Tumors (neoplasms) of peripheral nerves and autonomic nervous system

Introduction to Tumors of Peripheral Nerves and Autonomic Nervous System

Tumors arising from the peripheral nervous system (PNS) and the autonomic nervous system (ANS) encompass a diverse group of neoplasms, ranging from benign growths to highly malignant sarcomas. These tumors can originate from various cellular components of nerves, including Schwann cells, perineurial cells, fibroblasts, or sympathetic/parasympathetic ganglion cells. Understanding their origin, clinical presentation, and biological behavior is crucial for accurate diagnosis and appropriate management.

 

Tumors of the Peripheral Nerves

Neurinomas (Schwannomas)

Neurinomas, more commonly known today as **schwannomas**, are benign tumors that arise from Schwann cells, which are responsible for producing the myelin sheath that insulates peripheral nerves. These tumors are typically well-encapsulated, grow slowly, and can vary greatly in size. They present as dense, often spindle-shaped or rounded nodes located eccentrically along the course of a nerve trunk. While they originate from Schwann cells within the nerve, they tend to displace rather than infiltrate the nerve fascicles.

 

Clinical Features and Treatment of Schwannomas

Clinically, schwannomas most often manifest with painful symptoms of nerve irritation or compression. This can include:

• Localized pain at the site of the tumor.
• Radiating pain or paresthesias (tingling, numbness) along the distribution of the affected nerve, often elicited or exacerbated by palpation of the tumor (Tinel's sign).

Less commonly, especially with larger tumors or those in confined spaces, schwannomas may be accompanied by clinical signs of progressive loss of sensory and/or motor function of the involved nerve, or a combination of irritative and deficit symptoms. Palpation of a nerve tumor usually causes irradiation of pain and paresthesias along the nerve's peripheral branching pattern.

Treatment: Surgical removal is the mainstay of treatment for symptomatic schwannomas. The goal is complete excision while preserving the integrity of the nerve fascicles. The surgical approach typically involves incising the fibrous capsule (formed by connective tissue layers of the nerve, the epineurium) in a longitudinal direction. The tumor can then usually be carefully "exfoliated" or dissected bluntly from the nerve fascicles without much difficulty, as it tends to push them aside rather than engulf them. Only in rare cases, where the tumor is intimately adherent to or inseparable from essential nerve fibers, might it be necessary to resort to partial resection of the nerve along with the tumor, potentially followed by nerve suture (neurorrhaphy) or grafting if a significant nerve gap results. However, the maximum effort is always made to preserve nerve continuity and function.

 

Neurofibromas and Neurofibromatosis

Neurofibromas are another type of benign peripheral nerve sheath tumor, but unlike schwannomas, they arise from a mixture of cell types including Schwann cells, perineurial-like cells, and fibroblasts, and they tend to grow intraneurally, meaning the nerve fascicles are often incorporated within the tumor mass rather than being displaced. This makes them more difficult to resect without sacrificing nerve function.

 

Multiple Neurofibromatosis

The presence of multiple neurofibromas is a hallmark of **neurofibromatosis**, a group of genetic disorders. With multiple neurofibromatoses, individuals develop many tumors of various sizes along nerve trunks throughout the body. These tumors often do not cause serious functional disorders initially. Indications for surgery in cases of multiple neurofibromas arise primarily when:

• A specific node becomes significantly painful.
• A tumor grows to a very large size and causes compression of neighboring vital structures or cosmetic disfigurement.
• There is suspicion of malignant transformation (see MPNST below).
• Progressive neurological deficit occurs.

 

Recklinghausen's Disease (Neurofibromatosis Type 1 - NF1)

Recklinghausen's disease, now more commonly known as **Neurofibromatosis Type 1 (NF1)**, is the most common form of neurofibromatosis. It is an autosomal dominant genetic disorder characterized by a constellation of clinical features, including:

• Multiple cutaneous and subcutaneous neurofibromas (intradermal nodules and tumors of various sizes developing on thin nerve trunks and their cutaneous branches).
• Café-au-lait macules (age spots on the skin of a light coffee color).
• Axillary or inguinal freckling.
• Lisch nodules (hamartomas of the iris).
• Optic pathway gliomas.
• Skeletal dysplasias (e.g., sphenoid wing dysplasia, pseudoarthrosis).
• Increased risk of other tumors, including malignant peripheral nerve sheath tumors (MPNSTs).

