CHAPTER 102 TUMORS OF THE PERIPHERAL NERVES

The peripheral nervous system is affected by neoplastic disease in the following ways:

Tumors of the peripheral nerves (PNTs) are sufficiently common that they are encountered by surgeons or neurologists at regular intervals but infrequently enough to still cause perplexity in diagnosis and treatment. Too many cases of benign schwannoma are subjected to biopsy, which damages the parent nerve, inflicts pain, and increases the difficulties surrounding excision; too often the true nature of the swelling and of its anatomical relations is not appreciated, so that the nerve trunk is excised. Even worse, inadequate biopsy or incorrect interpretation of that biopsy in a malignant tumor of nerve leads to inadequate treatment.¹

Nerve sheath tumors develop within tissues of neuroectodermal (neural crest) origin. A schwannoma is composed of Schwann cells, and so it develops a true capsule, the perineurium of the fascicle of origin. Malignant transformation within a solitary neurofibroma is a definable risk; malignant tumors are an important cause of morbidity and mortality in neurofibromatosis type 1 (NF1).

In a number of the authors’ patients, the correct diagnosis of NF1 was made only when they presented with a PNT. For these patients, the involvement of other systems, the implications of transmission to children, and risks of malignant transformation require careful attention.

The classification used in this chapter is displayed in Table 102-1. The true nature of PNT has been greatly clarified by electron microscopy, immunohistochemistry, and genetic studies. Perineurial cells arise from fibroblasts.² Transmission electron microscopic studies have shown that schwannomas do indeed arise from Schwann cells; ultrastructural characteristics enable the distinction among schwannoma, neurofibroma, and perineurioma.³ Folpe and Gowan⁴ emphasized the role of immunocytochemistry in the analysis of PNT, whereby specific antigens on cells of neural origin can be demonstrated by polyclonal or monoclonal antibodies. The strong expression of S-100 by Schwann cells is particularly important in distinguishing between the large schwannomas of the retroperitoneum and soft tissue sarcomas. The perineurial cell does not express S-100 but does express the epithelial membrane antigen. Fibroblasts express vimentin and fibromentin. Immunoreactivity, cytogenetic, and molecular genetic analyses demonstrate that Ewing’s sarcoma, Askin’s tumor of the chest wall, the primitive neuroectodermal tumor of bone, and neuroepithelioma are variations from a common neural origin, distinct from neuroblastoma. The cells of Ewing’s sarcoma exhibit characteristic reciprocal translocation of the long arms of chromosomes 11 and 21, in common with other tumors of this group.^5–8

TABLE 102-1 Classification of Peripheral Nerve Tumors

The clinical diagnosis of most PNTs, whether benign or malignant, is usually fairly straightforward in cases in which the swelling is located within the limbs. Supplementary investigations are necessary to confirm that diagnosis and to clarify the location of the tumor, its size, and its relation to vital structures. The possibility of a second malignant peripheral nerve sheath tumor (MPNST) or of premalignant change within a benign lesion is a particular problem in NF1. A swelling of a nerve may masquerade as PNT and yet may, in fact, be an expression of generalized neuropathy (Figs. 102-1 and 102-2).

Figure 102-1 Massive intraspinal/extraspinal schwannoma in a 36-year-old man caused progressive tetraparesis over the course of 4 years. Plain radiographs of the neck were not performed until the condition was quite advanced.

Figure 102-2 Schwannoma of the tibial nerve at the knee in a 58-year-old man. Magnetic resonance image reveals a well-formed capsule and no surrounding edema. The popliteal vein is displaced, but there is no narrowing of the popliteal artery. The tumor, which measured 6 cm in maximum diameter, lies eccentrically to the tibial nerve. There is a characteristic heterogenic signal.

Plain radiographs of the affected anatomy should always be obtained before any computed tomography or magnetic resonance imaging. For most PNTs, magnetic resonance imaging is particularly valuable in showing the relations of the tumor and in indicating the extent of spread into the skeleton or spinal canal.⁹ Magnetic resonance angiography is probably superior to digital subtraction angiography in demonstrating the relation of the tumor to adjacent great vessels. Computed tomography with contrast enhancement is required in the analysis of tumors extending within the spinal canal (Fig. 102-3).

Figure 102-3 Malignant peripheral nerve sheath tumor arising from the seventh cervical nerve and eroding the intervertebral foramen in a 24-year-old man.

