Dermatologic Manifestations of Neurilemmoma Workup

• Microscopic examination of the tumor biopsy tissue and clinicopathologic correlation establishes the correct diagnosis. The diagnostic microscopic features are described in Histologic Findings.
• Masson trichrome stain can be used to demonstrate the presence of longitudinal striations observed in smooth muscle tumors to differentiate a cutaneous leiomyoma from a neurilemmoma, which lacks striations.
• Immunostaining using anti–S-100 protein antibody confirms the presence of Schwann cells.

• With routine radiographic examination, neurilemmomas generally appear as sharply circumscribed tumor masses.
• CT scan images show circumscribed, low-attenuation masses with uniform or heterogeneous contrast enhancement.
• MRI reveals a high T2 signal and heterogeneous contrast enhancement.
• Both CT scan images and MRI show that large tumors often have areas of cystic changes. Benign neurilemmomas do not show active irregular invasion of bone, as is observed in malignant peripheral nerve sheath tumors.

The correct diagnosis of neurilemmoma is established by microscopic examination of tumor biopsy tissue.

Gross appearance

In general, neurilemmomas are firm, smooth-surfaced tumors smaller than 10 cm. Most neurilemmomas affect small nerves. The smaller examples are rounded, somewhat elastic in consistency, and milky-white or semitranslucent. The larger tumors are lobulated irregularly and, by virtue of secondary degenerative changes, become partly or mainly cystic with calcification (ie, ancient change). Areas of hemorrhage and opaque creamy-yellow tumorous tissue are observed on the cut surface (see the image below).

Some tumors manifest as a firm rubbery nodule with a whorled appearance on the cut surface, resembling smooth muscle tumors of the uterus. The plexiform or multinodular variant, which accounts for approximately 5% of neurilemmomas, may be discernible upon gross examination (see the images below).

Microscopic appearance

Most tumors are unilocular masses surrounded by a fibrous capsule composed of epineurium and residual nerve fibers. While this capsule is evident in most tumors, those arising in mucosa (eg, nose, nasopharynx), the central nervous system, and viscera often lack a capsule. Intradermal neurilemmomas and the plexiform or multinodular growth pattern similar to a plexiform neurofibroma are rare. Histologically, the characteristic feature of a neurilemmoma is the pattern of alternating Antoni type A and B areas.

Antoni type A areas (as shown in the image) consist of compact, spindle-shaped cells with twisted nuclei, indistinct cytoplasmic borders, and, occasionally, clear intranuclear vacuoles.

The cells are arranged in short bundles or interlacing fascicles with nuclear palisading, whirling of the cells, and Verocay bodies. Verocay bodies are formed by 2 compact rows of well-aligned nuclei and cell processes that are arranged in a roughly oval shape (see the image below). Verocay bodies are more distinctive of schwannomas than the Antoni A and Antoni B patterns, but they are not seen in all schwannomas.

Mitotic figures are rare. S-100 protein, an acidic protein commonly found in the supporting cells of the central and peripheral nervous system, is demonstrated in neurilemmomas, particularly in the Antoni type A areas. Antoni B areas are less cellular and are often disorderly. The spindle or oval cells are arranged haphazardly in the loose matrix with microcystic changes, inflammatory cells, and delicate collagen fibers. Prominent, irregularly spaced blood vessels are present in the stroma. The psammomatous melanotic neurilemmoma (schwannoma) shows, in addition to the above features, melanin deposition and concentric calcified bodies (psammoma bodies).

Schwannomas have been variably observed to be glial fibrillary acid protein (GFAP) and occasionally keratin positive, with antibodies reacting with multiple keratins (pankeratins, keratin cocktail (CK) (AE1/AE3). Both markers highlighted the cellular Antoni A areas, particularly adjacent to the capsule, myxoid or degenerative areas, and perivascularly. In recent studies of a large series of retroperitoneal schwannomas, 84% of the tumors stained positive for both AE1/AE3 and GFAP. However, the tumor cells were negative for specific keratin polypeptides (K). The findings can be attributed to cross reactivity of AE1/AE3 with other intermediate filament proteins, such as GFAP.^[12] Schwannomas contain Leu7 and S-100 protein.

