Pedal plexiform neurofibroma: Review of the literature and case report

Pedal Plexiform Neurofibroma: Review of the Literature and Case Report Neal M. Blitz, OPM,1 Byron Hutchinson, OPM,2 and Michael V. Grabowski, M03 Plexiform neurofibroma typically occurs in the setting of neurofibromatosis type 1, and is included in the diagnostic criteria for neurofibromatosis. Plexiform neurofibromas generally affect larger peripheral nerves and are uncommon in the foot and ankle. While there are several reports of large neurofibromas involving the foot, they have been described on the plantar aspect. We report the first known case of plexiform neurofibroma involving the deep peroneal nerve of the foot. A review of the literature is also presented. (The Journal of Foot & Ankle Surgery 41(2):117 -124, 2002) Key words: benign nerve sheath tumors, neurofibromatosis, plexiform neurofibroma

Plexiform neurofibroma (PNF) is a benign nerve tumor resulting from aberrant growth of the cells of the nerve sheath (1). It is composed of schwann cells, perineurial-like cells, and fibroblasts (2). It originates from the central aspect of the nerve and involves multiple fascicles. Although the fascicles are usually preserved, a diffusely enlarged, thickened, irregular, and tortuous nerve is produced. Its morphologic appearance is classically compared to a "bag of worms" or "rosary beads"(3). The PNF typically occurs in the setting of neurofibromatosis (NF) and is considered the hallmark for neurofibromatosis type I (NF-I). A solitary PNF is not diagnostic of NF; however, its presence should alert the physician to search for other stigmata (4). Diagnosis of NF-I is clinically based on the National Institutes of Health criteria (Table 1) (5). In the lower extremity, most PNFs do not require medical management unless patients complain of pain, ambulation difficulties, gross disfigurement, ancl/or rapid tumor growth. Case Report

A 20-year-old female with NF presented with a 4month history of a growing mass on the dorsum of her foot resulting in difficulty ambulating in shoe gear. She denied a history of local trauma or neurologic symptoms, From Swedish Medical Center-Providence Campus, Seattle, WA. Address correspondence to: Neal M. Blitz, DPM, Swedish Medical Center - Providence Campus, 550 16th Avenue, Suite 302, Seattle, WA 98122. I Chief Surgical Resident, Northwest Podiatric Surgical Residency Program. 2 Attending Surgeon, Northwest Podiatric Surgical Residency Program. 3 Chairman, Department of Pathology. Received for publication January 30, 2001; accepted in revised form for publication November 15,2001. The Journal of Foot & Ankle Surgery 1067-2516/02/4102-0117$4.00/0 Copyright © 2002 by the American College of Foot and Ankle Surgeons

including paresthesias and motor dysfunction. On physical examination, a large movable soft mass was evident over the dorsal surface of the midfoot, with the bulk located at the level of the extensor digitorum brevis muscle belly. The skin was supple without discoloration. Muscle strength and vascular status were intact. She had several findings inclusive for a diagnosis of NF: multiple cafe-au-lair spots, axillary freckling, and a first-degree relative with NF. Plain-film radiographs were without abnormality. Magnetic resonance imaging demonstrated a large softtissue mass located over the tarsus that was hypointense to muscle on T'l-weighted images with a homogeneous increased signal on T2-weighted images (Fig. 1). The mass appeared to infiltrate surrounding soft-tissue structures, making its margins difficult to delineate. The osseous structures were without cystic changes or erosion. Surgical exploration revealed two large, irregular, tortuous masses corresponding to the medial and lateral branches of the deep peroneal nerve (Fig. 2). The medial mass was intertwined around the dorsalis pedis artery, which was sacrificed for complete removal. The lateral mass infiltrated the extensor digitorum brevis muscle belly by displacing the muscle fibers. A portion of muscle belly and tendons were excised to ensure complete removal. The lesions were removed as two specimens. The medial mass measured 7.2 cm in length with variable diameter of 0.5-1.7 em. The lateral mass measured 6.5 x 4.7 x 1.8 cm. Grossly, the specimens were tangled masses of discrete rope-like neurofibromatous tissue. Microscopic evaluation revealed pseudoencapsulated masses of rather uniform and bland small spindle shaped cells with tiny comma-like nuclei arranged in wavy patterns (Fig. 3). There was no mitotic activity, atypia, or pleomorphism. A diagnosis of PNF was made. At l-year follow-up, there was no sign of recurrence on physical examination. She is asymptomatic and ambulates in shoes without difficulty. She denies any hypesthesia to the dorsum of the foot. VOLUME 41, NUMBER 2, MARCH/APRIL 2002

