Kaplan Cancer Center, New York University School of Medicine and Medical Center, New York, NY. Accepted for publication May 2, 2001. Supported in part by Kaplan Cancer Center grant P30 CA16087. Address correspondence and reprint requests to Khush Mittal, MD, Department of Pathology, 4W35B, Bellevue Hospital, 27th St and 1st Ave, New York, NY 10016. Copyright © 2001 by W.B. Saunders Company 0046-8177/01/3209-0013$35.00/0 doi:10.1053/hupa.2001.27113
RESULTS Results are shown in Table 1 and Fig 1 through 4. Leiomyosarcomas showed increased MIB-1 and p53 expression and reduced ER and PR expression. MIB-1 expression of ⱖ15% was seen in 11 of 12 leiomyosarcomas, MIB-1 of ⱖ30% was seen in 10 of 12 leiomyosarcomas. The only leiomyosarcoma with ⬍15% MIB-1 expression showed MIB-1 in 10% of the cells and p53 in
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IMMUNOSTAINING IN UTERINE SMOOTH MUSCLE TUMORS (Mittal and Demopoulos)
TABLE 1. Expression of Various Markers in Uterine Smooth Muscle Tumors
Cellular leiomyata STUMP Leiomyosarcoma
MIB-1
p53
ER
PR
0.9 ⫾ 0.3 (0-5) 5.7 ⫾ 1.3 (0-10) 45.4 ⫾ 8.6 (10-70)*
0.1 ⫾ 0.09 (0-1) 0.1 ⫾ 0.1 (0-1) 21.9 ⫾ 9 (0-90)*
40 ⫾ 8.8 (0-90) 15 ⫾ 9 (0-50) 4 ⫾ 4 (0-50)
52 ⫾ 8.2 (0-90) 84 ⫾ 7.6 (40-95) 5 ⫾ 4.9 (0-60)*
NOTE. Results are presented as means ⫾ SE (range). *P ⬍ .00001 v STUMP and cellular leiomyata.
70% of the cells. Expression of p53 in ⱖ15% of cells was present in 5 of 12 leiomyosarcomas. p53 expression ⱖ40% was seen in 4 of 12 leiomyosarcomas. MIB-1 and/or p53 expression of ⬎15% was seen in all 12 leiomyosarcomas but in none of the 7 STUMP (P ⬍ .00001) or 15 cellular leiomyomatas (P ⬍ .00001). PR was present in only 2 of 12 leiomyosarcomas but in 8 of 8 STUMP (P ⬍ .00001) and 14 of 15 cellular leiomyomatas (P ⬍ .00001). MIB-1 expression of 5% to 10% was seen in 6 of 7 STUMP but in only 1 of 15 cellular leiomyomatas (P ⬍ .00001). The differences in ER expression were significant between cellular leiomyomata and STUMP (P ⫽ .022) but not between STUMP and leiomyosarcoma. All 7 patients with a diagnosis of STUMP were alive and well with a follow-up period varying from 14 to 48 months (average, 37 months). Of the 9 patients with a diagnosis of leiomyosarcoma with follow-up, 7 were
dead of disease at an interval varying from 2 to 23 months after diagnosis. The other 2 patients with a diagnosis of leiomyosarcoma and follow-up were alive and free of disease after 9 months and 40 months, respectively. None of the markers studied had prognostic significance for patients with a diagnosis of leiomyosarcoma. DISCUSSION We chose to measure immunostaining subjectively because this method is fast and does not require any equipment other than a microscope. This method can be used not only in academic settings, but also in private practice settings. Our results are in agreement with previous studies that have used counting of cells to measure the percentage of cells positive for p53, ER,
FIGURE 1. MIB-1 (Ki-67) expression in (A) cellular leiomyoma, (B) STUMP, and (C) leiomyosarcoma. Approximately 5%, 10%, and 70% of tumor cell nuclei are stained, respectively.
