Skeletal muscle-like and rhabdoid cells in uterine leiomyomas.

We describe eight unusual uterine leiomyomas characterized by a component of cells that suggested skeletal muscle differentiation or resembled the rhabdoid cells of extrarenal rhabdoid tumors. All of the tumors were referred because of problems in differential diagnosis, particularly distinction from an epithelioid smooth muscle tumor, a smooth muscle tumor of uncertain malignant potential, or a tumor with skeletal muscle differentiation. The patients were aged 27 to 50 (mean, 38) years, and the presenting clinical features and gross appearance of the tumors were similar to those of typical uterine leiomyomas. On microscopic examination, seven of the tumors were well circumscribed, whereas one showed slight irregularity of its margin. The characteristic feature of the tumors was a variable number of rounded, polygonal, or strap-shaped cells with abundant deeply eosinophilic cytoplasm and fibrillar, or occasionally hyaline, intracytoplasmic globules. Cytoplasmic cross-striations were not identified. The cells usually had eccentric, round-to-oval nuclei with conspicuous nucleoli. A variable number of the rhabdoid/skeletal muscle-like cells, as well as cells without these features, contained multiple or multilobed, pleomorphic, hyperchromatic nuclei, thus qualifying the tumors as leiomyomas with bizarre nuclei. Foci of hydropic change were present in all of the tumors. The mitotic index was low (<1 mitotic figure/10 high-power fields) and necrosis was absent in all the tumors. The rhabdoid/skeletal muscle-like cells were immunoreactive for desmin and h-caldesmon, but not for cytokeratin (AE1/AE3) or skeletal muscle markers (myoglobin, Myo-D1, or myogenin). Intracytoplasmic whorls of intermediate filaments were observed in the cells of one case examined by electron microscopy; there was no ultrastructural evidence of skeletal muscle differentiation. The histologic, immunohistochemical, and ultrastructural features indicated that the peculiar cells in these leiomyomas likely represented smooth muscle cells with an unusual phenotype rather than the cells of uterine tumors with skeletal muscle differentiation, extrarenal rhabdoid tumors, or epithelioid smooth muscle tumors. An association with leiomyomas with bizarre nuclei also was suggested.     

Expression of chemokines CCL5 and CCL11 by smooth muscle tumor cells of the uterus and its possible role in the recruitment of mast cells

OBJECTIVE: Smooth muscle tumors of uterus have been reported to contain considerable number of mast cells, especially cellular leiomyoma. However, to our knowledge the mechanism by which mast cells increased in them is not known. The purpose of this study was to reveal the different mast cell subsets in smooth muscle tumors of uterus and to investigate the mechanism of local increase of mast cells. METHODS: Tissue sections from 85 uterine smooth muscle tumors were studied using immunohistochemical double labeling techniques, including 40 cases of ordinary leiomyomas, 30 cases of cellular leiomyomas and 15 cases of leiomyosarcomas. The sections were double immunostained for mast cell tryptase and chymase, mast cell tryptase and ki-67, mast cell tryptase and chemokines (i.e., CCL2, CCL5, CCL11, TGFbeta), as well as tryptase and CCR3. RESULTS: MC(TC)-type of mast cells was the predominant type in ordinary leiomyoma and cellular leiomyoma, whereas MC(T)-type was seldom found in them. There was no MC(C) in smooth muscle tumors. The total intratumoral number of mast cells in cellular leiomyoma group was significantly higher than that in both leiomyosarcoma and ordinary leiomyoma (P<0.01). Mast cells proliferation was rarely detected in smooth muscle tumors, as revealed by constant negative labeling of the proliferation marker Ki-67 in mast cells. Almost all mast cells (tryptase positive) in smooth muscle tumors were also CCL2, CCL5, CCL11 and TGFbeta positive. Expressions of CCL5 and CCL11 in tumor cells in cellular leiomyoma were all significantly higher than that in both ordinary leiomyoma and leiomyosarcoma (P<0.01). While the expression of TGFbeta in tumor cells in cellular leiomyoma was not significantly different from that in ordinary leiomyoma, expression of CCL2 was not observed in smooth muscle tumor cells. There were positive correlations between CCL5 and the number of mast cells (r(s)=0.801, P<0.01) and between CCL11 and the number of mast cells (r(s)=0.744, P<0.01) in smooth muscle tumors as well. The vast majority of the mast cells in cellular leiomyoma were CCR3 positive. CONCLUSIONS: Using the monoclonal anti-mast cell tryptase antibody could detect all mast cells in smooth muscle tumor. The increased intratumoral mast cell counts in cellular leiomyoma might be the result of mast cells recruitment from the peripheral blood rather than local mast cells proliferation. CCL5 and CCL11, which are expressed by smooth muscle tumor cells, are possibly responsible for the recruitment of mast cells in uterine cellular leiomyoma. Whether they combine to CCR3 expressed by mast cells need further study.     

