Uterine smooth muscle tumor of uncertain malignant potential: A review of current knowledge

Uterine smooth muscle tumor of uncertain malignant potential is a subtype of uterine smooth muscle neoplasms. It is characterized by distinct pathologic findings with morphologic features intermediate between those of benign leiomyoma and malignant leiomyosarcoma. Clinically, STUMP is rare and its clinical picture is comparable to that of leiomyoma, with diagnosis typically being made postoperatively. Most patients with STUMP are uneventful after tumor resection. However, a small portion of patients may experience recurrence that may even lead to mortality. Given the uncommon occurrence of STUMP and the low frequency of malignant potential, currently there is still no standard guideline in treating patients with this disease and this can be challenging for physicians. Moreover, because cases are rarely available for study, investigating this tumor is difficult. Thus, matters such as the pathologic diagnostic criteria, strategy of clinical management, identification of prognostic factors, and the pathogenesis of this disease remain to be clarified. We collected and analyzed recently published case series studies of STUMP to obtain up-to-date clinical information. The current status of research in various basic and clinical aspects of this tumor was also reviewed.     

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.     

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.     

Uterine smooth-muscle tumor of uncertain malignant potential metastasizing to the humerus as a high-grade leiomyosarcoma

BACKGROUND: Smooth-muscle tumors of uncertain malignant potential represent a variant of uterine leiomyoma and remain a dilemma due to their uncertain clinical behavior. Most of these tumors have a benign clinical course, and coagulative tumor cell necrosis has usually been associated with worse outcome. CASE: We present a case of a uterine smooth-muscle tumor (SMT) of uncertain malignant potential without coagulative tumor cell necrosis that has metastasized to the humerus. The metastatic lesion was a high-grade leiomyosarcoma consistent with uterine origin. CONCLUSIONS: Smooth-muscle tumors of uncertain malignant potential that demonstrate a lack of coagulative tumor cell necrosis do not necessarily insure benign clinical outcome. These lesions can recur and metastasize to distant sites, thus requiring long-term follow-up.     

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.     

Report of an unusual problematic uterine smooth muscle neoplasm, emphasizing the prognostic importance of coagulative tumor cell necrosis

Follow-up data of the clinical behavior of uterine smooth muscle tumors with low malignant potential are scarce. We present a woman suffering from a uterine smooth muscle cell tumor with increased cellularity, absence of significant atypia, and two to three mitotic figures per 10 HPFs but with minimal focal coagulative tumor cell necrosis (CTCN). These microscopic features are currently accepted to label the lesion as a "smooth muscle neoplasm of low malignant potential, limited experience." After a disease-free survival of 4 years, two retroperitoneal tumors around the iliac vessels were extirpated. Both tumors consisted of smooth muscle cells with mild to moderate atypia and a mitotic index of 5-10 per 10 HPFs but with multifocal and extensive CTCN. These microscopic features were sufficient to establish the diagnosis of leiomyosarcoma. This case adds to the limited experience of the clinical behavior of problematic uterine smooth muscle cell neoplasms and underscores the prognostic importance of CTCN.     

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。     

Natural nutrient mixture effectively reduces collagen matrix contraction driven by human uterine smooth muscle cells

AIM: Abnormal uterine myometrial contractility causes preterm delivery, contributing to perinatal morbidity and mortality. Disturbances in hormonal regulation and inflammation-related processes have been attributed a role in the pathophysiological mechanisms of uterine contractility. We investigated the effects of natural nutrients on uterine tissue contractility in vitro. METHODS: We used an in vitro model of collagen I gel contraction driven by embedded cultured human uterine smooth muscle cells (SMC). The effects of tested compounds were evaluated using their capacity to affect gel contraction (measured by reduction in gel area during 24-h incubation in serum free medium). Cellular expression of matrix metalloproteinases (MMP) was followed by gel zymography. RESULTS: Collagen gel contraction driven by uterine SMC was significantly stimulated by potassium chloride, pituitary hormone oxytocin and by inflammatory cytokine alpha-tumor necrosis factor (TNF-alpha). Accelerated gel contraction was accompanied by elevated secretion of MMP-2 and MMP-9 into cell culture media. Among a variety of purified bioflavonoids and polyphenol-enriched plant extracts tested for their ability to counteract uterine SMC-dependent collagen gel contraction, the strongest effects were demonstrated by epigallocatechin gallate and green tea leaf extract, respectively. The addition of ascorbic acid and the amino acids lysine, arginine, cysteine and proline to green tea extract further increased its effectiveness. A reduction in gel contraction correlated with decreased MMP expression. CONCLUSION: Based on these findings, we found that nutrients can effectively counteract uterine myometrial contraction and MMP activity in vitro, suggesting that pathophysiological mechanisms of abnormal uterine myometrial contractility can be counteracted by a combination of naturally occurring nutrients. These mechanisms might involve extracellular matrix remodeling.     