BIOPSY

Biopsy should not be performed when the clinical diagnosis of benign PNT is secure. There are some objections to biopsy in MPNST: The intervention must breach tissue planes; an inadequate sample or incorrect analysis may lead to a false diagnosis of benign lesion in MPNST or of malignancy within a benign lesion. A biopsy specimen in MPNST should be adequate for defining the cell of origin, and this is particularly relevant in primitive neuroectodermal tumors, for which adjuvant therapy is an essential element in treatment. The staging of sarcomas of bone or of other soft tissues is a well-established and accepted practice. However, the compartment for an MPNST is the trunk nerve itself, and the authors have found centripetal extension of up to 20 cm within an apparently normal nerve trunk in some cases. Conventional staging investigations do not detect early malignancies at other sites in NF1, nor are they particularly good in detecting the early stages of transformation from benign to malignant lesions. MPNSTs are best treated in units that have access to all essential modalities of diagnosis. The operating surgeon should be responsible for the planning of biopsy and also for examination of all and of any material with colleagues in a multidisciplinary team (Fig. 102-4).

Figure 102-4 Schwannoma arising from the upper trunk in a 38-year-old man. Incomplete excision biopsy had been performed 6 weeks previously. This provoked severe pain and also paralysis of nerves C5 and C6. Good function was restored by repair of the lesion.

The authors’ unit has treated more than 450 patients with PNTs (Table 102-2). Their experience and those of others in the management of these tumors are summarized as follows.

TABLE 102-2 Peripheral Nerve Tumors Operated 1976-2006, Peripheral Nerve Injury Unit, RNOH

THE BENIGN SCHWANNOMA

This is the most common of all true PNTs, and it can be removed without impairment for function of the nerve of origin. Eighty percent of affected patients were between 30 and 69 years of age; 55% were male. The upper limb was the site of the tumor in more than 70% of cases; the brachial plexus and adjacent spinal nerves, in a little more than one third. Schwannomas can be found in bone, muscle, or viscera. Massive mediastinal or retroperitoneal tumors are not rare. The authors have found multiple schwannomas in 23 patients, and the tumor is common in NF1. Loss of function occurs when the tumor arises in an enclosed space. Most intraspinal/extraspinal tumors (dumbbell tumors) are schwannomas, and affected patients may present with quite advanced afflictions of the spinal cord. Bilateral vestibular tumors are pathognomonic of neurofibromatosis type 2 (NF2). Schwannomas arise from Schwann cells, which invest cranial nerves III to XII close to their origin. Malignant transformation of a benign schwannoma is rare.¹⁰

Pathology

The perineurium, with condensed internal layers, forms a capsule about the tumor that, in turn, forms an eccentric oval swelling, usually less than 3 cm in diameter, with nerve bundles stretched over it. It may be multinodular. The plexiform variation infiltrating the nerve of origin, so that enucleation is impossible, is rare. Larger tumors develop cysts and undergo degenerative changes of hemorrhage, calcification, and hyalinization. The appearance of the epineurial vessels coursing over the capsule of the tumor is quite characteristic; they are engorged and tortuous. The cut surface is yellowish. In larger tumors, it is cystic and it may be bloodstained.

The diagnostic feature is the organization of Schwann cells into areas of compact bundles (Antoni-A tissue) or a less orderly arrangement of spindle or oval cells in a loose matrix (Antoni-B tissue). There may be an abrupt change from one to the other. Palisades of compact parallel rows of cells forming Verocay bodies are a feature of Antoni-A tissue. In larger tumors, the nuclei may appear hyperchromatic, large, and multilobed (ancient schwannomas) and a misdiagnosis of malignancy may be made on the basis of these findings, as it may also be for schwannomas formed exclusively from Antoni-A tissue (the cellular variety). This error is prevented by consideration of the nature of the tumor as a whole and by immunohistochemistry. Strong expression of S-100 distinguishes the schwannoma from soft tissue sarcomas such as leiomyosarcoma (Figs. 102-5 and 102-6).¹¹

Figure 102-5 Schwannoma showing Antoni-A and Antoni-B tissue, palisades, and Verocay bodies. Ancient change is evident. Hyalinization of the walls of the small blood vessels, hemorrhage, and hemosiderin pigment and cystic changes are present. Hematoxylin and eosin stain; magnification, ×250.

(Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

Figure 102-6 Cellular plexiform schwannoma showing strong S-100 staining. Magnification, ×100.

(Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

Clinical Features

The most frequent manifestation is a swelling that is painful in response to pressure. A mass was detectable in 90% of affected patients, and this was almost always painful on palpation. Progressive neurological deficit occurs only when the tumor arises in a contained space, as in intraspinal extension. Diagnosis in the limb is straightforward. The lump is mobile from side to side but not in the longitudinal axis of the limb. Percussion induces painful paresthesia in the territory of the nerve of origin, similar to Tinel’s sign. This sign is the most useful finding in the diagnosis of schwannomas. At times, the schwannoma causes severe spontaneous pain, particularly when it arises in the sole of the foot or in the buttock and is exposed to pressure on walking or sitting. Spontaneous persistent pain was noted in more than 25% of the authors’ patients, and a degree of motor weakness was recorded in 13%.

