Tumors of Peripheral Nerves 20

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20.1 Introduction

Tumors of peripheral nerves most commonly originate from the nerve sheath. In this chapter, they will be re- ferred to as peripheral nerve sheath tumors (PNST).

Arthur Purdy Stout (1885–1967) was a pioneer in the development of our current understanding of the histo- genesis of these tumors. He was the ﬁrst to identify the Schwann cell as the major contributor to the formation of benign as well as malignant neoplasms of the nerve sheath [106].

Benign nerve sheath tumors are subdivided into two separate morphological groups with different histo- pathological characteristics: schwannoma (also known as neurilemoma or neurinoma) and neuroﬁbroma [30].

Intraneural ganglion is also considered to be a tumor of nerve origin. For a discussion on this tumor we refer to Chap. 1, Sect. 3.2.1.

Malignant nerve sheath tumors are known under a confusing multitude of names including malignant schwannoma, malignant neurilemoma, nerve sheath ﬁbrosarcoma, neurogenic sarcoma, and neuroﬁbrosar- coma. In this chapter we will use the generic and widely accepted term malignant peripheral nerve sheath tumor (MPNST).

20.2 Schwannomas

20.2.1 Epidemiology

Schwannomas represent approximately 5% of benign soft-tissue neoplasms. They can occur at all ages, though they are uncommon in children.While literature data indicate that they are most prevalent between the ages of 20 and 50 [29, 75], our own ﬁndings appear to indicate a bimodal age distribution with peak incidences in the third and seventh decades. Men and women are equally affected [30, 106]. The majority of schwannomas arise sporadically in patients without a genetic pre- disposition. However, histologically identical tumors

Chapter

Tumors of Peripheral Nerves

Paul M. Parizel, Catherine Geniets

20

20.1 Introduction . . . 325

20.2 Schwannomas . . . 325

20.2.1 Epidemiology . . . 325

20.2.2 Topography . . . 326

20.2.3 Histology . . . 326

20.2.3.1 General Histologic Features of Schwannomas . 326 20.2.3.2 Special Histologic Types of Schwannomas . . . 326

20.2.4 Clinical Presentation . . . 327

20.2.5 Imaging Characteristics . . . 329

20.2.5.1 Plain Radiography . . . 329

20.2.5.2 Ultrasound . . . 329

20.2.5.3 Computed Tomography . . . 329

20.2.5.4 Magnetic Resonance Imaging . . . 330

20.3 Neuroﬁbromas . . . 336

20.3.2 Topography . . . 336

20.3.3 Histology . . . 336

20.3.5.2 Ultrasound . . . 337

20.3.5.3 CT . . . 337

20.3.5.4 MRI . . . 340

20.4 Malignant Peripheral Nerve Sheath Tumors . . . . 341

20.4.2 Topography . . . 342

20.4.3 Histology . . . 342

20.4.5.2 CT and MRI . . . 344

20.4.5.3 Nuclear Medicine . . . 347

20.5 Association with NF . . . 347

20.5.1 NF and Neuroﬁbroma . . . 348

20.5.2 NF and Schwannoma . . . 349

20.5.3 NF and MPNST . . . 350

20.6 Association with Schwannomatosis . . . 350

References . . . 351 Contents

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also occur in patients with neuroﬁbromatosis type 2 (NF2), or schwannomatosis [51, 46]. Schwannomas associated with NF tend to occur in younger patients.

20.2.2 Topography

Schwannomas most commonly involve the major nerve trunks of the head, neck and limbs; the flexor surfaces of the extremities are more frequently affected, especially near the elbow, wrist and knee [30, 75, 98]. Conse- quently, the most common topographical locations of schwannomas include: the spinal roots and cervical plexus, the vagus, peroneal and ulnar nerves. Deeply situated schwannomas are predominantly found in the posterior mediastinum and the retroperitoneum [29, 75]. Relatively few schwannomas appear on the trunk, which contrasts with the distribution of neurofibromas in neurofibromatosis type 1 (NF-1). Other sites of involvement include the scalp and the hands; the feet are usually spared. Less frequently, schwannomas have been recorded in the tongue, palate and larynx. Although the stomach is also held to be a site, confusion here may occur with the common leiomyoma [98]. Solitary schwannomas of the viscera are exceptional in the absence of NF-1 but have been reported in the heart and in the lung [32, 101]. In this chapter, we will focus our discussion on peripheral schwannomas.

20.2.3 Histology

20.2.3.1 General Histologic Features of Schwannomas Schwannomas are benign, slowly growing neoplasms.

They originate in a nerve and are composed exclusively of Schwann cells in a collagenous matrix [46, 75]. In general, they are ﬁrm, circumscribed and encapsulated.

Unlike a neurofibroma, which incorporates axons, the schwannoma displaces normal elements of the nerve to one side [25]. This implies that surgical excision can usually spare the parent nerve because the schwannoma is separable from the underlying nerve fibers. Small schwannomas tend to be spheroid, whereas larger tumors can be ovoid, sausage-shaped, or irregularly lobulated [98]. Macroscopically, the cut surface is relatively homogeneous, tan or grey, with irregular yellow areas and cysts, particularly in large tumors. Sometimes, only a nodule of tumor remains in what is otherwise a fibrous-walled cyst, filled with watery fluid. Less often schwannomas can be (partially) hemorrhagic [46].

According to the morphology and spatial arrange- ment of tumor cells, two types of tissue are distinguished: Antoni A and B tissue [3, 75].

In the Antoni A type tissue, the texture is composed of compactly arranged spindle-shaped cells, with long oval

or rod-shaped nuclei, that are frequently oriented with their long axes parallel to one another, creating a pattern of palisades [46]. The cytoplasm is uniformly pale.

A characteristic feature, seen in sections stained with hematoxylin-eosin [46], is the alignment of nuclei in rows, separated by clear hyaline bands along the longitudinally cut bundles. These areas are often called Vero- cay bodies [98]. Commonly, but not invariably, a part of, or all of a schwannoma has a less cellular Antoni B type pattern [46]. It has a looser texture and the tumor cells are more polymorphic, with indefinite outlines and separated by a finely honeycombed eosinophilic matrix in which reticulin fibers are relatively sparse and unevenly distributed. Mucinous and microcystic changes occur more often in the type B tissue. When confluent, they presumably result in the production of intratumoral cysts [107].