Diagnostic criteria for uterine smooth muscle tumors: leiomyoma variants associated with malignant behavior

OBJECTIVE: To determine the prognostic accuracy of current diagnostic criteria for uterine smooth muscle tumors. STUDY DESIGN: Cases of uterine leiomyosarcoma (LMS) treated from 1976 to 1999 were analyzed retrospectively. Uterine LMS specimens were reevaluated using current criteria by a pathologist specializing in gynecologic diseases. Kaplan-Meier survival curves were evaluated. RESULTS: Specimens were available from 67 patients diagnosed with uterine LMS. On rereview, only 47 specimens were thought to represent uterine LMS. The 20 other patients were deemed to have leiomyomas or leiomyoma variants, including 13 cellular leiomyomas, 5 atypical leiomyomas and 2 leiomyomas. Median survival for patients with uterine LMS was 2.1 years. (Ninety-seven percent of disease-specific deaths occurred within 6 years after the diagnosis.) With leiomyoma variants, median survival was > 25 years. Among these 18 women were 3 disease-specific deaths (all > 6 years after diagnosis). CONCLUSION: Diagnostic criteria for uterine smooth muscle tumors require continued refinement. A small but significant number of patients diagnosed with leiomyoma variants will die of the disease. In contrast to the aggressive behavior of uterine LMS, disease-specific deaths attributed to leiomyoma variants occurred later. With this potential for delayed recurrence, these patients warrant close clinical surveillance.     

Ki-67 expression in patients with uterine leiomyomas, uterine smooth muscle tumors of uncertain malignant potential (STUMP) and uterine leiomyosarcomas (LMS)

BACKGROUND: The aim of the current study was to evaluate the expression of Ki-67 in uterine smooth muscle tumors, comparing leiomyomas, uterine smooth muscle tumors of uncertain malignant potential (STUMP) and uterine leiomyosarcomas (LMS) and to prove the accuracy of a Ki-67 expression as a useful parameter in the diagnosis of LMS. METHODS: Ki-67 was assessed using immunohistochemistry from paraffin-embedded tissue in 20 patients with uterine LMS, 22 cases of STUMP and 25 cases of leiomyomas. RESULTS: Ki-67 was present in 10/20 (50%) LMS, in 0/22 (0%) STUMP and in 2/25 (8%) leiomyomas. Significant differences regarding the frequency of Ki-67 expression were observed between LMS and STUMP (p = 0.0001) as well as between LMS and leiomyomas (p = 0.002), but not between STUMP and leiomyomas (p = 0.491). Likewise, the staining intensity differed significantly between LMS and leiomyomas (p = 0.018) as well as between LMS and STUMP (p = 0.002), but not between STUMP and leiomyomas (p = 0.368). CONCLUSIONS: Our results demonstrate that the significantly elevated Ki-67 antigen expression in LMS, which correlates well with the rapid growth of these malignant tumors, may be a useful immunohistochemical parameter to distinguish between cases of malignant smooth muscle tumors and those of uncertain or borderline histology.     