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FIGURE 2. PR expression in (A) cellular leiomyoma, (B) STUMP, and (C) leiomyosarcoma. Nearly all of the tumor cell nuclei are stained in leiomyoma and STUMP. Leiomyosarcoma is negative for PR. Note the lack of PR expression in smooth muscle of blood vessel walls in A and B.
PR, and MIB-1 in leiomyosarcomas. Percentage staining, rather than number of cells stained/10 HPF, was used because it provides a more accurate estimate of proportion of cells positive for a marker, regardless of the total number of cells in each HPF. Care should be taken to exclude lymphoid cells when evaluating MIB-1 expression, as many lymphoid cells are MIB-1 positive (Fig 4). In keeping with the excellent prognosis reported
FIGURE 3. Approximately 90% of tumor cell nuclei are stained for p53 in this leiomyosarcoma.
in patients with STUMP in this series and in previous reports,2 the immunoprofile of STUMP is much closer to leiomyomas than leiomyosarcomas. None of the patients with a diagnosis of STUMP died of the disease. It would be of interest to know if the immunoprofile of an occasional STUMP that behaves in a malignant fashion is closer to that of leiomyosarcomas than to that of STUMP.
FIGURE 4. Lymphoid aggregate in a leiomyoma showing positive staining for MIB-1. This staining should not be confused with staining of tumor cell nuclei.
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IMMUNOSTAINING IN UTERINE SMOOTH MUSCLE TUMORS (Mittal and Demopoulos)
Our results are in agreement with previous studies that report increased MIB-1 expression,3-8 p53 overexpression,4,7,9,10 and loss of PR4 in uterine leiomyosarcomas. Zhai et al4 found no or ⬍5% staining for p53 in all leiomyomas and cellular leiomyomas, and ⱖ5% staining in 7 of 14 leiomyosarcomas. They also found ⬎5% PR expression in all leiomyomas and cellular leiomyomas and ⬍5% staining in 7 of 14 leiomyosarcomas. Their results on MIB-1 staining cannot be compared with the present study because those results were based on the number of positive cells per 10 HPF. Amada et al7 found ⱖ3.6% MIB-1 expression in 21 of 24 leiomyosarcomas and in 1 of 25 leiomyomas. Review of their data show MIB-1 expression of ⱖ15% in 14 of 24 leiomyosarcomas and 0 of 25 leiomyomas. STUMP were not included in this study. The findings of the current and previous studies can be used to evaluate cases of uterine smooth muscle tumors in which histologic findings are ambiguous or borderline. These would include tumors where mitotic figures are clumped or poorly formed, and thus difficult to identify. Smooth muscle tumors in which nuclear atypia is moderate to severe with 5 to 9 mitoses/10 HPF can also be further evaluated. These findings can be used to evaluate cases in which only a small sample of the tumor is available for study, such as fragments of a smooth muscle tumor with marked nuclear atypia removed by endometrial curettage. As with evaluation of any lesion, the immunohistochemical findings should be used in concert with clinical, gross, and light microscopic findings to arrive at a final diagnosis. Negative immunohistochemical findings, in particular, should not be relied on solely to support a diagnosis. Smooth muscle from blood vessel walls should not be confused with the rest of the tumor. This smooth muscle is always negative for ER and PR (Fig 3) and for p53. Although leiomyosarcomas are usually negative for ER and PR, occasional cases show positive staining for
these receptors. Hormonal manipulation in these cases may be helpful in controlling these tumors. In conclusion, immunostaining for MIB-1, p53, and PR is useful in distinguishing leiomyosarcomas from STUMP and cellular leiomyomas.
