Traumatic neuroma

Traumatic neuroma also called post traumatic neuroma or amputation neuromas, is a disorganized proliferation of nerve tissue that commonly occurs after a cut or damage including previous surgery to a peripheral nerve bundle ¹. A traumatic neuroma is a tangle of neural fibers and connective tissue that develops following nerve injury. It usually presents as a firm, oval, whitish, slowly growing, palpable and painful nodule, not larger than 2 cm. It may be associated with paresthesia over the injured area ². Painful hypersensitivity to normal light tactile stimuli (dysesthesia) or a neuralgic pain with the presence of a typical trigger point in the area of a neuroma may be a prominent feature. Traumatic neuropathic pain can cause the patient to feel burning, stabbing, raw, gnawing or sickening sensations ². Traumatic neuromas can occur after amputation of a limb or autoamputation of a digit in utero. The clinical features of a traumatic neuroma include the formation of a solitary nodule less than 2 cm in diameter, neuralgic pain, tenderness, paresthesias and increased pain or tenderness on palpation over the lesion ³. Usually nerves can repair themselves by proximal to distal proliferation of Schwann cells; when this reparation is interrupted or cannot occur in an orderly manner, the proximal aspect of the nerve creates a disorganized proliferation of nerves, that is called a neuroma. Most authors consider the occurrence of traumatic neuroma to be related to excess hyperplasia and irregular hyperplasia after nerve injury, so they are often regarded as benign tumors ⁴.

Traumatic neuroma may occur in any part of your body, including your head, face, neck, limbs, gallbladder, thigh, mammary gland, penis, and other body parts ⁵. In the mouth, a traumatic neuroma is a rare disorder that occurs most commonly at the mental foramen, lower lip, tongue and intra-osseous areas ⁶. Jones and Franklin ⁷ reported that the frequency of traumatic neuromas was 0.34 % in the oral region. The most common sites for a traumatic neuroma in the head and neck are the inferior alveolar nerve, lingual nerve, and great auricular nerve ⁸. Traumatic neuroma is extremely rare in the palate.

The borders of diffuse traumatic neuromas are often unclear, and the extent of the actual tumor may be such that a complete excision would result in severe neurologic damage, such as an area of hypoesthesia or complete nerve palsy. In these cases, simple excision of the tumor using an electrical scalpel is an effective method of treatment, and reduces the likelihood that the residual traumatic neuroma tissue would cause repeat symptoms or a full recurrence of the tumor.

The treatment of traumatic neuroma is still considered controversial. Conservative and operative therapy both have its advantage and disadvantage. The recommended treatment of a traumatic neuroma is simple excision rather than nerve resection or alcohol blocks ⁹. Tay et al. ¹⁰ reported that monopolar diathermy reduces the rate of neuroma formation, and electrical coagulation of the proximal nerve stump can prevent the development of neuromas. Simple excision is therefore highly recommended in the treatment of traumatic neuromas ¹.

Figure 1. Traumatic neuroma in mouth

Footnote: (a) Photograph showing an obvious swelling of the left palatine mucosa (arrows). (b) A T2-weighted magnetic resonance image showing the lesion as an area of high-signal intensity (arrow).

[Source ¹¹ ]

Figure 2. Traumatic neuroma knee (MRI right leg)

Footnote: A 40-year-old man with a history of penetrating injury to the right lower leg complained of shooting pain along the distribution of the tibial nerve and the small nodule beneath the cutaneous scar. MRI demonstrated nonenhancing fusiform thickening of the tibial nerve, which was isointense to muscle with perineural scarring. The features were characteristic of posttraumatic neuroma-in-continuity of the right tibial nerve. (A) Sagittal T1-weighted precontrast without fat suppression and (B) T1-weighted postcontrast fat-suppressed MRI show fusiform thickening of the tibial nerve with nerve continuity on either side without significant enhancement of the lesion.