The difference in sex hormone dependence for gap junction formation in the muscles of uterine leiomyoma and normal myometrium

Gap junction is reported to be initiated by changes in levels of steroid hormones in the smooth muscle cells of myometrium. In order to clarify the difference in sex hormone dependence for gap junction formation in the muscles of uterine leiomyoma and normal myometrium, uterine leiomyoma and myometrial gap junctions, and serum estradiol and progesterone levels were determined simultaneously in 23 women who had undergone simple hysterectomy for leiomyomas of the corpus uteri. In all tissues of the myometrium from 23 women, at least three gap junctions were found between muscle cells in the series of photographs. On the other hand, there were 7 out of 23 uterine leiomyomas in which not even one gap junction was detected between muscle cells in the series of photographs. The phasic change in the number of gap junctions related to the menstrual cycle was detected in the muscles of uterine leiomyoma as well as normal myometrium. Uterine leiomyoma was characterized by less correlation between the number of gap junctions in the muscles and the concentration of serum sex steroids, compared with those of normal myometrium. Sex steroids may have a trophic effect on some uterine leiomyoma, but the sex hormone dependence of uterine leiomyoma for gap junction formation may be less than that of normal myometrium. The present study also showed that the increased gap junction formation in myometrial muscles from women with dysmenorrhea may be formed between myometrial cells in response to physiologic or pathologic stimuli, such as the production of local prostaglandins, and may result in hypercontraction of the uterus.     

Increased density of histiocytes in uterine leiomyomas

The histiocyte content of leiomyomata and adjacent, histologically normal myometrium has been quantified morphometrically with the help of recently developed immunostaining for tissue macrophages. Histiocytes identified by immunoreaction for Factor XII subunit A and by double immunofluorescent labelings were found to be identical with tissue macrophages present in normal uteri. Histiocyte counts were significantly higher in leiomyomatous areas than in adjacent normal myometrium, and the distribution of these cells was also changed. In the normal uterine wall, histiocytes could be detected only in the connective tissue septa separating smooth muscle bundles, while in the myomatous nodules they were diffusely scattered throughout the whole area. In addition to providing new information on the cellular composition of leiomyomas, the present observations also raise several questions concerning the possible pathogenetic role of FXIII-positive histiocytes in neoplastic proliferation of uterine smooth muscle.     

Maintenance of increased Bcl-2 expression in uterine leiomyomas after GnRH agonist therapy.

OBJECTIVE: To compare the immunohistochemical expression of Bcl-2 in uterine leiomyomas in patients undergoing myomectomy or hysterectomy with and without preoperative treatment with the gonadotropin-releasing hormone receptor agonist (GnRH-a) leuprolide acetate (LA). STUDY DESIGN: Retrospective case-control study. Seventeen patients with symptomatic uterine leiomyomata were included. Of the 17 patients, 7 were treated with LA (3.75 mg) in three monthly doses prior to myomectomy or hysterectomy. Ten patients who did not receive LA and underwent hysterectomy for leiomyomas served as controls. Formalin-fixed, paraffin-embedded archival tissue from 17 leiomyomas were immunostained with a monoclonal antibody against Bcl-2 protein. Positivity was scored semiquantitatively on a three-tier scale. RESULTS: Immunostaining for Bcl-2 protein was intense (2-3+) in 7 LA-treated and 10 untreated leiomyomas but was scarce (0-1+) in normal myometrial smooth muscle. CONCLUSION: Abundant expression of Bcl-2 protein may be responsible for the growth of leiomyomas by preventing apoptotic cell death. Its increased expression is maintained in GnRH-a-treated leiomyomas.     

