Leiomyosarcoma (LMS) is one of the most aggressive forms of soft tissue cancer, arising from smooth muscle cells within the body.¹ Although tumours have a similar appearance under a microscope regardless of the location, there is substantial evidence that suggests that uterine and extra-uterine (outside the uterus) LMS are different diseases at a molecular level. 

Introduction

LMS is a rare but serious type of cancer that develops from smooth muscle cells, which help blood vessels contract and relax to support normal body functions. There are two types:

• Uterine LMS occurs within the uterus, affecting women 
• Extrauterine LMS occurs outside the uterus (e.g abdomen, blood vessels, other soft tissue areas) and can affect both men and women

For years, these two types of LMS were considered identical due to their structural similarities, but they are now recognised as distinct diseases. Some patients responded well to specific treatments while others had different outcomes even when the tumours looked the same under a microscope and were at the same stage. 

The breakthrough in medicine was made possible due to genetic sequencing technology. Scientists could finally look beyond what tumours looked like to instead examine their molecular differences by analysing their DNA, the proteins they produced, and how their genes were turned on and off. 

Histological and clinical characteristics

When LMS tissues are assessed under a microscope, they have the same distinctive features regardless of where the tumour grew. The cells are spindle-shaped, elongated, and they arrange in bundles that showcase their smooth muscle cell origin. In addition, certain histological stains can be used to assess the aggressiveness of the tumour. Historically, these two LMS locations of tumours were classified as the same disease due to their appearance, but in truth, they are very different.

Signs and symptoms of uterine LMS

Uterine LMS may go undetected, as symptoms can be analogous to non-cancerous growths. They usually look like fast-growing uterine fibroids, which are prevalent benign tumours. 

Symptoms associated with uterine LMS include:

• Heavy or irregular periods that worsen over time
• Pelvic pressure
• Pain that increases as the mass grows
• Fullness of the abdomen
• Increase in urinary frequency if the mass presses on the bladder

There are no imaging tests, whether CT, ultrasound, or MRI, that can easily distinguish between a benign fibroid and a malignant LMS before surgery. This issue can lead to false diagnoses and ineffective treatment. 

Signs and symptoms of extrauterine LMS

Tumours outside the uterus present themselves differently depending on their location. Common sites include:

• Abdominal tumours may grow silently before causing apparent symptoms 
• Blood vessel tumours may result in arm or leg swelling, and, in some cases, bleeding
• Limb tumours generally appear as painless lumps, often mistaken for harmless soft tissue growths

Different patterns of spreading

Understanding where and to what extent LMS tumours can spread is essential for accurate diagnosis and proper care. Uterine LMS tend to spread to the lungs first, whereas extrauterine tumours spread to multiple areas simultaneously and follow a different pattern. A portion of extrauterine tumours metastasise to the liver, while others primarily remain localised before spreading to further sites.

These differences provide the first signs of distinguishing between the two types of LMS. 

Molecular pathogenesis 

Understanding the diseases at a molecular level requires examining DNA damage that transforms normal cells into cancer cells. 

All LMS have the same fundamental genetic problems that distinguish them from normal cells, such as:

1. Tumour suppressor gene damage: These genes act as the cell’s natural brakes to prevent cancer. The TP53 gene is a well-known example; damage to it is typical and plays a significant role in many types of cancer²
2. Cell cycle control disruption: When genes that regulate the cell cycle are affected, cells deviate from their normal growth and division patterns. Instead of dying when damaged, they continue to multiply uncontrollably
3. Chromosomal abnormalities: extra or missing chromosomes can disturb the normal organisation of genetic material, causing unrestricted cell behaviour and tumour growth

Where location makes a difference

When scientists looked into the genetic damage in uterine vs extrauterine LMS, distinct patterns emerged:

Uterine-specific growth characteristics

• More damaged genes involved in hormone signalling
• Higher rates of mutation in DNA repair genes, especially ATRX³
• Certain chromosome loss patterns 
• Increased level of growth-promoting genes such as MYC⁴
• Low number of genetic mutations in comparison to extrauterine tumours

Extrauterine-specific growth characteristics:

• More mutations in genes that control cell metabolism and energy production
• Chromosome gains and losses
• More genetic mutations lead to more treatment resistance

These differences explain why the same chemotherapy drug may be effective for one person but not for another. 