Increased expression of tuberin in human uterine leiomyoma

Female Eker rats harboring an insertional deletion in one copy of the tuberous sclerosis complex 2 (Tsc2) gene develop uterine leiomyoma, but the underlying mechanism of human uterine leiomyoma is not completely understood. To examine whether down-regulation of tuberin, a TSC2 gene product, is present in human uterine leiomyoma, we analyzed leiomyoma and matched myometrium tissues from 22 Chinese patients with Western blotting and real-time polymerase chain reaction analyses, and found that the expression of tuberin was significantly increased in leiomyoma tissues compared with matched myometrium tissues with inhibition of both the mammalian target of rapacmycin pathway and mitogen-activated protein kinase pathways.     

PTEN, tau-AP-3, thymidylate synthase immunohistochemistry scoring expression in patients with uterine leiomyomas, uterine smooth muscle tumors of uncertain malignancy potential and uterine leiomyosarcomas

Uterine smooth muscle tumors are frequently classified as benign and malignant. However, an assortment of mitotic counts and nuclear atypia can be indecisive between uncertain malignant potential, and malignant uterine smooth muscle tumors. We applied three immunohistochemical parameters to distinguish between cases of benign, malignant, and those with uncertain malignant histology.     

Pathophysiology of fibroid disease: angiogenesis and regulation of smooth muscle proliferation

Uterine fibroids are the most common tumours presenting in women. The pathophysiology of fibroids is poorly understood, but disordered angiogenesis and altered smooth muscle cell proliferation are believed to play a role. In this review, current knowledge of both of these processes will be summarized. Differences between 'normal' adjacent myometrium and fibroid tumours within the same uterus are outlined. Exploiting these differences represents one of the best opportunities for the development of medical treatments that target fibroid tissue selectively.     

Euonymus alatus (Thunb.) Sieb induces apoptosis via mitochondrial pathway as prooxidant in human uterine leiomyomal smooth muscle cells

Euonymus alatus (Thunb.) Sieb (EA) is a traditional Korean herbal medicine, commonly used to treat tumors in Korea and China for centuries. Our earlier studies have indicated that EA exhibits antitumor properties, but its mechanism remains to be elucidated. In this study, we evaluated the molecular mechanism of EA in a human uterine leiomyomal smooth muscle cell (ULSMC) line. Water extracts of EA have been reported to not only function as antioxidants but also cause cytotoxic effect. We investigated the mechanism of EA-induced cytotoxicity in human ULSMC. When cells were cultured with 20-200 microg/mL EA for 6 h, caspase-3 was activated and then cells fell into apoptosis. Induction of apoptosis by EA was accompanied with increase of the cytosolic fractions of cytochrome c prior to the activation of caspase-3. The preculture with 5 mM of buthionine sulfoximine, an inhibitor of glutathione synthesis, facilitated EA-induced induction of apoptosis. The preculture with N-benzyloxycarbonyl-valyl-alanyl-aspartyl fluoromethylketone, a pan-caspase inhibitor, partially suppressed the induction of apoptosis. EA showed little toxic effect on peripheral blood mononuclear cells from healthy volunteers. These results indicate that EA acts as a prooxidant and induces caspase-3 activation and apoptosis via mitochondrial pathway.     

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.     

Laparoscopy in the treatment of ovarian tumours of low malignant potential

Laparoscopy is increasingly used by gynaecologists for the investigation of adnexal masses. Uncertainty exists whether ovarian tumours of low malignant potential can effectively be treated by laparoscopy, whether staging bears a benefit for all patients, whether port-site metastases are a problem and how long patients need to be followed up after surgery. This review summarises the evidence to address these important questions.     

Contractile activity, membrane potential, and cytoplasmic calcium in human uterine smooth muscle in the third trimester of pregnancy and during labor

OBJECTIVE: This study was undertaken to investigate in human tissue samples the mechanisms underlying spontaneous and prostaglandin F(2)(alpha)-induced contractions during the final trimester of pregnancy and labor. STUDY DESIGN: Membrane potential and cytoplasmic calcium were recorded simultaneously with contraction in uterine strips obtained from the lower segment during cesarean delivery. RESULTS: Between week 28 of gestation and term there was a progressive increase in the frequency of spontaneous contractions and a decrease in the negative potential of the membrane. The response to prostaglandin F(2alpha) was biphasic. The initial excitatory component remained stable toward term. A later inhibitory component, which was underpinned by increased activity of the sodium-potassium adenosine triphosphatase pump, decreased at the time of labor. CONCLUSIONS: There is a gradual increase in excitability in uterine muscle throughout the third trimester of human pregnancy. The initial component of the prostaglandin response is a large contraction that is kept brief by a subsequent inhibitory component of the response, which ensures that full relaxation occurs between contractions.