Ultrastructural examination of the tumor reveals almost exclusively a single cell type (ie, Schwann cells). They have characteristic thin cell processes that arrange in undulating layers and are continuous from the cell body. The Schwann cell surface is coated with basal lamina composed of electron-dense material measuring approximately 50 nm (see the image).

The basal lamina lies in stacks between the cells along with typical and long-spacing collagen fibrils with a 130-nm periodicity. These collagen fibrils are often referred to as a Luse body (see the image).

The cytoplasm contains a flattened and sometimes invaginated nucleus, microfibrils, rare lysosomes, and scattered mitochondria. In Antoni B areas, the Schwann cells have increased numbers of lysosomes and myelin figures and fragmented basal lamina.

Immunohistochemical staining using anti–S-100 protein antibody demonstrates uniformly and intensely positive staining of Schwann cells in the tumor (see the image).

This technique serves as an important diagnostic tool, and, in severely degenerated neurilemmomas, S-100 protein stain is most valuable for confirming the diagnosis.

The results of immunostaining for myelin proteins used to identify benign and malignant Schwann cell tumors have been variable.

Histologic differential diagnosis

• Neurofibroma: The loose, myxomatous Antoni type B tissue of a neurilemmoma may mimic a neurofibroma. However, neurofibromas lack the thick collagenous capsule of neurilemmomas and instead are surrounded by a variably thickened perineurium and epineurium. Neurofibromas also lack the Antoni type A and B patterns and Verocay bodies typical of neurilemmomas. Neurofibromas are composed of a mucinous matrix containing scattered, myelinated, and nonmyelinated axons along with a heterogeneous cell population including Schwann cells, fibroblasts, and perineural cells. Consequently, immunoreactivity for S-100 protein is observed in only a portion of the cells comprising a neurofibroma, as opposed to uniform reactivity throughout a neurilemmoma.
• Palisaded encapsulated neuroma: This is an uncommon, generally solitary, asymptomatic intraneural neuroma that may arise in early childhood or adulthood. It appears as a firm, rubbery, skin-colored or pink papule commonly affecting the "butterfly area" of the face. Palisaded encapsulated neuromas are bulbous expansions of a peripheral nerve. They appear as well-circumscribed, ovoid, or rounded nodules in the dermis, which, in contrast to neurilemmomas, contain a greater number of axons and Schwann cells in interlacing fascicles along with characteristic cleftlike spaces.
• Schwannoma: These are distinguished from astrocytoma and ependymoma by their abundant parenchymal reticulin, which is positive for type IV collagen. Schwannomas have characteristic contiguous basement membranes along the exterior surfaces of their cells. Although occasionally focal positive staining for GFAP may be present, negative GFAP staining supports the diagnosis of schwannoma. Astrocytomas are generally GFAP positive.
• Fibrous meningiomas: These lack typical meningeal whorls and psammoma bodies, and they can be difficult to differentiate from schwannomas. EMA is a useful immunomarker for distinguishing the 2 tumors. Meningiomas are reactive with EMA, while schwannomas are not. GFAP can sometimes be used, because some schwannomas are positive but meningiomas are negative.
• Cutaneous leiomyoma

  • Leiomyomas are benign smooth muscle tumors. They are not derived from neural tissue and generally lack the thick, hyalinized capsule and vasculature of a neurilemmoma. Palisading resembling Verocay bodies may be observed. The blunt-ended nuclei and densely eosinophilic cytoplasm of smooth muscle cells showing distinct cell borders and perinuclear halos help distinguish them from Schwann cells (with their more tapered, spindle-shaped nuclei).
  • Immunohistochemical stains readily distinguish leiomyomas from neurilemmomas, the former staining with myogenic cell markers, such as smooth muscle actin and desmin, and the latter showing positive staining with S-100. Masson trichrome stain may be used to demonstrate the longitudinal striations characteristic of smooth muscle tumors. The ultrastructural features of smooth muscle cells are also highly characteristic, being bounded by a basement membrane and often containing parallel arrays of abundant cytoplasmic microfilaments (actin) with interspersed fusiform dense bodies and pinocytotic vesicles.
• Palisaded myofibroblastoma: These contain palisaded cells and Verocay bodies that may mimic neurilemmomas. However, palisaded myofibroblastomas involve lymph nodes, contain fibroblastic and myofibroblastic elements, and are negative for S-100 protein staining.