Introduction

Nodular fasciitis is a rare, benign, and rapidly growing soft tissue tumour that primarily affects the fascia, which is the connective tissue surrounding muscles, bones, and organs. It is composed of myofibroblasts and typically occurs in subcutaneous tissue, fascia, and/or muscles. Despite its benign nature, nodular fasciitis often mimics malignant tumours, making accurate diagnosis crucial to avoid unnecessary treatments for presumed cancerous growths.¹ 

Understanding the pathophysiology of nodular fasciitis is essential for several reasons. Due to its rapid growth and similarities to malignant tumours, nodular fasciitis is frequently misdiagnosed. Understanding its pathophysiological characteristics helps distinguish it from more serious conditions, ensuring appropriate treatment.² Additionally, the benign nature and typical behaviour of nodular fasciitis allow clinicians to opt for conservative management or minimal surgical intervention, thus avoiding overtreatment.² Understanding the underlying molecular and genetic mechanisms, such as the MYH9-USP6 gene fusion (the chromosomal mutation involved in nodular fasciitis), can lead to the development of targeted therapies and improved diagnostic techniques.²

Epidemiology

Nodular fasciitis predominantly affects young adults but can occur at any age, including children and infants. It most frequently occurs in individuals between the ages of 20 to40.¹

Aetiology

There is evidence to suggest that nodular fasciitis can develop as a reactive process following local trauma or injury. This could be due to a minor injury that may have gone unnoticed.³ In one case, a 17-year-old athlete developed nodular fasciitis following an injury to his dominant hand.³ 

Recent studies have identified specific genetic alterations associated with nodular fasciitis. A recurrent translocation involving the MYH9-USP6 genes has been observed in many cases. This genetic alteration leads to the overexpression of the USP6 gene, which is thought to drive the proliferation of fibroblasts, the cells that form connective tissue.⁴ 

Nodular fasciitis is often characterised by rapid growth, which can mimic malignant tumours. This rapid growth is believed to be due to an exaggerated inflammatory response, leading to the proliferation of fibroblasts and myofibroblasts.⁵ In many cases, the lesion appears without any identifiable cause or predisposing factors. This idiopathic development suggests that there might be other unidentified factors contributing to this condition.

Pathogenesis 

Cellular and molecular mechanisms

The pathogenesis of nodular fasciitis involves a series of events starting from initial triggers to the development of the characteristic lesion.⁶ Here are the key steps:

Initiation

• Trauma or injury: Nodular fasciitis is often, although not always, preceded by a history of minor trauma or injury. This trauma can initiate the local inflammatory response³
• Genetic factors: A specific chromosomal translocation t(17;22)(p13;q13) leading to MYH9-USP6 gene fusion has been identified. In many cases, this genetic alteration is considered a crucial initial event³

Genetic and molecular changes

• MYH9-USP6 gene fusion: The chromosomal translocation results in the fusion of the MYH9 gene with the USP6 gene, which leads to the overexpression of USP6⁷
• USP6 overexpression: USP6 encodes a ubiquitin-specific protease that is involved in regulating various cellular processes, including cell proliferation. Overexpression of USP6 promotes the rapid growth and proliferation of fibroblasts and myofibroblasts⁷

Cellular proliferation

• Fibroblast activation: Fibroblasts and myofibroblasts play a central role in the development and progression of nodular fasciitis. The overexpression of USP6 activates fibroblasts and myofibroblasts, which start proliferating rapidly^3,6
• Myxoid stroma formation: The fibroblasts and myofibroblasts involved in nodular fasciitis produce an extracellular matrix rich in collagen and myxoid stroma. This extracellular matrix supports the proliferation of these cells and contributes to the firmness and texture of the mass

Myofibroblasts, which are fibroblasts with smooth muscle cell features, contribute to wound healing and contraction. In nodular fasciitis, these cells exhibit a temporary, reactive phenotype, which means they proliferate and produce matrix components in response to stimuli, but do not persist indefinitely.³

Inflammatory response 

The inflammatory response is another crucial component of the pathogenesis of nodular fasciitis:⁹

