Introduction

Liposarcomas – think of them as the commonest of the rare. Imagine looking for jewels in a sandpit. The likelihood of finding them is already minimal, and then you find an emerald or two, but somewhere along the line, you just keep finding diamonds. Liposarcomas are those diamonds in the sarcoma family, rare in the grand scheme of things but more common than the rest.

So what is a sarcoma, and how do we connect it to liposarcomas? Sarcomas are tumours that develop from bone and soft tissue, while liposarcomas are a type of soft tissue sarcoma that are found in the soft tissue as well as the extremities. They develop from the fat tissuemost often in the retroperitoneum as well as in the extremities. like arms and legs. They represent one of the most common subtypes of soft tissue sarcomas in adults and account for approximately 13–20% of cases.¹ 

An accurate understanding of the pathophysiology of these tumours, how they develop, and their different histologic subtypes, as well as the distinct biological behaviour and genetic characteristics of these subtypes, could influence the treatment responses.² In this article, we will explore the pathophysiology and histological subtypes of liposarcoma.³

Pathophysiology of liposarcoma

Understanding the pathophysiology of a disease will always bring us one step closer to finding treatments for these diseases. Liposarcoma can have several pathways of development. 

Cellular origin

Liposarcomas develop from mesenchymal stem cells that have the capacity for adipogenic differentiation. To understand this further, you must first understand that mesenchymal stem cells are simply cells that can transform into other cells and tissues. In relation to adipocytes, or fat cells, some groups of mesenchymal stem cells have the ability to transform into adipocytes; however, in liposarcoma, these cells do not become mature adipocytes due to certain oncogenic alterations.⁴ 

Genetic and molecular pathways

Chromosomal aberrations

Each histopathological subtype of liposarcoma is associated with specific chromosomal aberrations. Well-differentiated (WDLPS) (a slow-growing type of liposarcoma where fat cells look almost normal) and dedifferentiated liposarcomas (DDLPS) (a more aggressive form that develops from well-differentiated liposarcoma) have amplification of the chromosome region 12q13-15 (an abnormal increase in copies of specific DNA segments on chromosome 12).⁵

Myxoid liposarcomas (MLPS) have a translocation in certain chromosomes, t(12;16)(q13;p11), or a gene fusion protein like FUS-DDIT3 (an abnormal protein formed when two genes join together).^5,6 This protein is produced as a result of chromosomal translocation and disrupts the normal maturation of fat cells (adipocytes).

 Pleomorphic liposarcoma (PLPS) (a rare, aggressive subtype with highly abnormal cells) often displays frequent mutations in TP53, RB1, and NF1 genes (genes that normally help control cell growth and prevent cancer).⁶ 

 Histological subtypes

The WHO classification of liposarcomas divides them into four main histological subtypes.

 Well-differentiated liposarcoma (WDLP)

Also known as an atypical lipomatous tumour, it is an indolent (slow-growing or inactive) tumour that presents as a growing mass made up of mature adipocytes with fibrous septa and scattered atypical stromal cells (abnormal supporting tissue cells). 

It is caused by the chromosomal amplification (increase in the number of DNA copies) of the chromosomes 12q13-15. This activity will, in turn, go on to amplify oncogenes, which are something like cancer-coding genes, MDM2, CDK4, and HMGA2.

It is more commonly seen to affect the extremities and retroperitoneum. It is also quite aggressive locally, with a high recurrence rate and little to no metastatic risk.^1,4 

Dedifferentiated liposarcoma

It has similar characteristics to WDLPS as it originates from WDLPS. It has the same chromosomal amplification on the same chromosomes as WDLPS. It has a higher potential for local recurrence and metastasis.⁵ It is a high-grade tumour. Together, WDLPS and DDLPS represent 60% of liposarcomas coexisting in the retroperitoneum and the extremities as well. 

 Myxoid liposarcoma round cell liposarcoma

Occurs due to a translocation in chromosomes t(12:16)(q13:p11); as a result, the formation of a fusion protein (an abnormal protein formed when two genes join together) is induced. The FUS and DDIT3 genes fuse together and form the FUS-DDIT3 fusion protein, which will go on to encourage the growth of cancerous cells.

