Neuroma

Neuroma Microchapters
Overview
Historical Perspective
Classification Morton's neuroma Acoustic neuroma Ganglioneuroma
Pathophysiology
Causes
Epidemiology and Demographics
Risk Factors
Natural History, Complications and Prognosis
Diagnosis
Treatment
Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [7]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[8], Maria Fernanda Villarreal, M.D. [9]

Synonyms and keywords: Traumatic neuroma; Morton neuroma; Amputation neuroma; Pseudoneuroma; Morton’s metatarsalgia; Plantar interdigital neuroma; Morton's intermetatarsal neuroma; Morton's entrapment; Morton's disease; Morton's neuropathy; Morton's neuralgia; Intermetatarsal neuroma; Intermetatarsal space neuroma; Intermetatarsal nerve entrapment; Interdigital neuroma; Interdigital nerve compression; Interdigital nerve enlargement; Joplin's neuroma; Plantar neuroma; Scar neuroma; Terminal neuroma; Stump neuroma

Overview

Neuroma (Neuro- is from the Greek for nerve) is defined as a benign tumor of a nerve. However, neuroma commonly refers to any tumor of cells of the nervous system. Neuromas form part of the peripheral nerve sheath tumors and belong to Reactive class of tumors. Neuroma was first described by Thomas Morton in 1876. Neuromas may be classified according to histopathological features into 3 groups: Morton's neuroma, traumatic neuroma, and neoplasic neuromas. The pathogenesis of neuroma is characterized by neural degeneration with epineural and endoneural vascular hyalinization, and perineural fibrosis. Neuroma is more commonly observed among patients aged between 15 to 50 years old. Neuroma is more commonly observed among middle aged adults. Females are more commonly affected with neuroma than males. The female to male ratio is approximately 5:1. Common risk factors in the development of neuroma include improper footwear and high impact sports (e.g., rock-climbing, ballet dancing). A major complication of neuroma is chronic neuropathic pain. On ultrasound, neuroma is characterized as a well-defined, hypoechoic lesion located in the intermetatarsal space proximal to the metatarsal head. Patients with neuroma usually appear with antalgic posture. Physical examination may be remarkable for tenderness to palpation and dysesthetic pain. Surgical excision is the treatment of choice for patients with neuroma; this surgical intervention is associated with a relatively favorable success rate, approximately 80%. The recurrence rate after surgery is as high as 50%.

Historical Perspective

• The term neuroma originates from the following two Greek words:
  • neuro- from the Greek word for nerve (νεῦρον)
  • -oma (-ωμα) from the Greek word for swelling
• In 1876, Neuroma was first described by Thomas Morton

Classification

• Neuroma may be classified according to histopathological features into following groups:

Classification of neuroma

Types of neuroma	Characteristic features	Neoplastic nature
Morton's neuroma	Symptomatic collapse of the transverse arch by perineural fibrosis around a plantar digital nerve of the foot due to traction and increased pressure/chronic compression on the interdigital nerve Usually located: Third intermetatarsal space (between third and fourth metatarsals) or At the bifurcation of the fourth plantar digital nerve	Non-neoplastic
Traumatic neuroma	Arises from nerve injury (often as a result of surgery) leading to interrupted axons termed as neurotmesis Regenerating axons lack an endoneurial tube to follow, resulting in a painful and tender mass of disorganized axons Occurs at the end of injured nerve fibers as a form of unregulated nerve regeneration Subtype of traumatic neuroma, called "Joplin neuroma" (a compression traumatic neuroma) Occurs most commonly near a scar Often very painful Also known as: Amputation neuroma Pseudoneuroma Scar neuroma
Palisaded encapsulated neuroma/solitary circumscribed neuroma	Nonpigmented, painless, small, firm nodules Present in proximity to mucocutaneous junctions, usually face Benign but can be mistaken for basal cell carcinoma Surgical removal is the curative treatment
Mucosal neuroma	Associated with MEN2B (inherited autosomal dominant trait caused by a single mutation in RET proto-oncogene) Grossly present as: Diffusely enlarged lips Tongue nodules Thickened eyelids (diffusely or nodularly), in the first or second decade of life Comprised of markedly enlarged nerve fibers on microscopy No specific treatment
Neoplasic neuroma	Solid nodular mass Usually, separate from nerve fibers	Neoplastic
Acoustic neuroma	It's a misnomer It's actually a Vestibular Schwannoma Slow-growing, benign tumor of acoustic nerve Symptoms usually start after the age of 30 and include: Dizziness Persistent headaches Vertigo Loss of balance Tinnitis Numbness Pain/weakness on one side of face Blurred/double vision (temporary) Ataxia Hoarseness of voice Dysphagia
Ganglioneuroma	Tumor of sympathetic nerve fibers arising from neural crest cells
Pacinian neuroma	Very rare Painful Benign hyperplastic tumor of Pacinian corpuscles (mechanoreceptors responsible for sensitivity to vibration and pressure) Sometimes associated with history of local trauma

