Types and Nomenclature

Different types of PNT can present different characteristics. BPNST are more commonly reported than nonneurogenic masses. ^{9,​ 10,​ 11} In this chapter, we will discuss the subtypes of BPNST and benign tumors of nonneural sheath origin.

22.2.1 Benign peripheral nerve sheath tumors

Schwannoma

Schwannomas (formerly called neurilemmomas) are the most common type of PNT in patients without NF1. ^{2,​ 5,​ 6,​ 11} They are typically well-circumscribed, encapsulated masses of neoplastic Schwann cell origin. ¹² These tumors arise from a single nerve root or peripheral nerve fascicle and grow in an eccentric fashion, progressively displacing uninvolved fascicles together with adjacent structures. ¹³

Schwannomas are characterized by degenerative changes and variable admixture of compact spindle cellular (Antoni A) areas and hypocellular, microcystic loose (Antoni B) areas, rich in macrophages and collagen fibers. ^{6,​ 12,​ 14} Distinct palisades with a fibrillary core (Verocay bodies) are usual features. ¹⁵ Although previously reported, intralesional axons are frequently not expected to be present. ¹⁶ These tumors typically show diffuse, strong expression of S100 protein by immunohistochemistry. ^{12,​ 13}

In most cases, schwannomas occur sporadically as solitary masses ( ▶ Fig. 22.1). However, they are also seen as part of complex disorders as NF2, schwannomatosis, Carney complex, and a syndrome characterized by multiple schwannomas, nevi, and vaginal leiomyomas. ^{3,​ 17,​ 18,​ 19} These tumors are not related with NF1. The association of schwannomas with NF2 and schwannomatosis will be discussed separately.

The main pathologic variants include cellular, melanotic, and plexiform schwannomas. ¹² Cellular schwannomas are relatively uncommon tumors composed mostly of Antoni A areas with increased mitotic activity, and occasional locally destructive behavior. ^{12,​ 13} They lack Verocay bodies and show only small very focal areas with Antoni B pattern (less than 10% of total tumor area). ¹² Melanotic schwannomas are rare, distinct subtypes of schwannomas characterized by marked accumulation of melanin in neoplastic cells, associated melanophages, and epithelioid cells with variable sized nuclei. ¹² They usually do not present Verocay bodies, microcysts, or a well-formed capsule. ^{12,​ 15} Other melanin-producing neoplasms appear as main differential diagnosis. The presence of psammomatous melanotic schwannomas (a subtype with round, laminated bodies of calcium called psammoma bodies) has to be taken into account, since it is listed as one of the major diagnostic criteria for Carney complex (a rare multiple neoplasia syndrome). ⁴ Unlike other schwannomas, these subtype can undergo malignant transformation. ¹⁴

Plexiform schwannomas are a rare, less circumscribed subtype usually composed of Antoni A areas. ¹² They are defined by a plexiform intraneural growth pattern often with multinodularity. ^{12,​ 13} There is a weak association between this subtype and schwannoma predisposing syndromes (e.g., NF2, schwannomatosis). ¹² As opposed to plexiform neurofibromas, they do not undergo malignant degeneration.

Degenerative changes such as nuclear pleomorphism, blood vessel hyalinization, hemorrhage, cystic changes, focal necrosis, and calcifications can be observed in longstanding schwannomas, referred to as “ancient schwannomas.” ¹⁴

Schwannomas, NF2, and Schwannomatosis

NF2 is an autosomal-dominant genetic syndrome with a birth incidence around 1 in 25,000. ²⁰ Individuals with this disorder are predisposed to present multiple tumors of the nervous system. ¹⁷ These patients have higher risk to develop multiple schwannomas involving spinal roots, plexuses, or peripheral nerves in association with bilateral vestibular tumors. ¹⁸ BPNST associated with NF2 rarely, if ever, undergo malignant transformation.

Schwannomatosis is the third major distinct form of NF, characterized by multiple nonintradermal schwannomas in the absence of the typical bilateral vestibular schwannomas typically observed in NF2. ¹⁹ The overwhelming majority of patients with this condition present one or more peripheral nerve schwannoma. They represent an important percentage of all individual undergoing schwannoma resections. ³ Although previously reported in a small number of patients, there is still need for more data to understand the risk of malignant transformation in patients with schwannomatosis. ²¹

Neurofibroma

Neurofibromas are among the most common types of PNST. ^{6,​ 9} They originate from Schwann cells lineage and have either a well-demarcated intraneural or a diffuse infiltrative growth pattern. ¹² These tumors are composed of constitutive elements of a normal nerve (Schwann cells, fibroblasts), and perineurial-like cells, intercalated with nerve fibers, embedded in a myxoid matrix. ^{13,​ 15} Single or multiple nerve fascicles that enter and leave the tumor can be identified. ² The fact that they present axons with the tumor is important to distinguish them from schwannomas. ²

Although there are several cases associated with NF1, a great proportion of neurofibromas occur sporadically. ^{2,​ 6} The association of neurofibromas with NF1 will be discussed separately.

