The clinical presentation may be completely asymptomatic, but most frequent symptoms in the setting of ULMS are vaginal bleeding, nonspecific pain in the pelvis and a palpable pelvic mass [8]. In the setting of NULMS, swelling of the affected area is frequently reported [1] but no other symptoms may be seen.

Imaging studies including CT or MRI are useful to assess the status of the adjacent tissue and organs, especially in the setting of a peritoneal tumor and both abdominal and thoracic evaluation should be performed, since the lungs and the liver (but also the skin) are the most common sites of metastasis [4]. On MRI, features of LMS include a large infiltrating myometrial mass of varying intensity on T1-weighted images, whereas an intermediate-to-high signal intensity may be observed on T2 [8]. Additionally, signs of hemorrhage, focal calcifications and extensive necrosis may be present [8]. Unfortunately, a significant proportion of patients is diagnosed with LMS incidentally, either after a surgical procedure that subsequently identifies a tumor (such as hysterectomy) or during other examinations [14]. To confirm LMS, it is necessary to perform a biopsy of the tumor and subsequent histopathological and immunohistochemical examination [9], but this procedure is also important in determining the therapeutic approach.

For ULMS, total hysterectomy and bilateral salpingo-oophorectomy is recommended, while proximal lymphadenectomy is performed when a suspicion of extrauterine disease is present [1] [15]. In advanced stages and in the case of involvement of other organs or tissues, surgical excision of the tumor with wide margins, is the recommended course of therapy [15], while cytoreductive surgery is performed if such approach is not possible [1] [9]. Depending on the site of the tumor, various surgical procedures have been recommended, such as prosthetic replacement of the infrahepatic inferior vena cava [16]. Chemotherapy, in addition to surgery, is the mainstay of treatment and doxorubicin is considered as first-line therapy, but because of its significant toxicity (cardiac changes, leukopenia and thrombocytopenia), as also due to development of resistance [6], gemcitabine and docetaxel, as well as ifosfamide pose as alternative regimens [17]. Trabectedin has also been used for patients who do not respond to standard regimens (or do not tolerate their toxic effects) [10]. For still unknown reasons, a response of the tumor to chemotherapy varies with the anatomical site and uterine LMSs respond more efficiently than vascular lesions [17]. Pazopanib, an inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), has shown some benefit in patients who do not respond to chemotherapy and is being used in advanced stages of the disease [9]. Most recent studies have evaluated experimental drugs that target the PI3K/AKT/mTOR pathway and promising results were obtained both in vitro and in vivo [6]. Although radiotherapy is used frequently in oncology, numerous reports have confirmed that adjunctive radiation therapy does not improve outcome in patients suffering from this tumor [18] [19].

The staging system for sarcomas is based on four cardinal features [7]:

• Histologic grade - Well-differentiated (G1), moderately differentiated (G2), poorly differentiated (G3) and undifferentiated (G4) tumors may be determined by histopathological examination.
• Tumor size - ≤ 5 cm (T1), ≥ 5 cm (T2), and involvement of the superficial (Ta) or deep fascia (Tb).
• Absence or presence of lymph node dissemination (N0 and N1, respectively).
• Metastatic spread (M0 or M1).

Depending on the presence of various features, the following stages have been recognized, with their established survival rates:

• Stage I - Divided into Stage IA (G1 or G2; T1a or T1b; N0; M0) and IB (G1 or G2; T2a; N0; M0), 5-year survival rates are estimated at 98.8%, showing that early recognition of the disease favors a very good prognosis.
• Stage II - Three substages are recognized - IIA (G1 or G2; T2b; N0; M0); IIB (G3 or G4; T1; N0; M0); and IIC (G3 or G4; T2a; N0; M0), with survival rates being around 82%.
• Stage III - G3 or G4; T2b; N0; M0 are typical features for this stage, which carries a somewhat poor prognosis, as 5-year survival is around 50%.
• Stage IV - G1-4, T1,2; N1; M0 or presence of distant metastases (M1) are markers of advanced disease and a very poor prognosis is expected, as 5-year survival is achieved in < 20% of patients recognized in this stage.

