Genetic predisposition to peripheral nerve neoplasia: diagnostic criteria and pathogenesis of neurofibromatoses, Carney complex, and related syndromes

Abstract

Neoplasms of the peripheral nerve sheath represent essential clinical manifestations of the syndromes known as the neurofibromatoses. Although involvement of multiple organ systems, including skin, central nervous system, and skeleton, may also be conspicuous, peripheral nerve neoplasia is often the most important and frequent cause of morbidity in these patients. Clinical characteristics of neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) have been extensively described and studied during the last century, and the identification of mutations in the NF1 and NF2 genes by contemporary molecular techniques have created a separate multidisciplinary field in genetic medicine. In schwannomatosis, the most recent addition to the neurofibromatosis group, peripheral nervous system involvement is the exclusive (or almost exclusive) clinical manifestation. Although the majority of cases of schwannomatosis are sporadic, approximately one-third occur in families and a subset of these has recently been associated with germline mutations in the tumor suppressor gene SMARCB1/INI1. Other curious syndromes that involve the peripheral nervous system are associated with predominant endocrine manifestations, and include Carney complex and MEN2b, secondary to inactivating mutations in the PRKAR1A gene in a subset, and activating mutations in RET, respectively. In this review, we provide a concise update on the diagnostic criteria, pathology and molecular pathogenesis of these enigmatic syndromes in relation to peripheral nerve sheath neoplasia.

Figure 1. Molecular basis of inherited tumor syndromes of nerve

Inherited predisposition to nerve sheath neoplasia involves germline mutations in key tumor suppressor genes. In NF1, neurofibromin loss leads to constitutive MEK/ERK pathway activation. NF2 is associated with Merlin loss, a tumor suppressor with multiple complex effects, regulating RAC, PI3K and receptor tyrosine kinases (including PDGFR). Less is currently known about the genetic basis of schwannomatosis, which is sporadic in most cases. Germline mutations in the SMARCB1 gene, encoding a component of the SWI/SNF chromatin remodeling complex, are present in approximately one third of familial cases and 10% of sporadic ones. Carney complex frequently results from mutations in the PRKAR1A gene, which encodes a regulatory subunit of protein kinase A. Conversely, MEN2b, caused by activating mutations in the RET oncogene, does not result in true neoplasms in the peripheral nerve, but rather hamartomatous growths.

Figure 2. Neurofibromatosis type 1: clinical and pathologic features

The most typical CNS manifestation of neurofibromatosis is optic nerve glioma (a, arrows), which almost always is a pilocytic astrocytoma. Multiple cutaneous neurofibromas are frequent in NF1 (b), and characterized by a proliferation of neoplastic schwann cells, fibroblasts and perineurial cells with associated wavy collagen (c). Diffuse neurofibromas are larger neoplasms that entrap adnexa and infiltrate fat (d), and may undergo conspicuous aggregation of pseudo-meissnerian corpuscles (e). Plexiform neurofibromas are defined by involvement of several nerve fascicles leading to « worm-like » growth (f). Malignant peripheral nerve sheath tumors are cellular, usually high grade spindle cell neoplasms(g). Heterologous elements, such as rhabdomyoblasts, may be present (h). Specfic immunohistochemical markers are confirmatory (myogenin, i). Massive soft tissue neurofibromas are large, benign distinctive neoplasms characterized by diffuse soft tissue infiltration (j). A cellular, round cell component may be present, but has no adverse prognostic implications (k,l).

Figure 3. Neurofibromatosis type 2 : clinical and pathologic features

Bilateral vestibular schwannomas represent a pathognomic finding of NF2(a). Ependymomas are an important CNS manifestation of NF2 (b, same patient as in a). Hairy cutaneous plaques are part of the NF2 syndrome (c), and a clinical finding allowing separation from schwannomatosis. Most sporadic or NF2 associated schwannomas are well circumscribed, tan-white appearing neoplasms with variable yellowish areas (d). Compact aggregates of schwann cells represent the most important feature (e). Alternating compact (Antoni A) and loose (Antoni B) areas in schwannomas are distinctive (f). Palisades of cells in schwannomas with empty cores are known as Verocay bodies (g). Although syndrome associated and sporadic schwannomas have many overlapping features, well formed whorls reminiscent of meningioma may be overrepresented in syndrome associated cases, including NF2 (h). Meningiomas (arrowheads) and schwannomas (arrows) may co-exist in the spine (i).

Figure 4. Schannomas in schwannomatosis

Whole body MR scans may demonstrate multiple schwannomas (arrows) in schwannomatosis patients (a)(Photo courtesy of Dr. Jaishri Blakeley). Schwannomas in schwannomatosis are usually circumscribed, but often expand the adjacent nerve (b). Myxoid patterns are also present in a subset of these schwannomas (c) as well as adjacent nerve. A mosaic pattern of INI1 immunoreactivity is present in the majority of syndrome associated schwannomas, including those of schwannomatosis (d)(Photo courtesy of Dr. Arie Perry).

Figure 5. Melanotic Schwannomas

Pigmented schwannomas represent the hallmark of peripheral nerve sheath neoplasia in Carney complex, lobulated melanin rich tumors (a). Cytologic atypia in the form of large, violaceous nucleoli may be present, particularly in some aggressive examples (b). The presence of psammoma bodies is typical of melanotic schwannomas in the setting of Carney syndrome (c)(photo courtesy of Dr. Caterina Giannini). Although expression of markers of melanocytic differentiation is the rule in these neoplasms, the presence of perilobular/pericellular reticulin suggests the diagnosis (d). Collagen IV immunoreactivity is variable in these tumors, and may highlight tumor lobules (e) or rarely be pericellular (f).

Figure 6. Ultrastructural features of melanotic schwannomas (Photo courtesy of Dr. Caterina Giannini)

Electron microscopy is an useful adjunct in the diagnosis of melanotic schwannomas, demonstrating dual melanocytic and schwannian differentiation. Electron dense intracytoplasmic melanosomes are conspicuous (a,b). The presence of surface basal lamina, often duplicated, (c) is an important diagnostic feature, which is absent in melanomas and melanocytomas.

Figure 7. Mucosal neuromas in MEN 2B (Photo Courtesy of Dr. J. Aidan Carney)

Mucosal neuromas are characterized by severely hypertrophic, rather than neoplastic, nerves (a,b)