The main imaging differential diagnosis in melanotic schwannoma is metastatic melanoma and hemorrhagic conventional schwannoma.

Schwannomatosis

Nonsyndromic schwannomas are almost always solitary lesions. Multiple schwannomas occur in the setting of two familial tumor syndromes, neurofibromatosis type 2 (NF2) and schwannomatosis. Bilateral vestibular schwannomas are pathognomonic of NF2. Multiple, mostly nonvestibular schwannomas in the absence of other NF2 features are characteristic of schwannomatosis. Both of these syndromes are discussed in Chapter 39.

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Neurofibromas

Intracranial neurofibromas (NFs) are much less common than schwannomas. NFs can affect the scalp, skull, some cranial nerves (especially CN V ), or—rarely—the brain. They are found at all ages. Both sexes are affected equally.

NFs can be solitary or multiple. Multiple NFs and plexiform NFs occur only in connection with neurofibromatosis type 1 (NF1).

The gross appearance of NFs is different from that of schwannomas. Schwannomas are well-delineated encapsulated lesions that arise eccentrically from their parent nerve. Schwannomas typically displace elements of the normal parent nerve to one side. In contrast, neurofibromas generally present as more diffuse nerve expansions. They display single or multiple fascicles that enter and leave the affected nerve. Axons of the parent nerve pass through

(23-78A) Axial T1WI in a

40y man with right sciatica shows a welldemarcated hyperintense mass in the right S1 nerve root. (23-78B) Axial T2WI in the same case shows that the mass is slightly lobulated and markedly hypointense .

(23-78C) Coronal T1WI in the same case shows the hyperintense, fusiform expansile lesion of the right S1 nerve root . (23-78D) Coronal T1 C+ FS shows that the lesion enhances intensely. Benign melanotic schwannoma, nonpsammomatous type, was found at histopathology.

(23-79A) Axial T2WI (L) in a 62y woman with a solitary scalp neurofibroma shows that the well-demarcated mass extends from the calvarium to the skin surface. The neurofibroma is hyperintense on FLAIR (R).

neurofibromas and are intermixed with tumor cells, distinguishing them from schwannoma.

The microscopic appearance of NFs also differs from that of schwannomas. Schwannomas are pure Schwann cell tumors. Neurofibromas consist of both Schwann cells and fibroblasts. NFs also contain other cell types, including perineural cells, mast cells, pericytes, endothelial cells, and smooth muscle cells. NFs also typically have a large amount of extracellular matrix with collagen.

In this section, we discuss both solitary and plexiform neurofibromas. Both neurofibromatosis types 1 and 2 are discussed in Chapter 39.

Solitary Neurofibroma

A solitary neurofibroma in the head and neck rarely—if ever—involves cranial nerves. Solitary neurofibromas affect patients of all ages and are usually sporadic (nonsyndromic). Most occur in the absence of NF1 and present as a painless scalp or skin mass.

Solitary neurofibromas are round or ovoid unencapsulated masses composed of Schwann cells and fibroblasts in a myxoid or collagenous matrix. Solitary neurofibromas are WHO grade I neoplasms.

Scalp solitary neurofibromas are seen on imaging studies as well-delineated, focal, enhancing masses that abut but do not invade the calvaria (23-79).

(23-79B) Axial precontrast T1WI (L) compared to the postcontrast fat-saturated scan (R) shows that the lesion enhances strongly in a somewhat "target" fashion .

Plexiform Neurofibroma

Terminology and Etiology

Plexiform neurofibromas (PNFs) are infiltrative intraand extraneural neoplasms that occur almost exclusively in patients with NF1 (23-80). Plexiform neurofibromas and neurofibromas of major nerves are considered potential precursors of malignant peripheral nerve sheath tumors (see below).

Pathology

Location. Approximately one-third of PNFs are found in the head and neck. Cranial PNFs usually involve CNs V, IX, or X. The most typical locations are the scalp, orbit, pterygopalatine fossa, and parotid gland. Scalp and orbital PNFs most commonly involve the ophthalmic branches of the trigeminal nerve. Parotid PNFs involve peripheral branches of the facial nerve.