REFERENCES 1. Clement PB: The pathology of uterine smooth muscle tumors and mixed endometrial stromal-smooth muscle tumors: A selective review with emphasis on recent advances. Int J Gynecol Pathol 19:3955, 2000 2. Zaloudek C, Norris HJ: Mesenchymal tumors of the uterus, in Kurman RJ (ed): Blaustein’s Pathology of the Female Genital Tract. New York, NY, Springer Verlag, 1994, pp 488-500 3. Chou CY, Huang SC, Tsai YC, et al: Uterine leiomyosarcoma has deregulated cell proliferation, but not increased microvessel density compared with uterine leiomyoma. Gynecol Oncol 65:225231, 1997 4. Zhai YL, Kobayashi Y, Mori A, et al: Expression of steroid receptors, Ki-67, and p53 in uterine leiomyosarcomas. Int J Gynecol Pathol 18:20-28, 1999 5. Jeffers MD, Oakes SJ, Richmond JA, et al: Proliferation, ploidy and prognosis in uterine smooth muscle tumors. Histopathology 29:217-223, 1996 6. Zhai YL, Nikaido T, Shiozawa T, et al: Expression of cyclins and cyclin-dependent kinases in smooth muscle tumors of the uterus. Int J Cancer 84:244-250, 1999 7. Amada S, Nakano H, Tsuneyoshi M: Leiomyosarcoma versus bizarre and cellular leiomyomas of the uterus: A comparative study based on the MIB-1 and proliferating cell nuclear antigen indices, p53 expression, DNA flow cytometry, and muscle specific actins. Int J Gynecol Pathol 14:134-142, 1995 8. Sprogoe-Jakobsen S, Holund B: Immunohistochemistry (Ki-67 and p53) as a tool in determining malignancy in smooth muscle neoplasms (exemplified by a myxoid leiomyosarcoma of the uterus). Acta Pathologica, Microbiologica et Immunologica Scandinavica 104: 705-708, 1996 9. Zhai YL, Nikaido T, Toki T, et al: Prognostic significance of bcl-2 expression in leiomyosarcoma of the uterus. Br J Cancer 80: 1658-1664, 1999 10. Hall KL, Teneriello MG, Taylor RR, et al: Analysis of Ki-ras, p53, and MDM2 genes in uterine leiomyomas and leiomyosarcomas. Gynecol Oncol 65:330-335, 1997
987
absent in 10 of 12 leiomyosarcomas but present in 7 of 7 STUMP and 14 of 15 cellular leiomyomas. MIB-1 of 5% to 10% was seen in 6 of 7 STUMP but in only 1 of 15 cellular leiomyomas. MIB-1, p53, and PR are useful in differentiating leiomyosarcoma from STUMP and cellular leiomyoma. MIB-1 is useful in distinguishing STUMP from cellular leiomyomas. HUM PATHOL 32:984-987. Copyright © 2001 by W.B. Saunders Company Key words: leiomyosarcoma, leiomyoma, smooth muscle tumor of uncertain malignant potential, smooth muscle tumor of uncertain malignant potential, MIB-1, Ki-67, p53, estrogen receptors, progesterone receptors, immunostaining. Abbreviations: STUMP, smooth muscle tumor of uncertain malignant potential; HPF, high-power fields; ER, estrogen receptor; PR, progesterone receptor.
The diagnosis of benign, uncertain malignant potential, and malignant uterine smooth muscle tumors depends on mitotic counts, nuclear atypia, and other morphologic features.1 The distinction between leiomyoma, smooth muscle tumor of low malignant potential, and leiomyosarcoma may at times be problematic because of difficulty in recognizing mitotic figures. At other times, clumped or degenerative nuclei may be misinterpreted as mitotic figures. It would be useful to have additional markers to distinguish among these tumors. This study was undertaken to evaluate the utility of selected immunohistochemical markers in differentiating among these tumors.