Epithelioid vascular leiomyoma of the uterus mimicking glomangiomyoma

Case report: An unusual case of epithelioid vascular leiomyoma mimicking glomangiomyoma arising in the uterine corpus of a 55-year-old Japanese woman is presented. The surgically resected uterine mass, measuring 4.0 × 3.5 cm², demonstrated a dark red well-circumscribed tumor. Histologically, the rounded epithelioid cells around the dilated vessels showed gradual transition to spindled smooth muscle cells. Immunohistochemistry was positive for smooth muscle actin, but negative for collagen IV. Conclusion: The experience in this case emphasizes that glomangiomyoma-like feature is interesting and might indeed be a new histological variant of uterine leiomyomas.     

Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium.

BACKGROUND AND AIM: Matrix metalloproteinase-2 and -9 (MMP-2 and -9) are proteolytic enzymes degrading extracellular matrix proteins, mainly collagen type IV. Recent reports show that these proteases may be implicated in the growth of uterine leiomyoma. The aim of the present study was to evaluate the activity of MMP-2 and MMP-9, the contents of their tissue inhibitors (TIMP-1 and TIMP-2) and the immunolocalization of collagen type IV in uterine leiomyoma and corresponding myometrium. MATERIALS AND METHODS: Material for the study comprised specimens of uterine leiomyomas and corresponding myometrium derived from 20 hysterectomized women. The activity of MMP-2 and MMP-9 in tissue extracts was evaluated by semi-quantitative zymography. TIMPs were measured by enzyme-linked inmmunosorbent assay. Protein immunohistochemistry was applied for detection of collagen type IV. RESULTS: Activity and activation ratio of MMP-2 were significantly higher in leiomyomas than myometrium. The activity of MMP-9 was weak and did not differ between the investigated tissues. Contents of TIPM-1 and TIPM-2 were similar in both tissues. In both leiomyomas and myometrium, collagen type IV was localized in the extracellular matrix embedding bundles of smooth muscle cells, but was absent in areas of extracellular matrix accumulation within leiomyomas and in larger septa separating muscle fibers in normal myometrium. CONCLUSION: MMP-2 may be implicated in pathogenesis of leiomyoma.     

Bcl-2 receptor expression in patients with uterine smooth muscle tumors: an immunohistochemical analysis comparing leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma

OBJECTIVE: Bcl-2 protein is an apoptosis-inhibiting gene product that prevents the normal course of apoptotic cell death in a variety of cells. Additionally, bcl-2 can promote cell replication by reducing the requirement for growth factors. This protein seems, therefore, to play an important role in the growth of tumors. Our aim was to investigate the different expression of bcl-2 in uterine leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMS). Furthermore, the correlation between bcl-2 expression and various clinicopathologic parameters in leiomyosarcomas was assessed to evaluate its prognostic value. METHODS: This study included 26 cases of leiomyoma, 22 cases of STUMP, and 21 cases of LMS of the uterus. Bcl-2 expression was investigated by immunohistochemistry from paraffin-embedded tissue. The immunohistochemical findings were compared and correlated with different clinicopathologic parameters. Clinical information, including follow-up data, was obtained from the database of the Department of Gynecology and Obstetrics. RESULTS: Bcl-2 was present in 12 of 21 LMS, eight of 22 STUMP, and 20 of 25 leiomyomas. Significant differences regarding the frequency of bcl-2 expression and the staining intensity were observed between LMS and leiomyoma as well as between STUMP and leiomyoma (P <.05) but not between LMS and STUMP (P >.05). Regarding the outcome of uterine LMS, patients with bcl-2 positive tumors showed less vascular space involvement and longer overall survival (P <.05). CONCLUSION: Bcl-2 was expressed more frequently and more strongly in leiomyomas compared with LMS and STUMP. Regarding the outcome of uterine LMS, patients with bcl-2-positive tumors showed less vascular space involvement and longer overall survival. The stronger bcl-2 expression in benign leiomyomas and the better clinical outcome of bcl-2-positive LMS indicate that this protein seems to act as a good prognostic factor. Further studies including larger numbers of patients are necessary to establish bcl-2 as a routine marker for improved prognosis in malignant uterine smooth muscle tumors.     

