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.     

Pathology of uterine leiomyosarcomas and smooth muscle tumours of uncertain malignant potential

Uterine leiomyosarcomas are the most common uterine sarcomas. For clinicians, they are difficult tumours to manage. Preoperative detection is difficult because of the similarity in clinical presentation to ordinary fibroids. They are highly aggressive tumours and the effectiveness of adjuvant therapy remains controversial with surgery remaining the mainstay of treatment. Despite treatment, disease frequently recurs. For pathologists, diagnosis of most leiomyosarcomas using current diagnostic criteria is usually straightforward, as most tumours often possess two or more diagnostic microscopic features, including diffuse atypia, high mitotic count and tumour cell necrosis. Diagnostic difficulties usually relate to tumours having only one of these worrisome features, with or without other additional unusual morphologic findings. These latter tumours have been labelled as uterine smooth-muscle tumours of uncertain malignant potential. Those that are followed by a recurrence are biologically low-grade leiomyosarcomas. Epithelioid and myxoid leiomyosarcomas are less common, and their diagnostic criteria are different to tumours of usual spindle cell differentiation. In this review, we discuss the pathology of leiomyosarcomas, including an update on smooth-muscle tumours of uncertain malignant potential, with emphasis on the controversy of labelling of atypical leiomyomas. The problems with histologic diagnosis, immunohistochemical studies and molecular pathology are reviewed.     

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.     

Estrogen and progesterone receptor expression in patients with uterine smooth muscle tumors

OBJECTIVE: To investigate the expression of estrogen and progesterone receptor in uterine leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMS), and to assess the correlation between steroid receptor expression and clinicopathologic parameters in LMS. DESIGN: Estrogen/progesterone receptor expression was investigated by immunohistochemistry. SETTING: Department of Gynecology and Obstetrics of the University Hospital of Vienna. PATIENT(S): Twenty-six women with leiomyoma, 24 with STUMP, and 21 with LMS of the uterus. INTERVENTION(S): Formalin-fixed, paraffin-embedded tissues were sectioned and stained. MAIN OUTCOME MEASURE(S): Number of tumor cells stained. RESULT(S): Significant differences regarding the frequency of estrogen receptor expression were observed between LMS and leiomyoma and STUMP and leiomyoma (P<.05). The progesterone receptor expression did significantly differ between LMS and STUMP (P=.05), and LMS and leiomyoma (P<.05). In uterine LMS, the relationship between estrogen/progesterone receptor expression and clinicopathologic parameters did not reach statistical significance (P>.05), and neither of the markers studied revealed prognostic significance (P>.05). CONCLUSION(S): The present study observed significant differences of steroid receptor expression between uterine leiomyoma, STUMP, and LMS. Our data indicate that the progesterone receptor may be an especially useful marker to distinguish cases of malignant smooth muscle tumors in which histological features are ambiguous or borderline.     

Expression of matrix metalloproteinases in patients with uterine smooth muscle tumors: an immunohistochemical analysis of MMP-1 and MMP-2 protein expression in leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma

OBJECTIVE: Matrix metalloproteinases (MMPs) have been suggested to play an important role in tumor invasion and metastasis. We compared the expression of MMP-1 and MMP-2 protein in patients with leiomyoma, uterine smooth muscle tumor of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). METHODS: MMP-1 and MMP-2 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 patients with STUMP, and in 21 patients with LMS. RESULTS: MMP-1 was expressed in 92% of leiomyomas, in 83% of STUMP, and in 86% of LMS, whereas MMP-2 was expressed in 12% of leiomyomas, in 17% of STUMP, and in 48% of LMS. A statistically significant difference regarding the frequency of MMP-2 expression was observed between LMS and STUMP (P =.025) as well as between LMS and leiomyoma (P =.006), but not between STUMP and leiomyoma (P >.05). Likewise, the staining intensity did significantly differ between LMS and leiomyoma (P =.025), but no statistical significant difference was observed between LMS and STUMP (P >.05) and between STUMP and leiomyoma (P >.05). CONCLUSION: The stronger MMP-2 expression in patients with LMS compared with STUMP and leiomyoma indicates that this protein might be a marker for tumor invasion or metastasis in patients with uterine LMS. Furthermore, MMP-2 seems to be a useful immunohistochemical parameter to distinguish cases of smooth muscle tumors in which histologic features are ambiguous or borderline. Further studies including larger numbers of patients are necessary to establish MMP-2 as a routine marker for tumor invasion and progression.     