Although 80% of the authors’ patients presented within 36 months of onset of symptoms, diagnosis was greatly delayed in others, up to 30 years in one case of schwannoma arising within the sciatic nerve. This delay in diagnosis is particularly common for the deep-seated tibial division of the sciatic nerve and for extraspinal and intraspinal tumors.

Treatment is by operation. The indications for operation are to confirm a clinical diagnosis, to remove a tumor that is causing pain, to prevent worsening of symptoms from continuing growth of the tumor, and to obviate the extremely low risk of malignant transformation. The aim of operation is to remove the tumor without damage to conducting tissue. The risk of worsening pain or leaving the patient with a permanent loss of function is less than 1% in a properly performed intervention. Earlier biopsy by incision or by needle led to fibrosis and distortion of the planes about and within the nerve trunk and increased the difficulty of excision.

Exposure of massive schwannomas in the mediastinum, in the retroperitoneum, or in close relation to the spinal canal is a considerable undertaking, fraught with potential hazard, but in these cases, the untreated tumor poses a very serious threat to adjacent vital structures distorted or compressed by the enlarging mass.

For tumors arising within the trunk nerves of the limbs, the exposure should be linear along the course of the nerve and long enough to enable display of the nerve trunk above and below the tumor of adjacent arteries, veins, and other tissues. Magnification with loupes or operating microscopes is helpful. With the tumor exposed and the nerve adequately mobilized, an incision is made in the epineurium, remote from intact bundles, which are seen coursing over the tumor and displayed around it. The plane of dissection lies between the true glistening capsule of the tumor and the bundles of the nerves lying within their epineurium. A nerve stimulator is an essential instrument during the operation, and it is particularly valuable in defining conducting elements within bundles that are so tightly splayed over the capsule of the tumor that they appear almost translucent. It is usual to find one slender bundle entering the proximal pole of the tumor and exiting at the distal pole, which is removed with the tumor. Conduction across this bundle is rare. A number of severe complications have been seen in patients referred to the authors after primary intervention. Among these are 24 cases of complete excision of a major nerve or nerves and another 18 in which there was partial excision of the nerve or nerves. Severe neuropathic pain complicated needle biopsy in 11 more patients (Figs. 102-7 and 102-8).

Figure 102-7 Schwannoma arising from the tibial nerve in a 48-year-old man. Note the intact, conducting bundles of the nerve splayed over the tumor, which is eccentric.

Figure 102-8 The conducting elements of the nerve are intact after enucleation of the tumor.

The brachial plexus and the superior mediastinum are common sites for large schwannomas. The transclavicular exposure was designed to provide adequate exposure and control of the venous trifurcation, the first part of the subclavian artery, the vertebral artery, and the recurrent laryngeal nerve, and it has been safely applied in more than 50 cases.¹² The posterior subscapular route is valuable for tumors that lie in the posterior mediastinum (Fig. 102-9).¹³

Figure 102-9 Large schwannoma arising from cervical nerve VI, displayed by the transclavicular approach, in a 53-year-old woman. The subclavian and vertebral arteries and the internal jugular vein are shown mobilized away from the tumor. The phrenic nerve is seen passing obliquely over the anterior face of the tumor.

THE SOLITARY NEUROFIBROMA

A typical neurofibroma arising in a major nerve trunk is easily recognizable. These tumors are significant for three reasons: They may grow to a very large size; they may extend along a spinal nerve into the spinal canal; and there is a slight but definite risk of malignant transformation.¹¹ The neurofibroma of a trunk nerve is not easily separable from nerve bundles; therefore, enucleation is not always possible. Most of the large peripheral neurofibromas arise from slender trunks, and so their removal is relatively straightforward and causes little loss of function (Figs. 102-10 and 102-11).

Figure 102-10 Magnetic resonance imaging scan showing a massive neurofibroma arising from T2 in a 33-year-old woman. It was successfully excised through the transclavicular approach.

Figure 102-11 Solitary benign neurofibroma. The matrix is fibrillary, and there are comma-shaped nuclei. Hematoxylin and eosin stain; magnification, ×960.

(Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

The tumors appear uniformly gray-white and translucent, and they are rubbery and fibrous in consistency. The tortuous epineurial vessels that are characteristic of the schwannoma are not seen in a neurofibroma.