Uterine lipoma and coincidental cervical cancer: a case report

Pure lipoma of the uterus is a rare clinical event, and only a few cases have been reported in the literature. Clinical symptoms and physical signs are similar to those found in leiomyomas. The histogenesis of these lesions is still unclear. However, adipose metaplasia of stromal cells or smooth muscle cells of leiomyoma were accepted hypothesis that explain histogenesis of lipomas of uterus. We report the case of a 55-year-old woman with pure uterine lipoma and coincidental cancer of uterine cervix.     

Positron emission tomography and leiomyomas: clinicopathologic analysis of 3 cases of PET scan-positive leiomyomas and literature review

INTRODUCTION: Studies have suggested that PET scans can differentiate between leiomyomas and leiomyosarcomas. Our experience, however, shows that PET scan-positive smooth muscle tumors are not necessarily malignant. CASE REPORTS: Three patients with cancer underwent PET imaging. In all three, the most worrisome finding was a PET scan-positive uterine tumor. After surgical extirpation, all three uterine tumors were found to be benign smooth muscle neoplasms. DISCUSSION: To explore the potential reason these tumors were positive on PET imaging, we performed a detailed histopathologic and immunohistochemical study of all specimens. Pathologic evaluation revealed a leiomyoma, a cellular leiomyoma, and a stromomyoma. There was no association between an increased Ki67 (proliferative) index and positivity on PET imaging. Increased vascularity, however, appeared to be a feature common to the leiomyomas that were PET-positive.     

Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium

Background and aim. Matrix metalloproteinase-2 and -9 (MMP-2 and -9) are proteolytic enzymes degrading extracellular matrix proteins, mainly collagen type IV. Recent reports show that these proteases may be implicated in the growth of uterine leiomyoma. The aim of the present study was to evaluate the activity of MMP-2 and MMP-9, the contents of their tissue inhibitors (TIMP-1 and TIMP-2) and the immunolocalization of collagen type IV in uterine leiomyoma and corresponding myometrium.

Materials and methods. Material for the study comprised specimens of uterine leiomyomas and corresponding myometrium derived from 20 hysterectomized women. The activity of MMP-2 and MMP-9 in tissue extracts was evaluated by semi-quantitative zymography. TIMPs were measured by enzyme-linked inmmunosorbent assay. Protein immunohistochemistry was applied for detection of collagen type IV.

Results. Activity and activation ratio of MMP-2 were significantly higher in leiomyomas than myometrium. The activity of MMP-9 was weak and did not differ between the investigated tissues. Contents of TIPM-1 and TIPM-2 were similar in both tissues. In both leiomyomas and myometrium, collagen type IV was localized in the extracellular matrix embedding bundles of smooth muscle cells, but was absent in areas of extracellular matrix accumulation within leiomyomas and in larger septa separating muscle fibers in normal myometrium.

Conclusion. MMP-2 may be implicated in pathogenesis of leiomyoma.     

Differential expression of P16 and P21 in benign and malignant uterine smooth muscle tumors

Purpose  

The diagnosis of benign and malignant uterine smooth muscle tumors depends on morphologic criteria such as nuclear atypia, coagulative tumor cell necrosis and mitotic activity. Most of these tumors are readily classifiable into benign or malignant categories using these criteria. However, the distinction between leiomyomas and leiomyosarcomas may at times be problematic. Hence, it would be useful to have additional markers which could help to distinguish these tumors. The aim of the study was to evaluate p16 and p21 expressions in uterine smooth muscle tumors and determine whether p16 and p21 have a potential value in the differential diagnosis of problematic cases. In addition, we evaluated whether the differential expression of p16 and p21 in uterine leiomyosarcomas correlated with tumor recurrence and patient survival.     