It can be concluded that factors such as observed mitotic rate, but also tumor size depth significantly impact the outcome and development of recurrent disease (which develops in approximately 6-9% of cases) [12] [13]. Even without tumor recurrence, reports show that 5-year survival rates across all stages are around 50% [14]. ULMS, in particular, has a poor prognosis, compared to NULMS, with studies reporting 5-year survival rates of 41.2% and 82.6%, respectively [1]. One of the reasons for such results may be the fact that the majority of ULMS patients are diagnosed when the disease has already advanced to later stages, primarily because little or no symptoms may be observed, while NULMS provokes an earlier appearance of symptoms [1].

LMS arises either from smooth muscle cells or mesenchymal stem cells that eventually differentiate into smooth muscle cells [4]. The exact cause remains unknown, but numerous mutations have been described. Defects in p53 tumor suppressor gene, retinoblastoma 1 (RB1) gene, phosphatase and tensin homolog (PTEN), FANCA, ATM, as well as increased expression of tyrosine kinase-like orphan receptor 2 (ROR2) have been documented [9], while additional genetic studies have shown that different subtypes of LMSs exist on the basis of their molecular structure [10]. In addition to genetic mutations, several pathological events have been associated with the development of sarcomas, most important being [11]:

• Viral infections - Human herpesvirus type 8 (HHV-8), the causative agent of Kaposi's sarcoma and Epstein-Barr (EBV) virus, the cause of infectious mononucleosis, have both shown carcinogenic properties, especially patients who suffer from chronic immunosuppression (HIV, transplant recipients).
• Ionizing radiation - various reports have shown a significantly increased risk of STS after exposure to high-dose radiation, but also cyclophosphamide (alkylating chemotherapeutic agent) and tamoxifen, which is frequently used for a treatment of breast cancer.
• Familial syndromes - Several hereditary syndromes, such as Li-Fraumeni syndrome, Rothmund-Thompson syndrome, neurofibromatosis, enchondromatosis, and retinoblastoma carry a much higher rate of sarcomas compared to the general population, especially in individuals with confirmed p53 mutations.

Other risk factors include a presence of diseases such as Diamond Blackfan anemia and Paget's disease, but also exposure to dioxin, chlorophenols and other organic solvents through industrial and medical occupations [11].

Epidemiology studies have shown that the incidence rate of LMS ranges between 0.5-1.8 per 100,000 individuals, depending on gender and ethnic background [3]. When it comes to ULMS, a significant predilection toward African American women was observed, with the majority of tumors appearing during childbearing age [3]. The fact that almost 80% of tumors express progesterone, estrogen and androgen receptors shows that a connection between hormonal changes during this age period and tumor growth may be present [3]. Other reports suggest that the overall incidence of NULMSs increases in older age and peaks around the seventh decade of life, like with all other soft tissue sarcomas [4]. By far, the most common site of LMS occurrence is the uterus and approximately 40% of all uterine sarcomas are LMSs [1]. Additional sites include the retroperitoneum and various parts of the abdominal cavity, whereas LMS arising in the extremities comprises approximately 10% of all STSs in adults [2]. Certain reports have estimated that LMS comprises approximately 1% of all uterine malignancies [3].

The pathogenesis model of LMS remains unclear. Several genetic mutations have been identified, however, most prominent ones being functional mutations of p53, one of the key tumor suppressor genes [6] [9]. The role of PRUNE gene in differentiation, invasiveness, and proliferation of neuroblastoma has been well-documented and its increased expression in LMS was established [5]. In fact, a correlation between high expression of PRUNE and both tumor size and overall survival has been made, suggesting that it plays an important role in tumorigenesis [5]. Additionally, the PI3K/AKT/mTOR pathway, which is activated by tyrosine kinases involved in signal transduction from the extracellular environment, was shown to be dysregulated through mutations of AKT or PTEN [6]. Once the tumor reaches an advanced stage of development, metastatic spread via hematogenous route occurs, most commonly to the lungs, the skin and the liver [4].

Current strategies for prevention do not exist, as the cause of tumorigenesis remains unknown.