Extracranial PNFs are often multicompartmental and do not respect fascial boundaries. Orbital PNFs may enlarge the superior orbital fissure and extend into the cavernous sinus as far as Meckel cave (23-81).

Size and Number. PNFs are typically extensive, diffusely infiltrating lesions. Multiple variably sized lesions are typical.

Gross and Microscopic Features. Grossly, PNFs have a distinctive "bag of worms" appearance (23-82). PNFs demonstrate a predominant intrafascicular growth pattern, with redundant loops of expanded nerve fascicles intermixed with collagen fibers and mucoid material (23-83).

Staging, Grading, and Classification. PNFs are WHO grade I neoplasms.

Clinical Issues

PNFs are a major cause of morbidity in patients with NF1. Approximately 5% of PNFs eventually degenerate into malignant peripheral nerve sheath tumors.

Imaging

General Features. PNFs are poorly delineated worm-like soft tissue masses that diffusely infiltrate the scalp, orbit, or parotid gland.

CT Findings. PNFs infiltrate and enlarge soft tissues, typically the scalp and periorbita. They are generally isodense with muscle. Calcification and hemorrhage are rare.

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CECT shows heterogeneous enhancement. Bone CT may show expansion of the superior orbital fissure and pterygopalatine fossa.

MR Findings. PNFs are isointense on T1WI and hyperintense on T2WI. Strong, sometimes heterogeneous enhancement is common (23-84).

A "target" sign of hypointensity within an enhancing tumor fascicle is seen in some PNFs but is not pathognomonic.

Differential Diagnosis

The major differential diagnosis of PNF is malignant peripheral nerve sheath tumor (MPNST). As many MPNSTs arise from PNFs, early differentiation may be difficult.

(23-84A) Axial T1WI in a patient with NF1 demonstrates a very large infiltrating mass in the left scalp that extends into the high deep masticator space .

NEUROFIBROMA

Solitary Neurofibroma

•Most are sporadic (nonsyndromic)

•All ages (children to adults)

•Nodular to polypoid

•Scalp, skin

•Rarely (if ever) involves cranial nerves

Plexiform Neurofibroma

•Pathology

○Composed of Schwann cells + fibroblasts, mucoid material

○Fusiform, infiltrates nerve

○Often multicompartmental

○Does not respect fascial boundaries

•Clinical Issues

○Usually diagnostic of NF1

○"Sporadic" PNFs can occur without other signs of NF1, but most have NF1 gene alterations

○Risk of malignant degeneration in PNF = 5%

○Rapid/painful enlargement, invasion? Suspect malignant peripheral nerve sheath tumor (MPNST)!

•Imaging

○Multifocal scalp, orbit lesions most common

○"Bag of worms" appearance

○May enlarge superior orbital fissure, extend into CS

○Intracranial involvement rare unless malignant degeneration

•Differential Diagnosis

○MPNST (invasive)

○Schwannoma (usually solitary; skin/scalp lesions, plexiform schwannoma rare)

○Metastases

(23-84B) T1 C+ FS in the same case shows that the extensively infiltrating plexiform neurofibroma of the scalp enhances intensely but heterogeneously. Note patulous Meckel caves , a finding of dural ectasia in some patients with NF1.

If a previously quiescent PNF enlarges rapidly or becomes painful, malignant degeneration into MPNST should be suspected. Most MPNSTs are invasive as well as infiltrating lesions.

Schwannomas are well-circumscribed solitary lesions that involve CNs, especially CN VIII. In contrast to PNF, scalp and orbital schwannomas are uncommon.

Basal cell carcinoma and infiltrating skin/scalp metastases without concomitant involvement of the underlying skull are rare.

Scalp sarcomas and lymphomas are also rare. When present, they are more diffusely infiltrating, homogeneous lesions without normal-appearing tissue interspersed within the mass.

Malignant Nerve Sheath

Neoplasms

Malignant Peripheral Nerve Sheath

Tumor

Terminology

A malignant peripheral nerve sheath tumor (MPNST) is any malignant tumor that arises from a peripheral nerve or shows nerve sheath differentiation. This term replaces designations such as malignant schwannoma, malignant neurofibroma, neurosarcoma, and neurofibrosarcoma.