In some schwannomas, tumor nuclei, especially in the Antoni B areas, may become enlarged and hyper- chromatic, and assume a bizarre appearance. This de- velopment is sometimes described as “ancient schwan- noma” and may also be reflected in the connective tis- sue of the tumor. The fibrous stroma becomes more abundant and consists of dense bands of hyalinized collagen. This change does not denote a malignant transformation, but refers to long standing lesions with ad- vanced degeneration exhibiting calcification, hyaliniza- tion, relative loss of Antoni A areas, and cystic avitation.

[98]. Therefore ancient schwannomas must be considered as a degenerative schwannoma subtype. [58].

Vessels in schwannomas are usually prominent [46], and are liable to spontaneous thrombosis with conse- quent necrosis, and sometimes hemorrhage, in the adjacent areas [98]. The rich vascular supply of schwannomas is reﬂected in the often intense enhancement of these tumors on imaging studies.

The histologic features of schwannomas can account for their occasional inhomogeneous appearance on computed tomography (CT) or magnetic resonance imaging (MRI) examinations and can be summarized as follows:

1. Areas of decreased cellularity (Antoni B) adjacent to areas of increased cellularity (Antoni A)

2. Cystic degeneration due to vascular thrombosis and subsequent necrosis

3. Xanthomatous regions, containing aggregates of lipid-laden (foam) cells [47, 98]

Calciﬁcations are seen less frequently in schwannomas than in neuroﬁbromas [13].

20.2.3.2 Special Histologic Types of Schwannomas Histologically, several variants of benign schwannoma can be distinguished.

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ﬂuenced by rest or activity. The tumor may be tender to palpation. On physical examination or at surgery, it can be moved from side to side, but not along the long axis of the nerve. Deep schwannomas can become sympto- matic because of increasing size and impingement on neighboring structures [46]. Muscle atrophy with fatty replacement can occur in muscle groups located distal- ly to the lesion.

In case of a melanotic schwannoma, over 50% of pa- tients develop Carney’s syndrome, i.e. myxomas, spotty pigmentation and endocrine overactivity producing Cushing’s syndrome [11].

In rare instances, the clinical history may indicate a specific diagnosis, as in the case of Morton’s neuroma. A Morton’s neuroma is a benign reactive perineural scle- rosing process, and is not a tumor originating from Schwann cells [30, 75]. The term “neuroma” is therefore misleading, and can be considered a misnomer. It is preferable to refer to these lesions as “Morton’s fibroma”. Morton’s fibroma typically originates from the interdigital nerves of the foot, usually in the third and less frequently in the second intermetatarsal space [30, 75, 118]. It has also been reported in the hands [75].

Morton’s ﬁbroma is probably due to repeated minor trauma, with compression of the interdigital nerve against the transverse metatarsal ligament [75, 118].

This entrapment hypothesis is favored by the presence of Renaut bodies (densely packed whorls of collagen) which are characteristically found in entrapped peripheral nerves [44, 58]. However, a biomechanical study has shown that in full plantar and dorsal ﬂexion the neurovascular bundle moves parallel to the surrounding structures such as this ligament. There is as yet no deﬁ- nite consensus as to the etiology of Morton’s neuroma, and other causes such as ischemia should also be considered [84, 99, 118, 119].

Morton’s ﬁbroma is more frequent unilateral than bilateral, and is more common in middle aged women than in men [30, 66] (Fig. 20.1). In early stages, patients may only complain of a mild ache or discomfort in the area of the metatarsal head. A burning sensation or tingling can be experienced. The type of shoe can be a contributory factor in the severity of symptoms. Gradu- ally, the sensations become more speciﬁc, often causing constant burning, radiating to the tip of the toes. Pa- tients feel as if a marble were inside the ball of the foot.

Diagnosis can be established by the characteristic clinical history and by palpation of the foot sole. Pain is elicited when pressure is exerted between the heads of the metatarsals. It is important to know that Morton’s fibroma can elicit pain that is related to another intermetatarsal space [44]. Frequently, Morton’s fibroma can be asymptomatic. Small Morton’s fibromas may be more commonly asymptomatic. A threshold of 5 mm for the transverse diameter is suggested beyond which the neuroma more commonly produces symptoms [94].

Cellular schwannomas have a predominantly cellular growth but no Verocay bodies, and are almost exclusively composed of Antoni A areas [75]. They appear circumscribed, if not encapsulated [30]. They typically occur in women and middle-aged people [34], and are more frequently found in deep structures, e.g. the retroperitoneum and posterior mediastinum [30]. They can cause erosion of bone and recur locally. Despite the increased cellularity, there is no basis for malignant behavior of a cellular schwannoma [70, 75, 115].

(Psammomatous) Melanotic schwannoma is charac- terized by a strong melanocytic -differentiation of the Schwann cells. Like classic schwannomas [81, 90, 92], they are usually diffusely and strongly reactive for S-100 protein and not infrequently reactive for Leu-7 and MBP [115]. Schwann cells and melanocytes share a common precursor stem cell derived from the neural crest, hence this differentiation [17, 83]. Melanotic schwannomas have a predilection for spinal nerve roots, and commonly arise near the midline [30]. It has been suggested that they display malignant behavior with local recurrence after surgery. Although melanotic schwannomas are very rare [74], they merit recognition because of the paramagnetic properties of melanin. CT cannot reliably discriminate these tumors from other neurogenic neoplasms, and is most useful in detecting bone erosion or intratumoral calcifications. MRI shows high signal intensity on T1-weighted MR images, re- flecting T1-shortening due to the presence of melanin [68]. Differential diagnosis includes benign and malignant melanotic tumors, pigmented neurofibroma, melanotic medulloblastoma, pigmented neuroblas- toma, ganglioneuroblastoma, neurotropic melanoma, and melanotic neuroendocrine carcinomas and carci- noids [76, 77, 96].

