Introduction

Nodular fasciitis (NF) is an uncommon, non-cancerous tumour in most cases. It can sometimes be mistaken for a malignant sarcoma because of its appearance and how quickly it grows. In 2011, a study found that over 90% of NF cases showed the joining of the MYH9 and USP6 genes, which increased the amount of the USP6 protein.¹ This contributes significantly to the development of NF. Other studies have supported this finding, although how USP6 leads to tumour development is not fully understood.^{2, 3} USP6 is involved in key cellular proliferation pathways, but too much of the protein can over-a0ctivate signalling, potentially leading to tumour development.^{4, 5, 6}

What is NF?

NF refers to inflammation of the fascia, the connective tissue that surrounds bones, organs, muscles and blood vessels, providing them with structural support. NF was originally referred to as ‘pseudosarcomatous fasciitis’ because it resembled sarcoma.⁷ This condition typically affects those aged 20-40 years old, although paediatric cases have been reported.

Types of NF

As well as affecting the fascia, NF can be classified as being:

• Intramuscular: inside the muscle
• Intermuscular: between muscles
• Intravascular: the tumour forms near blood vessels 
• Dermal: the lump is just beneath the top layer of skin, in the dermis

Diagram illustrating the different elements within the dermis and epidermis of the skin. Source: Wikimedia Commons by Cancer Research UK

Symptoms associated with NF

Patients typically present with a lump beneath the skin that has been rapidly growing. 4 in 10 adults with this condition see a tumour on the forearm. In children, the tumour is commonly found in the head or neck. However, this tumour can appear anywhere in the body, including:

• Legs
• Torso
• Upper arm
• Chest
• Back
• Breast

The lump may be:

• Firm to the touch
• Rubbery
• Tender
• Painful, (although not common)
• Solid
• Usually less than 4 cm in diameter, but cases have been reported where it is much larger

In some rare cases, the tumour can push against nerves and can result in:

• Temporary paralysis
• A tingling sensation
• Numbness in the body part affected by the tumour

Genetic component

Before discussing the genomic influence on NF, it’s important to understand some basic concepts. Within each cell of our body, we have 23 pairs of chromosomes, made up of DNA. Collectively, these make up our genome. A gene refers to a sequence of DNA along the chromosome and, when expressed, can produce a protein. This process of gene expression involves converting the DNA sequence into RNA, which is then used to make the protein. Because genes and their respective proteins often share the same name, italics are used to indicate the gene.

Schematic showing genes along a chromosome. Made in Biorender by Dania Salim.

Each gene contains a promoter, which is connected to the coding region. As the name suggests, the coding region contains the instructions to produce the protein. The promoter acts as a control switch, deciding how much protein is made. Some promoters are ‘stronger’ than others, enabling greater expression of their genes.

When a cell divides, the DNA gets copied so that each resulting cell has its own copy. Sometimes, a rearrangement known as translocation can occur, where a gene moves its position within the same chromosome (intrachromosomal) or between different chromosomes (interchromosomal). 

Image showing an example of interchromosomal translocation in Burkitt’s Lymphoma. Modified from Wikimedia Commons. The image’s author is unknown.

When a gene translocates across the genome, two genes can join together. Translocation can ‘plugin’ different promoters and coding regions, giving different gene expression levels. If the promoter of one gene fuses with the coding region of another gene, and the new promoter is stronger than that of the original gene, this can increase the protein production from the second gene.

USP6 and MYH9

Ubiquitin is a protein that can be attached, or ‘tagged’  to any other protein in the cell. It signals that the ‘tagged’ protein needs to be broken down as it’s no longer needed.

USP6, which stands for ubiquitin-specific peptidase 6, does the opposite, removing this ubiquitin tag. This can help the movement of key molecules across the cell, known as intracellular trafficking, as known as processes like inflammation.⁸

USP6 shows low expression levels in most cells, except for in the testes. However, no major difference is observed between the number of males and females who develop this condition.⁹

MYH9 is a non-muscular myosin that forms part of the cytoskeleton to support the cell structure. This gene is expressed everywhere in the body because it is a key to structural integrity.

Schematic showing the cytoskeleton within a general animal cell. Source: Wikimedia Commons by Ilse Yohn.