(23-85A) An NF1 patient with a longstanding PNF experienced rapid enlargement of the mass, which became painful. T1WI shows a massive soft tissue mass invading the skull base and upper cervical spine.

When it occurs intracranially, an MPNST is sometimes called a malignant intracerebral nerve sheath tumor or a primary malignant intracranial nerve sheath tumor.

Etiology

Approximately half of all cranial MPNSTs occur sporadically, most likely from pluripotent neural crest cells. The other half arise from a preexisting benign nerve sheath tumor.

Identifiable precursor lesions reported with MPNSTs include both plexiform and solitary intraneural neurofibroma. Malignant transformation of conventional or cellular schwannomas is exceptionally rare.

Approximately two-thirds of peripheral MPNSTs are associated with malignant degeneration of tumors associated with NF1. Diffuse loss of neurofibromin occurs in 90% of NF1-associated and 43% of sporadic MPNSTs. Genetic data suggest that combined inactivation of NF1, CDKN2A, and PRCD with aberrant activation of downstream RAS signaling is critical for MPNST pathogenesis.

The overall lifetime risk of developing an MPNST at any location in patients with NF1 is estimated at 8-13%. In a recent series of intracranial MPNSTs, 5 of 17 patients had NF1. Four had postirradiation MPNSTs.

Pathology

Location. MPNST is much more common in the peripheral or spinal nerves than in the cranial nerves. The most commonly affected cranial nerves are the vestibular, facial, and trigeminal nerves. Intracranial MPNSTs not associated with cranial nerves are extremely rare.

(23-85B) T1 C+ shows that the mass enhances intensely but very heterogeneously. The size, extent, and invasive nature of the mass were significantly different from prior baseline studies. Malignant peripheral nerve sheath tumor was found at biopsy.

Size and Number. The majority of MPNSTs are over 5 cm, although intracranial lesions may be smaller at initial diagnosis.

Microscopic Features. MPNSTs vary greatly in appearance. The majority are widely infiltrating, hypercellular lesions that show proliferating malignant spindle cells with numerous mitoses. The 2016 WHO now recognizes two subtypes of MPNST: epithelioid MPNST and MPNST with perineurial differentiation. Other variants such as Triton tumor (an MPNST with rhabdomyoblastic differentiation) are considered histologic patterns, not subtypes.

Immunohistochemistry differentiates malignant tumors of nerve sheath derivation from soft tissue sarcomas. The majority of MPNSTs show diffuse, strong immunoreactivity for p53 protein along with S100 and collagen IV-laminin staining.

Staging, Grading, and Classification. There is no clinically validated and reproducible grading system for MPNSTs. Lowgrade MPNSTs (15% of cases) are relatively well-differentiated tumors often arising in transition from neurofibroma. All the other MPNSTs are considered high-grade.

Clinical Issues

Epidemiology. MPNSTs are rare, accounting for only 0.001% of malignant neoplasms. MPNSTs that arise from cranial nerves are even rarer. Intracranial MPNSTs not associated with cranial nerves are exceptionally rare.

Demographics. Although they can occur at almost any age, sporadic MPNSTs are primarily tumors of middle-aged and older adults. Peak occurrence is in the fifth and sixth decades. NF1-associated MPNSTs occur earlier, with mean age 20-35 years. MPNSTs show a slight female predominance.

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Natural History. Intracranial MPNSTs are fast-growing, aggressive, highly invasive tumors that generally have the same poor prognosis as those of spinal and peripheral nerves. MPNSTs are fatal in two-thirds of all patients. Most die as a result of disseminated metastases despite surgery, radiation, and chemotherapy.

Treatment Options. Total tumor resection with adjuvant radiotherapy is the treatment mainstay. Even with tumor-free margins, recurrence is common (40-70%). Survival of patients with subtotal tumor removal is generally less than 1 year.