Plexiform (multinodular) schwannomas constitute 5% of all schwannomas. The multinodular or plexiform pattern of growth may or may not be apparent macroscopically [30]. Only 4% of all cases of this form reported in the literature occurred in patients with NF-1 [33, 54]; therefore, it is not to be considered associated with NF-1 [26, 33, 75]. Plexiform schwannoma arises in the dermis or subcutaneous tissues, and occurs predominantly in young adults, without sex predilection [33, 63].

Although it can display nuclear pleomorphism and increased cellularity in places, it appears to be a benign lesion [98].

20.2.4 Clinical Presentation

Small schwannomas are usually asymptomatic. Pares- thesias, pain or other symptoms can occur when the tumor reaches sufﬁcient size to compress the involved nerve. Pain may radiate along the course of the peripheral nerve, and can be constant and intractable, not in-

Chapter 20 Tumors of Peripheral Nerves 327

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The diagnosis of Morton’s fibroma on the basis of imaging findings should be made only in the context of the clinical setting [118]. The MR diagnosis of Morton’s fibroma is based on three criteria. First, the lesion has to be centered in the region of the neurovascular bundle within the intermetatarsal space, and must be situated on the plantar side of the transverse ligament. Second, the lesion should be well demarcated. This excludes par- tial volume effects with the adjacent joint capsule to be interpreted as a Morton’s fibroma, a frequent problem in hammer toe deformities. Third, the lesion is isointense relative to muscle on T1-WI, and homogeneously or inhomogeneously hypointense relative to fat tissue on T2-WI.

Moreover, MR plays an important role in excluding other pathologies that can mimic Morton’s ﬁbroma such as intermetatarsal or subcapitometatarsal bursitis (which occurs dorsal to the transverse metatarsal ligament), osteonecrosis of the metatarsal heads, metatar- sophalangeal joint synovitis or dislocation, tendon sheath ganglion, pigmented villonodular synovitis, stress fractures and other disorders associated with metatarsalgia [66, 118].

In most cases, therapy is conservative with perineural inﬁltrations of a local anesthetic and/or long acting corticosteroids. Surgical excision is only performed when necessary.

Traumatic neuroma is a painful lesion, which is also not a tumor of Schwann cell origin. It is a nonneoplastic reactive hyperplasia of nerve tissue and usually occurs at the proximal end of a nerve trunk that has been sev- ered, partially transected, or injured as a result of trauma. The most common location for traumatic neuromas is the lower extremity after amputation, followed by the head and neck, where they have been reported to occur after the extraction of teeth. In contradistinction to a Morton’s ﬁbroma, it is neatly circumscribed [80], and it displays mainly proliferative changes, whereas Morton’s ﬁbroma shows degenerative changes [30].

Fig. 20.1Ia, b. Morton’s neuroma in a 46-year-old woman: a oblique coronal precontrast spin echo T1-weighted MR image through the right forefoot; b post-contrast spin echo T1-weighted MR image (same location and imaging parameters). There is a sharply delineated ovoid lesion in the third intermetatarsal space, between the heads of the third and fourth metatarsals (arrow). The lesion has a maximum diameter of 13 mm and is isointense relative to muscle (a). After intravenous contrast injection, the nodular lesion enhances moderately and homogeneously (b). At the periphery, there is a hypointense non-enhancing rim. The location and morphology of the tumor are characteristic of Morton’s neuroma

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ential diagnosis [14] (Fig. 20.3). They almost never display a uniformly hypodense appearance.

Differential CT diagnosis should include: neuroﬁbro- mas, malignant peripheral nerve sheath tumors, enlarged lymph nodes [18], synovial cysts, and other soft tissue tumors.

20.2.5 Imaging Characteristics 20.2.5.1 Plain Radiography

Peripheral nerve schwannomas are usually not seen on plain radiography, unless the tumor is very large or appears as a round mass with a peripheral sulcus (Fig. 20.2). Some schwannomas exhibit a slightly lower attenuation of the X-ray beam than muscle. Bone erosion (scalloping) can be caused by benign schwannomas, especially the cellular variant [98]. Widening of neural foramina is a frequently encountered sign of schwannomas tracking along the exiting spinal nerves.

This can be documented on oblique X-ray ﬁlms of the spine. Rarely, rib notching can be seen in schwannoma of the intercostal nerves (Fig. 20.3). A posterior mediastinal mass on a chest radiograph, should suggest the possibility of a neurogenic tumor, for they account for 30% of posterior mediastinal mass lesions.

20.2.5.2 Ultrasound

On ultrasound, schwannomas are usually seen as a solid, ovoid, typically hypoechoic mass [9, 13, 36, 40, 50, 52]. Internal cystic cavities provide easier sound- through transmission [9, 13, 36, 39, 50, 52]. Posterior signal reinforcement is seen in 50% of cases [36, 39].

Schwannomas are usually eccentric in relation to the nerve axis. A schwannoma has hyperechoic boundaries.

It appears neatly circumscribed from the adjacent structures, which are not inﬁltrated by the neoplasm.

The schwannoma is attached to the band-like structure of the nerve from which it originates. Together, on a longitudinal projection along the axis of the nerve, they can produce an ultrasound image which resembles a spoon.

This spoon-like aspect can be considered as pathogno- monic for this nerve sheath tumor [39]. The nerve of origin retains its normal echoic qualities [36].

20.2.5.3 Computed Tomography

On unenhanced CT scans schwannomas are seen as well-circumscribed homogeneous lesions. They are hy- po- to isodense relative to muscle [14, 15, 63]. However, an inhomogeneous tumor appearance with low density areas is frequently seen in larger tumors. This is believed to reﬂect the histologic diversity (see Sect.

20.2.3.1.). As a rule, hyperdense areas do not occur in schwannomas [14, 63].