• Initial trigger: The inflammatory response is often initiated by minor trauma or injury, though it can also arise spontaneously due to genetic factors. The local injury or genetic alteration releases inflammatory mediators⁹
• Cytokine and growth factor release: Inflammatory cells such as lymphocytes and macrophages infiltrate the lesion and release various cytokines and growth factors. These signalling molecules include interleukins, tumour necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β), which further stimulate the proliferation of fibroblasts and myofibroblasts¹⁰
• Vascular changes: The inflammatory response also promotes angiogenesis, leading to increased vascularity (number of blood vessels) within the lesion. This increased blood supply provides the necessary nutrients and oxygen to the proliferating cells, supporting the rapid growth of the mass¹¹
• Resolution and self-limitation: Despite its rapid growth, nodular fasciitis is a self-limiting condition. The lesion often stabilises and can regress spontaneously over time. This self-limiting nature distinguishes it from malignant tumours, which would continue to grow and invade surrounding tissues¹¹
• Histological features: Under the microscope, nodular fasciitis shows a well-circumscribed lesion with spindle cells in a myxoid stroma. The spindle cells are typically arranged in short fascicles or a storiform pattern. Mitotic figures may be present but normal, distinguishing them from malignancies, which have atypical mitotic figures Additionally, areas of haemorrhage and extravasated red blood cells (leakage of blood into surrounding tissues) can often be observed, reflecting the rapid growth and vascular nature of the lesion³

Clinical presentation

Nodular fasciitis often presents as a rapidly growing mass. The growth can be alarming, as the lesion may increase significantly in size over the timespan of a few weeks to a few months. This rapid expansion often leads to concerns about malignancy.²Nodular fasciitis typically manifests as a palpable lump under the skin. Most individuals present with a single lump in one area of the body, usually smaller than 1.5 inches (4 centimetres) in diameter. However, these lumps can grow rapidly and reach sizes up to 5 inches (12 centimetres) in some cases.²

Location

• Common sites: Nodular fasciitis most commonly occurs in the upper part of the body (arms, particularly the forearm), followed by the head and neck, trunk, and lower parts of the body. It can develop in the subcutaneous tissue, fascia, or within the muscle²
• Uncommon sites: Although rare, nodular fasciitis can also occur in unusual locations such as the breast, parotid gland, and other visceral organs²

Characteristics of the mass

The mass is usually firm but can have a rubbery consistency due to its myxoid (gelatinous) stroma. It is typically well-circumscribed, meaning it has clear boundaries from the surrounding tissue.² Nodular fasciitis lesions are generally mobile under the skin, but this can vary depending on their location and depth.²

The mass may or may not be painful. When pain is present, it is usually mild to moderate and can be exacerbated by palpation or pressure on the lesion. Tenderness is more common if the lesion is located in a region subject to frequent mechanical irritation.¹ 

Diagnostic evaluation

Diagnostic evaluation of nodular fasciitis typically involves a combination of clinical examination, imaging studies, and cytological or histological analysis. The process can be challenging due to the condition's similarity to malignant tumours.¹² 

Imaging studies:¹

• Ultrasound can show well-defined isoechoic to hypoechoic nodules
• The appearance on MRI varies based on the lesion's composition (myxoid, cellular, or fibrous). Generally, lesions appear nearly isointense (having the same intensity) to skeletal muscle on T1WI imaging and hyperintense to adipose tissue on T2WI imaging
• CT scans may also be used to characterise the lesion

Fine needle aspiration cytology (FNAC):¹²

• FNAC is often used as an initial diagnostic tool
• Cytologically, nodular fasciitis reveals a hypercellular (abnormally high number of cells), polymorphic (occurring in several forms), and dispersed cell population
• It's frequently misdiagnosed as sarcoma due to its hypercellularity and the presence of mitotic figures

Histopathological analysis:¹³

• Often necessary for definitive diagnosis
• Shows a benign proliferation of fibroblasts and myofibroblasts
• Microscopic examination reveals spindle cells arranged in short fascicles or a storiform pattern in a myxoid stroma

Molecular testing:¹⁴

• Detection of the MYH9-USP6 fusion gene, characteristic of nodular fasciitis, can be helpful in diagnosis

Differential diagnosis:¹

• It is important to differentiate nodular fasciitis from malignant tumours, like spindle cell sarcoma, and from other benign conditions, like fibromatosis and fibrous histiocytoma

Follow-up:¹

• In some cases, the diagnostic process can include observation for spontaneous regression, which often occurs within a few weeks to months

Summary

Nodular fasciitis typically presents as a rapidly growing, painless mass that can be mistaken for a malignant tumour due to its fast growth rate and cellularity. However, it is benign and often resolves spontaneously or after surgical excision.⁴ Nodular fasciitis is caused by a combination of genetic abnormalities that cause cell proliferation, an exacerbated inflammatory response, and the subsequent formation of a matrix of supportive tissue. Despite its alarming clinical presentation, it is a benign and self-limiting condition, typically resolving with or without surgical intervention.