Pathomechanisms in schwannoma development and progression

Abstract

Schwannomas are tumors of the peripheral nervous system, consisting of different cell types. These include tumorigenic Schwann cells, axons, macrophages, T cells, fibroblasts, blood vessels, and an extracellular matrix. All cell types involved constitute an intricate "tumor microenvironment" and play relevant roles in the development and progression of schwannomas. Although Nf2 tumor suppressor gene-deficient Schwann cells are the primary tumorigenic element and principle focus of current research efforts, evidence is accumulating regarding the contributory roles of other cell types in schwannoma pathology. In this review, we aim to provide an overview of intra- and intercellular mechanisms contributing to schwannoma formation. "Genes load the gun, environment pulls the trigger." -George A. Bray.

Fig. 1. Histopathology of Antoni A tissue and Verocay bodies in schwannomas.

a HE staining of a schwannoma. An Antoni A area with densely packed cells is shown. Most cell nuclei appear elongated, indicating the presence of tumor cells. Scale bar = 100 µm. b HE staining of a schwannoma. Zones lacking any nuclei alternate with areas of fusiform, fibrillary organized, elongated nuclei of tumor cell origin. These are typical Verocay bodies that are embedded into Antoni A tissue. Scale bar = 100 µm.

Fig. 2. Histopathology of Antoni B tissue and transition zones in schwannomas.

a HE staining of a schwannoma. All visible cells are loosely arranged and do not exhibit any particular organizational pattern. Various cell nuclei of different shape and size are shown, indicating the presence of various cell types. The stroma is loosened, the cellular organization exhibits a microcystic pattern. These vacuoles usually contain lipids. The presented tissue structure is typical for an Antoni B area. Scale bar = 100 µm. b HE staining of a schwannoma. A transition of Antoni A tissue (left; elongated, spindle-shaped nuclei) into Antoni B tissue with small and round nuclei and microcystic stroma (right) is depicted. Scale bar = 100 µm. c HE staining of a schwannoma. A transition of a Verocay body (in the center of the image) into Antoni B tissue is shown. The borders of the Verocay body merge into large vacuoles, indicating extensive tissue degradation. Scale bar = 100 µm.

Fig. 3. Myelin degradation and phagocytosis are common features of schwannomas.

a Immunohistochemistry for the lysosomal marker protein CD68 (purple color) in an Antoni A area (left side), Antoni B area (right side), and a transition zone of a schwannoma. Based on the staining pattern, lysosomes appear to be predominantly present in the Antoni B area, in addition to Antoni B-specific tissue features like vacuoles/microcysts and presence of foamy macrophages. Scale bar = 50 µm. b Electron micrograph depicting the cytoplasm of a tumor cell inside a schwannoma. A large number of granules (G) can be seen, presumably phagocytic vesicles. Furthermore, a myelin figure (MF) as a sign of myelin phagocytosis and degradation by the tumor cell is present. This image has been reprinted from [8].

Fig. 4. Macrophages and T-cells are part of the schwannoma microenvironment.

a Immunohistochemistry for the macrophage marker protein MAC387 in a schwannoma. Numerous foamy macrophages are seen within the depicted Antoni B tissue. These are characterized by a large, loosened cytoplasm and small nuclei of different shapes, in contrast to elongated nuclei from tumor cells seen in Antoni A areas. Scale bar = 50 µm. b Immunohistochemistry for the T-cell marker protein CD3 in a schwannoma. Heterogenously distributed T cells with small nuclei and cytoplasm are spread throughout this Antoni B tissue. Scale bar = 100 µm.

Fig. 5

Simplified scheme illustrating major intra- and intercellular signaling pathways implicated in schwannoma growth.

Fig. 6

Simplified scheme featuring three possible scenarios that may occur after nerve injury, depending on the underlying genotype regarding the Nf2 gene and DNA damage/mutations that may occur during nerve regeneration.