The recognition of malignancy in these tumors is particularly difficult. If the neurofibroma extends into adjacent viscus or if it recurs after adequate primary excision, then it must be treated as malignant, regardless of the pathological characteristics of the tissue removed. The slow but inexorable progression of some of these tumors is reminiscent of the behaviors of certain other soft tissue sarcomas. A large neurofibroma is always potentially malignant.

NEUROFIBROMATOSIS

NF1 is much more common than NF2, with an incidence of about 1 per 3000 persons in comparison with 0.1 per 100,000 (Table 102-3). Only one half of the authors’ patients were aware of their condition, and the complications of the disease for themselves and their families were known to only a few. The surgeon may be the first to make the diagnosis and should work closely with a clinical geneticist so that the patient and family are adequately advised and supported. Support groups such as LINK in the United Kingdom, have produced excellent fact sheets on NF1 and NF2, and patients have been much helped by contact with such groups. NF1 is a disorder of the central and peripheral nervous systems, the skeleton, and the blood vessels. It is progressive, and there are four major causes of premature death: massive plexiform neurofibroma in the mediastinum, involving the airways; astrocytoma of the optic chiasm, brain, or cerebellum; cervicoparaspinal neurofibroma; and MPNST. The risk of MPNST in a patient with NF1 is about 3%. These tumors are rare in the first decade, manifest during adolescence or early adulthood, and their prognosis is poor (Fig. 102-12).^6,15

TABLE 102-3 Diagnostic Features of Neurofibromatosis Types 1 and 2

Feature	Type 1 (Peripheral Neurofibromatosis)	Type 2 (Central Neurofibromatosis)
Incidence	1 to 3 per 4000	0.1 per 100,000
Inheritance	Autosomal dominant	Autosomal dominant
Gene locus	Proximal long arm of chromosome 17	Distal long arm of chromosome 22
	New mutations account for one third to one half of new cases	New mutations account for up to two thirds of new cases
Diagnostic criteria
1	Six or more café-au-lait macules over 5mm in greatest diameter in prepubertal individuals and over 15mm in greatest diameter in postpubertal individuals	Bilateral cranial nerve VIII masses seen with appropriate imaging techniques (e.g., CT or MRI)
2	One plexiform neurofibroma	Or two or more neurofibromas of any type A first-degree relative with type 2 and either unilateral eighth nerve mass or two of the following: 1. Neurofibroma 2. Meningioma 3. Glioma 4. Schwannoma 5. Juvenile posterior subscapular lenticular opacity

3 Freckling in the axilla or inguinal region   4 Optic gliomas 5 A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis 6 Two or more Lisch nodules (iris hamartoma) 7 A first-degree relative (parent, sibling, or offspring) with type 1 by the previous criteria

CT, computed tomography; MRI, magnetic resonance imaging.

Figure 102-12 Neurofibromatosis type I in a 24-year-old man. There was no family history of this disease, and the diagnosis was made when he presented with a benign tumor arising within the axilla.

Malignant Peripheral Nerve Sheath Tumors

The most dangerous of these arise in patients with NF1 and account for about one third of all these tumors. The patients are younger, the incidence peaking between the ages of 20 and 30 years, and there is a tendency for tumors to arise more centrally. The prognosis is worse than it is for the solitary malignancy. MPNST develops in about 3% to 5% of patients with NF1. The rate of survival 5 years after the diagnosis ranges from 16% to 30% in published series (Figs. 102-13 and 102-14).¹⁶

Figure 102-13 Malignant peripheral nerve sheath tumor arising from the sciatic nerve in a 14-year-old boy with neurofibromatosis type 1. The tumor provoked intense pain and rapidly progressing sciatic paralysis. Excision of the tumor relieved pain, but the patient died of widespread pulmonary and visceral metastases 20 months after surgery.

Figure 102-14 Massive malignant peripheral nerve sheath tumor arising from the medial cord of the brachial plexus in a 34-year-old man with neurofibromatosis type 1. There was severe pain, resistant to opiates, and rapidly progressing palsy of the whole of the plexus. Forequarter amputation relieved pain. The patient died of intraspinal extension 22 months after operation.

The second group includes tumors caused by irradiation and accounts for about 10% of all MPNSTs.⁶ It is important to distinguish these tumors from recurrence of primary malignancy, because some of them can be treated successfully by resection.

The prognosis for solitary MPNST is similar to that for soft tissue sarcomas in general, with a 5-year survival rate of about 50%. The incidence peaks in the fourth, fifth, and sixth decades of life, and the tumor tends to arise more peripherally.¹⁶

The most important factors in the prognosis for all of these tumors are their size and manifestation. Tumors in NF1 tend to arise more centrally in deep-seated locations, and the rate of growth is faster.

