What Are Nerve Sheath Tumors?

Introduction

Definition of nerve sheath tumours

Nerve sheath tumours are neoplasms that grow in and around the protective layer surrounding nerve fibres. This protective layer is known as the nerve or myelin sheath.¹ 

Nerve sheath tumours are relatively sporadic - appearing in different places on the body and affecting both genders equally. It is the peripheral nervous system (nervous system outside the brain and spinal cord) that these tumours tend to affect.²

Patients may not experience any symptoms, but typically, nerve sheath tumours present as lumps under the skin accompanied by neuropathy.¹

Types of nerve sheath tumours

Benign nerve sheath tumours

Neurofibromas and Schwannomas are the 2 most common forms of benign nerve sheath tumours, with neurofibroma being the most common nerve sheath tumour across malignant and benign classifications. 

Neurofibromas typically present on the subcutaneous surfaces, i.e., under the skin or on smaller peripheral nerves - they seldom present in the central regions of the spinal cord and brain. It is believed that neurofibromas arise as a result of a genetic disorder, namely neurofibromatosis type 1 (NF1). The presence of neurofibromas varies between patients and can be sporadic. Patients may present with only a few neurofibromas, and other patients may present with many peripheral neurofibromas.³ 

Scwannomas originate from the Scwann cells - a group of cells that insulate nerve sheaths as a form of protection and support. Schwannomas tend to form on nerves or nerve roots in the peripheral regions. Although both are nerve sheath tumours, Neurofibromas and Schwannomas are different at a cellular level - where Schwannomas exclusively originate from Schwann cells, Neurofibromas form a range of cells such as mast cells, collagen and different nerve cells. Most Schwannomas are benign in nature. However, around 5% eventually develop into malignant nerve sheath tumours.⁴

Malignant nerve sheath tumours

Malignant nerve sheath tumours are a type of cancerous sarcoma. This type of sarcoma develops from the nerve sheaths in the peripheral regions of the body. Although rare in occurrence, malignant nerve sheath tumours have an aggressive nature and tend to grow and spread quickly.⁵ Malignant nerve sheath tumours are associated with a genetic condition - neurofibromatosis type 1 (NF1). NF1 is a loss of the tumour suppressor gene neurofibromin. It is estimated that around 25% to 50% of patients with malignant nerve sheath tumours simultaneously present with NF1. The prognosis for malignant sarcomas is generally very poor and has a high relapse rate after multimodal therapy (i.e. chemotherapy/surgery/radiotherapy combination treatments) - overall, most patients are observed to have rapid disease progression.⁶ 

Understanding nerves and nerve sheaths

Anatomy of nerve sheaths

Myelin sheaths (or nerve sheaths) are extended plasma membranes composed of proteins and fatty substances. They provide protective and electrical insulation covering both the peripheral regions and central regions. In the peripheral regions, the myelin sheath originates from Schwann cells, whereas in the central regions, it originates from oligodendroglial cells.⁷  The membrane of the myelin sheath is structured in layers and covers most regions of nerve axons, though some specific regions remain uncovered and are referred to as the nodes of Ranvier. The function of these nodes is to speed up electrical conduction.⁸ 

Role of Schwann cells in nerve sheath tumours

The role of Schwann cells in carcinogenesis or cancer cell progression was a field of study not well investigated until quite recently. Newer studies have shown that the nature and abundant presence of Schwann cells in most peripheral regions and organs, in addition to their plasticity (the ability to grow and differentiate into another group of cells) allows for the promotion of carcinogenesis.⁹  

In particular, Schwann cells, compared to other glial cells, such as oligodendrocytes, have a larger role in carcinogenesis due to their ability to regenerate if any damage occurs.⁹ Recent studies observing the pathogenesis of pancreatic cancer cells detected the migration and presence of Schwann cells in regions where neoplasms grow. These studies observed how Schwann cells appear typically pre-malignancy, thus supporting early detection of neoplasm growth. Overall, Schwann cells promote the formation of a tumor-microenvironment by contributing to perineural invasion.⁹