Clinicopathologic markers of uterine leiomyosarcoma originating from smooth muscle tumors of low malignancy

The aims of the study were (1) to increase the limited knowledge on molecular markers contributing to uterine leiomyosarcoma (LMS) tumorigenesis and (2) to test the ability to predict the clinical course of smooth muscle tumors of low malignancy (SMTLM). Retrospectively, 2,360 uterine smooth muscle tumors were classified according to the Stanford criteria. After central review, the clinical course of the SMTLM was traced, and immunohistochemical stainings for p53, p16, p21, Rb, estrogen receptor, progesterone receptor (PR), cyclin A, cyclin D1, vascular endothelial growth factor, WT-1, and Ki-67 were performed on paraffin-embedded tissue of the primary tumor and recurrences. On the same tissues, fluorescence in situ hybridization (FISH) analysis was performed to determine differences in HMGA2, p53, Rb, and 1p36 loci involvement. Five SMTLM were identified, of which two relapsed after 2 and 3 years, respectively. Recurrence tumors were surgically resected, and 3 years later, both patients are alive and there is no evidence for progression of disease. The age at diagnosis in the group with benign course was lower (39, 40, 43 years) than that in the group that recurred (48, 53 years). Both recurrent SMTLMs expressed less PR and, only quantitatively, more p53. One case expressed more cyclin D1 when compared to its primary. p16 level was reduced in one recurrent SMTLM. FISH of both SMTLMs that recurred revealed homozygous deletion of p53 and Rb loci in one of each primary and recurrent tumor. Loss of 1p36 loci was found in both recurrent SMTLMs, and in one case, this genetic imbalance was already present in the primary tumor. The current data provide evidence that the age at diagnosis of SMTLM is a prognostic factor and that LMS originating from SMTLM carries an overall better prognosis than primary LMS. Recurrent tumors showed decreased PR levels. Accumulation of genetic losses, including p53, Rb, and 1p36 loci, may identify a subgroup of SMTLMs with a higher potential towards malignancy.     

Immunohistochemical analysis of p16 expression in uterine smooth muscle tumors

The expression of p16 as a tumor suppressor protein was evaluated in a retrospective analysis of paraffin-embedded tissue specimens of leiomyosarcoma (LMS), leiomyoma (LM) and normal myometrium. In this study, we investigated by immunohistochemistry p16 expression in 15 LMSs, 15 LMs and ten normal myometrium. Strong expression of p16 was found in 12 of the 15 LMSs and in three cases weak expression; three LMs had focal and weak p16 staining but none of the normal myometrium. A statistically significant difference regarding the frequency of p16 protein expression was observed between LMS and LM (p: 0.0001). We concluded that the results of this study confirm the overexpression of p16 in LMS. Therefore, the present study suggests that p16 might be a useful immunohistochemical marker which could help in distinguishing uterine LMS from LM and its benign variants.     

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.     