Intraepithelial mucinous carcinoma arising in an endocervical-type mucinous polypoid adenomyoma of the uterine corpus: a case report

BACKGROUND: Benign endocervical-type mucinous adenomyoma arising in the uterine corpus is a rare entity. We report a case of intraepithelial mucinous adenocarcinoma arising in an endocervical-type mucinous adenomyoma of the uterine corpus in a previously healthy woman. CASE: A 55-year-old, white woman presented with postmenopausal bleeding. Uterine leiomyomas and endometrial polyps were suggested by ultrasonography. Endometrial curettage showed multiple polypoid tissue fragments, each composed of glands lined with tall columnar endocervical-type mucinous epithelium lying within a background of endometrial-type stroma and smooth muscle fibers. The mucinous glandular epithelium showed a spectrum of architectural and cytologic changes ranging from benign to severe atypia and occasional back-to-back cribriform glands, consistent with adenocarcinoma. The surrounding smooth muscle fibers and endometrial stromal cells were benign. A diagnosis was made of intraepithelial adenocarcinoma arising in a mucinous adenomyoma in the uterine corpus. CONCLUSION: Endocervical-type mucinous adenomyoma, although previously reported as a benign entity, may contain areas of adenocarcinoma.     

Growth potential of human uterine leiomyomas: some in vitro observations and their implications

Tissue culture techniques commonly applied to the study of human vascular smooth muscle were used to evaluate in vitro survival and proliferation of normal and neoplastic human myometrial cells. Despite their growth advantage in vivo, leiomyoma cells displayed a growth disadvantage in vitro compared with normal myometrium from the same patient. Hormonal supplementation with alpha-estradiol, progesterone, and insulin-stimulated myometrial proliferation, whereas beta-estradiol appeared ineffective at the doses tested. Hormonal supplementation also stimulated leiomyoma proliferation in vitro, but there appeared to be heterogeneity in hormonal responsiveness. Heterogeneity in the host hormonal milieu and in the ability of uterine leiomyomas to respond to various hormones may be important factors contributing to the wide variation in growth potential observed in leiomyomas.     

Gutartige Uterustumoren

Leiomyomas are the most common tumors of the uterus. They arise from smooth muscle cells of the myometrium and are most prevalent in premenopausal women. Typical symptoms of uterine leiomyomas are abnormal uterine bleeding and bulk-related symptoms or pain. Leiomyomas can cause difficulties in conceiving a pregnancy and an increased risk of miscarriage. Usually the diagnosis of uterine myoma is based on a bimanual pelvic examination and can be confirmed using transvaginal ultrasound. Other benign tumors of the uterus are adenomyomas and endometrial polyps. They have to be carefully distinguished from malignant diseases. The treatment of uterine myomas includes watchful waiting, medical therapy, surgery and interventional radiology.     

GDF-9和BMP-15在子宫肌瘤中的表达

目的:了解GDF-9和BMP-15在子宫肌瘤及邻近正常平滑肌中的表达,为进一步探讨子宫肌瘤发病机制提供实验依据。方法:免疫组织化学方法检测手术切除的子宫肌瘤和邻近平滑肌组织中蛋白的表达;消化法和组织块贴壁法进行子宫肌瘤细胞和邻近平滑肌细胞原代培养,Real-time PCR(RT-PCR)检测所培养子宫肌瘤和邻近平滑肌细胞中GDF-9和BMP-15的表达。结果:GDF-9和BMP-15蛋白在子宫肌瘤和邻近平滑肌组织中的表达无统计学差异;消化法和组织块贴壁法2种细胞培养法均建立了有限细胞系,Real-time PCR检测结果显示GDF-9和BMP-15mRNA在子宫肌瘤细胞中的表达均高于邻近平滑肌细胞。结论:GDF-9和BMP-15在mRNA水平对基因信号调控方面有影响,可能促进子宫肌瘤的增殖、肥大,与子宫肌瘤的发生发展有一定的相关性。     