On contrast-enhanced CT scans, most schwannomas become iso- or hyperdense to muscle. Non-enhancing cystic or necrotic areas are typically found in large schwannomas, and are a valuable element in the differ-

Fig. 20.2Ia, b. Schwannoma of the right hand in a 73-year-old man:

aplain radiograph of the right hand; b axial spin echo T1-weighted MR image after gadolinium-contrast injection. A soft tissue mass is seen between the ﬁrst and second metacarpal of the right hand. The ovoid soft tissue mass is outlined by a translucent rim, possibly representing displaced fatty tissue (a). MRI examination conﬁrms the presence of a well circumscribed soft tissue tumor, with minimal peripheral enhancement (b). Histology showed a schwannoma

a

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20.2.5.4 Magnetic Resonance Imaging

Prior to performing the MRI examination, it is useful to mark the palpated abnormality by placing a skin marker, which is visible on MRI. For this purpose, a small cod-liver oil (retinol and cholecalciferol) or vitamin E capsule can be used. These markers display a high signal intensity on all pulse sequences. This is especially important in T1-weighted MR images, in which the tumor can be isointense to skeletal muscle (Fig. 20.4).

If the tumor arises at the level of a nerve bifurcation, this can result in a typical forked appearance on parallel scans, or in a bilobed appearance on perpendicular MR or CT images. (Fig. 20.6). Also of importance is the fact that schwannomas grow eccentrically in relation to the nerve of origin (Fig. 20.7), whereas neuroﬁbromas do not (Fig. 20.9).

On nonenhanced T1-weighted MR images, schwannomas have an identical or slightly higher signal intensity than muscle (Figs. 20.4, 20.5 and 20.7). Sometimes they are hardly visible (Fig. 20.6). On proton density- weighted MR images, they are hyperintense to muscle (Fig. 20.6). Signal intensity is markedly increased on T2- weighted MR images (Figs. 20.4–20.6), resulting in a sharp contrast between the hyperintense nerve sheath tumor, medium intensity fat, and lower intensity muscles [8]. Cystic or pseudocystic lesions display a low signal intensity on T1-weighted MR images and a high signal intensity on proton density- and T2-weighted MR images (Fig. 20.8). Solid, highly cellular lesions have an intermediate signal intensity on T1-weighted MR images. In our experience, small schwannomas tend to enhance brightly and uniformly after gadolinium injection, whereas the enhancement pattern in larger lesions

Fig. 20.3Ia–c. Schwannoma of the chest wall in a 16-year-old boy:

aplain radiograph of the rib cage; b CT scan after iodinated-con- trast injection at the level of the upper abdomen; c coronal spin echo T1-weighted MR image after gadolinium-contrast injection.

Irregular scalloping (notching) of the inferior border of the left 10th rib and widening of the intercostal space can be seen (a). CT displays a large, irregularly enhancing, sharply deﬁned tumor.

Within the tumor mass, necrotic or cystic non-enhancing cavities are observed (b). MRI examination shows a markedly enhancing tumor subjacent to the 10th rib (c). The tumor inhomogeneity can be caused by cystic degeneration, necrosis, xanthomatous change or heterotopic calciﬁcations. At surgery a large tumor mass (23¥10¥8 cm) was resected. Histology revealed a benign schwannoma

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c

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usually are not [29]. However, this parameter is not reliable. In one study 30% of all neuroﬁbromas were found to be encapsulated and 30% of all schwannomas nonencapsulated [12]. It has been suggested that the relationship between the nerve and the tumor is a more useful differential diagnostic tool [5, 12, 30, 31]. It was reported that in the case of a schwannoma the nerve could be seen along one side of the mass, whereas in a neuroﬁbroma the nerve was either trapped within the tumor, or was obliterated by it and no longer visible [5, 12, 30, 31] (Figs. 20.7 and 20.9). Unfortunately the relationship between nerve and tumor suffers from a high interobserver variability. Some authors have questioned whether the location of a tumor in relationship to the nerve can be determined accurately, unless high resolu- tion thin section images are used [102].

Characteristic MR imaging signs of PNSTs include the split fat sign, fascicular sign and associated muscle atrophy. The split-fat sign represents a rim of fat sur- rounding the tumor, due to the fact that the neurovascular bundle is normally surrounded by fat. The split fat sign is more common in benign PNSTs. The detection on MRI of a split-fat sign can be used as a criterion for differentiating benign from malignant PNSTs [69].

may be more heterogeneous (Figs. 20.2–20.8). It has been suggested that the enhancement pattern of nerve sheath neoplasms could be used to predict benign versus malignant behavior [63] or to differentiate schwannomas from neuroﬁbromas [14]. This hypothesis is still controversial and needs to be conﬁrmed by larger pa- tient series [57].

Nonenhanced and enhanced MR images are superior in depicting intratumoral inhomogeneities, which re- ﬂect the histologic nature of the lesion (see Sect.

20.2.3.1). Differential diagnosis must be made with malignant neoplasms, in which inhomogeneities also can occur as a result of hemorrhage or necrosis [16, 63, 67, 113]. As a consequence, tumor heterogeneity is of limit- ed value in predicting the histologic nature of nerve sheath tumors [16, 63, 67].

MR examination is reliable in discriminating between intramuscular and extramuscular tumors, which is of importance for preoperative staging [28].

The detection on MRI of a capsule, visualized as a thin hyperintense rim along the margin of the tumor, has been proposed as a criterion for differentiating schwannomas from neuroﬁbromas [57]. Schwannomas are frequently encapsulated, whereas neuroﬁbromas

Fig. 20.4Ia–c.Schwannoma of the right leg in a 62-year-old woman. A cod-liver oil skin marker is used to locate the small soft tissue tumor: a axial spin echo T1-weighted MR image through the lower leg, 1.5 cm below the tibial plateau; b axial turbo spin echo T2-weighted MR image; c axial spin echo T1-weighted MR image after gadolinium-contrast injection with spectral fat saturation.

On a T1-weighted scan, the skin marker is of high signal intensity, whereas the tumor is completely isointense to the adjacent mus- cles (a). On a T2-weighted scan, both the skin marker and the tumor display a high signal intensity (b). On the fat-saturated post-contrast T1-weighted scan, the tumor enhances intensely and homogeneously (c). Note that, even though the subcutaneous fat signal is suppressed on this sequence, the skin marker remains hy- perintense (c). At histology after surgery, the tumor, located along the course of the ﬁbular nerve, turned out to be a schwannoma

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The fascicular sign represents multiple small ring- like structures (with higher signal intensity peripheral- ly) on T2-weighted images, corresponding to fascicular bundles seen in neurogenic neoplasms [69]. The detection on MRI of the fascicular sign has been proposed as a criterion for differentiating schwannomas from neu- roﬁbromas. However, this parameter is not reliable for deﬁnitive differentiation [57].