Expression of p16 protein in patients with uterine smooth muscle tumors: an immunohistochemical analysis

OBJECTIVE: The loss of cell cycle control is a critical step in the development of neoplasia. The p16 protein has been identified as a tumor suppressor protein, which binds specifically to the cyclin-dependent kinase CDK-4, inhibiting the catalytic activity of the CDK4-cyclin D complex, and thereby acts as a negative cell cycle regulator. In the present study, we compared the expression of p16 protein in cases with leiomyoma, uterine smooth muscle tumor of uncertain malignant potential (STUMP), and leiomyosarcoma (LMS). METHODS: P16 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 patients with STUMP, and in 21 patients with LMS. RESULTS: P16 was expressed in 12% of leiomyomas, in 21% of STUMP, and in 57% of LMS. A statistically significant difference regarding the frequency of p16 protein expression was observed between LMS and STUMP (P < 0.05) as well as between LMS and leiomyoma (P < 0.05), but not between STUMP and leiomyoma (P > 0.05). Likewise, the staining intensity did significantly differ between LMS and leiomyoma and between LMS and STUMP (P < 0.05), but no statistical significant difference was observed between STUMP and leiomyoma (P > 0.05). No statistically significant correlation between p16 expression and clinical stage, age, vascular space involvement, and recurrence disease could be found in patients with LMS (P > 0.05). Additionally, the overall survival did not significantly differ between p16-positive and p16-negative cases (P > 0.05). CONCLUSIONS: We found that p16 was more frequently and more strongly expressed in LMS compared to STUMP and leiomyoma. We therefore concluded that p16 might play an important role in sarcomagenesis. Furthermore, p16 might be a useful immunohistochemical marker, which could help to distinguish cases of smooth muscle tumors in which histologic features are ambiguous or borderline, but the use of p16 in a diagnostic setting should await further clinical studies and clarification of the mechanisms.     

Unexpected uterine smooth muscle tumor of uncertain malignant potential and sarcoma: A single center cohort study in South Korea

ObjectiveTo evaluate the risk of encountering unexpected uterine smooth muscle tumors of uncertain malignant potential (STUMPs) or sarcomas during surgical treatment of mesenchymal tumors of the uterus using morcellation.Material and methodsData were collected retrospectively from subjects who were pathologically diagnosed with uterine leiomyoma or its variants, STUMP or other premalignant mesenchymal tumors of uterus, or sarcoma during surgical treatment between July 2014 and June 2017.ResultsA total of 3785 women were investigated; 2824 laparoscopic procedures (74.6%) were performed, and an electronic power morcellator was used in 1636 patients (43.2%). Sixteen women (0.42%) were diagnosed with STUMP and 14 (0.37%) were diagnosed with uterine sarcoma. The incidence rate of unexpected STUMP or uterine sarcoma was 0.61% (23 of 3785 women); unexpected STUMP in 13 (0.34%), and unexpected sarcoma was in 10 (0.26%). Moreover, the unexpected leiomyosarcoma rate was 0.08% (3 in 3785). The rate of unintended morcellation of STUMPs was relatively high at 0.26% (10 in 3785), however, that for uterine sarcomas was 0.05% (2 in 3785).ConclusionThe risks of unintended morcellation were very low for sarcomas and STUMPs, although the risk of the latter was approximately 5-fold that of the former. To reduce the unintended dissemination of tumors, patients suspected of having malignancies should be provided adequate information regarding their treatment options as well as their associated risks. Meanwhile, improved preoperative screening methods for STUMP and sarcoma should be established.     