[Source ¹² ]

Traumatic neuroma causes

Traumatic neuromas can develop after blunt or sharp trauma or traction injury. An essential step in neuroma formation is widely accepted to be the injury of the perineurium as, without an intact perineurium, the axon fibers cannot go through ¹³. As soon as perineurium is damaged, the axons will escape. Another critical step is thought to be neuroinflammation ¹⁴. As the axons get to the extraperineurial space where there is already tissue damage, there will be inflammation. The compounds released during inflammation can aid neuroma formation.

The injured nerve endings start to regenerate in an unregulated fashion disrupting the mostly linear organization of fibers resulting in an unorganized growth. This growth will create and transmit signals which the central nervous system can interpret as pain.

A traumatic neuroma is formed from one of two main processes:

1. Spindle neuroma: which commonly occur from a reactive fibroinflammatory disorganized regeneration around a nerve after an injury, such as traction injury or chronic repetitive stress (e.g. Morton neuroma) ¹⁵
2. Terminal neuroma such as “stump neuroma”: can occur after transection of the proximal nerve terminal after injury or operation (e.g. limb amputation, ilioinguinal pain post herniorrhaphy).  It is common to see neuroma formation following elective hand surgery, especially the superficial radial nerve is susceptible, or after knee arthroplasty, the saphenous nerve is vulnerable ¹⁶. After nerve division, distal axons begin apoptosis. To reconstruct nerve continuity, Schwann cells of the distal nerve will generate a channel for ingrowth of adjacent axons ¹⁷. However, in cases of too long distance between two segments of the injured nerve, proximal axons will grow toward multiple directions around so as to find a way for growth; thus, the appearance generally overgrows in bulbous-end-like shape ¹⁷ and besides, as nerve tissues grow more slowly than surrounding soft tissues, they will be mixed with other kinds of cells, such as fibroblast and mastocyte ¹⁸.
3. There is also a report indicating that facial nerve hemangioma also can lead to traumatic neuroma under the condition of no trauma or operation history and no chronic stimulation and compression ¹⁹.
4. Causal factors for traumatic neuroma in mouth include tooth extraction, orthognathic surgery, ill-fitting dentures and intra-oral incisions ³.

Mortons neuroma (localized interdigital neuroma) is a traumatic neuroma of the third metatarsal interspace.

Neuromas can develop after amputation called stump neuroma. The symptoms they produce should not be confused with phantom limb pain.

The pain may be generated for the following reasons or mechanisms:

1. stretched by surrounding scar tissues ²⁰;
2. compression on sensitive teleneuron by surrounding soft tissues ²¹;
3. nerve tissue ischemia ²²;
4. ectopic foci of ion channels ²³;
5. P substance, calcitonin gene related peptide and 5-hydroxytryptamine are released by mastocyte ¹⁸; and
6. peripheral regulation of kinds of ion channels or receptors (sodium channels, TRPA1, alpha1C receptors, and nerve growth factor) ²⁴.

This kind of pain is difficult to control because it is often accompanied by central sensitization and social-psychological factors ²⁵ and the change of voltage-gated calcium channels (VGCCs) may be the important element of central sensitization²⁶.

Traumatic neuroma differential diagnosis

Neuromas can be part of a syndrome such as neurofibromatosis or multiple endocrine neoplasia type 2B (MEN2B). Neurofibroma (or neurofibromatosis) is a genetic condition in which multiple neuromas form in various places of the central and peripheral nervous system. They can present as skin lesions, can cause hearing and balance issues or pain. There is no known cure; surgery has a role in symptom control. Multiple endocrine neoplasia 2B (MEN2B) is a genetic syndrome consisting of medullary thyroid carcinoma, pheochromocytoma, and mucosal neuromas.

