Leiomyosarcoma (LMS)

Leiomyosarcoma (LMS) is a common subtype of soft-tissue sarcoma (STS) and is referred to as a malignant smooth muscle tumor.¹ LMS constitutes approximately 7% of all STSs.² It has been categorized into site-specific subgroups owing to remarkable clinical and biological dissimilarity. STSs comprise a group of rare, heterogeneous tumors showing variable mesenchymal differentiation, with >70 histological subtypes. LMS arises mainly from the embryonic mesoderm with some contribution from the neuroectoderm.³ This type of cancer is highly unpredictable and resistant and can recur in the later stages of life.¹ 

 LMS can arise in any organ type.¹ Although these cells are present everywhere, LMS shows a predilection for soft tissues and abdominopelvic organs (abdomen, retroperitoneum, large blood vessels, gastrointestinal tract, and uterus) compared to extremities, where it comprises 10–15% of all extremity-associated sarcomas.^1–3 Together with unspecified sarcomas and liposarcomas, LMS is the most common subtype of STS.⁴ 

LMSs originating in the retroperitoneum and blood vessels are more common in women, while LMSs originating in both cutaneous and non-cutaneous soft tissue are more commonly found in men.⁵ 

Uterine sarcomas comprise about 3–7% of all uterine malignancies;⁶ of these, LMS is the most common subtype, consisting of up to 80% of uterine sarcomas when malignant mixed Müllerian tumors are excluded.⁷ 

The exact pathophysiology of LMS is not clearly understood.⁷ However, the diverse genomic profile of these tumors often exhibits chromosomal losses that involve hyperactivation of cell proliferation pathways or tumor suppressor genes.⁷ 

A query of The Cancer Genome Atlas (TCGA) showed that out of 98 tumor samples profiled, the most frequently mutated genes were: TP53 (51%), RB1 (15.3%), and ATRX (13.3%).⁷ TP53 was also the most commonly mutated gene in 84 samples of LMS as listed in the COSMIC database at 24%, followed by MED12 (7%) and KRAS (7%).⁷ The discrepancies in the frequency of gene mutations observed may be accounted for by the absence of either database differentiating uterine LMS from extra‐uterine sites.⁷ In addition, mutations in genes of a number of other factors have been proposed by retrospective studies to have a possible role in LMS carcinogenesis. These include proteins involved in:^7,10 

• Apoptosis/cell survival (p53, MDM2, Bcl‐2) 
• Cell-cycle regulation (Rb, p16), invasion (MMP-2, MMP-9) 
• Angiogenesis/growth factor signaling (VEGF, PDGFR, PDGF)

An integrative genomic and transcriptomic analysis of LMS provides potentially actionable genetic features:¹¹  

• Universal biallelic inactivation of TP53 and RB1: biallelic inactivation results from mutation of one allele and then by gene deletion of the remaining allele. This occurs in more than 90% of cases, establishing this as a unifying feature of LMS development, in keeping with previous studies 
• BRCAness: defined as alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures 
• Alternative lengthening of telomeres (ALT): ALT is found in 78% of cases and the identification of recurrent alterations in telomere maintenance genes, such as ATRX, RBL2, and SP100, provides insight into the genetic basis of this mechanism 

Overarchingly, LMS is driven by a perturbed tumor suppressor network which gives rise to whole-genome duplication (WGD) and large-scale genomic instability accelerating tumor evolution, in the majority of cases.¹¹ 

However, the mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, remain to be deciphered.¹ 

An analysis of incidence patterns of STCs reveals that LMS occurs with a frequency of 1.2 cases per 100,000 person-years.¹² The annual incidence of LMS is less than 2 women per 100,000 based on the population‐based Surveillance, Epidemiology and End Results (SEER) database from the National Cancer Institute.¹³ Approximately 4,000 patients are diagnosed with LMS annually in the United States.¹⁴ 

As in STSs in general, the overall incidence of LMS increases with age and peaks in people’s 70s.⁵ Uterine LMS, however, appears earlier, presenting from the 30s into old age, being most prevalent in perimenopausal women – typically in their 50s.⁵ The incidence according to sex depends on tumor location, with a greater predominance of women among patients with retroperitoneal and inferior vena cava LMS. In contrast, men show a mild prevalence among patients with noncutaneous soft tissue sites and cutaneous LMS.⁵ 