Occasionally, with Recklinghausen's disease, neurofibromas and schwannomas (neuromas) can affect cranial nerves (e.g., auditory/vestibular nerve - vestibular schwannoma, trigeminal nerve) or spinal nerve roots. These central neurofibromas or schwannomas can cause compression of the brain or spinal cord, leading to neurological deficits, and in such cases, surgical intervention becomes indicated.

 

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) / Malignant Sarcomatous Tumors

Malignant sarcomatous tumors arising from peripheral nerves are generally referred to as Malignant Peripheral Nerve Sheath Tumors (MPNSTs). These are aggressive sarcomas with a high tendency for local recurrence and distant metastasis. They can arise de novo or from malignant transformation of a pre-existing benign neurofibroma, especially in patients with NF1.

MPNSTs typically exhibit infiltrative and rapid growth. Treatment involves wide surgical resection of the tumor along with a margin of surrounding healthy tissue. Due to their infiltrative nature, achieving clear margins can be challenging and may necessitate significant functional sacrifice. In some cases of extensive limb involvement, amputation may be necessary to achieve local control. However, even with aggressive local treatment, metastasis (spread to distant sites like the lungs) is a common and serious concern, often limiting long-term survival. Adjuvant radiation therapy and sometimes chemotherapy are often employed in the management of MPNSTs.

 

Melanoma (Nerve Ending Origin - A Specific Viewpoint)

Melanoma is a malignancy arising from melanocytes, which are pigment-producing cells. While most melanomas are cutaneous, they can rarely occur in other locations. The text mentions melanoma (pigmented nevus) as belonging to a group of tumors of nerve endings, formed from Schwann cells or sensitive bodies in the skin. This perspective links melanocytes embryologically to the neural crest, from which Schwann cells also derive. Cutaneous melanoma can present as a pigmented "birthmark" (nevus) that undergoes malignant change, or as a de novo lesion. It can appear as an extensive flat lesion or a brown papillary tumor.

For malignant melanoma, the standard treatment involves wide surgical excision of the primary tumor with adequate margins. Depending on the stage and depth of invasion, sentinel lymph node biopsy or regional lymph node dissection may be indicated. Adjuvant therapies, including immunotherapy (e.g., checkpoint inhibitors) and targeted therapy (for specific mutations like BRAF), have significantly improved outcomes for advanced or metastatic melanoma. Radiation therapy may be used in certain situations.

 

Tumors of the Autonomic Nervous System

Classification and Types

Tumors arising from the autonomic nervous system originate from sympathetic or parasympathetic ganglion cells or their precursors. They are classified based on their cellular origin and degree of differentiation/malignancy:

• Benign Tumors:
  • Ganglioneuromas: Mature, benign tumors composed of ganglion cells, Schwann cells, and nerve fibers. They typically occur in the posterior mediastinum, retroperitoneum, or adrenal medulla.
• Relatively Benign / Tumors with Malignant Potential:
  • Ganglioneuroblastomas: Tumors with mixed features, containing both mature ganglion cells and immature neuroblasts. Their behavior can range from benign to more aggressive.
  • Pheochromocytomas (typically of the adrenal medulla) and Paragangliomas (extra-adrenal): Tumors arising from chromaffin cells of the sympathetic nervous system that often secrete catecholamines (adrenaline, noradrenaline), leading to symptoms like hypertension, palpitations, and headaches. Most are benign, but a small percentage can be malignant.
• Malignant Tumors:
  • Neuroblastomas: Highly malignant tumors of primitive neuroblastic cells, primarily occurring in infants and young children. They commonly arise in the adrenal medulla or sympathetic ganglia along the spine.

The therapeutic tactics for tumors of the autonomic nervous system will be built based on their specific type, location, extent, presence of hormonal activity, and the patient's overall condition. This often involves a multidisciplinary approach including surgery, chemotherapy, radiation therapy, and management of hormonal effects.