Pathophysiology

• The pathogenesis of neuroma is characterized by neural degeneration with epineural and endoneural vascular hyalinization, and perineural fibrosis
• The pathogenesis of traumatic neuroma is characterized by:
  • Tangle of neural fibers and connective tissue that develops following a peripheral nerve injury
  • Interruption in continuity of nerve causing wallerian degeneration (loss of axons in proximal stump and retraction of axons in distal segment), followed by exuberant regeneration of nerve and formation of mass of Schwann cells, axons and fibrous cells
  • Chronic reactive fibroinflammatory disorganized regeneration around a nerve after an injury (such as traction injury or chronic repetitive stress)
• Morton's neuroma is characterized by being located in the 3rd web-space, between 3rd and 4th metatarsal heads, or sometimes in the second or fourth interspaces
• Another subtype of traumatic neuroma is terminal neuroma (also known as "stump neuroma") which can occur after transection of the nerve (e.g. limb amputation)
• There are no genetic mutations associated with the development of neuroma
• On gross pathology, characteristic findings of neuroma, includes:
  • Adherent fibrofatty tissue
  • Small, firm, oval, yellowish-white, slowly growing, palpable nodule on skin (no discoloration of skin on the top of nodule)
  • </=2cm in size
• On microscopic histopathological analysis, characteristic findings of neuroma, include:
  • Extensive fibrosis around and within the nerve
  • Digital artery
  • Thrombosis
  • Arterial thickening

S-100 Immunostain of Palisaded and Encapsulated Neuroma Source: Ed Uthman at flickr

Histopathology of Palisaded and Encapsulated Neuroma Source: Ed Uthman at flickr

Histopathology of Palisaded and Encapsulated Neuroma [1]

Histopathology of Palisaded and Encapsulated Neuroma [2]

Histopathology of traumatic neuroma

• Numerous well formed small nerve twigs
• Limited soft tissue infiltration
• Contains axons in haphazardly arranged nerves within mature collagenous scar with entrapped smooth muscle

Traumatic neuroma Source: Libre Pathology

Traumatic neuroma [3]

Traumatic neuroma [4]

Traumatic neuroma [5]

Traumatic neuroma [6]

Common sites of involvement by traumatic neuroma

• Most common oral locations are:
  • Tongue
  • Near mental foramen of mouth
• Rarely involves:
  • Head
  • Neck

Causes

• Common causes of neuroma include:
  • Indirect nerve trauma
    • Especially during a surgery
    • Cone biopsy (rare complication)
    • 55% of hysterectomy patients have microneuromas, associated with childbirth
    • Traction injury
    • Chronic repetitive stress
• Morton's neuroma is associated with:
  • Wearing tight shoes and high heels
  • Overpronation
  • Abnormal positioning of toes
  • Flat feet
  • Forefoot problems such as:
    • Bunions
    • Hammer toes
  • High foot arches

Epidemiology and Demographics

• Neuroma is an uncommon disease

Age

• Neuroma is more commonly observed among patients aged between 15 to 50 years old
• Neuroma is more commonly observed among middle aged adults

Gender

• Females are more commonly affected with neuroma than males
• The female to male ratio is approximately 5:1

Race

• There is no racial predilection for neuroma

Risk Factors

• Common risk factors in the development of neuroma include:
  • Improper footwear/tight shoes
  • High-impact sports (e.g., rock-climbing, ballet dancing, jogging, running, snow skiing)
  • Overpronation