子宫恶性潜能未定的平滑肌肿瘤29例临床病理分析

目的:分析子宫恶性潜能未定的平滑肌肿瘤(STUMP)的临床及病理学特点,探讨其诊断和治疗方法。方法:收集2008～2018年北京大学人民医院收治的病理科诊断为STUMP的29例患者的临床病理资料,回顾分析患者的临床表现、影像学检查、病理特征、治疗及预后。结果:29例患者的平均年龄为42.3岁(26～76岁),最常见临床症状为月经紊乱(51.7%,15/29)。肿瘤平均最大直径7.24cm(2.50～16.10cm)。切面大部分呈灰白或淡黄色,质地较软、细腻,漩涡结构不清,偶见出血及水肿。镜下21例(72.41%)全部由丰富的梭形细胞构成,6例(17.24%)伴有上皮样分化,2例(6.90%)伴有黏液样分化。肿瘤细胞有中-重度异型者9例(31.03%),核分裂象计数为3～20个/10HPF,其中3例可见病理性核分裂象。有5例(17.24%)出现坏死,包括3例不能明确类型坏死及2例可疑肿瘤细胞坏死。初次手术时19例行子宫肌瘤切除术、7例行全子宫切除术、2例行全子宫+双侧输卵管卵巢切除术、1例曾行全子宫切除术的患者行盆腔肿物切除术+双侧输卵管卵巢切除术。术后随访26例(89.7%),平均随访时间43.8个月(6～123个月),6例有生育要求者中2例术后自然妊娠并足月剖宫产分娩。2例(6.9%)STUMP复发,复发仍均为STUMP; 1例因心脑血管意外死亡,其余患者均存活未复发。结论:STUMP无特殊临床表现,确诊依靠术后病理及免疫组化检测,有生育要求者可严密随访下保留子宫,无生育要求者应切除子宫。     

Expression of thrombospondin 1 (TSP 1) in patients with uterine smooth muscle tumors: an immunohistochemical study

OBJECTIVE: Angiogenesis is an essential component for tumor development regulated by both proangiogenic and antiangiogenic factors. Thrombospondin 1 (TSP 1) suppresses angiogenesis by inhibiting endothelial cell proliferation and inducing endothelial cell apoptosis. The aim of this study was to compare the expression of TSP 1 in cases with leiomyoma, uterine smooth muscle tumor of uncertain malignant potential (STUMP) and leiomyosarcoma (LMS). Furthermore, we evaluated the prognostic relevance of TSP 1 in uterine LMS. METHODS: TSP 1 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 patients with STUMP and in 21 patients with LMS. Standard immunohistochemical techniques were used to study the expression of TSP 1 in 5-mum-thick tumor sections. TSP 1 expression was correlated with survival using the Kaplan-Meier method and log-rank test for univariate analysis. RESULTS: TSP 1 was expressed in 77% of leiomyomas, in 13% of STUMP and in 24% of LMS. A statistically significant difference regarding the frequency of TSP 1 expression was observed between leiomyoma and LMS (P < 0.05) as well as between leiomyoma and STUMP (P < 0.05), but not between LMS and STUMP (P > 0.05). Furthermore, a statistically significant correlation between vascular space involvement and TSP 1 expression was observed in patients with uterine LMS, with patients without vascular space involvement having more frequently TSP 1 positive tumors (P = 0.04). No statistically significant correlation between TSP 1 and clinical stage, age and recurrence disease could be detected (P > 0.05). CONCLUSIONS: We found that TSP 1 was more frequently expressed in leiomyoma compared to STUMP and LMS. Additionally, the statistically significant negative correlation between vascular space involvement and TSP 1 expression in patients with uterine LMS shows that TSP 1 might work as a predictive factor in patients with LMS. Further clinical studies are necessary to prove our results and to clarify the role of TSP 1 in uterine smooth muscle tumors.     

The pathology of uterine smooth muscle tumors and mixed endometrial stromal-smooth muscle tumors: a selective review with emphasis on recent advances.

This review focuses on the pathology of uterine smooth muscle tumors (SMTs), with a particular emphasis on those studies published in the past 15 years that have expanded our knowledge of these tumors which still present diagnostic challenges for the pathologist. Leiomyoma variants, leiomyosarcoma, SMTs of low or uncertain malignant potential, epithelioid SMTs, SMTs with unusual growth patterns, and mixed endometrial stromal-SMTs are discussed.     