The MR imaging characteristics of neurogenic tumors are not specific, and can be mimicked by other neoplasms. The most common mimickers are myxofi- brosarcoma (formerly known as malignant fibrous his- tiocytoma) and metastases [102].

Fig. 20.5Ia–f. Benign schwannoma at the flexor surface of the left lower leg in a 41-year-old woman: a ultrasonography of the left lower leg; b axial spin echo T1-weighted MR image; c axial spin echo T2-weighted MR image; d axial spin echo T1-weighted MR image after gadolinium-contrast injection; e coronal spin echo T1-weighted MR image; f coronal spin echo T1-weighted MR image after gadolinium-contrast injection. A fusiform, sharply defined, homogeneously hyporeflective tumor is seen, in close re- lationship to the nerve at the flexor surface of the left lower leg (a).

Axial T1-weighted image shows a well delineated, homogeneous, hypointense mass, isointense to the adjacent muscles (b). On a T2-weighted MR image the tumor has a high signal intensity with fascicular sign (c). Axial contrast-enhanced T1-weighted image shows an marked and homogeneous enhancement (d). Coronal T1-weighted image shows a well demarcated, fusiform mass with entering and exiting nerve, a split fat sign and an intense enhance- ment (e,f)

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Fig. 20.6Ia–d. Bilobed schwannoma of the upper arm in a 31-year- old man: a axial spin echo T1-weighted MR image through the right upper arm, 3 cm proximal to the elbow joint; b axial turbo spin echo T2-weighted MR image; c axial spin echo T1-weighted MR image after gadolinium-contrast injection; d sagittal spin echo T1-weighted MR image after gadolinium-contrast injection. On

the T1-weighted MR image, the tumor is completely isointense to muscle and nearly indiscernible (a). On the T2-weighted MR im- age (b), the tumor is markedly hyperintense to muscle. After gadolinium injection (c,d), the tumor enhances homogeneously.

Note the bilobed appearance, which is typical for a neurogenic tumor

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Fig. 20.7Ia, b. Solitary schwannoma of the brachial plexus in a 24-year-old woman: a coronal spin echo T1-weighted MR image;

bcoronal T1-weighted MR image after gadolinium-contrast injection. A sharply deﬁned, fusiform tumor of intermediate signal in- tensity is identiﬁed in the right brachial plexus (a). Note that the tumor is eccentric to the nerve trunk of origin, which is displaced upwards. After gadolinium injection, intense but inhomogeneous tumor enhancement is recognized. The tumor can now easily be discerned from the adjacent scalenus muscle (b). At surgery, an oblong, well circumscribed tumor was resected (7¥5¥3 cm), with slightly tapered edges. Histology established the diagnosis of a benign schwannoma (Antoni type B)

Fig. 20.8Ia, b. Peripheral neuroﬁbroma of the popliteal fossa in a 62-year-old man: a sagittal spin echo T1-weighted MR image;

bsagittal spin echo T1-weighted MR image after Gd-contrast injection. There is a rounded lesion within the subcutaneous fat, pre- senting with homogeneous signal intensity and sharp margins.

The lesion has a “bead on a string” appearance, and is situated along the course of the ﬁbular nerve, with entering and exiting the nerve. On the precontrast images, it is isointense to muscle (a).

After intravenous contrast administration, central enhancement is noted (b). The superﬁcial localization in the subcutaneous fat and the relationship with the nerve are suggestive for a peripheral nerve sheath tumor

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b

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Fig. 20.9Ia–e.Schwannoma of the right calf in a 58-year-old man:

aaxial spin echo T1-weighted MR image through the right calf approximately 5 cm below the knee joint; b axial spin echo T2- weighted MR image; c axial spin echo T1-weighted MR image after gadolinium contrast injection; d axial gradient echo T1-weighted MR image, dynamic image obtained in 2 s; e time-intensity curve of tumor enhancement (solid line) vs muscle enhancement (dotted line). On transverse MR images the tumor has a heterogeneously layered appearance. The central necrotic portion is hypointense on T1-weighted MR image (a), hyperintense on T2-weighted MR image (b) and does not enhance (c). The irregular peripheral rim displays patchy enhancement (c). Sequential rapid acquisition (2 s) gradient echo images (d), permit the calculation of time-in- tensity curves (e), where tumor enhancement is characterized by a steep and rapid slope, as compared with a slow increase in signal intensity observed in the adjacent muscle. The MRI characteristics correlated well with the macroscopic tumor appearance after surgery. A 7¥5 cm tumor was resected. Macroscopically, the lesion presented with a heterogeneous appearance (brown-yellow), with cystic cavities. Microscopy conﬁrmed a benign schwannoma with areas of ischemic hemorrhagic necrosis

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20.3 Neurofibromas

There is no obvious predilection for any racial or ethnic group to develop neuroﬁbromas, and these lesions have been described throughout the world [46]. They represent approximately 5% of benign soft-tissue neoplasms. [67].

Three types of neuroﬁbromas are classically described: localized, diffuse, and plexiform.

The localized neurofibroma variety is the most com- mon, representing approximately 90% of these lesions, and the vast majority is solitary and not associated with NF-1 [22, 29]. They develop mostly between the ages of 20 and 30. Like schwannomas, they affect both sexes equally [75]. The diffuse neurofibroma is an uncommon but distinctive form of neurofibroma, that primarily af- fects children and young adults. The majority of diffuse neurofibromas are isolated lesions not associated with NF-1. Plexiform neurofibromas are essentially patho- gnomonic of NF-1 (see below), and development of these lesions usually occurs in early childhood. Neuro- genic tumors in the setting of NF-1 constitute a special entity, because they are always a local expression of a larger, dispersed disorder [17].