Causes and risk factors

As with most cancers, the exact causes of nerve sheath tumours are not clear but can be attributed to a few factors and genetic abnormalities. NF1 and neurofibromatosis 2 (NF2) are inherited genetic disorders observed in a large percentage of nerve sheath tumour patients⁶. NF1 is characterized by the presence of café-au-lait spots on the body (light-brown spots) - typically, patients with inherited NF1 have 6 or more of these spots. Mainly benign tumours develop in NF1 patients. Around 10% of NF1 patients will eventually develop malignant nerve sheath tumours. Although there is a lack of investigation and studies conducted into the cancer risk of NF1, it is typically associated with eye tumours, nerve sheath tumours, breast cancer and adrenal gland tumours.¹⁰ 

NF2 is also known as NF2-related schwannomatosis due to its association with bilateral vestibular schwannomas. There are associations with other (generally benign) nerve sheath tumours. Schwannomas, meningiomas and gliomas all have associations in patients presenting with inherited NF2. Similar to NF1, NF2  patients may also present with café-au-lait spots on the body, but they tend to be fewer..¹¹ 

Symptoms and clinical presentation

As discussed above, due to the relative rarity and frequency of nerve sheath tumours in clinical settings, many symptoms may go unnoticed by clinicians. However, it is widely reported that the most common symptoms tend to be pain, especially in the area where the tumour first develops. The tumour can also cause nerve invasion and destruction, leading to loss of nerve function accompanied by nerve pain.¹² 

Below are some other relatively common symptoms associated with nerve sheath tumours:

• Swelling or lumps (both painful or painless)
• Difficulty using limps
• Loss of sensation in legs or arms
• Soreness
• Loss of coordination (more common with vestibular schwannomas)

A recent study found that most symptomatic cases of nerve sheath tumours are benign - around 85-90%.¹² Despite this, early diagnosis should be encouraged.

It is important to note that some nerve sheath tumours may clinically present as asymptomatic. Any lumps should be reported to your healthcare provider as soon as possible. Early diagnosis generally means a better overall prognosis. 

Diagnosis of nerve sheath tumors

Like most tumours, the presence of a visible neoplasm is what normally leads to a diagnosis. Imaging diagnostic tools such as MRIs and ultrasounds can also show the presence of a tumour and its spread.  A biopsy may be ordered, especially if there are concerns of malignancy. The biopsy will use pathological tools to determine the cancerous nature of the mass from a sample of its cells. CT and PET scans may also be used to diagnose and indicate the size of the tumour.¹ 

Treatment options

Surgery is the main treatment option for tumours,  irrespective of their malignancy ¹³ With malignant tumours, total resection may need to be considered to prevent the further spread of the tumour, and the surrounding tissue can also be removed. In most cases, however, clinicians will aim to save the surrounding tissue. Benign nerve sheath tumours, especially if diagnosed early, will only need to be observed whilst withholding treatment. 

Chemotherapy and radiotherapy tend to be add-ons to surgery. If the tumour is too difficult or too large to be surgically removed, then chemotherapy will initially be used to shrink the tumour and then removed via surgery.¹

Prognosis

The prognosis of nerve sheath tumours varies between each clinical presentation and patient. It is determined by many clinical factors, such as the malignancy of the tumour, where it presents, how early it was diagnosed, etc. The five-year survival rate for malignant peripheral nerve sheath tumours can be anywhere between 23-69%.⁵ Worse prognoses are associated with larger tumour size in patients who present with neurofibromatosis 1. The location may also influence the prognosis, with the neck, trunk and head having the worst outcomes.¹⁴

Summary

Overall, the future of diagnosing and treating nerve sheath tumours lies in further research being conducted. It is also important for patients to report any suspected or unexplained lumps anywhere in the body.