Myxoid liposarcomas contain a myxoid stroma (a jelly-like connective tissue), highly branching capillaries (tiny, branching blood vessels), and lipoblasts (immature fat cells that can become cancerous). It is an intermediate-grade malignancy with unusual metastases to bone and soft tissue.⁶

Round cell liposarcomas are high-grade variants that have dense round cells. It has a lower chance of recovery or survival and increased metastatic potential.⁶

Pleomorphic liposarcoma

This is also a high-grade tumour, with aggressive behaviour and a poor survival rate.⁵

It has diverse genomic changes with frequent mutation of the TP53, RB1, and NF1 genes, which go on to cause the dysregulation of the tumour-suppressing pathway. 

Diagnostic approach

Liposarcoma can be diagnosed through a few methods:

• Imaging 
• Histopathology and Immunohistochemistry 
• Molecular and Cytogenetic Testing

While these methods may not be conclusive, using MRI or CT, especially, is a good way of narrowing down the results. 

Imaging

 MRI and CT help identify the tumour's composition.

WDLPS

 In plain radiography, there is soft tissue calcification (hard mineral deposits in the tissue), while MRI helps distinguish the internal structure and fat composition of the tumour. They also show the irregular septa (uneven internal partitions within the tumour). 

MLPS 

MLPS are best viewed using CT scans, especially chest, abdomen, or pelvic CT scans, and this is because this form of liposarcoma tends to metastasise or spread to the lungs, abdomen, and spine. It shows soft tissue within a fat mass as well as the invasion of mediastinal structures.

Histopathology and immunohistochemistry

With this diagnostic method, identifying lipoblasts (immature fat cells that can turn cancerous), atypia (abnormal cell shape or size), and architectural patterns of each subtype will aid diagnosis. The immunohistochemistry for the genes MDM2 and CDK4 (genes linked to tumour growth) will greatly help in distinguishing WDLPS and DDLPS from benign lipomas (non-cancerous fatty tumours).⁵

 Molecular and cytogenetic testing

With molecular and cytogenetic testing, FISH (Fluorescence In Situ Hybridisation—a test to find specific DNA sequences in cells) or PCR (Polymerase Chain Reaction—a technique to detect or amplify genetic material) is useful for testing MDM2CDK4 amplification (increase in the number of copies of these cancer-related genes), which allows us to differentiate between WDLPS and DDLPS.⁶

Clinical implications of subtype classification

Prognostic significance and influence on treatment decision

The different histologic subtypes that have been discussed play a role in the patient's recovery; some have better outcomes than others: ^1,5,6

• WDLPS: Patients with this form of liposarcoma have an excellent prognosis with appropriate excision of the tumour and have a higher chance of survival 
• DDLPS and PLPS: Dedifferentiated and Pleomorphic Liposarcomas have a poorer prognosis because of the higher metastatic potential 
• MLPS: It is an intermediate-grade tumour but has the potential to become a high-grade tumour, so patients require close monitoring

With the following information and the patient's total history, the physician is able to make a treatment plan that would be beneficial to the patient in the short term and in the long run. 

While surgical excision, which is the total removal of the tumour, is the gold standard of treatment for all subtypes, with hopes to resect the tumour totally, other treatment methods are useful.⁷ 

 Radiation therapy is often used in extremity tumours to reduce recurrence.² While chemotherapy is effective in MLPS, it has a limited efficiency in WDLPSDDLPS.

Summary

While liposarcomas are malignant tumours that are derived from adipocytes, popularly known as fat cells, these malignancies have a variety of biological differences; they are divided into subtypes that have their differing pathophysiology, genetic alterations, and histological features.

Each of these factors will determine the clinical outcomes and treatment. While treatment at this point depends mainly on surgery and chemotherapy or radiation for the more aggressive subtypes, the accuracy of the classification using histopathology, imaging, and molecular tools is essential for optimal patient care, as it will lend a hand to research targeting molecular targets of these individual subtypes.