Most localized, solitary neurofibromas are superficial lesions of cutis or subcutis (Fig. 20.8) [75]. Obviously, neurofibromas can also occur in conjunction with NF-1 [46]. Neurofibromas in NF-1 are relatively frequent on the trunk, which contrasts with the distribution of peripheral nerve schwannomas, which are more frequent in the extremities [98]. The diffuse neurofibromas demonstrate a plaque-like elevation of the skin with thickening of the entire subcutis. Plexiform neurofibromas may involve any or all of the following sites: cranial

and spinal nerve roots and ganglia, the major nerves of the neck, trunk and limbs, including the sympathetic system and its ganglia, the subcutaneous branches of the major nerves and the visceral sympathetic plexuses [98]. Below the diaphragm, plexiform neurofibromas are typically located in the retroperitoneal space and paraspinal region [38]. Representative retroperitoneal localizations are (bilateral) parapsoatic and presacral neurofibromas. Less commonly, retroperitoneal neurofibromas are found in the region of the celiac axis and near the origin of the superior mesenteric artery [4].

Involvement of the myenteric plexuses and mesentery of the gastro-intestinal tract by plexiform neuroﬁbromas is rare [38]. Neuroﬁbromas in this location cause pain, intestinal bleeding and obstruction [42]. The regional nerves are enlarged and nodules of varying size are found, especially in Auerbach’s plexus. The most common site is the jejunum, followed by the stomach [49].

Typically, the solitary neurofibroma (Table 20.1) is a benign, slowly growing, and variably encapsulated neoplasm, originating in a nerve [12, 46, 75]. Neurofibromas are intimately associated with the parent nerve, growing in a longitudinal fusiform manner with the nerve “entering and exiting” from the lesion. Surgical resection re- quires sacrificing the parent nerve because the neurofibroma cannot be separated from the nerve fibers [25].

As opposed to schwannomas, most neurofibromas are solid tumors macroscopically. Areas of cystic degeneration, hypocellularity and xanthomatous material are uncommon. Calcifications and ossification occur more frequently in neurofibromas than in schwannomas [47, 98]. Neural axons traversing the tumor often follow a tortuous course [46]. As in schwannomas, the capacity of neurofibromas for melanogenesis, although rare, has been well documented [2, 6, 21, 46, 74, 87, 89].

Table 20.1. Comparative pathology of schwannoma and neuroﬁbroma

Schwannoma Neuroﬁbroma

Cell type Schwann cells Schwann cells and ﬁbroblasts

Capsule Usually encapsulated Usually nonencapsulated

Extension along nerve bundle Focal Inﬁltrative growth

Tumor shape Round or fusiform Fusiform

Tumor topography Eccentric tumor Central

Displacing tissue along axis nerve Separates tissue

Intratumoral cysts Common Rare

Intratumoral necrosis Common Rare

Intratumoral hemorrhage Common Rare

Malignant degeneration None More frequent

Blood supply Thickened arteries, prominent veins No thickened arteries, no prominent vessels

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ﬁbromas [37]. Neuroﬁbromas tend to be less sharply delineated. Like schwannomas, they do not always show distal acoustic enhancement [13, 36, 50].

20.3.5.3 CT

On unenhanced CT scans neurofibromas mostly appear as hypodense lesions, due to the presence of Schwann cells, neural elements and adipocytes. Occasionally, hyperdense areas are found in neurofibromas, and this feature is uncommon in schwannomas. They are believed to result from dense bands of collagen tissue, produced by fibroblasts [63]. On enhanced CT scans, neurofibromas usually show little or no contrast uptake (Fig. 20.10). More than half of neurofibromas remain hypodense after contrast injection [14]. In some cases, ill-defined, cloudy areas of enhancement are found (Fig. 20.11). Retroperitoneal plexiform neurofibromas are usually bilateral and symmetric. They display special imaging characteristics on contrast-enhanced CT.

They are mostly homogeneously hypodense, but unusu- al swirling and serpiginous patterns of increased attenuation superimposed on a low attenuation background have been described [4]. No calciﬁcation is identiﬁed.

Generally, plexiform neurofibromas have well-defined margins, but in some cases, the margins are indistinct, suggesting possible infiltration into the iliopsoas muscle. Such apparent infiltration should not be considered indicative of malignancy [4]. Bilateral parapsoas or presacral masses are characteristic for retroperitoneal plexiform neurofibromas, corresponding to the distribution of the lumbosacral plexus [1]. Nevertheless rare cases of unilateral retroperitoneal plexiform neurofibroma have been reported [20, 88, 95]. This pattern is apparently a less common manifestation of the disease.

The bilaterally symmetric nature of retroperitoneal neuroﬁbromas facilitates differentiation from malignant nerve sheath neoplasms. Some authors have demonstrated that when bilateral lesions are present, asymmetry in axial diameter of more than 2 cm, and asymmetric attenuation pattern are always associated with malignant tumors [4]. When assessing a unilateral retroperitoneal mass, distinction of malignant versus benign behavior is unreliable by imaging criteria [4].

CT ﬁndings of multiple soft-tissue nodules within the mesentery, distributed along the course of peripheral nerves, and wall thickening of the affected bowel loops can suggest a diagnosis of plexiform neuroﬁbromatosis in patients with NF-1. In contrast to the solitary mass lesion, there is normal appearing fatty tissue trapped between the small nodules. Differential diagnosis includes: Crohn’s disease, ileocecal lymphoma, carcinoid, intraperitoneal seeding of malignancy, mesenteric pan- niculitis, and tuberculosis [38, 109].

Plexiform neuroﬁbroma relates to a diffuse enlargement and distortion of a major nerve trunk. Disorga- nized growth of nerves is noticed within and occasionally also outside the nerve trunk [75]. Multiple masses are found along the course of nerve bundles or trunks, with irregular cylindrical enlargement of the affected nerves [107]. Fusiform or spherical neuroﬁbromas along their course can produce a moniliform effect, or sometimes give rise to massive growths of a similar character [98].

Many tumors have a central zone composed of tight- ly packed eosinophilic fibers with a highly cellular com- ponent and sparse non-fibrillary stromal substance (such as myxoid material). The peripheral zone is composed of loosely arranged eosinophilic fibers with less cellular components but abundant nonfibrillary stromal material. This histologic pattern is called a zonal distinction [107]. This concept is important to understand because it is presumed to be the histologic correlate of the so-called ’target-appearance’ of neurofibromas on CT and MR imaging studies.