they had ⱖ10 mitoses/10 HPF and as STUMP if they had 5 to 9 mitoses/10 HPF. Tumors with mild nuclear atypia and ⱖ5 mitoses/10 HPF were classified as STUMP. A myxoid smooth muscle tumor with 2 mitoses/10 HPF and invasive growth pattern was diagnosed as leiomyosarcoma. Tumors without nuclear atypia or with fewer mitoses than outlined above were diagnosed as leiomyomas. Leiomyomas with markedly crowded nuclei and scant cytoplasm were diagnosed as cellular leiomyomas. A representative block was selected from each case. Blank slides were obtained from this block and immunostained using mouse monoclonal antibodies for MIB-1 (Immunotech, Cedex, France), p53 (Ventana, Tucson, AZ), estrogen receptor (ER; Ventana), progesterone receptor (PR; Ventana), and the avidin-biotin-peroxidase method. Antibodies were from clone6F11 for ER and from clone 1A6 for PR. The antibody for ER recognizes the classical ER or ER-␣. The final reaction product was developed with diaminobenzidine. Antigens were retrieved by microwaving in citrate buffer for 20 minutes for ER, PR, and p53 and 30 minutes for MIB-1. The immunostaining was carried out in automated Ventana ES immunostainer. The percentage of cells stained was subjectively assessed to the nearest 5% by the 2 authors. One percent was used for rare positive cells. Clinical follow-up was obtained for patients with diagnoses of STUMP or leiomyosarcoma. Results of follow-up were correlated with findings on immunostaining. The data were analyzed statistically using the Kruskal-Wallis test (nonparametric analysis of variance). All P values are 2 tailed.
MATERIALS AND METHODS Fifteen cases of cellular leiomyomata, 7 cases of smooth muscle tumor of uncertain malignant potential (STUMP), and 12 cases of leiomyosarcoma were retrieved from the files of the division of gynecologic pathology at New York University Medical Center. The diagnosis of leiomyosarcoma and STUMP was based on previously published criteria.2 Tumors with marked nuclear atypia were classified as leiomyosarcoma if they had ⱖ5 mitoses/10 high-power fields (HPF) and as STUMP if they had 1 to 4 mitoses/10 HPF. Tumors with moderate nuclear atypia were classified as leiomyosarcoma if
From the Kaplan Cancer Center, New York University School of Medicine and Medical Center, New York, NY. Accepted for publication May 2, 2001. Supported in part by Kaplan Cancer Center grant P30 CA16087. Address correspondence and reprint requests to Khush Mittal, MD, Department of Pathology, 4W35B, Bellevue Hospital, 27th St and 1st Ave, New York, NY 10016. Copyright © 2001 by W.B. Saunders Company 0046-8177/01/3209-0013$35.00/0 doi:10.1053/hupa.2001.27113
RESULTS Results are shown in Table 1 and Fig 1 through 4. Leiomyosarcomas showed increased MIB-1 and p53 expression and reduced ER and PR expression. MIB-1 expression of ⱖ15% was seen in 11 of 12 leiomyosarcomas, MIB-1 of ⱖ30% was seen in 10 of 12 leiomyosarcomas. The only leiomyosarcoma with ⬍15% MIB-1 expression showed MIB-1 in 10% of the cells and p53 in
984
IMMUNOSTAINING IN UTERINE SMOOTH MUSCLE TUMORS (Mittal and Demopoulos)
TABLE 1. Expression of Various Markers in Uterine Smooth Muscle Tumors
Cellular leiomyata STUMP Leiomyosarcoma
MIB-1
p53
ER
PR
0.9 ⫾ 0.3 (0-5) 5.7 ⫾ 1.3 (0-10) 45.4 ⫾ 8.6 (10-70)*
0.1 ⫾ 0.09 (0-1) 0.1 ⫾ 0.1 (0-1) 21.9 ⫾ 9 (0-90)*
40 ⫾ 8.8 (0-90) 15 ⫾ 9 (0-50) 4 ⫾ 4 (0-50)
52 ⫾ 8.2 (0-90) 84 ⫾ 7.6 (40-95) 5 ⫾ 4.9 (0-60)*
NOTE. Results are presented as means ⫾ SE (range). *P ⬍ .00001 v STUMP and cellular leiomyata.