The histologic differential diagnosis for oral traumatic neuromas includes mucosal neuromas (multiple endocrine neoplasia type 2B), neurofibromas, palisading neuromas, and neurovascular hamartomas. On histological examination, mucosal neuromas resemble traumatic neuromas because of the presence of many nerve bundles ²⁷. However, the absence of inflammatory cells in a normal or loose fibrous connective tissue background can lead to the diagnosis of a mucosal neuroma. Neurofibromas and traumatic neuromas both have fibrous connective tissue and non-encapsulated lesions, but neurofibromas have mast cells and nuclei with a wavy or serpiginous prolife, and do not contain the abundant, haphazardly arranged axons that are unique to traumatic neuromas ²⁸. Although palisading neuromas and traumatic neuromas both form nerve bundles ²⁹, the absence of inflammatory cells and fibrous connective tissue and the existence of spindle cells showing palisading arrangement and generally circumscribed margin is more indicative of a palisading neuroma. Neurovascular hamartomas are rarely described in the oral cavity. The histopathologic features of neurovascular hamartomas include poorly circumscribed masses of closely packed nerve bundles and blood vessels in a loose matrix, containing minimal to no inflammation ³⁰. Given all the histologic similarities between these masses, identifying a traumatic neuroma is especially difficult. Allon et al. ³⁰ noted that neurovascular hamartomas are unique histologically because their neural and vascular components are separate, with a dominant neural component. Immunohistochemical staining for factor VIII suggested that the neural and vascular components were separate. In addition, palpable bulging and pain on palpation are signs of a traumatic neuroma. Neurogenic tumors of the head and neck generally do not produce neurologic signs or symptoms ³.

Table 1. Clinical and histopathological differential diagnosis of traumatic neuroma versus other neurogenic tumors

	Clinical features	Histopathological features
Traumatic neuroma	Symptomatic (anesthesia, dysesthesia, and pain), solitary	Many nerve bundles, fibrous connective tissue background containing inflammatory cells
Mucosal neuroma	Asymptomatic, typically multiple, associated with multiple endocrine neoplasia type 2B	Many nerve bundles, normal or loose fibrous connective tissue background without inflammatory cells
Neurofibroma	Asymptomatic, solitary, or multiple	Nuclei with wavy or serpiginous prolife, fibrous connective tissue background containing mast cells
Palisading neuroma	Asymptomatic, solitary	Circumscribe, spindle cells showing palisading arrangement
Neurovascular hamartoma	Asymptomatic, solitary	Many nerve bundles containing vessels, fibrous connective tissue background without inflammatory cells

Traumatic neuroma prevention

Traumatic neuroma prevention is essential as it can result in traumatic neuropathic pain, functional impairment and psychological distress, severely decreasing the quality of life ³¹. Following injuries or during elective operations after transection of a nerve is transected, the surgeon should reconnect the two nerve endings where possible. Following injuries where the nerve damage is suspected, patients must seek medical attention in centers where usually plastic surgeons can diagnose, explore, and treat nerve damage. Many different surgical strategies exist to prevent neuroma formation after trauma, none of which are superior to each other. Neurorraphy significantly reduces neuroma formation to 1% from 7.8% untreated or amputated ³². Generally accepted principal surgical aims are: repair should not be under tension, in a theater environment with loupe or microscope magnification, align nerve so that same axon can reconnect. Careful and minimal debridement is also accepted. If there is a gap, it is common to sacrifice a less crucial sensory nerve to provide a nerve graft for the repair, which can be multi-stranded. If the two ends cannot be rejoined (amputation), it is common to bury the nerve or suture it onto muscle to help prevent neuroma formation; this is called targeted nerve implantation (TNI) ³³.

The CoNNECT randomized trial still in progress is looking at end to end, end to end plus conduit, and no direct suture only conduit secured repairs to determine if tubes are beneficial and if sutureless solutions merit consideration.

A study is looking at a local tacrolimus (FK506) embedded polylactide-co-caprolactone films that actively decreased neuroma formation when continuously released to repair site ³⁴.

A group of Chinese scientists is looking into autologous vein grafts to be used instead of nerve grafts to bridge short gaps after nerve injury ³⁵.

There is also work being done to use stem cells to help nerves regenerate after an injury. Although the main aim is to improve function rather than to reduce neuroma formation ³⁶.