The activity of cancer procoagulant in cases of uterine leiomyomas

PURPOSE: It is currently believed that cancer procoagulant (CP), an enzymatic protein, is a product of malignant neoplastic cells. The present study was designed to test whether it is also synthesized by benign neoplastic cells, namely uterine leiomyomas. MATERIALS AND METHODS: We determined the activity of CP in the blood serum of women with uterine leiomyomas (N = 24), normal women (N = 15), and genital cancer patients (N = 6) by the coagulative method according to Gordon and Benson. Also, the CP activity in 10% tissue homogenates of uterine leiomyomas, normal uterine muscle and tissues of cervical and endometrial carcinoma was determined by the chromogenic method according to Colucci et al. RESULTS: The mean CP activity in the sera of women with uterine leiomyomas was 181.1 seconds (s) +/- 19.9 s, in healthy women--293.2 s +/- 33.8 s, and in genital cancer patients--78.8 +/- 18.5 s (all differences: p < 0.001). Similarly, in homogenates of uterine leiomyomas the CP activity was 19.6 +/- 3.8 nmoles pNa/ml, in normal uterine muscle it was 13.2 +/- 2.2 nmoles pNa/ml, and in cancerous tissue--28.0 +/- 6.6 nmol pNa/ml (all values being significantly different from each other). There was a strong correlation (r = -0.8122; p < 0.001) between the CP activity in uterine leiomyomas and serum activity, suggesting that the source of the serum CP activity was from the leiomyoma. The coagulation time of 120 to 240 s by the Gordon and Benson method supported the diagnosis of uterine leiomyoma, and a value below 120 s--the suspicion of genital cancer. CONCLUSIONS: Uterine leiomyomas, representing benign genital neoplasia, synthesize CP and are the likely origin of CP activity in blood, as has been described for malignant tumors, but to a lesser degree. There may be a role for CP as a tumor marker of genital neoplasia.     

High expression of cyclooxygenase-2 in uterine fibroids and its correlation with cell proliferation

Objective

To investigate the expression of cyclooxygenase-2 (COX-2) in uterine fibroids and healthy uterine smooth muscle as well as its role in the pathogenesis of uterine fibroids.

Methods

We collected uterine fibroid tissues and their paired adjacent healthy uterine smooth muscle tissues from 30 cases of uterine fibroids. We used immunohistochemistry and quantitative real-time PCR, as well as western blot to detect COX-2 expression. Using the COX-2 inhibitors NS-398 and celecoxib, we observed the response to the inhibitors in the healthy and fibroid smooth muscle cell pairs.

Results

COX-2 was detected by immunohistochemistry in both uterine fibroids and uterine smooth muscle, with higher immunoreactivity in uterine fibroids; the positive index of the smooth muscle cells was 11.90 and the positive index of uterine fibroids cells was 46.50 (P < 0.05). The expression of COX-2 mRNA in uterine fibroids was higher (0.122 ± 0.062) than in normal smooth muscle tissue (0.025 ± 0.009; P < 0.05). Also, the western blot results showed that COX-2 expression was significantly higher in uterine fibroid cases, as compared to the expression in uterine smooth muscle. Immunofluorescence showed that the occurrence of COX-2 was obviously higher in smooth muscle cells of uterine fibroids than in the healthy smooth muscle cells. NS-398 or celecoxib significantly inhibited the proliferation of smooth muscle cells of uterine fibroids, but did not inhibit the proliferation of healthy smooth muscle cells. Accordingly, NS-398 or celecoxib significantly reduced the expression of the downstream metabolite of COX-2, PGE2, in the smooth muscle cells of uterine fibroids, but not in healthy smooth muscle cells.

Conclusion

COX-2 expression in uterine fibroids was significantly higher than in healthy uterine smooth muscles. The inhibition of COX-2 activity significantly reduced the proliferation of smooth muscle cells of the uterine fibroids, suggesting that COX-2 plays an important role in the pathogenesis of uterine fibroids.