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Nerve tumors of the hand and upper extremity
Hand Clin 20 (2004) 233–242
Nerve tumors of the hand and upper extremity Christopher L. Forthman, MD, Philip E. Blazar, MD* Department of Orthopaedic Surgery, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
Nerve tumors arise in a similar fashion as other upper extremity neoplasms. Benign nerve tumors typically grow slowly and with few symptoms, whereas malignant tumors tend to grow faster and with more pain. Neural dysfunction is not typically a feature in either case [1–5]. Consequently, confusion with other more common neoplasms and tumor-like processes is frequent [2,3,6]. Nerve tumors are overlooked in the differential diagnosis, because they comprise only 5% of upper extremity tumors in adults [7–9] and 2% in children [10]. Inappropriate surgery can be disastrous, resulting in irreversible loss of function [1,11]. The evaluation of upper extremity soft tissue masses includes CT and MRI. Although useful for delineating the surrounding anatomy and planning a surgical approach, neither technique reliably distinguishes tumors of nerve origin from other neoplasms [12]. Rarely localization of the tumor to the vicinity of a large nerve trunk suggests a peripheral nerve tumor [13]. More commonly these imaging techniques are useful for demonstrating characteristics of a malignant neoplasm, such as large size, invasion into adjacent tissues, and tumor necrosis. Management of the patient with any upper extremity mass must be undertaken recognizing the possibility of a peripheral nerve neoplasm. All patients must be warned of postoperative pain at the tumor site and possible loss of nerve function. Strict tumor surgery techniques should be followed. When malignancy is suspected, an incisional biopsy is appropriate, with definitive
* Corresponding author. E-mail address: [email protected] (P.E. Blazar).
treatment delayed until the histologic diagnosis is confirmed.
Peripheral nerve anatomy Tumors of the peripheral nerve usually arise from and resemble cellular components of the nerve sheath. The normal sheath consists of a thin outer layer of fibrous tissue, the epineurium. Deep to the epineurium there are one or more nerve fascicles, each surrounded by a flattened, lamellated, perineurial cell layer. Within each fascicle, bundles of axons are encased within endoneural tubes, the protective and supportive coverings formed by Schwann cells and endoneural fibroblasts. Peripheral nerve tissue components may be differentiated by light microscopy, electron microscopy, and immunohistochemistry. These diagnostic techniques assist the pathologist in determining the cell of origin for any given tumor (Table 1). Schwann cells characteristically have a small cell body with processes enwrapping other structures; the axon in the normal situation. Electron microscopy confirms these features together with a pathognomonic basal lamina and granular intercellular basement membrane. Schwann cells always stain with antigenic markers for S-100 and frequently stain for Leu-7 (HNK-1). Perineurial cells, in contrast, are larger, spindleshaped cells with elongated nuclei and long tapering cell processes. Electron microscopy is capable of identifying such features and the characteristic micropinocytotic vesicles. Perineurial cells do not stain for S-100 and Leu-7 proteins, but they do stain for epithelial membrane antigen (EMA) [14,15].
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Table 1 Features of benign peripheral nerve tumors Tumor
Cell origin
Schwannoma
Schwann
Neurofibroma
Schwann
Granular cell
Schwann
Neurothekeoma
Unclear
Nerve sheath Myxoma PerineuriomaSoft tissue PerineuriomaIntraneural
Schwann, Perineural Perineural Perineural Neoplastic ?
Malignant change
Immunohistochemistry
Genetics
Strongly stain for S-100 and moderately stain for Leu-7. No neurofilament staining within the lesion. Poorly stain for S-100 and Leu-7. Neurofilament stain identifies nerve fibers in the lesion. Moderately stain for S-100 and Leu-7 Poorly stain for S-100 and Leu-7 Strongly stain for S-100, Leu-7, and EMA Strongly stain for EMA but not S-100 Strongly stain for EMA but not S-100
50% of sporadic tumors have mutation in chromosome 22, similar to NF-2 Plexiform neurofibromas have mutation in chromosome 17, similar to NF-1 Unclear
Very rare in the absence of NF-1. Plexiform type has a high risk for malignant change. Less than 3%
Unclear
Not reported
Unclear
Not reported
Common monosomy of chromosome 22 Common monosomy of chromosome 22
Few reports
Schwannoma The schwannoma is a benign peripheral nerve sheath tumor arising from the Schwann cell. It is the most common solitary tumor of the peripheral nerve [1]. The tumor typically presents in the middle decades of life [1,11], although childhood cases have been reported [3,16]. Patients with neurofibromatosis type 1 (NF-1 or von Recklinghausen disease) may suffer from multiple schwannomas involving large peripheral nerve trunks. Patients with neurofibromatosis type 2 (NF-2) suffer from bilateral acoustic schwannomas. Multiple tumors occasionally are found in patients without neurofibromatosis [17,18]. Schwannomas are typically painless, slowgrowing, isolated, firm, round, soft tissue masses. Discomfort and paresthesias may occur [1– 3,9,11,19]. In the upper extremity, the flexor surface is the most common site owing to the presence of the large nerves in the volar forearm and palm [1,2,4,20]. The tumor may be of variable size depending on the anatomic location, although most schwannomas are less than 2.5 cm in diameter [4]. The tumors may be found tethered in the longitudinal axis of the limb and in the line of a peripheral nerve. In some cases, there is no apparent nerve association. At surgery, the tumor is found to arise eccentrically from the nerve sheath, often with
Extremely rare
Not reported
a pedicle or in a multilobulated shape. The tumor is well encapsulated, preventing nerve fasciculi from entering the lesion. Tumors of large nerves may be draped with fasciculi, whereas tumors of small nerves may expand the entire nerve. On gross examination, the cut surface is a homogenous, firm, whorling pattern of yellow-gray or gray-white striae with occasional cystic and hemorrhagic areas. Microscopic examination demonstrates interlacing fascicles of spindle cells with large oval nuclei giving a palisade-like appearance called Antoni type A. Less cellular regions with more abundant extracellular ground substance and less well defined patterns are termed Antoni type B areas. Pericapsular tissue may contain nerve fibers, but axons are not found within the lesion itself. Tumor cells are diffusely reactive to S-100 protein and somewhat less so to Leu-7 [21,22]. Mutations in a gene called schwanomin located on chromosome 22 can be found in 50% of sporadic schwannomas and in all acoustic schwannomas in patients with NF-2 [23]. The natural history of a schwannoma is benign, with malignant degeneration of a true schwannoma being exceedingly rare. Operative treatment may be indicated for symptomatic tumors or to reach a diagnosis in cases in which there is concern for a potential malignancy. Surgery involves an excisional biopsy with