Gene expression and epigenetic profiles

DNA provides the basic instruction manual for the functions of cells, and gene expression tells you about whether the instructions are being followed. 

Hormone receptor discovery

One of the most significant discoveries in LMS research involves the expression of hormone receptors on uterine tumours, which allow the binding of oestrogen and progesterone.⁵

This is important because the majority of uterine LMS have oestrogen receptors, and some have progesterone receptors; however, extrauterine LMS rarely express these receptors. This led to the use of hormone-blocking treatments.

Gene expression signatures

Researchers have also identified specific distinct patterns that occur when multiple genes work together, allowing for the differentiation between uterine and extrauterine tumours. These patterns reveal that there are:

• Metabolic differences: Tumours use energy in distinct ways based on their location
• Immune system interactions: differences in how tumours interact with or escape the immune system
• Growth factor dependencies: tumours depend on different growth signals to empower cell division

Epigenetic modifications

 The cells can also modify how the genes are expressed through chemical signals. This doesn't alter the DNA sequence, but it indicates whether it is on or off. It is seen by:

• DNA methylation patterns: chemical changes that silence genes 
• Histone modifications: changes in the proteins that package DNA
• Chromatin accessibility

Proteomics and biomarker discovery

Genes provide the basic instructions, but proteins are responsible for the main work. Therefore, analysing the work proteins do gives further information about the differences between uterine and extrauterine LMS. The proteins that can be looked into are:

• Hormone-related proteins
• DNA repair proteins
• Growth factor proteins
• Metabolic enzymes

Looking into biomarkers

Several biomarkers are available for use in the clinical setting to distinguish between uterine and extrauterine LMS. These include:

• Hormone receptor testing
• IGF1R
• PARP1 protein⁶
• mTOR pathway proteins

Metabolic protein differences:

As both uterine and extrauterine tumours have different metabolic needs, specific metabolic processes can also be assessed:

• Glucose metabolism
• Fatty acid metabolism and extrauterine tumours show higher dependence on fat metabolism
• Mitochondrial proteins

Diagnosis and treatment

Various diagnostic and treatment plans can be followed. 

The first issue depends on distinguishing between malignant LMS and benign fibroids. This can be done through:

• Blood-based biomarkers
• Advanced imaging combined with biomarkers 
• Molecular analysis of small biopsy samples

There are ways of classifying tumours, but molecular testing is used to determine where they originated from, whether they resemble other tumours, and to predict how aggressive they are likely to be.

As a result, there are now multiple treatment approaches:

• Hormone therapy via:
  •  Oestrogen-blocking drugs
  • Oestrogen receptor degraders

These factors together help lower toxicity levels and reduce the likelihood of side effects, as well as potential long-term disease control. 

Current research and future directions

This field is progressing fast, and new treatments are emerging as we speak. Some of the latest technologies that exist or are emerging are:

• Single cell analysis:
  • Investigating stem cells, resistance mechanisms, and heterogeneity of individual tumour cells 
• Artificial intelligence:
  • Pattern recognition, drug discovery, treatment optimisation
• Liquid biopsies:
  • A blood test that can look into the tumour DNA 
• Immunotherapy-based:
  • CAR-T cell therapy, engineering a patient's immune cells 
  • Cancer vaccines

Conclusion

The molecular differences unveiled within the uterine and extrauterine LMS  significantly changed how scientists understand and treat these cancers. This disease, once considered a single entity in different locations, is now easily depicted as two distinct diseases occurring in various locations that happen to share a similar microscopic appearance.