Traumatic neuroma symptoms

The main manifestation of traumatic neuroma is pain, especially intense neuralgia ³⁷. Neuroma pain can be burning, sharp, tingling sensation, or numbness. The pain is often characterized by chixuxi low-intensity dull pain or intense paroxysmal burning pain and also can be induced by various outside simulations, such as temperature and touch. Tinel’s sign is usually positive ³⁸.

There is also another pain that may be related to traumatic neuroma, called phantom pain, which results from sensing of the existence of amputated part ³⁹. Ectopic discharge from a stump neuroma has been thought to be an important peripheral mechanism of phantom pain ³⁹. Traumatic neuroma may also be characterized by paresthesia, such as hyperesthesia or feeling of numbness. One study reports on a case traumatic neuroma may have no manifestation during its development ¹⁷. Traumatic neuroma symptoms may develop 1-12 months after nerve injury.

There should also be a history of injury (including iatrogenic injury, i.e. surgery) to the area.

Traumatic neuroma diagnosis

The diagnosis of traumatic neuroma is mainly dependent on history and examination. The history of trauma or surgery is very important in the diagnosis of a traumatic neuroma. Special care should be taken to establish where and how was the injury treated, was there any attempt at repairing the nerve. If there is no history of trauma, the differential should shift towards genetic causes of the neuroma and true neoplasms.

On examination, a well defined hard lump is usually palpable, which can be adherent to nearby structures. On pressure, patients can experience a sensation similar to electric shock.

In cases where there is uncertainty, X-rays can be taken to rule out bone injury as a cause of pain and to rule out bone malignancy. Ultrasound, computed tomogram (CT) and magnetic resonance imaging (MRI) will show well-defined soft tissue mass but are rarely necessary investigations.

Ultrasonography is one of most valuable methods in the diagnosis of traumatic neuroma. The position and size of lesion and the relation between lesion and surrounding tissues and nerves can be detected directly via ultrasonography examination. Ultrasonography examination is inexpensive, noninvasive, and non-harmful. Futhermore, local nerve blocking can be conducted under the guidance of ultrasonography for the enhancement of the diagnosis, and pathological examination of living tissue can be implemented for the definite diagnoses ⁴⁰. Ultrasound image of traumatic neuroma is generally oval, low-echo enclosed mass, clear and irregular probable boundary, diameter being greater than that of nerve trunk, and continuity with nerve ¹⁷.

MRI is only used in differential diagnosis with other soft tissue diseases ⁴¹ and its cost is high; patients have discomfort and real-time imaging cannot be used for display; thus, MRI has a limited value in diagnosis of traumatic neuroma.

There are no laboratory tests that would aid diagnosis. After surgical excision, it is common practice to send lesions for histopathology examination to rule out malignancy.

At histopathology, traumatic neuromas generally show in the following appearance: nonencapsulated tangled mass formed by Schwann cell, endoneurial cell, perineurial cell, and surrounding fibroblast ¹⁵.

Traumatic neuroma treatment

There is no consensus on how to best treat an already formed neuroma ⁴². The recommended treatment of a traumatic neuroma is simple excision rather than nerve resection or alcohol blocks ⁹. Tay et al. ¹⁰ reported that monopolar diathermy reduces the rate of neuroma formation, and electrical coagulation of the proximal nerve stump can prevent the development of neuromas. Simple excision is therefore highly recommended in the treatment of traumatic neuromas ¹.