 

Diagnosis of Peripheral and Autonomic Nerve Tumors

Diagnosing tumors of the peripheral and autonomic nervous systems involves a comprehensive approach:

1. Clinical History and Physical Examination: Detailed history of symptoms (pain, numbness, weakness, palpable mass, autonomic dysfunction). Neurological examination to assess sensory, motor, and reflex changes in the distribution of affected nerves. Palpation for masses.
2. Imaging Studies:
   • Magnetic Resonance Imaging (MRI): The preferred imaging modality for visualizing peripheral nerve tumors and their relationship to surrounding structures. Specific sequences (e.g., T1-weighted, T2-weighted, STIR, contrast-enhanced) help characterize the lesion. MR neurography can provide detailed images of nerves.
   • Ultrasound (High-Resolution): Can be useful for evaluating superficial peripheral nerve tumors, guiding biopsies, and assessing tumor characteristics (e.g., cystic vs. solid, vascularity).
   • CT Scan: May be used to assess bony involvement or calcification within a tumor.
   • PET-CT Scan: For evaluating metabolic activity, staging malignant tumors (e.g., MPNSTs, neuroblastomas), and detecting metastases.
   • MIBG Scintigraphy: For locating pheochromocytomas, paragangliomas, and neuroblastomas that take up metaiodobenzylguanidine.
3. Electrodiagnostic Studies (EMG/NCS): Can help localize nerve dysfunction, assess the severity of nerve involvement (axonal vs. demyelinating), and differentiate nerve tumors from other neuropathic conditions. However, they may be normal if the tumor is small and not significantly compressing nerve fibers.
4. Biopsy:
   • Fine Needle Aspiration (FNA) or Core Needle Biopsy: May be performed under imaging guidance for accessible lesions to obtain a cytological or histological diagnosis before definitive surgery.
   • Excisional or Incisional Biopsy: Surgical biopsy is often required for definitive diagnosis and grading, especially for suspected malignancies.
5. Laboratory Tests:
   • Blood and urine tests for catecholamines and their metabolites (e.g., metanephrines, vanillylmandelic acid - VMA) if pheochromocytoma, paraganglioma, or neuroblastoma is suspected.
   • Genetic testing for conditions like NF1, NF2, or familial paraganglioma syndromes.

 

General Treatment Principles for Nerve Tumors

Treatment strategies are highly individualized based on tumor type, location, size, patient symptoms, and overall health.

• Observation ("Watchful Waiting"): For small, asymptomatic, clearly benign tumors (e.g., incidental schwannomas), periodic imaging surveillance may be an option.
• Surgical Excision: The mainstay of treatment for most symptomatic benign tumors and for resectable malignant tumors. The goal is complete removal with preservation of nerve function whenever possible (nerve-sparing surgery). Microsurgical techniques are often employed.
  • For encapsulated benign tumors like schwannomas, enucleation from the nerve is often possible.
  • For infiltrative tumors like neurofibromas or MPNSTs, resection may involve sacrificing part or all of the involved nerve, potentially requiring nerve grafting or transfers to restore function.
• Radiation Therapy:
  • May be used as adjuvant therapy after surgery for MPNSTs or incompletely resected benign tumors with aggressive potential (e.g., some plexiform neurofibromas).
  • Stereotactic radiosurgery (e.g., Gamma Knife) can be an option for some benign intracranial nerve sheath tumors (e.g., vestibular schwannomas) or as an alternative to surgery for small, difficult-to-access lesions.
  • Primary radiation therapy for some unresectable malignant tumors or for palliative care.
• Chemotherapy: Primarily used for malignant tumors like MPNSTs and neuroblastomas, often in combination with surgery and/or radiation. Also used for metastatic disease.
• Targeted Therapies and Immunotherapies: Emerging treatments for specific molecular subtypes of nerve tumors or associated syndromes (e.g., MEK inhibitors for NF1-related plexiform neurofibromas).
• Symptomatic Management: Pain control (neuropathic pain medications), physical therapy, and rehabilitation.