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TABLE 1 Diagnostic criteria for neurofibromatosis type 1(5) The patient should have two or more of the following: 1. Six or more cate-au-lait macules larger than: 1.5 cm or larger in postpubertal individuals 0.5 cm or larger in prepubertal individuals 2. Two or more neurofibromas of any type or one plexiform neurofibroma 3. Freckling in the axillary or inguinal regions 4. Optic glioma 5. Two or more Lisch nodules 6. A distinctive osseous lesion: Dysplasiaof the sphenoid bone or thinning of long bone cortex 7. A first degree relative with NF-1 (with the above criteria)

Discussion Plexiform neurofibroma typically occurs in the setting of neurofibromatosis and is included in the criteria for its diagno sis. Neurofibromatosis is a genetic disorder of chromosonal mutation resulting in cutaneous lesions, skeletal abnormalities, and neuro geni c neoplasia. Any peripheral nerve is susceptible to PNF form ation ( I ). However, there is a predilection for larger

periph eral nerves of the face, neck , and extremities (2). Because deeper nerves are intimately associated with a vascular network, these structures may be intertw ined within the tortuou s nature of PNF. Moreover, they are unencapsulated and may infiltrate surrounding muscle fibers and adipo se tissue. Some tumors may be a few centimeters in both diamet er and length while others involve an entire limb , a condition referred to as elephantiasis neuromatosa (6, 7). Congenital gianti sm of the foot is kno wn to occur with NF and is usuall y unilateral (8). The onset is variable since PNF may develop throu ghout life and are usuall y present since birth (9). Increased grow th rates occur durin g childhood or hormonal change s, such as puberty or pregnanc y ( 10). Trauma is thou ght to be an inciting factor, but no clear association has been made (1,9). Because they are typically painless, PNFs may go unnoticed until they become palpable or cause dysfun ction of surrounding structures . Deeper lower extremity tumors may result in venous stas is. Pre ssure from shoe gear and difficult y ambul ating may unm ask masses in the foot and ankle sooner than areas padd ed by more soft tissue, such as the thigh, abdomen, or upper extremities .

FIGURE 1 A, Sagittal T1-weighted magnetic resonance images exhibiting inhomogenous large mass of intermediate signal intensity. Note extent of the mass across the foot (closed arrows). (Continued).

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FIGURE 1 arrows).

(Continued). B, Sagittal fat-suppressed magnetic resonance image of PNF demonstrating an increased signal intensity (open

FIGURE 2

Intraoperative photograph revealing large PNF of the deep peroneal nerve of the foot infiltrating the extensor digitorum brevis

muscle.

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FIGURE 3 A, A photomicrograph cross section showing the nerve tissue surrounding the adjacent skeletal muscle fibers. Hematoxylin and eosin, original magnification x 40. B, A photomicrograph demonstrating thin spindle-shaped cells with wavy nuclei. Hematoxylin and eosin, original magnification x 40.

Plexiform neurofibroma may have dramatic effects on surrounding skin, soft tissues, and osseous architecture. Overlying skin and soft tissue may undergo hypertrophy as well as pigmentary changes (7,11). In some instances, 120

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the skin may develop an orange discoloration (II). Cafeau-lait spots are often cutaneous markers for underlying PNF. A large variety of bony abnormalities are associated with NF, and may be directly associated with PNF.