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intraneural dissection enucleating the tumor and leaving other funicular groups intact. As many schwannomas arise eccentrically, they are often easily ‘‘shelled out’’ without damage to the underlying nerve fascicles [1]. If the tumor is not encapsulated or is adherent to the adjacent soft tissue, an incisional biopsy should be performed and further surgery delayed pending pathologic examination. Following excision, transient paresthesias may occur, but permanent neurologic deficits or tumor recurrence are unusual [1,2,11]. Neurofibroma The neurofibroma is another benign peripheral nerve sheath tumor that contains cells with Schwann cell origin. Neurofibromas occur in several forms: localized, dermal, and plexiform. Solitary localized tumors are the most common type, constituting 85% of upper extremity cases. Clinical symptoms and signs are indistinguishable from schwannomas [2,7,8], although pathologic features and surgical techniques differ (Table 2). NF-1 should be suspected in the setting of multiple neurofibromas, cafe-au-lait spots, iris Lisch nodules, other characteristic tumors, including optic gliomas, lipomas, sebaceous adenomas, and intestinal tumors, and specific bony lesions, such as kyphoscoliosis and tibial pseudoarthrosis. In the presence of neurofibromatosis, dermal and plexiform neurofibromas are common. Dermal neurofibromas originate from small
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nerves in the skin and infiltrate the dermis and subcutaneous tissue to form plaque-like swellings. Plexiform neurofibromas form palpable masses of thickened tortuous tissue along the course of small and large nerves. Local elephantiasis of an extremity or local gigantism of the hand may occur [24,25]. Surgical exploration of the localized or plexiform neurofibroma reveals a characteristic incorporation of nerve fascicles within the lesion. Unlike the eccentric and globoid-shaped schwannoma, the neurofibroma usually is located centrally, expanding the nerve in a fusiform fashion [11] (Fig. 1). Localized neurofibromas are not as well encapsulated as schwannomas and are not usually adherent to the adjacent soft tissues. The mass is palpably dense and the cut surface is gray to tan and without visible necrosis. Microscopy of the localized neurofibroma demonstrates interlacing bundles of an assortment of spindle-shaped cells that resemble Schwann cells, perineurial cells, and fibroblasts to varying degrees. Nerve fibers, highlighted by immunohistochemical staining for neurofilaments, arborize throughout the tumor mass, helping differentiate the neurofibroma from the schwannoma. Plexiform neurofibromas have a more expanded extracellular matrix with nodules of tortuous nerve branches cut in various planes of section. In general, neurofibromas stain poorly for S-100 and Leu-7 antigens compared with the schwannoma cell population [21,22]. Plexiform neurofibromas demonstrate
Table 2 Schwannoma and neurofibroma contrasted Feature
Schwannoma
Neurofibroma
Symptoms
Mass, occasional pain and Paresthesias Well encapsulated eccentric tumor mass displacing nerve fascicles Cellular and acellular areas with interlacing fascicles of spindle cells but no axons within the lesion itself Strong S-100 and Leu-7 staining Tumors may be ‘‘shelled-out’’ with preservation of nerve fascicles
Same as schwannoma
Gross pathology Histology
Immunohistochemistry Surgical technique
Caution
Cellular schwannomas must be distinguished pathologically from malignancy to avoid over treatment
Fusiform swelling of the nerve with tumor mass and fascicles intertwined Interlacing bundles of spindle cells with nerve fibers arborizing throughout the lesion Weaker S-100 and Leu-7 staining; neurofilament staining within the lesion Complete excision may require sacrifice of the nerve, although microdissection is sometimes possible Plexiform neurofibromas have a high risk for malignant change and should be biopsied in the setting of new pain, rapid growth, or neurologic deficit
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Fig. 1. (A) Coronal and (B) sagittal magnetic resonance images showing localized ring finger neurofibromas with fusiform swelling of both proper digital nerves.
mutations in chromosome 17 consistent with the genetic mutation inherited in NF-1 [26]. Malignant degeneration of a neurofibroma is rare in the absence of NF-1 [27]. In contrast, plexiform neurofibromas, seen almost exclusively in NF-1, have a high risk for progression to malignancy [28,29]. In this setting a mass that changes suddenly in size, becomes painful, or is associated with a neurologic deficit, must be biopsied to exclude malignant degeneration. Intraoperatively, tumors that are irregular in contour or invasive into the adjacent tissue should raise suspicion for malignancy. An incisional biopsy should be performed and a diagnosis reached before the definitive excision of the tumor. Removal of a neurofibroma is challenging because of the possibility of structural damage to the nerve during excision. Because the neurofibroma is intertwined intimately with the nerve fascicles, surgical excision may result in an increase in symptoms [1,3]. Traditionally, complete excision of a neurofibroma requires resection of the affected part of the nerve [11]. When nerve resection is performed, reconstruction by direct
approximation or nerve graft is recommended [8]. Alternatively, neurofibromas sometimes may be microdissected from large nerves, sparing many of the normal fascicles [7]. With microsurgical techniques, neurofibromas potentially may be dissected from digital nerves also [30]. Fascicle repair or nerve grafting may be indicated to decrease the risk for a neuroma-in-continuity. Microdissection usually is not feasible with the plexiform pattern. Granular cell tumor Granular cell tumors are benign peripheral nerve sheath tumors that arise most commonly in the tongue. Ten to twenty percent of granular cell tumors are found in the upper extremity. Most appear as a small, nontender, subcutaneous mass, occasionally firm and adherent to the dermis. Pain and pruritus occur in a minority of cases. Ten to twenty-five percent of granular cell tumors are multifocal [31–33]. A granular cell tumor may be found in association with a named nerve [34], digital nerve [35], or with no apparent nerve association.