A common finding in cases of NF is high amounts of the USP6 protein compared to other tissues.^{1, 3, 10} A recent study has also reported that ‘younger’ cases of NF have increased expression of the USP6 gene than older cases, which may explain why the tumour often goes away on its own.¹⁰ Research has shown that over 90% of NF cases show the USP6 gene moving across the genome.^{1, 2, 3}

Over 65% of cases also involve the USP6 gene joining the MYH9 gene.^{1, 2, 3} Research has consistently found that the promoter for MYH9 is fused to the coding region of USP6, which enables the overexpression of the USP6 protein.

Since MYH9 is expressed everywhere across the body, its promoter is designed to constantly produce small amounts of the product of the gene attached to it. Since the USP6 protein is produced in tiny amounts throughout the body, even the smallest increase in USP6 expression can likely develop into NF. 

It might be tempting to think that the MYH9-USP6 gene fusion leads to NF. However, other genes combined with USP6 have been studied, and all showed their promoter attached to the USP6 coding region.

When the authors of this study grafted cells expressing high levels of the USP6 protein into mice, they saw the development of a tumour similar to that in NF.

Both of these results indicate that it’s the overexpression of the USP6 gene, rather than the gene fusion itself, which is the key player in the development of NF. It is also interesting to note that the authors did not see a case of MYH9 being re-arranged across the genome unless USP6 was too.

Molecular pathways

It is still unclear how increased expression of USP6 manifests in the development of NF. However, several studies have found the USP6 protein to be involved in key cellular pathways which regulate cell survival and proliferation^{4, 5, 6, 11}

A study from 2016 proposed that USP6 removes the ubiquitin tag from Jak1, enabling the activation of the STAT3 protein.⁴ The overactivation of this pathway enables excess cell survival and proliferation, which may explain the growth of the NF tumour.¹² When the activity of both proteins was inhibited, they saw decreased tumour growth.

Another study suggests that USP6 is involved in the Wnt/ꞵ-catenin signalling pathway, which can contribute to tumour development when overactive.^{6, 13} USP6 increases the number of Wnt receptors in the cell membrane, increasing the rate of cellular proliferation through this pathway.¹³ USP6 also prevents the removal of the Wnt receptors from the membrane, which would otherwise reduce Wnt signalling.⁶ When this pathway was inhibited, the authors noted a decrease in tumour size.

USP6 has also been shown to bind the Arf6 protein, a key player in intracellular trafficking. Arf6 can interact with the MAPK1/ERK pathway, which is involved in many cellular processes, including proliferation, movement and cell death.¹⁴ It has been suggested that Arf6 can stimulate the Wnt pathway by using the MAPK/ERK pathway, which may be another way in which the tumour can begin to grow in the body.¹⁵

Diagnosis

It can be difficult to tell the difference between NF and a sarcoma visually, so a biopsy is typically required. This may be a needle biopsy (wherein a needle is used to draw cells or part of the tissue for imaging) or an excisional biopsy (wherein the entire lump is removed).

Once this has been done, a histopathologist can take a look at the sample using a microscope and may be able to determine whether it is NF. An MRI or ultrasound can also be considered to assess the growth.

In recent years, the WHO has pushed for the use of genetic testing to detect USP6 gene re-arrangement.¹⁰ This can help distinguish NF from other tumours, such as sarcomas, where USP6 translocation is not seen.⁴

It’s important to see a doctor, even if you think it might be NF. Although extremely rare, NF can become cancerous. 

Treatment

Since the tumour often goes away on its own within 3 months, medical practitioners can take a wait-and-watch approach. In some cases, patients may require surgery to remove the growth that rarely returns after complete removal. In cases of NF on the face where the growth can return after surgery, corticosteroids injected into the tumour have shown treatmentsuccess.¹⁶

Summary

Nodular fasciitis (NF) is generally a benign, rapidly growing tumour which can be mistaken for malignant sarcoma. It typically affects people aged 20-40 and can appear anywhere in the body. Typical locations include the forearms, torso, and legs. NF is driven by a genetic translocation, commonly between the MYH9 and USP6 genes, leading to high levels of USP6. It’s important to see a doctor if you notice any lump growing quickly on your body. Even if it is NF, there is a small chance it could be cancerous. Diagnosing NF involves biopsies and genetic testing for USP6 rearrangements. Since this condition often resolves on its own, a wait-and-see approach can be taken, although surgery or corticosteroid injections may be necessary.