Leiomyosarcoma (LMS) is a rare but very aggressive tumor that belongs to a large group of soft tissue sarcomas (STSs), comprising 24% of all tumors encompassed in this group [1] [2]. In theory, LMS can appear at any site in the body, but the most common sites are the retroperitoneum, upper and lower extremities (designated as non-uterine LMS or NULMS) and the uterus (ULMS) [1]. Large-scale reports have estimated that ULMS is responsible for approximately 1% of all uterine malignancies and a significant predilection toward women of African American ancestry was documented [3]. In fact, ULMS is the most common sarcoma of the uterus, but one of its main features is a very poor prognosis, especially if recognized in advanced stages of the disease, which is rather common [1]. This tumor is most prevalent in women of childbearing age, whereas older age is shown to be a risk factor for a development of LMS in sites other than the uterus [3] [4]. The pathogenesis remains unclear, but mutations of p53 tumor suppressor gene, prune homolog 2 (PRUNE) and the PI3K/AKT/mTOR pathway have been discovered [5] [6]. The prognosis depends on tumor staging, which is based on the degree of cellular differentiation, tumor size, depth of invasion and presence of dissemination into either lymph nodes or distant organs and survival rates range from 98% in initial stages to < 20% in advanced disease [7]. The clinical course of LMS is often insidious and little or no symptoms may be present. In ULMS, vaginal bleeding, nonspecific pain in the pelvic area and a palpable mass in the pelvis were reported as most frequent complaints [8]. On the other hand, local swelling is characteristic for NULMS [1] [8]. Unfortunately, many women are diagnosed with ULMS incidentally, during hysterectomy or myomectomy, primarily because nonspecific abdominal symptoms mask the true nature of the disease [1]. For these reasons, it is imperative to perform either computed tomography (CT) or magnetic resonance imaging (MRI) prior to surgery or during assessment for the mentioned complaints, in order to define the exact stage of the tumor (achieved only through biopsy and histopathology) and determine optimal therapy [8]. Wide excision surgery and adjunctive procedures (depending on the site of the tumor), together with chemotherapy, are main therapeutic modalities, but survival rates are still very poor, as median survival times are around 12-15 months, indicating the aggressive nature of this tumor [9]. One of the biggest concerns is that almost 90% of tumors are either moderate or high-grade [9], meaning that more needs to be done when it comes to early diagnosis so that better patient outcomes can be achieved.

Leiomyosarcoma (LMS) is an aggressive tumor that originates from smooth muscles and belongs to a large group of malignancies called soft tissue sarcomas (STSs). LMS most commonly develops in the uterus, but because of its origin, it may appear anywhere in the body. Approximately 0.5-1.8 per 100,000 individuals develop this tumor around the world and a significant predilection toward individuals of African American ancestry (especially women) has been observed. In terms of age, it is known that LMS of the uterus most commonly develops in women of childbearing age, while advanced age is a recognized risk factor for tumors that develop in other sites, most commonly the abdomen and the extremities. The cause and the mechanism of disease remain unclear, but several genetic mutations were established. LMS is characterized by an insidious onset and clinical presentation, since the majority of patients are diagnosed in advanced stages of the disease, suggesting a poor overall prognosis. Most common symptoms are vaginal bleeding, nonspecific pain in the abdomen and a palpable mass in the pelvis in the setting of LMS in the uterus, whereas local swelling of tissues surrounding the tumor may be present if this malignancy develops in other sites. The diagnosis is most often made during evaluation for other conditions or surgical procedures (such as hysterectomy), but if the physician is considering LMS in the differential diagnosis, computed tomography (CT scan) and magnetic resonance imaging (MRI) should be performed to assess the status of the organs and determine the stage of the tumor as well. Depending on the size of the tumor, a degree of invasion and findings obtained during biopsy, stages range from 1 (a minimally invasive tumor) to 4 (presence of distant metastases) may be confirmed. 5-year survival rates range from 98% in stage 1 to < 20% in stage 4, implying that early recognition of the disease is detrimental to achieving good patient outcomes. Treatment comprises surgery that aims to remove tumor tissue as much as possible and chemotherapy, mostly used for patients in advanced stages of the disease. The emphasis on early recognition should be strengthened because of the fact that only 30% of patients respond to chemotherapy and surgical management of a metastatic disease is extremely difficult.

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