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Sometimes the tumor is associated intimately with the nerve fascicles, although most lesions are differentiated easily from the adjacent soft tissues. Granular cell tumors formerly were called myoblastomas based on the large elongated cells with abundant granular eosinophilic cytoplasm seen under light microscopy. Analysis of the ultrastructure and histologic staining demonstrating the presence of antigenic markers for S-100 and Leu-7 now suggest a Schwann cell origin. Excisional biopsy is the treatment of choice for a granular cell tumor. Most tumors may be excised easily without disrupting a major motor or sensory nerve. As these lesions may be firm and tethered to the dermis, biopsy confirmation of a benign lesion is reassuring for the patient and surgeon. True malignant granular cell tumors comprise less than 3% of all reported cases [31,36] but have been reported in the upper extremity [34]. Resection of benign and malignant granular cell tumors may be curative [31,37–39]. When a large nerve is involved, fascicular dissection or nerve sacrifice and reconstruction should be considered.
Neurothekeoma and nerve sheath myxoma Neurothekeoma and nerve sheath myxoma are a benign, cutaneous tumor group that originates at least in part from the Schwann or perineurial cell. Most tumors arise as isolated, small, dermal lesions in the face or upper extremities of young adults and may be confused with neurofibromas [40–43]. A case involving the digital nerve has been reported [44]. Pathologic examination reveals nests and cords of large cells in a variably mucinous matrix and often in the proximity of small nerves. Myxoid (nerve sheath myxoma) and more cellular (neurothekeoma) configurations recently have been distinguished. The myxoid variant reliably demonstrates nerve sheath origin by immunohistochemistry, whereas the origin of the neurothekeoma remains unclear [45,46]. In either case, there is no tendency to undergo malignant degeneration, and excisional biopsy is usually curative [40,41].
Perineurioma The term perineurioma refers to two clinically distinct but cytologically related entities, the soft tissue perineurioma and the intraneural perineurioma. Both tumors stain positively for EMA and
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negative for S-100 protein, consistent with perineurial cell origin [47]. Monosomy of chromosome 22 also has been demonstrated in both lesions [48,49]. The soft tissue perineurioma was recognized only recently as a distinct benign peripheral nerve tumor [50], whereas the intraneural perineurioma, also called localized hypertrophic neuropathy, may not be a true neoplastic process [51,52]. Both lesions tend to occur in young adults and less commonly in children. Soft tissue perineuriomas arise as slow-growing, painless nodules in the trunk or extremities usually without a clear association to a nerve [47,53–55]. Grossly, soft tissue perineuriomas form well circumscribed unencapsulated lesions in the dermis or deeper subcutaneous tissues. A sclerosing subtype occurs in the fingers and palms [50,56,57]. Microscopically, soft tissue perineurioma are composed of perineurial cells arranged in whorls and interweaving fascicles [50]. Excision is performed with little risk for recurrence or neurologic injury [56–58]. Recently malignant peripheral nerve sheath tumors with perineurial differentiation have been reported [59,60]. Intraneural perineuriomas arise within peripheral nerves, resulting in severe motor and sensory loss. In the upper extremity, the brachial plexus, radial, ulnar, or median nerves may be involved [49,61–63]. Surgical exploration demonstrates localized, cylindric enlargement of the affected nerve. A proliferation of perineurial cells forming tightly packed pseudo-onion-bulb formations is seen microscopically [50]. There is no consensus regarding the management of intraneural perineuriomas. Malignant degeneration has not been reported. When necessary, resection combined with autogenous interpositional nerve grafting has restored some function compared with the preoperative state [61–63]. Nevertheless the natural history of the untreated disorder is not fully understood.
Malignant peripheral nerve sheath tumor Malignant peripheral nerve sheath tumors (MPNST) arise de novo or from malignant degeneration of a benign tumor, usually a plexiform neurofibroma. The cell of origin is believed to be the Schwann cell, although features of perineurial cells and fibroblasts are seen. The terms malignant schwannoma and neurofibrosarcoma have fallen out of favor, because distinguishing between these entities is problematic [64].