p21~(WAF1/CIP1)和P53蛋白在子宫平滑肌肿瘤的表达和意义

目的 :探讨p2 1WAF1/CIP1和P5 3蛋白在子宫平滑肌肿瘤 (USMTs)的表达和意义。方法 :应用免疫组织化学法检测 2 0例普通型子宫平滑肌瘤 (UL) ,18例子宫平滑肌肉瘤 (LMS)及 70例交界性子宫平滑肌瘤 (BLM) :包括 4 0例富于细胞型子宫平滑肌瘤 (CL)、13例奇异型子宫平滑肌瘤 (BL)、4例核分裂活跃型子宫平滑肌瘤 (ML)、10例不典型子宫平滑肌瘤 (AL)及 3例恶性潜能未定型子宫平滑肌瘤 (STUMP)的p2 1WAF1/CIP1和P5 3蛋白的表达。结果 :LMS组p2 1WAF1/CIP1蛋白表达阳性率明显高于UL组 (P <0 .0 1)和BLM组 (P<0 .0 1) ;LMS组P5 3蛋白表达阳性率显著高于UL组 (P <0 .0 1)和BLM组 (P <0 .0 1)。结论 :LMS的发病机制涉及P5 3基因功能的丧失 ;p2 1WAF1/CIP1在USMT细胞的增殖和灭活中可能起到不同的作用     

子宫平滑肌肿瘤AgNOR的图像分析

探讨子宫平滑肌肿瘤细胞的增殖活性。方法：对９３例子宫平滑肌肿瘤（ ｕｓＭＴ）应用ＡｇＮＯＲ染色图像分析进行研究。结果：ＡｇＮＯＲ计数及核仁直径对普通平滑肌瘤,交界性平滑肌瘤（ＢＬＭ）及平滑肌肉瘤（ＬＭＳ）有意义（Ｐ＜０．０５）。结论：在ｕｓＭＴ中,ＡｇＮＯＲ数量随病理程度加重有增加趋势。ＡｇＮＯＲ计数及核仁形态有助于ＢＬＭ及ＬＭＳ的诊断。     

Uterine smooth muscle tumors of uncertain malignant potential: diagnostic challenges and therapeutic dilemmas. Report of 2 cases and review of the literature

Morphologically, there exist variants of uterine smooth muscle tumors that cannot be clearly interpreted and classified as benign or malignant. Because their behavior and clinical prognosis is also uncertain, the World Health Organization has termed these "smooth muscle tumors of uncertain malignant potential" (STUMP). Herein we describe 2 cases, present a review of the literature, and highlight the diagnostic challenges and therapeutic dilemmas associated with uterine STUMP in myomectomy specimens from women who wish to maintain or enhance their fertility. The clinical course of residual STUMP remains speculative.     

Prostaglandin and leukotriene receptors in pulmonary, vascular, and uterine smooth muscle

Prostaglandins are currently used to maintain patency of the ductus arteriosus and to elicit uterine contractions. Prostaglandin synthesis inhibitors are used to promote closure of the ductus and their administration in pregnant animals has produced fetal pulmonary hypertension. Exposure of the human fetus to inhibitors of prostaglandin synthesis has been associated with persistent pulmonary hypertension. A case report of a child with primary hypertension supports the hypothesis that the balance of prostaglandin metabolites plays an important role in maintaining PVR. Leukotrienes have been identified in the sputum of allergic asthmatic patients, patients with cystic fibrosis and infants with persistent pulmonary hypertension. Leukotriene inhibition in rats and newborn lambs prevented and reversed HPV. Receptors for prostaglandins have been identified in smooth muscle preparations of the uterus and renal glomerulus. Further studies have characterized the binding sites in lung tissue, giving supportive evidence for the existence of receptor sites there. Specific receptor sites for LTC4 and LTD4 have been demonstrated in lung tissue. Temperature, pH, and the presence of cations and guanine nucleotides have been shown to affect the receptor density and affinity. Lewis et al demonstrated that the characteristics of the receptor for [3H]LTD4 in the human lung are identical in adult and fetal tissue. This leads to the need for further investigation of the receptors and the effects of the local environments in an attempt to explain the physiologic changes seen in the successful and unsuccessful transition from fetal to neonatal circulation.