A world health organisation perspective on liposarcoma: An overview of subtypes and treatment

Introduction

Liposarcoma is a type of cancer that grows from fat cells and is very rare. This disease can manifest in various locations throughout the body, with a higher prevalence observed on the torso, limbs, and within the retroperitoneal space, which is situated at the back of the abdomen, behind the peritoneum(the lining of the abdominal cavity). Liposarcoma represents a specific type of soft-tissue sarcoma, a general classification for cancers that start in soft tissues. This condition mainly occurs in older adults and is quite uncommon in individuals younger than 30 years old.

Four primary classifications of liposarcoma include:

• Well-differentiated liposarcoma
• Dedifferentiated liposarcoma
• Myxoid liposarcoma
• Pleomorphic liposarcoma

The approach to managing liposarcoma varies according to its subtype, but generally includes surgical intervention to remove the tumour. This may be accompanied by radiotherapy or chemotherapy to eliminate cancer cells in areas that are next to each other.¹

The underlying cause of liposarcoma is yet unknown. Although the American Cancer Society has found certain risk factors for soft tissue sarcomas, e.g, radiation, damage to the lymphatic system, and exposure to toxic chemicals, can lead to the disease. However, a few cases have been reported in which patients show no obvious risk factor for the disease. The precise genetic change causing these cancers is still under research.²

History and physical 

The history and manifestation of liposarcoma depend on the tumour's location. Liposarcoma most frequently occurs in the extremities(arms and legs), with the retroperitoneum being the next most common site, and it is least often found in the oesophagus (food pipe). Myxoid liposarcoma in the extremities manifests as a deep-seated mass in the lower limb. Reports detailing instances of primary subcutaneous masses have also been documented. The majority of individuals diagnosed with liposarcoma do not exhibit any symptoms. Symptoms occur only when the tumour expands sufficiently to impact adjacent structures through mass effect. The symptoms observed may consist of pain or tenderness, swelling, or a decrease in function that happens from the compression of neurovascular bundles. Additional symptoms noted are pins and needles(paresthesia), varicose veins, fatigue, weight loss, nausea, and vomiting. Liposarcoma in the retroperitoneum can also be asymptomatic(have no symptoms) and remain undiagnosed until advanced stages, because of the subtlety of its symptoms. Nonspecific abdominal symptoms represent the sole recognised indicators, with the tumour frequently reaching several pounds or kilogrammes before diagnosis. 

During physical examination, liposarcoma presents as a non-tender lump that can be felt. Individuals with retroperitoneal disease might exhibit widespread abdominal swelling. 

The most common place for liposarcoma is the upper oesophagus, which accounts for the majority of the symptoms linked to this tumour (neoplasm). Individuals typically exhibit a gradual onset of difficulty swallowing and a decrease in body weight. In certain instances, when the tumour is of considerable size, patients may also have a polyp or lump in the mouth. Food may be vomited back into the mouth. Symptoms such as shortness of breath and cough from the narrowing of the trachea (windpipe) are relatively uncommon ². 

WHO classification of liposarcoma

Well-differentiated liposarcoma (WDLPS) / atypical lipomatous tumour (ALT)

WDLPS represents the major subtype of liposarcoma, accounting for around 40–60% of cases.^2,3,4,5 This condition generally impacts people between the ages of 50 and 70, showing no preference for either gender ⁵. It can happen in the extremities (referred to as “ALT”), torso, and retroperitoneum, with rare cases around the testicles, the space between the lungs, and the head and neck.^5,6,7 WDLPS presents as slow-growing, painless tumours that can grow into nearby tissues but rarely spread to other parts of the body.

Essential clinical characteristics:^3,4,5,6,7

• The likelihood of the tumour recurring is high in  L deep-seated tumours, reaching as high as 50% in retroperitoneal lesions and ranging from 30% to 50% overall
• Transformation risk: In approximately 10% of cases, there is a risk of the tumour turning into a more aggressive version; retroperitoneal WDLPS presents a higher risk (over 17%) compared to ALT (less than 7%), with an average time for this change to happen ranging from 7 to 9 years
• Most people (nearly 100%) are still alive five years after diagnosis, and about 87% make it to ten years

The location of the tumour can have a negative effect on the outlook because it might make it harder to remove with surgery and could lead to problems later on. 

Dedifferentiated liposarcoma (DDLPS)

DDLPS can either develop on its own or grow from 

WDLPS.  It makes up approximately 30–37% of retroperitoneal LPS and around 18–20% of all LPS cases.^3,4 It generally affects people between the ages of 60 and 70 and is just as common in men as in women.