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In general, MPNST arise in the fourth and fifth decades of life except in patients with NF-1 for whom onset is typically a decade earlier [11,27]. Half of MPNST occur in patients with NF-1 [5,27,65]. The incidence of an MPNST in patients with NF-1 has been reported to be 2%–5% [27,66,67], although a recent longitudinal study suggests a lifetime risk as high as 13% [68]. Children are rarely affected [10,65]. MPNST usually involve large, deep nerves, although a nerve association is not always apparent [5]. Superficial cases, including digital nerve involvement, also have been described [69,70]. Approximately 20% of MPNST occur in the upper extremities [5], constituting approximately 3% of all malignant tumors of the hand [71,72]. Patients generally are not aware of these tumors until they become large. Symptoms such as pain, weakness, and numbness occur late [5]. Surgical exploration reveals a fusiform or oblong tumor mass with a thick pseudocapsule or intimate involvement with the adjacent soft tissue. Fascicles are found running through the lesion. The cut surface is firm and may demonstrate foci of necrosis unlike a schwannoma or neurofibroma. Light microscopy demonstrates interlacing and woven fascicles of spindle-shaped cells with the malignant characteristics of hyperchromasia, pleomorphism, and frequent mitosis. Approximately half of MPNST are reactive for S100 protein. Perineurial cell differentiation is sometimes seen and may confer a better prognosis [59,60,73]. The natural history of the untreated MPNST is metastasis by way of hematogenous spread and eventual death. Perineural extension and embolization of lymphatics also occurs. Early diagnosis and treatment provides the best chance of survival [5,27]. In patients with NF-1, any rapid growth of a neurofibroma or the development of symptoms such as pain or a neurologic deficit should raise concern for malignant degeneration. An incisional or needle biopsy provides definitive diagnosis. Treatment for nonmetastatic tumors involves radical resection or limb amputation. Local recurrence and metastasis are common and portend a poor prognosis [5,27,74]. Radiotherapy may help, but no chemotherapeutic regimen has proven effective [5,27,52]. Ducatman et al reported a median survival of 3 years from the time of diagnosis, with a 23% survival rate at 10 years. The presence of neurofibromatosis and tumor size greater than 5 cm was associated with a poor prognosis [27].
Miscellaneous tumors and tumor-like conditions Management of peripheral nerve tumors requires consideration of other neoplastic and tumor-like conditions that involve the peripheral nervous system. Rarely, lesions arise from local neoplastic proliferation of non-nervous tissues (eg, endothelial or adipose cells) [75–78] or from intraneural metastatic disease [79–81]. More commonly, nerves undergo hamartomatous, hyperplastic, traumatic, or other processes resulting in a mass that must be differentiated from a peripheral nerve sheath tumor. The more common examples are discussed below. Fibrolipomatous hamartoma of nerve is a benign tumor-like condition affecting children and young adults. Most reported cases involve the median nerve causing unilateral volar forearm and palm swelling, with carpal tunnel-like symptoms. Up to two thirds of patients also have distal soft tissue and bone overgrowth causing macrodactyly [82,83]. Less commonly, the ulnar, radial, or digital nerves may be involved [84–86]. Surgical exploration reveals fusiform expansion of the nerve by a fibrofatty infiltrate [87]. Consistently good outcomes with biopsy, limited soft tissue excision, and carpal tunnel release have been reported, although recurrent compressive neuropathy and tissue overgrowth is possible [83,87]. Neuromuscular hamartoma (also known as benign triton tumor) describes an exceedingly rare multilobulated proliferation of mature skeletal muscle and neural elements typically located about the large nerve trunks of infants and young children. The brachial plexus and sciatic nerve are involved most commonly. Functional impairment of affected nerves has not been reported in the upper extremity. Although complete surgical excision without recurrence is possible, postoperative nerve deficits have occurred [88–90]. The mass may regress with time, arguing against complete excision [89]. A hyperplastic proliferation of pacinian corpuscles forms the so called ‘‘Pacinian neuroma.’’ This rare tumor-like process usually manifests as a painful, solid dermal nodule on the digit of a middle-aged adult [41]. Fletcher and Theaker reported two cases out of 824 peripheral nerve sheath tumors (0.2%) [91]. The lesion also may occur in children [92]. Surgery reveals a nonencapsulated, soft, yellow, lobulated mass resembling adipose tissue. The mass may be fixed to a digital nerve but usually can be excised with preservation of the nerve fascicles.
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A traumatic neuroma on occasion may need to be differentiated from a benign or malignant nerve tumor. A neuroma forms following disruption of a peripheral nerve. The lesion consists of a nonneoplastic proliferation of Schwann cells with aimless growth of endoneural tubes and axons. A variety of treatment options exist for traumatic neuroma, but persistent symptoms are common. A nerve sheath ganglion is a mucin-filled cyst that arises within the epineurium. Most nerve sheath ganglia occur about the peroneal nerve, although cases involving the median, ulnar, and radial nerves have been reported [93–100]. When nerve compression causes pain or neural disturbance, careful excision with preservation of nerve fascicles is warranted. Summary Tumors of peripheral nerve origin are usually slow growing and minimally symptomatic. Differentiation from other soft tissue neoplasms often requires microscopic examination, including ultrastructural and immunohistochemical analysis. Complete excision of benign nerve tumors actually may result in an unsatisfactory outcome because of the difficulty of separating neoplastic tissue from normal nerve fascicles. Malignant peripheral nerve sheath tumors have a poor prognosis and should be suspected when a tumor is large or invasive. Radical resection provides the greatest chance of survival. A host of other neoplastic or tumor-like lesions also occur within the peripheral nerve. As preoperative diagnosis is difficult, strict adherence to the principles of tumor biopsy and excision is essential. References [1] Phalen GS. Neurilemomas of the forearm and hand. Clin Orthop 1976;114:219–22. [2] Holdsworth BJ. Nerve tumours in the upper limb. A clinical review. J Hand Surg [Br] 1985;10(2):236–8. [3] Kehoe NJ, Reid RP, Semple JC. Solitary benign peripheral-nerve tumours. Review of 32 years’ experience. J Bone Joint Surg [Br] 1995;77(3):497–500. [4] Das Gupta TK, Brasfield RD, Strong EW, Hajdu SI. Benign solitary Schwannomas (neurilemomas). Cancer 1969;24(2):355–66. [5] Nambisan RN, Rao U, Moore R, Karakousis CP. Malignant soft tissue tumors of nerve sheath origin. J Surg Oncol 1984;25(4):268–72. [6] Bogumill GP, Sullivan DJ, Baker GI. Tumors of the hand. Clin Orthop 1975;108:214–22.