Natural History, Complications and Prognosis

• The majority of patients with neuroma are symptomatic at the time of diagnosis
• Early clinical features include neuropathic pain or local tenderness
• If left untreated, the majority of patients with neuroma may progress to develop difficulty walking and limping
• A significant complication of neuroma is chronic neuropathic pain
• Prognosis is generally good, and the survival rate of patients with neuroma is 99%

Diagnosis

Symptoms

• Neuroma is usually asymptomatic
• Symptoms of neuroma may include:
  • Focal area of traumatic neuropathic pain radiating to toes, with the presence of a typical trigger point in the area of a neuroma (especially with the pressure application) causing the patient to feel:
    • Shooting
    • Burning
    • Stabbing
    • Raw
    • Gnawing
    • Sickening sensations
  • Numbness
  • Paresthesia over the injured area
  • Dysesthesia (painful hypersensitivity to normal light tactile stimuli)
  • Functional impairment
  • Psychological distress (severely decreasing the quality of life)

Physical Examination

• Patients with neuroma usually appear with antalgic posture
• Physical examination may be remarkable for:
  • Tenderness to palpation
  • Limitation of range of motion
  • Dysesthetic pain
  • Mulder's sign:
    • Replication of symptoms or clicking sensations upon direct pressure between the metatarsal heads or compression of transverse arch in forefoot between the finger and thumb

Laboratory Findings

• There are no specific laboratory findings associated with neuroma

Imaging Findings

MRI

• On MRI, characteristic findings of neuroma include:
  • Dumbbell/ovoid-shaped lesion at a similar position to that described on ultrasound
  • T1: typically low-to-iso signal
  • T2: typically low signal but can sometimes be intermediate in signal
  • T1 C+ (Gd): tends to show intense enhancement
• On MRI, characteristic findings of traumatic neuroma include:
  • Fusiform swelling of a nerve or a bulbous mass at a nerve end
  • The parent nerve of some small nerve may difficult or impossible to discern
  • T2/STIR: inhomogeneous hyperintensity (may have a hypointense rim)
  • T1 C+ (Gd): variable contrast enhancement

Morton neuroma MRI Source: Radiopedia

Ultrasound

• Ultrasound can help distinguish neuroma from:
  • Intermetatarsal bursal swelling or
  • Synovitis in adjacent joints
• On ultrasound, neuroma is characterized by the following findings:
  • Round to ovoid
  • Well-defined, hypoechoic lesion
  • Located in the intermetatarsal space proximal to the metatarsal head
• On ultrasound, traumatic neuroma is characterized by the following findings:
  • Swollen nerve (mass-like)
  • Hypoechoic
  • Loss of normal fibrillar pattern
  • Usually small, but may be as large as 5 cm

Treatment

Medical Therapy

Conservative therapy for Morton's neuroma

• Morton's neuroma should be managed conservatively before proceeding to expensive diagnostic procedures
• Conservative measures for pain relief include:
  • Decreasing pressure on the metatarsal heads by using:
    • Metatarsal support
    • Metatarsal bars
    • Padding techniques (it's important to place inserts properly just proximal to the metatarsal head), such as:
      • Metatarsal pads
      • Toe crest pads
    • Tapping the toe area
    • Shoe inserts (orthotics) help in correcting any mechanical imbalance in the foot
    • Specialized orthopedic shoes
    • Comfortable shoes (with the help of a professional shoe fitting device) having:
      • Wider toe box allowing spread of metatarsal heads
      • Low heels
      • Good arch support
  • Physical therapy
  • Ice massage
  • Strength exercises for intrinsic foot muscles
  • Resting

Non-conservative medical therapy

• When conservative measures fail, following medical therapy is used for non-surgical treatment of neuroma:
  • Tricyclic antidepressants
  • Anticonvulsants (more effective)
  • Serotonin-norepinephrine reuptake inhibitors
  • Ultrasound-guided interdigital injection of following nerve blocking agents via dorsal approach into the site of tenderness:
    • Steroid
    • Local anaesthetic
  • Anti-inflammatory drugs (orally or injected into the toe area), such as:
    • Ibuprofen (Advil, Motrin)
    • Naproxen (Aleve, Naprosyn)
  • Painkillers (not recommended for long-term treatment)