20.3.4 Clinical Presentation

Solitary neuroﬁbroma presents as a relatively non-tender mass in the skin or subcutaneous tissue. It is some- what movable and moderately ﬁrm but compressible.

An isolated neuroﬁbroma in the skin usually does not exhibit an associated local change in pigmentation of the skin, although hyper- or hypopigmentation is possible. If a solitary neuroﬁbroma occurs along the course of a peripheral nerve, the clinical symptoms are usually related to a space-occupying lesion but can be much the same as those described for schwannoma [46].

The clinical presentation of NF-associated neuro- ﬁbroma will be discussed below (see Sect. 20.5).

20.3.5 Imaging Characteristics 20.3.5.1 Plain Radiography

The appearance of neuroﬁbromas on plain radiography is similar to that of schwannomas.

20.3.5.2 Ultrasound

Like schwannomas, neuroﬁbromas are hypoechoic (Fig. 20.10) [9, 13, 36, 50, 52]. High frequency ultrasound can visualize the junction between the hypoechoic tumor and the parent nerve [36]. Neuroﬁbromas are often elongated along the nerve axis and lobulated. Never- theless, there is a considerable overlap between the appearance on ultrasound of schwannomas and neuro-

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Fig. 20.10Ia–f. Neurofibroma of the cutaneous tributary of the left superficial fibular nerve in a 14-year-old boy: a axial ultrasound image 8 cm proximal to the left fibular malleolus; b CT scan after iodinated-contrast injection, proximal to the left ankle joint; c axi- al spin echo T2-weighted MR image 7 cm proximal to the ankle joints; d axial spin echo T2-weighted MR image 3 cm proximal to the ankle joints; e coronal spin echo T1-weighted MR image;

fcoronal spin echo T1-weighted MR image after gadolinium-contrast injection. This young man presented with a painful mass above the left lateral malleolus. Ultrasound examination showed a well circumscribed anechoic mass (a). Contrast -enhanced CT

scan conﬁrmed the mass lesion in the subcutaneous fat next to the extensor digitorum longus muscle. The central part of the lesion shows a slightly higher density than the peripheral rim (target ap- pearance) (b). Axial T2-weighted MR image conﬁrms the target appearance, with a central area of moderately high signal intensity surrounded by a rim of extremely high signal intensity. In the inferior part of the lesion, there is a bifurcation (c, d). On the T1- weighted MR image, the tumor is isointense relative to muscle (e).

After gadolinium injection, the central part of the tumor enhances (f). Histology revealed a neuroﬁbroma

a b

c d

e f

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Fig. 20.12Ia–d. Neuroﬁbroma of the right upper arm in an 11-year-old boy: a coronal spin echo T1-weighted MR image through the posterior compartment of the right upper arm;

bcoronal turbo spin echo T2-weighted MR image; c coronal spin echo T1-weighted MR image after gadolinium contrast injection;

daxial turbo spin echo T2-weighted MR image. A large heterogeneous tumor is seen in the posterior muscle group of the right upper arm. On the precontrast T1-weighted MR image, the tumor is isointense with muscle, and is interspersed with fatty tissue (a). On the T2-weighted MR images, the lesion is hyperintense throughout (b, d). After contrast administration, there is heterogeneous enhancement of the tumor (c). The lesion occurred in the clinical setting of NF-1. Note the invasion of multiple muscles by the neoplasm

a b c

d

Fig. 20.11Ia, b. Neuroﬁbroma in the presacral region in a 46-year- old man: a CT scan through the sacrum after iodinated-contrast injection; b CT scan late after iodinated-contrast injection, same

level as (a). On the early phase contrast CT, the tumor is predomi- nantly hypodense, relative to muscle tissue (a). Late after contrast, ill-deﬁned, cloudy areas of enhancement are seen (b)

a b

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20.3.5.4 MRI

Neurofibromas display an intermediate signal intensity on T1-weighted MR images, i.e. they are isointense or slightly hyperintense to muscle (Figs. 20.9, 20.10 and 20.12). On proton density-weighted images, they are hyperintense to muscle tissue. On T2-weighted scans, neurofibromas are usually hyperintense (Figs. 20.11 and 20.12). This provides a sharp contrast difference between the hyperintense nerve sheath tumor, medium intensity fat, and lower intensity muscles [8]. They can display a salt-and-pepper appearance on T2-weighted images, though this so-called fascicular sign is more common in schwannomas [57, 103]. Central areas of decreased signal intensity may be due to condensations of relatively fibrous cellular tissue (decreased amount of intercellular water) (Fig. 20.12b). Cystic or pseudocystic transformation is less common in neurofibromas than in schwannomas. After intravenous injection of gadolinium, the enhancement pattern is variable. In our experience, approximately two-thirds enhance inhomogeneously (Fig. 20.11), while one-third enhance brightly and uniformly. A dumbbell-shape is characteristic for spinal nerve root neurofibromas, which may enlarge the neuroforamen. Another typical feature is a fusiform shape oriented longitudinally in the nerve distribution.

쮿 Target-appearance. Neuroﬁbromas can display a

“target-appearance”. On T2-weighted MR images, the target appearance is characterized by a peripheral rim of increased signal intensity, while the central part of the tumor is less hyperintense (Fig. 20.10). This pattern

corresponds to a distinctive zonal histologic appearance that can be found in neurofibromas [107]. The high signal-intensity in the peripheral zone may be related to more myxoid tissue with high water content. The central area of lower signal intensity is probably related to the amount of dense collagen and fibrillary tissue which causes T2 shortening [107]. The target appearance on T2-weighted scans is suggestive of neurofibroma (p<0.05), though it can also occur in schwannomas (58% in neurofibromas vs 15% in schwannomas) [57 ].

On Gd-enhanced studies, the target appearance is reflected by the more intense central enhancement. Cen- tral enhancement is equally suggestive of neurofibroma, since this finding is much less common in schwannomas (75 vs 8%) [57]. The combination of both findings, i.e. target appearance on T2-weighted scans and central enhancement pattern is useful in differentiating neurofibromas from schwannomas (63 vs 3%) [57, 95].