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Nerve tumors of the hand and upper extremity Christopher L. Forthman, MD, Philip E. Blazar, MD* Department of Orthopaedic Surgery, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA
Nerve tumors arise in a similar fashion as other upper extremity neoplasms. Benign nerve tumors typically grow slowly and with few symptoms, whereas malignant tumors tend to grow faster and with more pain. Neural dysfunction is not typically a feature in either case [1–5]. Consequently, confusion with other more common neoplasms and tumor-like processes is frequent [2,3,6]. Nerve tumors are overlooked in the differential diagnosis, because they comprise only 5% of upper extremity tumors in adults [7–9] and 2% in children [10]. Inappropriate surgery can be disastrous, resulting in irreversible loss of function [1,11]. The evaluation of upper extremity soft tissue masses includes CT and MRI. Although useful for delineating the surrounding anatomy and planning a surgical approach, neither technique reliably distinguishes tumors of nerve origin from other neoplasms [12]. Rarely localization of the tumor to the vicinity of a large nerve trunk suggests a peripheral nerve tumor [13]. More commonly these imaging techniques are useful for demonstrating characteristics of a malignant neoplasm, such as large size, invasion into adjacent tissues, and tumor necrosis. Management of the patient with any upper extremity mass must be undertaken recognizing the possibility of a peripheral nerve neoplasm. All patients must be warned of postoperative pain at the tumor site and possible loss of nerve function. Strict tumor surgery techniques should be followed. When malignancy is suspected, an incisional biopsy is appropriate, with definitive
* Corresponding author. E-mail address: [email protected] (P.E. Blazar).
treatment delayed until the histologic diagnosis is confirmed.
Peripheral nerve anatomy Tumors of the peripheral nerve usually arise from and resemble cellular components of the nerve sheath. The normal sheath consists of a thin outer layer of fibrous tissue, the epineurium. Deep to the epineurium there are one or more nerve fascicles, each surrounded by a flattened, lamellated, perineurial cell layer. Within each fascicle, bundles of axons are encased within endoneural tubes, the protective and supportive coverings formed by Schwann cells and endoneural fibroblasts. Peripheral nerve tissue components may be differentiated by light microscopy, electron microscopy, and immunohistochemistry. These diagnostic techniques assist the pathologist in determining the cell of origin for any given tumor (Table 1). Schwann cells characteristically have a small cell body with processes enwrapping other structures; the axon in the normal situation. Electron microscopy confirms these features together with a pathognomonic basal lamina and granular intercellular basement membrane. Schwann cells always stain with antigenic markers for S-100 and frequently stain for Leu-7 (HNK-1). Perineurial cells, in contrast, are larger, spindleshaped cells with elongated nuclei and long tapering cell processes. Electron microscopy is capable of identifying such features and the characteristic micropinocytotic vesicles. Perineurial cells do not stain for S-100 and Leu-7 proteins, but they do stain for epithelial membrane antigen (EMA) [14,15].
0749-0712/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.hcl.2004.03.003
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Table 1 Features of benign peripheral nerve tumors Tumor
Cell origin
Schwannoma
Schwann
Neurofibroma
Schwann
Granular cell
Schwann
Neurothekeoma
Unclear
Nerve sheath Myxoma PerineuriomaSoft tissue PerineuriomaIntraneural
Schwann, Perineural Perineural Perineural Neoplastic ?
Malignant change
Immunohistochemistry
Genetics
Strongly stain for S-100 and moderately stain for Leu-7. No neurofilament staining within the lesion. Poorly stain for S-100 and Leu-7. Neurofilament stain identifies nerve fibers in the lesion. Moderately stain for S-100 and Leu-7 Poorly stain for S-100 and Leu-7 Strongly stain for S-100, Leu-7, and EMA Strongly stain for EMA but not S-100 Strongly stain for EMA but not S-100
50% of sporadic tumors have mutation in chromosome 22, similar to NF-2 Plexiform neurofibromas have mutation in chromosome 17, similar to NF-1 Unclear
Very rare in the absence of NF-1. Plexiform type has a high risk for malignant change. Less than 3%
Unclear
Not reported
Unclear
Not reported
Common monosomy of chromosome 22 Common monosomy of chromosome 22
Few reports
Schwannoma The schwannoma is a benign peripheral nerve sheath tumor arising from the Schwann cell. It is the most common solitary tumor of the peripheral nerve [1]. The tumor typically presents in the middle decades of life [1,11], although childhood cases have been reported [3,16]. Patients with neurofibromatosis type 1 (NF-1 or von Recklinghausen disease) may suffer from multiple schwannomas involving large peripheral nerve trunks. Patients with neurofibromatosis type 2 (NF-2) suffer from bilateral acoustic schwannomas. Multiple tumors occasionally are found in patients without neurofibromatosis [17,18]. Schwannomas are typically painless, slowgrowing, isolated, firm, round, soft tissue masses. Discomfort and paresthesias may occur [1– 3,9,11,19]. In the upper extremity, the flexor surface is the most common site owing to the presence of the large nerves in the volar forearm and palm [1,2,4,20]. The tumor may be of variable size depending on the anatomic location, although most schwannomas are less than 2.5 cm in diameter [4]. The tumors may be found tethered in the longitudinal axis of the limb and in the line of a peripheral nerve. In some cases, there is no apparent nerve association. At surgery, the tumor is found to arise eccentrically from the nerve sheath, often with
Extremely rare
Not reported
a pedicle or in a multilobulated shape. The tumor is well encapsulated, preventing nerve fasciculi from entering the lesion. Tumors of large nerves may be draped with fasciculi, whereas tumors of small nerves may expand the entire nerve. On gross examination, the cut surface is a homogenous, firm, whorling pattern of yellow-gray or gray-white striae with occasional cystic and hemorrhagic areas. Microscopic examination demonstrates interlacing fascicles of spindle cells with large oval nuclei giving a palisade-like appearance called Antoni type A. Less cellular regions with more abundant extracellular ground substance and less well defined patterns are termed Antoni type B areas. Pericapsular tissue may contain nerve fibers, but axons are not found within the lesion itself. Tumor cells are diffusely reactive to S-100 protein and somewhat less so to Leu-7 [21,22]. Mutations in a gene called schwanomin located on chromosome 22 can be found in 50% of sporadic schwannomas and in all acoustic schwannomas in patients with NF-2 [23]. The natural history of a schwannoma is benign, with malignant degeneration of a true schwannoma being exceedingly rare. Operative treatment may be indicated for symptomatic tumors or to reach a diagnosis in cases in which there is concern for a potential malignancy. Surgery involves an excisional biopsy with