According to architectural growth patterns, neurofibromas are divided in localized, diffuse, plexiform, and massive soft-tissue neurofibromas. ¹² The most common are localized cutaneous neurofibromas, small nodular masses arising from small cutaneous nerve. ^{12,​ 15} Localized intraneural neurofibromas are deeper, focal, lesions that may involve major peripheral nerve or plexus and result typically in fusiform expansion of the nerve trunk. ¹² On the other hand, a plaquelike enlargement, usually in the head and neck region, characterizes the second subtype, diffuse neurofibromas. ^{6,​ 15}

Plexiform neurofibromas are nondiscrete multinodular, tortuous, elongated masses characterized by the involvement of multiple adjacent nerve fascicles or components of a nerve plexus ^{12,​ 15} ( ▶ Fig. 22.2). Their gross appearance has been described as resembling a “bag of worms.” ⁶ Rarely seen as sporadic lesions, they have potential for malignant transformation. ¹² Histologically, an admixture of areas resembling the two previously cited subtypes of neurofibromas can be often observed. ¹² Massive soft-tissue neurofibromas represent a very rare subtype characterized by large size, diffuse infiltration of soft-tissue and skeletal muscle, usually causing regional or single-limb enlargement. ¹³ The two last cited neurofibroma subtypes are almost always associated with NF1. ¹⁵

A more pronounced fascicular growth with increased cellularity (characteristic of cellular neurofibroma) and degenerative cytological atypia are unusual features shown by atypical neurofibromas or neurofibroma with ancient change, often raising the suspicion for malignant tumors. ^{12,​ 15} Glandular differentiation, metaplastic bone, and presence of melanin pigment are other very rare morphological findings reported in neurofibromas. ¹²

Neurofibromas and Neurofibroma Type 1

NF1 is an autosomal-dominant genetic disorder with full penetrance and a birth incidence of approximately 1 in 2,600 to 3,000 individuals. ²² Patients diagnosed with NF1 present substantially higher risk of developing different types of neurofibromas. ^{2,​ 23} Furthermore, the presence of two or more neurofibromas of any type or one plexiform neurofibroma is included in the NIH (National Institutes of Health) diagnostic criteria for this syndrome (of which two clinical feature are necessary and sufficient for the diagnosis). ²⁴ In a whole body imaging study, plexiform tumors were revealed in 40% of the NF1 patients. ²⁵

Although it rarely occurs in solitary neurofibromas, malignant transformation of neurofibromas are not uncommon in patients with NF1. ²⁶ MPNST are aggressive tumors known to arise from peripheral nerves or a preexisting PNST, especially plexiform neurofibromas with invasive or displacing growth pattern. ¹² Possibly due to this association MPNST appear in 2 to 5% of NF1 patients, compared to only 0.001% of the healthy population. ^{23,​ 27}

Perineurioma

The PNT comprised of perineurial cells are called perineurioma. These are uncommon, benign tumors that can mimic a number of benign and malignant soft-tissue lesions. ²⁸ Perineuriomas have not been associated with NF but can be the source of an MPNST. ²⁹

Immunohistochemical and/or ultrastructural confirmation of perineurial cell differentiation are necessary for the diagnosis of such neoplasms. They are positive for epithelial membrane antigen (EMA) and claudin-1 and negative for S100 and neurofilaments, indicating their perineurial cell origin. ²⁸ The immunoreactivity for EMA and lack of immunoreactivity for S100 allows the distinction of perineurial cells, which normally surround the nerve fascicles within a nerve, contrary to schwannomas.

They can be classified in two main forms: a rare intraneural perineurioma or a relatively more common extraneural soft-tissue perineurioma. ¹² Intraneural perineuriomas seem to affect most often individuals in the second or third decades and appear as fusiform masses along the path of large nerves. ²⁸ They can be accompanied by neurological deficit and/or mass effect. On the contrary, extraneural soft-tissue perineuriomas are usually asymptomatic and seem to occur typically in middle-aged adults, with a slight preference for females. ²⁸

Hybrid Nerve Sheath Tumors

Hybrid nerve sheath tumors represent a rare entity bearing features of more than one histologic type of nerve sheath tumor ( ▶ Fig. 22.3). ³⁰ They can be either solitary or multiple, as well presented by patients with other types of PNST.