Some of the more peripheral neuroﬁbromas have a mixed signal intensity. The target-pattern may not be seen in very small lesions. Likewise, it can be absent in large tumors and lesions with cystic, hemorrhagic, or necrotic degeneration, though these features are relatively uncommon in neuroﬁbromas (Fig. 20.14). Prior surgical intervention or malignant change can also dis- turb the zonal architecture [107, 111].

The target appearance can also occur in schwannomas, be it much less frequently. As a rule, MPNST do not exhibit such a target pattern on MRI.

In conclusion, the target pattern is an indication of the benign character of the lesion, and exhibits a high speciﬁcity for benign peripheral nerve sheath tumors.

Fig. 20.13Ia–c.Subcutaneous neuroﬁbromas in a 41-year-old woman with NF-1: a axial spin echo T1-weighted MR image through the brain; b axial turbo spin echo T2-weighted MR image (same level); c contrast-enhanced axial spin echo T1-weighted MR image (same level). There are two subcutaneous nodules in the right frontal and parietal region (arrows). The lesions are sharply demarcated and are hypointense relative to the subcutaneous fatty

tissue (a). On a T2-weighted scan, the anterior nodule is hyper- intense and appears bilobed; the posterior nodule is iso- to hypointense, presumably reﬂecting ﬁbrous cellular tissue (b).After intravenous injection of gadolinium contrast, both lesions en- hance, indicating a vascular supply (c). Note that the underlying temporalis muscle enhances to a much lesser degree (c)

a b c

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20.4 Malignant Peripheral Nerve Sheath Tumors

MPNST (Fig. 20.15) represent about 6% of all malignant soft tissue tumors [ 62]. In sporadic cases of MPNST, the sex ratio is approximately equal, whereas in the setting of NF-1, MPNST are four times more frequent in men than in women [75]. The mean age of incidence of MP- NST is 42 years, with 80% of all cases occurring between ages 17 and 70 [62]. In up to 50% of MPNST, an association with NF-1 is found [24, 43, 46, 75, 104]. On the other hand only a small fraction of patients with NF-1 (approximately 5%) develop MPNST.

Unfortunately it has a low sensitivity, and it does not reliably allow differentiation between a schwannoma and a neurofibroma. It should be kept in mind that, even for the pathologist, it is sometimes difficult to distinguish a neurofibroma from a schwannoma. Thus it is not sur- prising that MR signal intensity patterns may be similar in these lesions [111].

According to some authors, tumor capsule and relationship of the tumor with the nerve can be used as a criterion to differentiate between neuroﬁbromas and schwannomas. For this we refer to Sect. 20.2.5.4.

Fig. 20.14Ia–d. Neuroﬁbroma of the right axilla in a 33-year-old woman with NF-1: a coronal spin echo T1-weighted MR image through the thorax; b axial spin echo T2-weighted MR image through the supraclavicular fossa; c axial spin echo T2-weighted MR image through the axilla; d coronal spin echo T1-weighted MR image after gadolinium contrast injection. A large, bilobed tumor extends along the nerves of the right brachial plexus. There is a small tumor nodule in the supraclavicular fossa and a large fusiform mass extending into the right axilla (a). On the T2- weighted MR images, the small nodule in the supraclavicular fossa shows a typical target appearance with peripheral hyperintense rim, whereas the large lesion in the right axilla shows a much more heterogeneous internal architecture. Note the presence of a third lesion in the anterior chest wall on the left (b, c). After intravenous gadolinium contrast administration, there is predominantly central enhancement of the small supraclavicular tumor, and hetero- geneous enhancement of the right axillary tumor (d). The lesions occurred in the clinical setting of NF-1

a

b

c

d

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MPNST can develop as a possible delayed sequel of radiation therapy. One study showed 11% of all MPNST to be post-radiation sarcomas [24]. The mean latency period ranges from 5 to 40 years [23, 24, 35]. The simul- taneous presence of NF-1 does not seem to be an inﬂu- encing factor [24].

MPNST have a propensity to occur in the proximal limbs and trunks [75]. They typically affect the large nerves of the neck, and proximal extremities (including the sciatic nerve, brachial plexus and sacral plexus), as well as the retroperitoneum, mediastinum and viscera [87] (Fig. 20.15). In a landmark review study on malignant soft tissue tumors, 775 malignant schwannomas were registered with the following distribution according to their anatomic location: lower extremity (25%), trunk (17%), upper extremity (12%), head and neck region (11%), proximal limb girdle (9%), retroperitoneum (8%), hips and buttocks (8%), foot and ankle (4%), hand and wrist (3%), other (7%) [65]. Primary intraosseous origin of malignant peripheral nerve

sheath tumors is exceedingly rare, particularly involv- ing a long bone; such lesions most commonly arise from the mandible [108].

However, tumor topography must not be used as a differential diagnostic criterion, since many other malignant soft tissue tumors, and notably myxoﬁbrosarco- ma, display a similar pattern of anatomic distribution.

MPNST complicating NF-1 usually arise from one of the large peripheral nerves. Those originating from the intracranial nerves are quite exceptional [98].

By definition, a malignant nerve sheath tumor is a malignant neoplasm of nerve sheath origin that locally infiltrates and also metastasizes. It can develop in an unaltered nerve or in a neurofibroma. Many of the malignant tumors arising from, or in association with neurofibromas in NF-1, are indistinguishable from fibrosar- comas of soft tissue [46]. It is estimated that between 5 and 13% of neurofibromas in NF-1 eventually become malignant. Conversely, malignant transformation of schwannomas is extremely rare [87].

Fig. 20.15Ia–d. Fast growing MPNST of left ankle in a middle aged man: a coronal STIR T2-weighted MR image; b axial T1-weighted MR image; c axial contrast-enhanced T1- weighted MR image; d axial fat-suppressed contrast-enhanced T1-weighted MR image.

There is a large, fusiform, ill defined soft tissue mass at the left ankle, with some perile- sional edema (a). The tumor is heteroge- neous and hypointense with cortical bone invasion at the distal fibula (b). The contrast enhanced MR images show an inhomogeneous enhancement with ill-defined tumor margins maybe due to perilesional lym- phangitis (c, d). Histology showed a MPNST originating from the peroneal nerve

a

c d

b