The cardinal clinical feature of MPNST is pain, and this is usually associated with progressive impairment of nerve function. Spontaneous neuropathic pain with loss of nerve conduction in association with a palpable mass is indicative of MPNST until proven otherwise. Errors in diagnosis are not uncommon; there are numerous descriptions of unnecessary laminectomy or excision of a cervical rib before correct diagnosis was made. Clinical features and findings at surgery are more important in diagnosis than are histological characteristics, most of all in the so-called low-grade malignant neurofibromas.

Small tumors appear as fusiform swellings in the nerve trunk. They are hard, the nerve is surrounded by vascular adhesions, and edema of adjacent tissues is a particularly significant finding. In larger tumors, the diagnosis is all too evident. The mass may have burst out of the epineurium, extending into muscle or bone. Larger tumors develop as multilobular masses, and there may be cystic changes, hemorrhage, and, in the most malignant and rapidly growing tissue, extensive areas of necrosis.

The most common histological appearance is reminiscent of fibrosarcoma with masses of spindle-shaped cells organized into wavy lamellae. Irregularity of the cells and a wavy or buckled appearance of the nuclei are often found. Metaplastic differentiation occurs in about 20% of patients. Bone, cartilage, and muscle are the most commonly affected tissues; epithelioid differentiation into glandular or squamous tissue is less common. The prognosis for the “triton” tumor, which shows differentiation into skeletal muscle, is particularly poor. Transmission electron microscopic studies suggest that about 25% of these tumors show features of Schwann cells; fibroblasts predominate in about another 25%. Many MPNSTs do not stain for the S-100 protein, and examination for multiple neural markers is advised (Figs. 102-15 to 102-17).¹⁶

Figure 102-15 Malignant peripheral nerve sheath tumor. The tumor is densely cellular with moderate pleomorphism and high mitotic index. Hematoxylin and eosin stain; magnification, ×400.

(Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

Figure 102-16 Malignant peripheral nerve sheath tumor in a patient with neurofibromatosis type 1, arising from the brachial plexus. A proportion of the tumor cells are expressing myoglobin (Triton tumor). Magnification, ×400.

(Courtesy of Dr. Kim Suvarna.)

Figure 102-17 Neuroepithelioma arising from the sciatic nerve in a 14-year-old boy with neurofibromatosis type 1. There are areas of rosette formation. Hematoxylin and eosin stain; magnification, ×400.

(Courtesy of Dr. Jean Pringle, Royal National Orthopaedic Hospital.)

Management

These tumors do not respond to irradiation or to chemotherapy, and the correct treatment is adequate excision of the nerve trunk. Frozen examination of the proximal stump is essential for ruling out intraneural extension. The authors have seen such extension of up to 20 cm from the proximal pole of the tumor. This material should be reviewed by the operating surgeon before completion of the operation. The authors have found it necessary to section the spinal nerve at the foramen in six patients, and in two more, the spinal nerve proximal to the dorsal root ganglion was excised by means of hemilaminectomy.

There is no case at all for attempting repair of the nerve. Local recurrence after “limb sparing” operations is much more common with MPNSTs than it is for nonneural soft tissue tumors.

With sarcomas arising in the extremity, adequate excision of an MPNST will leave a gap, at the very least, of 20 cm, and attempts to restore function by grafting onto such a defect are futile.

Amputation is necessary when the epineurium has been breached or with recurrence. Lusk and colleagues¹⁷ advised forequarter amputation in patients with MPNSTs arising within the brachial plexus. This is necessary for recurrence after an apparently adequate excision or when there is such involvement of the plexus that no function can be preserved. It may be necessary for palliation even if it cannot be cured. Of 15 patients with tumors in known NF1 in the authors’ experience, 13 died within 2 years of diagnosis, and only one patient remained apparently disease free at 3 years. Of the 35 patients with solitary tumors, six died within 2 years of diagnosis, and seven more are known to have disease. Of the 22 apparently disease free at a minimum of 5 years after surgery, 14 were treated by excision of the nerve, 5 by amputation of the limb, and 3 by forequarter amputation.

KEY POINTS

• Management of PNTs requires expert multidisciplinary care.

• Biopsy of a PNT is not always required or appropriate.

• Careful surgical treatment can help maintain function, ensure full excision, and enable accurate histological diagnosis.

• Seventy percent of schwannomas are in the upper limb.

• Approximately 10% of schwannomas are multiple.

• Malignant transformation of schwannomas is rare.

• Painful, tender swelling and a positive percussion sign are characteristic clinical features of schwannomas.