Imaging

There are no obvious characteristics that would differentiate MPNST from benign nerve sheath tumor on a single baseline imaging study (23-86). Gross necrosis or hemorrhage is rare. A few tumors may initially show frank brain or skull invasion, poor margination, and edema. MRS findings are nonspecific. Elevated choline is common.

(23-86A) Axial bone CT in a 42y man with progressive numbness of his right cheek and jaw shows a mass in the high deep masticator space remodeling and partially eroding the posterior maxillary sinus wall and expanding the pterygopalatine fossa . (23-86B) T2 FS shows a hyperintense fusiform mass in the masticator space extending posteriorly through the enlarged pterygopalatine fossa into the cavernous sinus .

(23-86C) Axial T1WI shows that the fusiform mass expands the cavernous sinus and appears isointense with brain. (23-86D) T1 C+ FS in the same case shows that the mass enhances strongly, somewhat heterogeneously. Preoperative diagnosis was trigeminal schwannoma. Malignant peripheral nerve sheath tumor was found at histopathology.

It is the behavior on serial imaging studies that helps distinguish MPNST from benign nerve sheath tumors. Aggressive growth with brain and bone invasion is typical (2385).

CSF dissemination often rapidly ensues after the initial diagnosis is established. Distant extracranial metastases, most often to the lung, are common.

Differential Diagnosis

Small MPNSTs may be indistinguishable from benign nerve sheath tumors. The major differential diagnosis of a scalp or skull base MPNST is plexiform neurofibromas.

Both are diffusely infiltrating, poorly marginated lesions. When plexiform neurofibromas extend intracranially, they expand natural foramina and fissures but do not directly invade bone or brain. Rapid enlargement and bone destruction are more consistent with MPNST.

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR

Terminology

•MPNST is the accepted term (replaces malignant schwannoma, neurofibrosarcoma)

Pathology

•Location

○Peripheral/spinal > > cranial nerves

○Vestibular, facial, trigeminal most common intracranial locations

•Features

○Widely infiltrating

○Malignant spindle cells, numerous mitoses

○Immunohistochemistry distinguishes MPNST from other sarcomas

○Low-grade (15%) MPNSTs more differentiated, often from neurofibroma

○High-grade (85%) MPNSTs include spindle cell, pleomorphic, sarcomatous differentiation

Clinical Issues

•Rare; usually middle-aged, older adults

•Younger if neurofibromatosis type 1 associated

•Many arise de novo or from malignant degeneration of neurofibroma

•8-13% risk of MPNST in plexiform neurofibroma

Imaging

•No distinctive imaging features

•Behavior on serial imaging best indicator

•Rapid aggressive growth

•Invasion, CSF dissemination

The rare brain parenchymal MPNST that is not associated with a cranial nerve is indistinguishable from other highly aggressive, invasive malignant neoplasms. The major differential diagnoses include glioblastoma, gliosarcoma, fibrosarcoma,and malignant fibrous histiocytoma.

Other Nerve Sheath Tumors

A number of other neoplasms and tumor-like conditions occasionally involve cranial nerves although most are much more common in peripheral nerves and soft tissues. Examples include perineurioma, solitary fibrous tumor, and neurofibrosarcoma.

Intraneural perineuriomas account for just 1% of nerve sheath tumors. Perineuriomas involving cranial nerves are very rare, usually involving extracranial branches of CNs V or VII. Solitary fibrous tumors that arise from intracranial cranial nerves are indistinguishable from schwannomas on imaging studies, so the definitive diagnosis is histopathologic. Neurofibrosarcomas are more properly considered malignant nerve sheath tumors (whether peripheral or intracranial).

Chronic interstitial demyelinating polyneuropathy (CIDP) and Charcot- Marie-Tooth disease are benign conditions that rarely affect cranial nerves. When they do, diffuse enlargement and enhancement of one or more cranial nerves can be seen (23-87) (23-88).

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(23-87A) Coronal STIR shows symmetric, fusiform enlargement of both intraand extracranialtrigeminal nerve segments.

(23-87B) Coronal T1 C+ FS shows the enlarged, enhancing trigeminal nerves . This is chronic interstitial demyelinating polyneuropathy (CIDP).