 

Differential Diagnosis of Palpable Nerve Lesions or Neuropathic Symptoms

When a palpable mass along a nerve or symptoms suggestive of nerve tumor are present, other conditions must be considered:

Condition	Key Differentiating Features
Benign Nerve Sheath Tumors (Schwannoma, Neurofibroma)	Often slow-growing, may be palpable, can cause pain, paresthesias, or weakness in nerve distribution. MRI typically shows characteristic features.
Malignant Peripheral Nerve Sheath Tumor (MPNST)	Often rapid growth, persistent pain, neurological deficits. May arise in NF1. MRI often shows aggressive features. Biopsy essential.
Ganglion Cyst (near a nerve)	Fluid-filled benign cyst, often near joints or tendons. Can compress adjacent nerves. Ultrasound or MRI can differentiate.
Lipoma (near a nerve)	Benign fatty tumor. Can cause compression if large or strategically located. MRI characteristic.
Chronic Nerve Entrapment/Compression (non-neoplastic)	E.g., carpal tunnel syndrome, cubital tunnel syndrome. Symptoms of nerve compression without a distinct mass (though fibrosis can occur). Electrodiagnostics helpful.
Inflammatory Neuropathy/Neuritis (e.g., focal hypertrophic neuropathy)	Nerve thickening and inflammation. May mimic tumor on imaging. Biopsy may be needed.
Traumatic Neuroma (Stump Neuroma)	Painful nodule at site of previous nerve injury/transection, due to disorganized axonal regeneration. History of trauma.
Metastatic Tumors to Nerves or Surrounding Tissue	History of primary cancer elsewhere. Can directly invade or compress nerves.
Lymphoma (involving nerves - neurolymphomatosis)	Can infiltrate peripheral nerves, causing pain, weakness, sensory loss. Systemic symptoms of lymphoma may be present. MRI, PET-CT, nerve biopsy.

 

Prognosis and Complications

Prognosis:

• Benign Tumors (Schwannomas, most Neurofibromas): Excellent prognosis with complete surgical removal. Recurrence is uncommon if fully excised. Nerve function can often be preserved or may recover.
• Neurofibromatosis (NF1, NF2): Lifelong monitoring is needed due to the risk of multiple tumors and potential for malignant transformation (especially in NF1).
• Malignant Peripheral Nerve Sheath Tumors (MPNSTs): Guarded prognosis due to aggressive behavior, high local recurrence rates, and propensity for distant metastasis. Survival rates are significantly lower than for benign tumors.
• Autonomic Nervous System Tumors: Varies widely. Ganglioneuromas have excellent prognosis. Neuroblastomas have variable prognosis depending on age, stage, and molecular features. Pheochromocytomas/paragangliomas are mostly benign but can cause severe cardiovascular complications if hormonally active; malignant forms have poorer outcomes.

Potential Complications:

• Postoperative neurological deficits (sensory loss, weakness, pain) if nerve fibers are damaged during tumor removal.
• Tumor recurrence.
• Metastasis (for malignant tumors).
• Complications related to tumor location (e.g., compression of vital structures).
• Side effects of radiation or chemotherapy.
• Chronic pain.

 

When to Consult a Specialist (Neurosurgeon, Neurologist, Oncologist)

Consultation with appropriate specialists is crucial if a tumor of the peripheral or autonomic nervous system is suspected or diagnosed. This often involves a multidisciplinary team:

• Neurologist: For initial evaluation of neurological symptoms, electrodiagnostic testing, and medical management of neuropathic pain or non-surgical conditions.
• Neurosurgeon or Specialized Peripheral Nerve Surgeon: For surgical evaluation and resection of nerve tumors.
• Oncologist (Medical and Radiation): For management of malignant tumors (chemotherapy, radiation therapy).
• Geneticist: If a hereditary syndrome like neurofibromatosis is suspected.
• Endocrinologist: For hormonally active autonomic tumors like pheochromocytoma.
• Radiologist: For performing and interpreting imaging studies.
• Pathologist: For accurate histological diagnosis and grading of tumors.

Seek medical attention for any new or growing palpable lump along a nerve, unexplained persistent pain, numbness, tingling, weakness in a specific nerve distribution, or symptoms suggestive of autonomic dysfunction.