Figure 3. A flowchart of treatment principles for neuropathic pain

[Source ⁴³ ]

Conservative therapy

1. Medications: Opioid analgesics, antidepressant drugs, antispasmodic drugs, α receptor blockers, and lidocaine are all used in the treatment of traumatic neuroma, but only have short-term therapeutic effect, and show significant side effects and declined therapeutic effect in long-term use ⁴⁴. Gabapentin and pregabalin are considered the effective medicine to inhibit central sensitization through affecting the calcium channels and reduce the excessive neurotransmitter release ⁴⁵.
2. Repeated injection of lidocaine with steroid: It shows the symptom is improved in painful neuroma but has significant side effects with long-term injection ⁴⁶.
3. B ultrasound-guided percutaneous ethanol injection: can relieve painful neuroma significantly with continuous injection, and has high remission rate ⁴⁷.
4. Transcutaneous magnetic stimulation (TMS): a rapid discharge of electric current is converted into dynamic magnetic flux for modulating neuronal functions ⁴⁸. This analgesic effect seemed to be sustainable with repeated treatment delivered at a 6- to 8-week duration ⁴⁸.
5. Injection of a tumor necrosis factor etanercept to peripheral nerves can relieve the pain significantly ⁴⁹.
6. Cryotherapy and radiofrequency ablation are both used in clinical treatment, but the therapeutic effect is unsatisfactory. Six months after radiofrequency ablation, there was significant decline in pain relief ⁵⁰.

Other treatments for traumatic neuropathic pain are mainly physiotherapy. Therapeutic massage is advised by Faith ⁵¹ and which is preferred for the treatment of Morton’s neuroma. Electrical stimulation is another common conservative treatment choice. In Stevanato’s et al. study ⁵², they use an implanted peripheral nerve stimulator applied directly to the nerve branch involved into the axillary cavity. A quadripolar electrode lead was placed directly on the sensory peripheral branch of the main nerve involved, proximally to the site of lesion, into the axillary cavity. According to their “gate-control” theory, the peripheral nerve stimulation produces direct electrical effects by recruitment of primary afferent A-beta and A-delta fibres that project at the spinothalamic tract and dorsal columns and A-alpha fibres that cause segmental inhibition through presynaptic inhibitory interneurons. It can be considered as a reasonable treatment of patients suffering from otherwise intractable painful neuropathies of the upper arm.

Surgery

For patients who undergo intractable traumatic neuropathic pain, which is refractory to medication, surgical procedure is advised. The key of surgical procedure is to remove external pressure thus preventing simultaneous proliferation of nerve and fibrous connective tissue and to maintain the dynamic balance of the microenvironment surrounding the injured nerve. Reinnervation of the distal target or translocation from the distal end organ to a site with minimal potential for further stimulation is the usual treatment ⁵³. As for which kind of surgery should be performed, it depends on which particular nerve is injured. Evans et al. ⁵⁴ combined resection of the neuroma with implantation of the palmar cutaneous branch of the median nerve into the pronator quadratus muscle, which allowed the nerve to be isolated from wrist motion and denervated skin. The efficacy of this treatment modality was examined, follow-up data were obtained on all patients at a mean of 19 months after surgery, and subjective improvement in pain was reported in 12 of the 13 patients ⁵⁴. Koch and his team ⁵⁵ suggested the possibility of inhibiting the formation of painful neuromas by nerve transposition into a vein. Balcin ⁵³ compared the two methods of surgical treatment for painful neuroma by transposition of the nerve stump into an adjacent vein or muscle. Compared to their pre-operative levels in the muscle group three and 12 months after surgery, translocation into a vein led to reduced intensity and evaluative levels of pain, as well as improved sensory as assessed by visual analogue scale and McGill pain score. This was associated with an increased level of activity and improved function. Transposition of the nerve stump into an adjacent vein is preferred to relocation into a muscle. Recently, Martins ⁵⁶ analyzed data from seven patients using interdigital neurorrhaphy for treatment of digital neuromas. All patients showed some temporary pain relief after nerve block, and therapeutic results were observed during later follow-up. Their findings indicated that interdigital neurorrhaphy achieved satisfactory improvement of symptoms and hand dysfunction ⁵⁶. Classical surgeries are mostly used in clinical practice and they can indeed provide a certain treatment efficacy. However, all these treatment modalities do have certain respective limitations in practice, for instance, the method of nerve transposition into a vein requires the existence of a suitable vein for the nerve stump to relocate in. The technique like interdigital neurorrhaphy is technically demanding and sometimes no corresponding nerve to be sutured with.