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intraneural dissection enucleating the tumor and leaving other funicular groups intact. As many schwannomas arise eccentrically, they are often easily ‘‘shelled out’’ without damage to the underlying nerve fascicles [1]. If the tumor is not encapsulated or is adherent to the adjacent soft tissue, an incisional biopsy should be performed and further surgery delayed pending pathologic examination. Following excision, transient paresthesias may occur, but permanent neurologic deficits or tumor recurrence are unusual [1,2,11]. Neurofibroma The neurofibroma is another benign peripheral nerve sheath tumor that contains cells with Schwann cell origin. Neurofibromas occur in several forms: localized, dermal, and plexiform. Solitary localized tumors are the most common type, constituting 85% of upper extremity cases. Clinical symptoms and signs are indistinguishable from schwannomas [2,7,8], although pathologic features and surgical techniques differ (Table 2). NF-1 should be suspected in the setting of multiple neurofibromas, cafe-au-lait spots, iris Lisch nodules, other characteristic tumors, including optic gliomas, lipomas, sebaceous adenomas, and intestinal tumors, and specific bony lesions, such as kyphoscoliosis and tibial pseudoarthrosis. In the presence of neurofibromatosis, dermal and plexiform neurofibromas are common. Dermal neurofibromas originate from small
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nerves in the skin and infiltrate the dermis and subcutaneous tissue to form plaque-like swellings. Plexiform neurofibromas form palpable masses of thickened tortuous tissue along the course of small and large nerves. Local elephantiasis of an extremity or local gigantism of the hand may occur [24,25]. Surgical exploration of the localized or plexiform neurofibroma reveals a characteristic incorporation of nerve fascicles within the lesion. Unlike the eccentric and globoid-shaped schwannoma, the neurofibroma usually is located centrally, expanding the nerve in a fusiform fashion [11] (Fig. 1). Localized neurofibromas are not as well encapsulated as schwannomas and are not usually adherent to the adjacent soft tissues. The mass is palpably dense and the cut surface is gray to tan and without visible necrosis. Microscopy of the localized neurofibroma demonstrates interlacing bundles of an assortment of spindle-shaped cells that resemble Schwann cells, perineurial cells, and fibroblasts to varying degrees. Nerve fibers, highlighted by immunohistochemical staining for neurofilaments, arborize throughout the tumor mass, helping differentiate the neurofibroma from the schwannoma. Plexiform neurofibromas have a more expanded extracellular matrix with nodules of tortuous nerve branches cut in various planes of section. In general, neurofibromas stain poorly for S-100 and Leu-7 antigens compared with the schwannoma cell population [21,22]. Plexiform neurofibromas demonstrate
Table 2 Schwannoma and neurofibroma contrasted Feature
Schwannoma
Neurofibroma
Symptoms
Mass, occasional pain and Paresthesias Well encapsulated eccentric tumor mass displacing nerve fascicles Cellular and acellular areas with interlacing fascicles of spindle cells but no axons within the lesion itself Strong S-100 and Leu-7 staining Tumors may be ‘‘shelled-out’’ with preservation of nerve fascicles
Same as schwannoma
Gross pathology Histology
Immunohistochemistry Surgical technique
Caution
Cellular schwannomas must be distinguished pathologically from malignancy to avoid over treatment
Fusiform swelling of the nerve with tumor mass and fascicles intertwined Interlacing bundles of spindle cells with nerve fibers arborizing throughout the lesion Weaker S-100 and Leu-7 staining; neurofilament staining within the lesion Complete excision may require sacrifice of the nerve, although microdissection is sometimes possible Plexiform neurofibromas have a high risk for malignant change and should be biopsied in the setting of new pain, rapid growth, or neurologic deficit
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Fig. 1. (A) Coronal and (B) sagittal magnetic resonance images showing localized ring finger neurofibromas with fusiform swelling of both proper digital nerves.
mutations in chromosome 17 consistent with the genetic mutation inherited in NF-1 [26]. Malignant degeneration of a neurofibroma is rare in the absence of NF-1 [27]. In contrast, plexiform neurofibromas, seen almost exclusively in NF-1, have a high risk for progression to malignancy [28,29]. In this setting a mass that changes suddenly in size, becomes painful, or is associated with a neurologic deficit, must be biopsied to exclude malignant degeneration. Intraoperatively, tumors that are irregular in contour or invasive into the adjacent tissue should raise suspicion for malignancy. An incisional biopsy should be performed and a diagnosis reached before the definitive excision of the tumor. Removal of a neurofibroma is challenging because of the possibility of structural damage to the nerve during excision. Because the neurofibroma is intertwined intimately with the nerve fascicles, surgical excision may result in an increase in symptoms [1,3]. Traditionally, complete excision of a neurofibroma requires resection of the affected part of the nerve [11]. When nerve resection is performed, reconstruction by direct
approximation or nerve graft is recommended [8]. Alternatively, neurofibromas sometimes may be microdissected from large nerves, sparing many of the normal fascicles [7]. With microsurgical techniques, neurofibromas potentially may be dissected from digital nerves also [30]. Fascicle repair or nerve grafting may be indicated to decrease the risk for a neuroma-in-continuity. Microdissection usually is not feasible with the plexiform pattern. Granular cell tumor Granular cell tumors are benign peripheral nerve sheath tumors that arise most commonly in the tongue. Ten to twenty percent of granular cell tumors are found in the upper extremity. Most appear as a small, nontender, subcutaneous mass, occasionally firm and adherent to the dermis. Pain and pruritus occur in a minority of cases. Ten to twenty-five percent of granular cell tumors are multifocal [31–33]. A granular cell tumor may be found in association with a named nerve [34], digital nerve [35], or with no apparent nerve association.