Surgery

• Surgical excision is the treatment of choice for neuroma
• Surgical excision is associated with a relatively favorable success rate of approximately 80%
• Recurrence rate after surgery is as high as 50%

Prevention

• There are no primary preventive measures available for neuroma
• Secondary prevention measures include: personal hygiene measures, such as wearing ergonomic shoes

Differential Diagnosis

• Neuroma must be differentiated from other diseases that cause forefoot pain and numbness such as:
  • Stress fracture (neck of the metatarsal)
  • Rheumatoid arthritis
  • Hammer toe
  • Neurofibroma

Differentiating neuroma from other causes of intermetatarsal pain

Disease/Condition	Underlying Etiology	Pathophysiology	Clinical presentation	Other associated features
Neuroma	Indirect nerve trauma Especially during a surgery Cone biopsy (rare complication) 55% of hysterectomy patients have microneuromas, associated with childbirth Traction injury Chronic repetitive stressImproper footwear/tight shoes High-impact sports (e.g., rock-climbing, ballet dancing, jogging, running, snow skiing) Overpronation	Neural degeneration with epineural and endoneural vascular hyalinization, and perineural fibrosis Gross pathologicalfindings of neuroma include: Adherent fibrofatty tissue Small, firm, oval, yellowish-white, slowly growing, palpable nodule on skin (no discoloration of skin on the top of nodule) </=2cm in size Microscopic histopathological analysis of neuroma shows: Extensive fibrosis around and within the nerve Digital artery Thrombosis Arterial thickening	Focal area of traumatic neuropathic pain radiating to toes: Shooting Burning Stabbing Raw Gnawing Sickening sensations Numbness Paresthesia over the injured area Dysesthesia (painful hypersensitivity to normal light tactile stimuli) Functional impairment Psychological distress (severely decreasing the quality of life) Local tenderness Limited range of motion Mulder's sign Difficulty walking Limping	Most common oral locations are: Tongue Near mental foramen of mouth Rarely involves: Head Neck
Metatarsal stress fracture (Neck of metatarsal bone)	Repeated extraordinary stress, overuse, or trauma to the bone caused by any of the following: Sudden undertake of a burst of exercise in a sedentary person Olympic-class athletics (extraordinary quantities of high-impact exercise) Long distance marches (militaryrecruits) Running (track and field athletes) Jumping Sports such as soccer, tennis, gymnastics & basketball Muscle fatigue Previous stress fracture Osteoporosis (weakens the bone, causing stress fracture by just normal activity) Flat feet High or rigid foot arch Lack of nutrients due to eating disorders, lack of vitamin D & calcium Menopause (or women with abnormalmenstrual cycles)	Over the time, if enough stressis placed on the bonerepetitively, it exhausts the capacity of the bone to remodel without enough timefor recovery resorb cells faster than body can replace them, resulting in a weakened site causing tiny cracks in a bone, or severe bruising within a bone leading to stress fracture	Local pain (worsens with time) Local tenderness (originates from a specific spot & decreases during rest) Swelling around the painful area	Stress fracture can be prevented by following measures: Starting new exercise gradually with slow progression Using proper footwear Adding low-impact activities to the exercise regimen to avoid putting stress on a particular body part Strengthening exercises for calf and shin muscles to avoid muscle fatigue Getting appropriate nutrition(especially in osteoporosis & menopause) having adequateamounts of: Vitamin D Calcium Essential nutrients
Rheumatoid arthritis	Common causes include: Idiopathic Genetic (HLA-DR4 cluster, HLA-DR1) Environmental (smoking) Hormonal (hyperprolactinemia) Immunologic Infections (mycoplasma, epstein-Barr virus, rubella virus, porphyromonas gingivalis) Socioeconomic factors Psychological factors Lifestyle factors (obesity, poor health)	On gross pathology, following features may be noticed: Irregular surface, seen due to synovial hyperplasia Subchondral cysts(usually present at the later stage of disease) Microscopic histopathologicalanalysis shows: Formation of new synovialblood vessels (earliest finding) Hypertrophy of synovial lininglayer Infiltration of mononuclear cells Chronic