Long bones may exhibit cortical dysplasia, metaphyseal and diaphyseal sclerosis, intramedullary linear sclerosis, subperiosteal or cortical cystic lesions, pathological fracture, and pseudoarthrosis (6, 12). The diagnosis of PNF is usually straightforward in patients with known NF, underscoring the need to search for the stigmata of NF. Clinically, the lesions are often asymptomatic and may be discovered by palpation, revealing a soft movable mass. Radiographically they are not identifiable, although a soft-tissue shadow may be seen. Rather, conventional radiographs are utilized to evaluate for osseous invasion, suggesting sarcomatous transformation. Because of the osseous irregularities associated with NF-l, the presence of osseous changes does not dictate sarcomatous transformation (13). Softtissue mineralization is suggestive of malignancy; however, it may occur in other benign lesions of heterotopic calcification, lipomas, chondromas, and hemangiomas (14). Plexiform neurofibroma typically reveals a noncharacteristic appearance with MR imaging and is often misdiagnosed when a history of NF is unclear. With Tlweighted images, PNFs have a varied appearance, but are usually isointense with respect to muscle. On T2-weighted imaging, they often exhibit increased signal intensity with a central zone of lower signal intensity, coined the "target sign" (1, 15). This central inhomogeneity is due to hemorrhage, fibrosis, necrosis, and/or variations in cellularity (16, 17). The high water content results in the signal characteristics on T2-weighted images (13). A variety of neurogenic soft-tissue tumors are common to NF-l: neurofibroma, plexiform neurofibroma, and malignant peripheral nerve sheath tumor (MPNST) (16). Neurofibromas are cutaneous nodules which are soft, movable, and painless. Some patients may have few to none while others exhibit total body involvement. A history of trauma associated with paresthesias, pain, hypersensitivity, and possibly phantom limb pain suggests a traumatic neuroma. Sites of previous surgery are suspicious for stump neuromas. Morton's neuroma typically occurs in the third intermetatarsal space of the foot and is easily diagnosed. It may have a plexiform appearance but should not be confused with a PNF (18). Neuronal fibrolipoma generally involves the median nerve of the upper extremity in infants and children (19). Lipomas demonstrate an identical signal appearance to adipose tissue on all MRI sequences (13, 20). An intraneural ganglion may affect any nerve; however, it most often involves the common peroneal nerve at the fibular head and patients may present with a dropfoot (21). An eccentrically situated encapsulated mass originating from a peripheral nerve on a flexor surface suggests a benign schwannoma (neurilemmoma). Malignant peripheral nerve sheath tumor developing from pre-existing

PNF is a rare event but should be considered in the NF population. In the absence of NF, synovial sarcoma may be confused with PNF because both present with indolent symptoms (14, 20, 22). Magnetic resonance scanning shows findings that may be indistinguishable. However, invasion of surrounding structures is likely to occur with synovial sarcoma (23). Mineralization with calcification occurs in 40% of patients, and should not occur with PNF (24). Because synovial sarcoma bears a mortality rate up to 57%, histologic diagnosis is mandatory in suspected cases (24). Currently, surgery is the only definitive treatment for PNF. The indications for surgical intervention include pain, dysfunction, diagnostic biopsy, and/or suspected malignancy. Elective/cosmetic surgery is reserved for tumors involving the head and neck because of the visible disfiguration and its associated social stigma. Surgical resection of PNF is complicated by a high rate of recurrence. Needle et al. reported an overall progression rate of 44% in 168 PNFs after surgical intervention (25). Incomplete resection and diagnostic biopsies demonstrated a statistically significant recurrence rate. Younger patients were more likely to have a recurrence, which often occurs at puberty. In addition, PNFs of the extremities were less likely to progress when compared to those of the head and neck because the latter are often incompletely excised. A series by Donner et al. involving 288 tumors (85 schwannomas, 197 neurofibromas, and six PNF) demonstrated favorable results with respect to motor function and pain after removal of benign nerve tumors of major peripheral nerves (26). Additionally, biopsy or partial removal reflected a poor long-term functional outcome with multiple surgical procedures. The PNF group had the worst results, demonstrating recurrence in all partially excised tumors. Tumors suggestive of malignant changes require a diagnostic biopsy for histopathologic evaluation and should be evaluated by surgeons with experience in tumor resection. Location, size, and invasiveness should be considered prior to diagnostic biopsy. Small tumors, less than 1.5 em, with minimal disruption to surrounding structures may be easily excised (14, 20). Magnetic resonance imaging may be useful prior to biopsy in larger tumors. Localization of pain and a change in consistency with palpation should be considered when obtaining a specimen. Also, areas of viable healthy tissue should be targeted for proper diagnosis. In some circumstances, surrounding structures may be sacrificed for complete removal, especially in the smaller nerves of an extremity. Malignant transformation of PNF into a malignant peripheral nerve sheath tumor (neurogenic sarcoma, neurofibrosarcoma, and malignant schwannoma) is a VOLUME 41, NUMBER 2, MARCH/APRIL 2002