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Sometimes the tumor is associated intimately with the nerve fascicles, although most lesions are differentiated easily from the adjacent soft tissues. Granular cell tumors formerly were called myoblastomas based on the large elongated cells with abundant granular eosinophilic cytoplasm seen under light microscopy. Analysis of the ultrastructure and histologic staining demonstrating the presence of antigenic markers for S-100 and Leu-7 now suggest a Schwann cell origin. Excisional biopsy is the treatment of choice for a granular cell tumor. Most tumors may be excised easily without disrupting a major motor or sensory nerve. As these lesions may be firm and tethered to the dermis, biopsy confirmation of a benign lesion is reassuring for the patient and surgeon. True malignant granular cell tumors comprise less than 3% of all reported cases [31,36] but have been reported in the upper extremity [34]. Resection of benign and malignant granular cell tumors may be curative [31,37–39]. When a large nerve is involved, fascicular dissection or nerve sacrifice and reconstruction should be considered.
Neurothekeoma and nerve sheath myxoma Neurothekeoma and nerve sheath myxoma are a benign, cutaneous tumor group that originates at least in part from the Schwann or perineurial cell. Most tumors arise as isolated, small, dermal lesions in the face or upper extremities of young adults and may be confused with neurofibromas [40–43]. A case involving the digital nerve has been reported [44]. Pathologic examination reveals nests and cords of large cells in a variably mucinous matrix and often in the proximity of small nerves. Myxoid (nerve sheath myxoma) and more cellular (neurothekeoma) configurations recently have been distinguished. The myxoid variant reliably demonstrates nerve sheath origin by immunohistochemistry, whereas the origin of the neurothekeoma remains unclear [45,46]. In either case, there is no tendency to undergo malignant degeneration, and excisional biopsy is usually curative [40,41].
Perineurioma The term perineurioma refers to two clinically distinct but cytologically related entities, the soft tissue perineurioma and the intraneural perineurioma. Both tumors stain positively for EMA and
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negative for S-100 protein, consistent with perineurial cell origin [47]. Monosomy of chromosome 22 also has been demonstrated in both lesions [48,49]. The soft tissue perineurioma was recognized only recently as a distinct benign peripheral nerve tumor [50], whereas the intraneural perineurioma, also called localized hypertrophic neuropathy, may not be a true neoplastic process [51,52]. Both lesions tend to occur in young adults and less commonly in children. Soft tissue perineuriomas arise as slow-growing, painless nodules in the trunk or extremities usually without a clear association to a nerve [47,53–55]. Grossly, soft tissue perineuriomas form well circumscribed unencapsulated lesions in the dermis or deeper subcutaneous tissues. A sclerosing subtype occurs in the fingers and palms [50,56,57]. Microscopically, soft tissue perineurioma are composed of perineurial cells arranged in whorls and interweaving fascicles [50]. Excision is performed with little risk for recurrence or neurologic injury [56–58]. Recently malignant peripheral nerve sheath tumors with perineurial differentiation have been reported [59,60]. Intraneural perineuriomas arise within peripheral nerves, resulting in severe motor and sensory loss. In the upper extremity, the brachial plexus, radial, ulnar, or median nerves may be involved [49,61–63]. Surgical exploration demonstrates localized, cylindric enlargement of the affected nerve. A proliferation of perineurial cells forming tightly packed pseudo-onion-bulb formations is seen microscopically [50]. There is no consensus regarding the management of intraneural perineuriomas. Malignant degeneration has not been reported. When necessary, resection combined with autogenous interpositional nerve grafting has restored some function compared with the preoperative state [61–63]. Nevertheless the natural history of the untreated disorder is not fully understood.
Malignant peripheral nerve sheath tumor Malignant peripheral nerve sheath tumors (MPNST) arise de novo or from malignant degeneration of a benign tumor, usually a plexiform neurofibroma. The cell of origin is believed to be the Schwann cell, although features of perineurial cells and fibroblasts are seen. The terms malignant schwannoma and neurofibrosarcoma have fallen out of favor, because distinguishing between these entities is problematic [64].