inflammation with lymphocytic infiltration Pannus formation(fibrovascular tissue or granulation tissue)	Common symptoms of rheumatoid arthritis include: Joint pain involving small joints of the hands, wrist, and foot Joint swelling Morning joint stiffness classically lasting for more than an hour Decreased grip strength Generalized aching Fatigue Weight loss Depression Less commonly, involvement of cervical spine leads to neurologicalsymptoms such as: Tingling in the arm Numbness in the arm Weakness in the arm	Conditions associated with rheumatoid arthritis include: Osteopenia Myositis Vasculitis Uveitis Scleritis Peripheral ulcerative keratitis Interstitial fibrosis Pulmonary nodules Bronchiolitis obliterans Organizing pneumonia Venous thromboembolism Pericarditis Myocarditis Congestive heart failure Atrial fibrillation Sjogren's syndrome Felty's syndrome Patients with rheumatoid arthritis may have a positive history of: Smoking Family history Autoimmune disease
Hammer toe	Can be caused by muscle, nerve, or joint damage due to any of the following: Wearing poorly-fitting shoes (high heels, too short or narrow shoes) Trauma Osteoarthritis Rheumatoid arthritis Stroke Charcot-Marie-Tooth disease Diabetes	Abnormal permanent bend at the proximal interphalangeal joint of a toe due to imbalance in the muscles, ligaments, or tendons which normally hold the toe in a straight position	Usually affects second, third, or fourth toe Abnormal bend in the joint of one or more toes resembling a hammer Painful or difficult movement of the affected toe Painful calluses & corns may form (due to rubbing of hammer toes against the inside of the shoes)	Also known as: Claw toe Hammer toe syndrome Mallet toe (when affects the distal interphalangeal joint)
Neurofibroma	Can be sporadic or as a part of Neurofibromatosis 1 and 2 NF1 gene located at chromosomal region 17q11.2, codesforneurofibromin Functional part of neurofibromin GAP (or GTPase-activating protein) accelerates the conversionof the active GTP-bound RAS to its inactive GDP-bound form Loss of RAS controlleads to increased activity of other signaling pathwaysincluding RAF, ERK1/2, PI3K, PAK, MAPK, SCF/c-kit and mTOR-S6 kinase	Uniphasic, low to moderate cellularity No peripheral perineural capsule Random pattern, only rare palisading No well formed verocy bodies Hypocellular with abundant mucinous/myxoid matrixwithout hypercellular areas Frequent mast cells Contains neural fibroblastsand fibrillary or shredded carrot collagen Random proliferation of Schwann cells and scattered admixed axons No nevoid cells No epithelial component Diffuse growth pattern Scant cytoplasm Wavy spindle cells with buckled nuclei Pseudomeissnerian bodiesrepresenting specific differentiation may be present Lacks storiform pattern Neurofibroma with degenerativeatypia ("ancient change") has following microscopic features: Localized cells with large pleomorphic nuclei, cytoplasmic nuclearinclusions, smudgy chromatin, and inconspicuous nuclei Absent or very low mitotic activity Low to moderate cellularity	Can occur anywhere Diffuse neurofibromas commonly involve scalp Soft masses/bumps on or under skin (internal or superficial) Transient itching (mast cellsrelease histamine) Transient pain Numbness and tingling in the affected area Severe bleeding (sign of tumorgrowth) Physical disfiguration Cognitive disability Stinging Neurological deficits Changes in movement(clumsiness in hands, trouble walking) Bowel incontinence Scoliosis (an abnormal curvature of the spine, if the tumor creates muscular imbalance or erodes bones of the spine) Following symptoms may occur with genitourinary tractinvolvement (rarely): Urinary tract infection (most common clinicalmanifestation) Urinary retention Urinary frequency Urgency Hematuria Pelvic mass Hydronephrosis Urinary incontinence(decreased bladder capacity or compliance) Appears as a focal mass or diffuse bladder wall thickening in case of a plexiform neurofibroma	Nerve often not identified, incorporates nerve, axonsoften present in lesion Seldom cystic Frequently multiple Widespread soft tissueinfiltration Tends to displace adnexa <2cm in diameter Lacks distinct lobulation Lacks fat Affects individuals between 20-40 years of age Men and women are equallyaffected Plexiform neurofibroma are thought to be congenital and occur earlier in life