Clinical presentation of LMS, as with other STSs, is often associated with non-specific symptoms caused by the displacement of structures in specific anatomic locations of the primary tumor and its metastases, rather than invasion.⁵ 

Generally, if the tumor is cutaneous, it appears as solitary, small nodules. LMS may arise near medium to large veins if the tumor is deep.¹⁵ In rare cases, LMS can be found near large, vascularized structures. In these cases, the tumor obstructs the vessel, leading to decreased blood flow.¹⁵ This occurs most frequently in the pulmonary artery.¹⁵  

As LMS is commonly found in the abdominopelvic organs, patients with uterine LMS may present with abnormal uterine bleeding or abnormal uterine growth.^3,7 

There is no specific laboratory or radiographic test that can help in the diagnosis of LMS.³ 

Morphologic diagnosis based on microscopic examination remains the gold standard. Other testing that supports this means of diagnosis includes immunohistochemistry (IHC), classical cytogenetics, and molecular testing.³ IHC is particularly useful in the diagnostic process.³ 

Overlapping morphologic features of benign and borderline malignant smooth muscle neoplasms further complicate the diagnostic process.¹⁶ Commonly overlapping conditions include:³ 

• Meningioma 
• Gastrointestinal stromal tumors  
• Leiomyoma: IHC can help to differentiate LMS from leiomyoma 
• Dedifferentiated liposarcoma 
• Endometrial stromal sarcoma 
• Smooth muscle tumors of uncertain malignant potential 
• Inflammatory myofibroblastic tumor 
• Perivascular epithelioid cell tumor 

Alongside IHC, imaging modalities are useful in the diagnosis of LMS and can inform staging.³ These include ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI).^3,7 CT favored for imaging retroperitoneal and visceral lesions; MRI is better at evaluating tumors arising in the extremities and head and neck.³ On ultrasound, LMSs may appear as large heterogeneous masses with areas of central vascularity or necrosis.⁷ 

Of the similarly presenting conditions, CT, MRI, and ultrasound can be particularly useful for distinguishing between LMS and leiomyoma.¹⁷ Given that leiomyomas require minimally invasive treatment to manage, it is particularly important to distinguish them from LMSs at the preoperative stage.¹⁷ Moreover, the misdiagnosis of an LMS for a benign leiomyoma could result in treatment delays and greater morbidity, given its poor prognosis and high risk of local recurrence and metastasis.¹⁷

In patients diagnosed with LMS, histologic grade, tumor size, and tumor depth are the three most important prognostic factors.³ Tumor depth is a strong prognostic factor for disease recurrence and mortality, with deep tumors having a worse outcome.¹⁸  

The heterogeneity of sarcomas is significant, with at least 50 different histologic subtypes, all of which have distinct biologic behavior and therapy response.¹⁸ 

For prognostic and treatment purposes, soft tissue LMS has been subdivided into 3 groups: somatic soft tissue LMS, cutaneous LMS, and LMS of vascular origin.¹⁹ 

An analysis of data on 1,775 patients with high-grade malignant soft tissue tumors shows a low rate of survival for patients with LMS.²⁰ Moreover, the Musculoskeletal Tumor Society (MSTS) stage, the presence of metastases, and the size of the primary lesion are closely and statistically related to patient death at a mean of 3 years after discovery.²⁰ However, in patients with MSTS stages 1 or 2 (non-metastatic), the survival rate is improved.²⁰ In addition, the survival rate is dependent on the tumor site; a retrospective study of 29 consecutive cases of histologically proven soft tissue LMS found the 5-year survival of the following regions:¹⁹ 

• Upper limbs: 50% 
• Lower limbs: 23% 
• Trunk wall: 29% 

LMS of vascular origins display a similarly poor course, with 5-year disease-specific survival of 65% and the 5-year recurrence-free survival of 35%.²¹ In patients with LMS of cutaneous origins, studies show that, like soft tissue LMS, several factors are correlated to prognosis. These include tumor size, high mitotic rate, presence, or absence of necrosis, and intratumoral vascular invasion.²² The survival rate for tumors smaller than 2 cm is found to be 95%, while in tumors that exceeded 5 cm, survival drops to 30%.²²

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