70% of the cells. Expression of p53 in ⱖ15% of cells was present in 5 of 12 leiomyosarcomas. p53 expression ⱖ40% was seen in 4 of 12 leiomyosarcomas. MIB-1 and/or p53 expression of ⬎15% was seen in all 12 leiomyosarcomas but in none of the 7 STUMP (P ⬍ .00001) or 15 cellular leiomyomatas (P ⬍ .00001). PR was present in only 2 of 12 leiomyosarcomas but in 8 of 8 STUMP (P ⬍ .00001) and 14 of 15 cellular leiomyomatas (P ⬍ .00001). MIB-1 expression of 5% to 10% was seen in 6 of 7 STUMP but in only 1 of 15 cellular leiomyomatas (P ⬍ .00001). The differences in ER expression were significant between cellular leiomyomata and STUMP (P ⫽ .022) but not between STUMP and leiomyosarcoma. All 7 patients with a diagnosis of STUMP were alive and well with a follow-up period varying from 14 to 48 months (average, 37 months). Of the 9 patients with a diagnosis of leiomyosarcoma with follow-up, 7 were
dead of disease at an interval varying from 2 to 23 months after diagnosis. The other 2 patients with a diagnosis of leiomyosarcoma and follow-up were alive and free of disease after 9 months and 40 months, respectively. None of the markers studied had prognostic significance for patients with a diagnosis of leiomyosarcoma. DISCUSSION We chose to measure immunostaining subjectively because this method is fast and does not require any equipment other than a microscope. This method can be used not only in academic settings, but also in private practice settings. Our results are in agreement with previous studies that have used counting of cells to measure the percentage of cells positive for p53, ER,
FIGURE 1. MIB-1 (Ki-67) expression in (A) cellular leiomyoma, (B) STUMP, and (C) leiomyosarcoma. Approximately 5%, 10%, and 70% of tumor cell nuclei are stained, respectively.
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FIGURE 2. PR expression in (A) cellular leiomyoma, (B) STUMP, and (C) leiomyosarcoma. Nearly all of the tumor cell nuclei are stained in leiomyoma and STUMP. Leiomyosarcoma is negative for PR. Note the lack of PR expression in smooth muscle of blood vessel walls in A and B.
PR, and MIB-1 in leiomyosarcomas. Percentage staining, rather than number of cells stained/10 HPF, was used because it provides a more accurate estimate of proportion of cells positive for a marker, regardless of the total number of cells in each HPF. Care should be taken to exclude lymphoid cells when evaluating MIB-1 expression, as many lymphoid cells are MIB-1 positive (Fig 4). In keeping with the excellent prognosis reported
FIGURE 3. Approximately 90% of tumor cell nuclei are stained for p53 in this leiomyosarcoma.
in patients with STUMP in this series and in previous reports,2 the immunoprofile of STUMP is much closer to leiomyomas than leiomyosarcomas. None of the patients with a diagnosis of STUMP died of the disease. It would be of interest to know if the immunoprofile of an occasional STUMP that behaves in a malignant fashion is closer to that of leiomyosarcomas than to that of STUMP.
FIGURE 4. Lymphoid aggregate in a leiomyoma showing positive staining for MIB-1. This staining should not be confused with staining of tumor cell nuclei.