In recent years, several new surgical strategies for traumatic neuropathic pain have attracted interest. The use of soft tissue ⁵⁷ and the use of conduits ⁵⁸ have showed great potential in the treatment of traumatic neuropathic pain. Research has shown that myofibroblasts are highly expressed in the neuroma, it is speculated that myofibroblasts may contribute to pain by contracting the collagen matrix around the sensitive non-myelinated fibers that grow astray to form a neuromatous bulging ⁵⁹. Krishnan ⁵⁹ concludes that vascularized soft tissue coverage of painful peripheral nerve neuromas can be an effective, but also a complex method of treatment. All kinds of nerve conduits have been popularized in the treatment of nerve defects for years ⁶⁰ and they have also been introduced in the management of painful neuromas ⁶¹. A research conducted by Marcol et al. ⁵⁷ found microcrystallic chitosan conduit could efficiently prevent the neuroma formation and traumatic neuropathic pain in a rat sciatic nerve model. Clinically, Peterson et al. ⁶² also achieved satisfactory outcomes using an acellular dermal matrix conduit in treatment of traumatic neuropathic pain at the wrist. The key of these treatment modalities is to cover or protect the injured nerve stump from physical and chemical stimulation, thus eliminating the external stimuli and keeping the injured nerve stump under a relatively stable environment. Similarly, Gennady ⁶³ demonstrates a minimally invasive neurectomy to treat painful medial branch neuroma, which poses little damage to surrounding tissue and indirectly provides good prognosis. Yan et al ⁶⁴ used aligned nanofiber conduits in the management of painful neuromas in rat sciatic nerves. They found that aligned nanofiber conduits can significantly facilitate linear nerve regeneration, inhibit neuroma growth, and reduce traumatic neuropathic pain after neurectomy ⁶⁴. Synthetic conduits can be a promising field in the treatment of traumatic neuropathic pain, as the material science evolves.

In general, resection of the existing neuroma is strongly advised for all the patients with traumatic neuropathic pain ⁴³. Transposition and relocation of the nerve stump into a biological tunnel away from partial compression, for instance, muscles, bones and veins are necessary to assure long term efficacy. Artificial conduits can be used under the circumstances that no suitable biological tunnel can be found. Soft tissues treatment, for instance, flaps and lippofilling can provide better prognosis for those patients with large scale of tissue defect and deep soft tissue injury.

Lastly, for patients with intractable traumatic neuropathic pain refractory to medication and refuse any surgical treatment or have little satisfaction with surgery, physiotherapy as electrostimulation and massage may also be good choices.

1. Neuroma resection: Simple neuroma resection tends to have short-term therapeutic effect, together with relapse of neuroma ⁶⁵.
2. Neuroma resection and ethanol injection: Appears to be only effective for patients who only suffer from short pain before operation, one-time nerve injury and one neuroma ⁶⁶.
3. Neuroma resection and targeted nerve implantation (TNI): Such surgical method has been performed many times, and it is speculated to have a great role for prevention and treatment of neuroma ⁶⁷. Its mechanism is as such: The proximal nerve ending at a secondary motor point is transplanted to an adjacent denervated muscle, and the regenerated axons may bifurcate and enter the myenteric motor nerve branches, so as to prevent formation of traumatic neuroma ⁶⁷.

Traumatic neuroma prognosis

After digital amputation, 6% of people will develop a neuroma ⁶⁸. When operated at the time of injury, this can decrease to 1%.

Neuromas are a benign condition, however, it can increase in size, become more painful, become tethered. A neuroma is a painful condition with no other significant symptom or complication. This pain, however, is often so severe that patients have to undergo surgery.

There are no studies that are looking at traumatic neuroma regression. However, there are multiple studies which are looking at acoustic neuroma regression rates, which appear around the 4% mark ⁶⁹. This action results in some patients having active observation rather than surgery.

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