The most common type is a hybrid schwannoma/perineurioma. ³⁰ Immunohistochemistry with double staining for different proteins can reveal parallel layers of alternating S100 and EMA-positive cells with no co-expression of antigens by the same cell. ³¹ The size of these tumors has been reported to be up to 17.5 cm. ³¹ They usually arise in the dermis and subcutis and occur in a wide anatomical distribution, although they typically occur at the extremities. ³¹

Hybrid nerve sheath tumors, especially hybrid neurofibroma/schwannomas, are common in patients with schwannomatosis and have also shown association with NF1 or NF2. ³²

Dermal Nerve Sheath Myxoma

In many contexts, this tumor type has been conflated with neurothekeomas due to ill-defined pathological criteria and unclear determination of specific cell origin in the past. Currently, dermal nerve sheath myxomas are established as an uncommon benign neoplasm, significantly rarer than neurothekeomas.

Dermis and subdermis are involved by this type of tumor, which also present a peripheral fibrous border and abundant myxoid matrix. Schwann cells appear to be predominant. ³³ In immunohistochemical staining, dermal nerve sheath myxoma are positive for S100 and GFAP, which indicates their Schwann cell origin. ³³ Axons only appear scattered. Due to these features, nerve sheath myxomas are suspected to be related to schwannomas.

Dermal sheath myxomas are typically solitary, superficial, painless, multinodular masses in the 0.5- to 2.5-cm size range and located in the distal extremities. ³³ They can grow slowly over several years and present a peak incidence in the fourth decade.

Ganglioneuroma

Ganglioneuromas are rare tumors that arise from sympathetic ganglion cells. They are large, slow-growing, encapsulated tumors histologically consisting of mature ganglion cells (neurons), axons, satellite cells, Schwann cells, and fibrous stroma. ¹³ As opposed to schwannomas and neurofibromas, the tumor is not generated by Schwann cells, but by neurons (in fact, their axons).

More frequent in young females, such masses can occur anywhere along the sympathetic chain. Mediastinum, retroperitoneum, and adrenal glands are common locations. ³⁴ Although usually asymptomatic, they can also be related to specific complains due to local mass effect. Malignant transformation has been reported in some cases.

Hemangioblastoma

Hemangioblastomas are rarely seen involving proximal nerve roots or peripheral nerves. The literature on peripheral nerve hemangioblastomas is limited to a few cases. ³⁵ Although this type of tumor is commonly associated with Von Hippel–Lindau syndrome, most cases seems to be sporadic.

They tend to grow outward beyond the surface of the epineurium from which they arise. Similarly to central hemangioblastomas, pathology consists of neoplastic vacuolated stromal cells within interspersed, highly developed capillary blood vessels. ³⁵

Due to the vascular nature of hemangioblastomas, the risk of significant blood loss at surgery is increased for these tumors. ³⁵ For this reason, they should not be omitted in the differential diagnosis.

22.2.2 Benign tumors of nonneural sheath origin

Several different types of benign masses of nonneural sheath origin can affect peripheral nerves. In this chapter, we will discuss the characteristics of desmoid tumors and neurothekeomas, which are the most commonly reported neoplasms of this kind. ^{36,​ 37}

Desmoid tumor

Also known as aggressive fibromatosis, desmoid tumors rarely affect nerves. ³⁸ This usually happens by secondary involvement. ³⁸ These neoplastic masses are often firm masses of fibrous tissue. ³⁶

Muscle or muscle fascia are usually the origin site of these infiltrative tumors. ⁷ They are often painful masses, usually affecting proximal and truncal areas. ³⁶ Whenever these tumors involve nerves, focal sensorimotor deficits can occur. ³⁶

Neurothekeoma

The name “neurothekeoma” is used to designate superficial tumors of variable pathology involving small cutaneous nerves. As opposed to nerve sheath myxomas, cellular neurothekeomas have negative S100 staining, which indicates they are not of Schwann cell origin. ³⁷ These two distinct clinical entities were inappropriately considered to be of the same type in the past. Additionally, they are negative for EMA, indicating they are not of perineurial cell origin either.