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In general, MPNST arise in the fourth and fifth decades of life except in patients with NF-1 for whom onset is typically a decade earlier [11,27]. Half of MPNST occur in patients with NF-1 [5,27,65]. The incidence of an MPNST in patients with NF-1 has been reported to be 2%–5% [27,66,67], although a recent longitudinal study suggests a lifetime risk as high as 13% [68]. Children are rarely affected [10,65]. MPNST usually involve large, deep nerves, although a nerve association is not always apparent [5]. Superficial cases, including digital nerve involvement, also have been described [69,70]. Approximately 20% of MPNST occur in the upper extremities [5], constituting approximately 3% of all malignant tumors of the hand [71,72]. Patients generally are not aware of these tumors until they become large. Symptoms such as pain, weakness, and numbness occur late [5]. Surgical exploration reveals a fusiform or oblong tumor mass with a thick pseudocapsule or intimate involvement with the adjacent soft tissue. Fascicles are found running through the lesion. The cut surface is firm and may demonstrate foci of necrosis unlike a schwannoma or neurofibroma. Light microscopy demonstrates interlacing and woven fascicles of spindle-shaped cells with the malignant characteristics of hyperchromasia, pleomorphism, and frequent mitosis. Approximately half of MPNST are reactive for S100 protein. Perineurial cell differentiation is sometimes seen and may confer a better prognosis [59,60,73]. The natural history of the untreated MPNST is metastasis by way of hematogenous spread and eventual death. Perineural extension and embolization of lymphatics also occurs. Early diagnosis and treatment provides the best chance of survival [5,27]. In patients with NF-1, any rapid growth of a neurofibroma or the development of symptoms such as pain or a neurologic deficit should raise concern for malignant degeneration. An incisional or needle biopsy provides definitive diagnosis. Treatment for nonmetastatic tumors involves radical resection or limb amputation. Local recurrence and metastasis are common and portend a poor prognosis [5,27,74]. Radiotherapy may help, but no chemotherapeutic regimen has proven effective [5,27,52]. Ducatman et al reported a median survival of 3 years from the time of diagnosis, with a 23% survival rate at 10 years. The presence of neurofibromatosis and tumor size greater than 5 cm was associated with a poor prognosis [27].
Miscellaneous tumors and tumor-like conditions Management of peripheral nerve tumors requires consideration of other neoplastic and tumor-like conditions that involve the peripheral nervous system. Rarely, lesions arise from local neoplastic proliferation of non-nervous tissues (eg, endothelial or adipose cells) [75–78] or from intraneural metastatic disease [79–81]. More commonly, nerves undergo hamartomatous, hyperplastic, traumatic, or other processes resulting in a mass that must be differentiated from a peripheral nerve sheath tumor. The more common examples are discussed below. Fibrolipomatous hamartoma of nerve is a benign tumor-like condition affecting children and young adults. Most reported cases involve the median nerve causing unilateral volar forearm and palm swelling, with carpal tunnel-like symptoms. Up to two thirds of patients also have distal soft tissue and bone overgrowth causing macrodactyly [82,83]. Less commonly, the ulnar, radial, or digital nerves may be involved [84–86]. Surgical exploration reveals fusiform expansion of the nerve by a fibrofatty infiltrate [87]. Consistently good outcomes with biopsy, limited soft tissue excision, and carpal tunnel release have been reported, although recurrent compressive neuropathy and tissue overgrowth is possible [83,87]. Neuromuscular hamartoma (also known as benign triton tumor) describes an exceedingly rare multilobulated proliferation of mature skeletal muscle and neural elements typically located about the large nerve trunks of infants and young children. The brachial plexus and sciatic nerve are involved most commonly. Functional impairment of affected nerves has not been reported in the upper extremity. Although complete surgical excision without recurrence is possible, postoperative nerve deficits have occurred [88–90]. The mass may regress with time, arguing against complete excision [89]. A hyperplastic proliferation of pacinian corpuscles forms the so called ‘‘Pacinian neuroma.’’ This rare tumor-like process usually manifests as a painful, solid dermal nodule on the digit of a middle-aged adult [41]. Fletcher and Theaker reported two cases out of 824 peripheral nerve sheath tumors (0.2%) [91]. The lesion also may occur in children [92]. Surgery reveals a nonencapsulated, soft, yellow, lobulated mass resembling adipose tissue. The mass may be fixed to a digital nerve but usually can be excised with preservation of the nerve fascicles.
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A traumatic neuroma on occasion may need to be differentiated from a benign or malignant nerve tumor. A neuroma forms following disruption of a peripheral nerve. The lesion consists of a nonneoplastic proliferation of Schwann cells with aimless growth of endoneural tubes and axons. A variety of treatment options exist for traumatic neuroma, but persistent symptoms are common. A nerve sheath ganglion is a mucin-filled cyst that arises within the epineurium. Most nerve sheath ganglia occur about the peroneal nerve, although cases involving the median, ulnar, and radial nerves have been reported [93–100]. When nerve compression causes pain or neural disturbance, careful excision with preservation of nerve fascicles is warranted. Summary Tumors of peripheral nerve origin are usually slow growing and minimally symptomatic. Differentiation from other soft tissue neoplasms often requires microscopic examination, including ultrastructural and immunohistochemical analysis. Complete excision of benign nerve tumors actually may result in an unsatisfactory outcome because of the difficulty of separating neoplastic tissue from normal nerve fascicles. Malignant peripheral nerve sheath tumors have a poor prognosis and should be suspected when a tumor is large or invasive. Radical resection provides the greatest chance of survival. A host of other neoplastic or tumor-like lesions also occur within the peripheral nerve. As preoperative diagnosis is difficult, strict adherence to the principles of tumor biopsy and excision is essential. References [1] Phalen GS. Neurilemomas of the forearm and hand. Clin Orthop 1976;114:219–22. [2] Holdsworth BJ. Nerve tumours in the upper limb. A clinical review. J Hand Surg [Br] 1985;10(2):236–8. [3] Kehoe NJ, Reid RP, Semple JC. Solitary benign peripheral-nerve tumours. Review of 32 years’ experience. J Bone Joint Surg [Br] 1995;77(3):497–500. [4] Das Gupta TK, Brasfield RD, Strong EW, Hajdu SI. Benign solitary Schwannomas (neurilemomas). Cancer 1969;24(2):355–66. [5] Nambisan RN, Rao U, Moore R, Karakousis CP. Malignant soft tissue tumors of nerve sheath origin. J Surg Oncol 1984;25(4):268–72. [6] Bogumill GP, Sullivan DJ, Baker GI. Tumors of the hand. Clin Orthop 1975;108:214–22.
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