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well recognized consequence (6, 27). Some reports suggest an incidence rate up to 30%; however, this figure may be grossly inflated (26). It is estimated to occur in approximately 2-5% of cases, even in predisposed individuals (26, 27) McCarron et al. found 80% of malignancy associated with PNF occurred in patients afflicted with NF-l (28). Rhabomyosarcomatous differentiation of neurogenic sarcomas, termed the triton tumor, carries an even worse prognosis with extensive metastases (29). Because of the rarity and aggressiveness of all malignant peripheral nerve sheath tumors, suspicious PNF should be referred to specialized centers. Sarcomatous transformation is suggested when a softtissue mass becomes symptomatic as demonstrated by rapid growth and possible association with pain (30). Donner et al. noted two of six patients with PNFs presented with an associated pain syndrome. In the same study, radicular pain accompanied 48 of 57 patients with neurofibromas (26). In a case report by Feldkamp et al. on neurogenic sarcoma involving the median nerve, pain and paresthesia were identified as the initial presentation (31). Nonetheless, the presence of pain or new onset of pain, especially in large lesions greater than 10 em, should be evaluated thoroughly for malignancy (14, 21). Advanced diagnostic imaging of suspected PNF should only be exercised with uncertain diagnoses and/or suspected malignancy. Magnetic resonance imaging is the modality of choice for the evaluation of soft-tissue tumors; however, its ability to distinguish benign from malignant neuronal tumors remains poor (32, 33). A prospective analysis performed by Ma et al. reported 17% specificity and 58% diagnostic accuracy of magnetic resonance in differentiating benign and malignant soft-tissue lesions (34, 35). Additionally, MR imaging may not detect osseous invasion (36). Unfortunately, there is no radiographic study able to definitively distinguish between neurofibroma, plexiform neurofibroma, schwannoma, or neurogenic sarcoma and creates a diagnostic dilemma (26). In cases of suspected PNF, especially in the NF population, MRI may be used periodically in lesions suspect for malignant transformation, and for surgical anatomy and margin definition. Some investigators advocate advanced imaging at initial clinical assessment as a baseline for possible future comparison (I). The basic histology of neurofibromas consists of small bland elongated spindle cells with characteristic wavy or comma-shaped nuclei, arranged in a myxomatous stroma (2). Definitive diagnosis is obtained by histopathologic evaluation, and in some cases immunohistochemical studies. Histologically, PNF may be confused with schwannomas, malignant peripheral nerve sheath tumors, and other spindle cell sarcomas. Suspicious cases should undergo immunohistochemical studies. The S-IOO protein is an immunohistochemical maker found in schwannian 122