These tumors occur in the dermis and are composed of nests and bundles of epithelioid to spindled cells. ³⁷ No well-defined encapsulation can be observed. In contrast to nerve sheath myxomas, neurothekeomas have a predilection for the upper limbs and head and neck of pediatric and young adult females. ³⁷

22.3 Clinical Presentation

The clinical presentation of PNT ranges from an asymptomatic mass growth to unspecific signs and symptoms related to local mass effect, involvement of surrounding tissues, or direct nerve invasion. ^{5,​ 39} More specific clinical presentations can be observed in the setting of NF1, NF2, or schwannomatosis. ^{3,​ 4,​ 18}

The first step is the assessment for any feature that may indicate whether the mass can represent a PNT ( ▶ Fig. 22.4). Together with a location in the surrounding areas of peripheral nerves or plexus, the presence of Tinel’s sign can point toward this diagnosis. In several published series, prevalence of a positive Tinel’s sign in nerve tumors ranged from 25 to 97%. ^{2,​ 5} In our experience, around 95% of the patients with PNT present a positive Tinel’s sign. Although it is clear that such feature cannot be used for the suspicion of different subtypes of PNT, our experience is in agreement with some authors suggesting that Tinel’s sign is extremely useful to raise the differential diagnosis of a PNST on clinical examination. ^{5,​ 10}

Clinical presentation of PNT may also have specific features according to the different types. ^{1,​ 5} The most significant differences can be noted when comparing the signs and symptoms of benign and malignant PNT. ⁴⁰ Although there is no reliable clinical criteria for the distinction between benign and malignant PNT, several characteristics pointing toward one or another diagnosis must be taken into account in order to guide the therapeutic management. ⁸

Even though this may vary according to tumor location and patient’s profile, BPNT are often less symptomatic. ⁵ Sometimes, these tumors are incidentally found during the clinical investigation or imaging of patients with unspecific or nonrelated conditions. ⁴¹ In other cases, the clinical presentation of a BPNT can be only a lump, without any other symptom. ² Pain is the most common complaint for both benign and malignant PNT. ^{11,​ 42} However, further description of this symptom may provide hints about the diagnosis. ⁵ For example, pain at rest is rare at benign tumors, but almost always present in cases of malignancy. In the same way, nocturnal and/or severe pain may argue against the diagnosis of BPNT. Also, rapidly intensified pain is not usually observed in benign masses. Sensory-motor deficit is another important finding that can be present in 5 to 84% of PNST. ^{2,​ 6,​ 10,​ 11} However, it becomes evident that further investigation is needed when we take a look at the variability in the prevalence of this symptom in different series. Despite the fact that some deficits can be present in BPNT, significant neurological deficits are not common in cases of BPNT. ^{1,​ 5} Sudden enlargement of a known benign lesion together with acute development of neurological deficits may be an indicator of possible malignant transformation in a patient with NF. ²³

Most commonly, BPNT is slow growing, painless, smaller than 5 cm, and present a regular shape. ⁸ Such masses usually do not evidence hard consistency on palpation. ²³ Subcutaneous hemorrhage, which can rarely appear in some cases of PNT, may not be observed in cases of BPNT. ⁴³

When a possible PNT is detected, imaging examinations are necessary to confirm this diagnosis and to try to identify other signs of malignancy. Later, it will be important to investigate the combination of clinical and imaging features of those masses in order to check for possible surgical indications.

22.4 Imaging (Magnetic Resonance Imaging)

Magnetic resonance imaging (MRI) is the most important imaging modality for the diagnosis, evaluation, and surgical planning of PNT. ^{2,​ 44} Over the last decades, several MRI features have been demonstrated useful for the characterization of tumorlike conditions and the distinction between different types of PNT. ^{40,​ 45} Still, the imaging of schwannomas and neurofibromas is similar, which prevents the distinction between those tumors.

Both malignant PNT and BPNT can present in variable sizes. However, benign masses are significantly associated with smaller size. Median lesion size for BPNT ranges from 2.7 to 5.0 cm, against tumor sizes from 7.5 to 9.9 cm for MPNST. ^{2,​ 46} Mean size for BPNT and malignant PNT varies from 3.4 to 5.5 cm and from 7.2 to 10 cm, respectively. ^{2,​ 47,​ 48} Chhabra et al defined 6.1 cm as the optimal cut-off value of PNT size for predicting malignancy. ⁴⁵ In our experience, the majority of benign tumors were less than 5 cm, in contrast to what was observed in the majority of malignant tumors. ⁸

MRI can accurately determine the relationship between the PNT and the adjacent structures ( ▶ Fig. 22.5). ⁴⁹ BPNT are usually not adhered to other tissues, nor located deeper than fascial planes. ⁴⁰ Absence of perilesional edema and/or invasion of adjacent tissue is also related to benign tumors. ^{45,​ 50} In their series, Ogose et al reported geographic central enhancement to be present only in BPNT. ⁵

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