Key features:^3,4,5,8,9

• Under the microscope, this tumour consists of mature fat cells (adipocytes) and non-fatty cells
• How it acts:
  • Comes back locally: In about 40–80% of cases, the tumour can return in the same area after treatment 
  • In 15-30% of cases, the tumour can spread to other parts of the body, most often the lungs 
  • About 44–55% of people are still alive five years after diagnosis. More aggressive tumours (grade 3) have a lower survival rate of around 41%
• Genetics: In 90% of these cases, the is an increase in gene expression of certain genes( MDM2/CDK4) often linked with another protein known as HMGA2⁴  

Diagnosis and treatment^3,6

• To confirm the diagnosis, the tumour must be closely examined under a microscope. Special lab tests like FISH are used to look at certain proteins or genetic markers
• Surgery is the main treatment for this subtype of LPS. The aim is to remove the tumour completely; however, tumours in the retroperitoneal area can make it hard to get all the tumour out. 
• Standard chemotherapy and radiotherapy do not work as well for this type of tumour 
• Medicines like anthracyclines, trabectedin, and eribulin can be given if the tumour can’t be removed or has spread to other parts of the body  

Pleomorphic LPS 

PLPS is the rarest subtype of tumour (5–10 % of LPS cases are PLPS). It is most commonly found in the arms, legs, and/or body, with occasional cases in the retroperitoneum. It mostly affects people over the age of 50 and is more common in females. This type of tumour is very aggressive and grows very quickly^,5,11.

Outlook and characteristics⁶

• This type of tumour is aggressive and has an increased risk of spreading to the lungs early.  It happens in 30–50% of cases
• The average survival rate isn’t very good, with only  29% of people still alive after five years 
• The main treatment is surgery to remove the tumour, and alternative therapies like chemotherapy do not have much effect on the tumour 

Myxoid LPS 

MLPS accounts for approximately 30% of liposarcomas. It mainly affects people between the ages of 35 and 55. Tumours can develop in the thigh or the upper parts of the arms and legs (proximal extremities). Under a microscope, this type of tumour has a gelatinous-like tissue (known as a myxoid stroma) with immature fat cells (known as lipoblasts)^5,11.

Important facts³

• MLPS can spread to the lungs, retroperitoneum, bone, serosa, and, sometimes, the gastrointestinal tract (digestive tract)
• The tumours have round cells that make them behave more aggressively and spread faster
• MLPS responds well to radiotherapy and chemotherapy, which can help with effective treatment when caught early

Molecular and genetic insights

Liposarcomas exhibit several subtypes-specific to genomic changes. The most common defect in WDLPS and DDLPS is amplification of chromosome 12q13-15, which causes overexpression of oncogenes including MDM2, CDK4, YEATS4, CPM, TSPAN31, and FSR2. There are extra rings and giant rod chromosomes that carry these genes most of the time. Besides that, frequencies in DDLPS are amplitudes on 1p32 (involving JUN) and 6q23 (involving MAP3K5/ASK1), which help to explain poor differentiation and aggressive behaviour. Further contributing to tumour progression are documented tumour suppressor losses impacting RB1, ATM, CHEK1, RunX3, and ARID1A.

Pathognomonic gene fusions—FUS-DDIT3 or EWSR1-DDIT3—arising from t(12;16)(q13;p11) or t(12;22)(q13;q12) respectively define MLPS. By overexpression of CHOP, these fusions induce transcriptional dysregulation and inhibit adipocyte development, therefore offering diagnostic value via RNA sequencing or CHOP immunohistochemistry.

PLPS shows quite complicated, chaotic karyotypes devoid of pathogenic genetic events. Common are frequent mutations in TP53, deletions in RB1, and loss of NF1. Furthermore, involvement in cancer could be epigenetic inactivation of p14ARF.

These molecular profiles not only support correct diagnosis but also show possible treatment targets. Agents under research include medicines aiming at the FGFR/FSR2, DDR2, and ERBB3 pathways, as well as CDK4 inhibitors and MDM2 antagonists.⁹

FAQ’s 

Who will treat me?

People diagnosed with sarcoma would be directed to a specialised team for accurate diagnosis and appropriate treatment.

A team of specialists known as a multidisciplinary team (MDT) will oversee your case. Your multidisciplinary team will consist of your primary contact or sarcoma clinical nurse specialist, surgeon, and other healthcare professionals engaged in your treatment. They will assist you during your treatment journey to guarantee you receive the appropriate care at the right time.¹

What happens after the treatment?

Following your treatment, you will be scheduled for routine follow-up appointments over the next few years. A follow-up schedule will be provided to you by your clinical nurse specialist specialising in sarcoma. The standard procedure will contain a thorough assessment to check for any indications of the sarcoma's return. This may involve an MRI or ultrasound if deemed necessary following the examination. Additionally, a chest x-ray may be performed to exclude the possibility of secondary cancers in the lungs, as sarcoma cancer has the potential to return in the same region following the treatment of a prior tumour.¹

Conclusion

Liposarcomas represent a diverse group of soft tissue sarcomas, and the WHO classification system plays a critical role in distinguishing their subtypes by looking at the cells and their genetic features. Well-differentiated liposarcoma (WDLPS/ALT) is the most common and typically has a favourable prognosis, though it can change into the more aggressive DDLPS. Myxoid liposarcoma (MLPS)  has a specific way of spreading but responds well to radiation and chemotherapy, while pleomorphic liposarcoma (PLPS) remains the most aggressive subtype with the poorest prognosis.

 To make the right diagnosis and choose the best treatment, doctors use lab tests that look at the tumour’s appearance under a microscope and check for specific genetic changes, like MDM2, CDK4, or certain fusion genes.

The main treatment for all types is surgery, but other treatments like chemotherapy or radiation may help depending on the type. Understanding the biological and clinical distinctions among liposarcoma subtypes is key to improving patient outcomes and guiding future therapeutic strategies.