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cells and aids in the differentiation of neurogenic sarcoma from other soft-tissue sarcomas (37, 38). Plexiform neurofibroma cells are usually S-100 positive, and in cases with less well-defined patterns or sparse cellularity, this characteristic staining pattern can be used to confirm the diagnosis (2). Because S-100 staining demonstrates schwann cell origination, a positive staining is seen in schwannomas and many neurogenic sarcomas (39). Immunoreactivity is also seen with leiomyosarcoma, clear cell sarcoma, ossifying fibromyxoid tumor, and monophasic synovial sarcoma (37, 39). Therefore, positive S-100 staining tumors must be correlated with the histopathologic findings and other immunohistochemical markers. It was once thought schwannomas and neurofibromas were the same clinical entity. Although they are histologically similar, the larger collagen content in neurofibromas distinguishes them. Schwannomas may occur in the setting of NF-2 as bilateral acoustic neuromas or as a distinct syndrome called multiple peripheral schwannomatosis. Some investigators argue that multiple schwannomatosis may be a variant of NF-2 (40). Moreover, a distinction from NF-I is vital because PNFs possess the potential for malignant change, whereas schwannornas occurring in schwannomatosis do not, and misdiagnosis may lead to inappropriate treatment (41). However, radiation-induced malignancy is a known complication and should not be overlooked (42). Additionally, PNFs differ from schwannomas and neurofibromas, in that the former are unencapsulated and involve several fascicles rendering their internal margins almost indistinguishable (Fig. 4) (26). Because of this, the latter two are amenable to excision by neurolysis, whereas the PNFs are not, reflecting the high recurrence rate reported in the literature with partial excision. The terminal portion of the deep peroneal nerve contains both motor and sensory components. It supplies motor innervation to the extensor digitorum brevis muscle and sensation to the first interspace. The morbidity associated with the resection on the deep peroneal nerve in the foot is minimal, in that the overall function of the lower extremity should not be compromised. Interestingly, our patient did not exhibit any major sensory changes after nerve resection, suggesting collateral sensation to the interspace or anatomic variance. Summary

The association between PNF and NF has been well established. The danger of PNF is the potential for malignancy. Because patients with NF may have a multitude of soft-tissue tumors, evaluating these masses is often challenging, thus necessitating the need for aggressive and periodic re-evaluation. PNF is a benign soft-tissue

Schwannoma

Neurofibroma

Plexiform neurofibrom a FIGURE 4 Drawing demonstrating the clinical distinction between the benign neural sheath tumors. Note with PNF the multifasicular involvement creating a tortuous, nodular nerve. (Reprinted, with permission, from Donner, T. R.. et al. J. Neurosurg. 81(3):362-373,1994.)

tumor whose only definitive treatment option is surgical excision; however, it has a high rate of recurrence. Plexiform neurofibroma is an uncommon nerve sheath tumor typically involving the large deep peripheral nerves of the extremities. While there are several reports of large neurofibromas involving the foot, they have been described on the plantar aspect (43-49). To our knowledge, this is the first case of PNF involving the dorsum of the foot, arising from the deep peroneal nerve. References 1. Korf, B. R. Plexiform neurofibromas. Am. J. Med. Genet. 89:31-37, 1999. 2. Woodruff, J. M. Pathology of tumors of the peripheral nerve sheath in type I neurofibromatosis. Am. J. Med. Genet. 89:23-30, 1999. 3. Momoh, J. T Plexiform neurofibroma in children. East Afr. Med. J. 63:334-338. 1986. 4. Fisher, D. A., Chu, P., McCalmont, T Solitary plexiform neurofibroma is not pathognomonic of von Recklinghausen's neurofibromatosis: a report of a case. Int. J. Dermatol. 36:439-442, 1997. 5. Neurofibromatosis Conference Statement. National Institutes of Health Consensus Development Conference, July 13-15, 1987, Bethesda, MD. 6. Munte, T. F., Matzke, M., Johannes, S., Dietrich, B., Dengler, R. MRI of elephantiasis neuromatosa [letter]. J. Neurol. 243:619, 1996. 7. Roy, S. M., Ghosh, A. K. Elephantiasis neuromatosa: a clinicopathologic study of four cases. J Indian Med. Assoc. 90: 185 - 187, 1992.

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