986
IMMUNOSTAINING IN UTERINE SMOOTH MUSCLE TUMORS (Mittal and Demopoulos)
Our results are in agreement with previous studies that report increased MIB-1 expression,3-8 p53 overexpression,4,7,9,10 and loss of PR4 in uterine leiomyosarcomas. Zhai et al4 found no or ⬍5% staining for p53 in all leiomyomas and cellular leiomyomas, and ⱖ5% staining in 7 of 14 leiomyosarcomas. They also found ⬎5% PR expression in all leiomyomas and cellular leiomyomas and ⬍5% staining in 7 of 14 leiomyosarcomas. Their results on MIB-1 staining cannot be compared with the present study because those results were based on the number of positive cells per 10 HPF. Amada et al7 found ⱖ3.6% MIB-1 expression in 21 of 24 leiomyosarcomas and in 1 of 25 leiomyomas. Review of their data show MIB-1 expression of ⱖ15% in 14 of 24 leiomyosarcomas and 0 of 25 leiomyomas. STUMP were not included in this study. The findings of the current and previous studies can be used to evaluate cases of uterine smooth muscle tumors in which histologic findings are ambiguous or borderline. These would include tumors where mitotic figures are clumped or poorly formed, and thus difficult to identify. Smooth muscle tumors in which nuclear atypia is moderate to severe with 5 to 9 mitoses/10 HPF can also be further evaluated. These findings can be used to evaluate cases in which only a small sample of the tumor is available for study, such as fragments of a smooth muscle tumor with marked nuclear atypia removed by endometrial curettage. As with evaluation of any lesion, the immunohistochemical findings should be used in concert with clinical, gross, and light microscopic findings to arrive at a final diagnosis. Negative immunohistochemical findings, in particular, should not be relied on solely to support a diagnosis. Smooth muscle from blood vessel walls should not be confused with the rest of the tumor. This smooth muscle is always negative for ER and PR (Fig 3) and for p53. Although leiomyosarcomas are usually negative for ER and PR, occasional cases show positive staining for
these receptors. Hormonal manipulation in these cases may be helpful in controlling these tumors. In conclusion, immunostaining for MIB-1, p53, and PR is useful in distinguishing leiomyosarcomas from STUMP and cellular leiomyomas.
REFERENCES 1. Clement PB: The pathology of uterine smooth muscle tumors and mixed endometrial stromal-smooth muscle tumors: A selective review with emphasis on recent advances. Int J Gynecol Pathol 19:3955, 2000 2. Zaloudek C, Norris HJ: Mesenchymal tumors of the uterus, in Kurman RJ (ed): Blaustein’s Pathology of the Female Genital Tract. New York, NY, Springer Verlag, 1994, pp 488-500 3. Chou CY, Huang SC, Tsai YC, et al: Uterine leiomyosarcoma has deregulated cell proliferation, but not increased microvessel density compared with uterine leiomyoma. Gynecol Oncol 65:225231, 1997 4. Zhai YL, Kobayashi Y, Mori A, et al: Expression of steroid receptors, Ki-67, and p53 in uterine leiomyosarcomas. Int J Gynecol Pathol 18:20-28, 1999 5. Jeffers MD, Oakes SJ, Richmond JA, et al: Proliferation, ploidy and prognosis in uterine smooth muscle tumors. Histopathology 29:217-223, 1996 6. Zhai YL, Nikaido T, Shiozawa T, et al: Expression of cyclins and cyclin-dependent kinases in smooth muscle tumors of the uterus. Int J Cancer 84:244-250, 1999 7. Amada S, Nakano H, Tsuneyoshi M: Leiomyosarcoma versus bizarre and cellular leiomyomas of the uterus: A comparative study based on the MIB-1 and proliferating cell nuclear antigen indices, p53 expression, DNA flow cytometry, and muscle specific actins. Int J Gynecol Pathol 14:134-142, 1995 8. Sprogoe-Jakobsen S, Holund B: Immunohistochemistry (Ki-67 and p53) as a tool in determining malignancy in smooth muscle neoplasms (exemplified by a myxoid leiomyosarcoma of the uterus). Acta Pathologica, Microbiologica et Immunologica Scandinavica 104: 705-708, 1996 9. Zhai YL, Nikaido T, Toki T, et al: Prognostic significance of bcl-2 expression in leiomyosarcoma of the uterus. Br J Cancer 80: 1658-1664, 1999 10. Hall KL, Teneriello MG, Taylor RR, et al: Analysis of Ki-ras, p53, and MDM2 genes in uterine leiomyomas and leiomyosarcomas. Gynecol Oncol 65:330-335, 1997
987