Malignant Peripheral Nerve Sheath Tumour

Not clinically relevant

Conventional MPNSTs have complex karyotypes. Despite different clinical presentations (e.g., NF1-associated, sporadic de novo, or radiotherapy-associated), recent genomic studies of MPNSTs demonstrated highly frequent and concurrent inactivating mutations in three pathways: NF1, CDKN2A/CDKN2B, and PRC2 core components (EED or SUZ12), resulting in complete loss of function. In NF1-associated peripheral nerve sheath tumors, as benign precursor plexiform neurofibroma progresses into atypical neurofibroma / atypical neurofibromatous neoplasm of uncertain biological potential and/or transforms to high-grade MPNST, it is accompanied by progressive genomic alterations that inactivate the neurofibromin (NF1), p16/p15 (CDKN2A/CDKN2B), and PRC2 pathways and increased genomic copy-number variations, respectively. About 80% of all high-grade MPNSTs exhibit complete loss of PRC2 activity through loss of the PRC2 core component (EED or SUZ12) and complete loss of H3K27me3 expression. The loss of H3K27me3 expression has become a useful diagnostic tool in high-grade MPNST. Given the critical role of PRC2 in development and cell-lineage specification, PRC2 loss may underlie the molecular mechanisms of the histological phenotype of heterologous differentiation in MPNSTs.

Epithelioid MPNSTs are distinct from conventional MPNSTs molecularly. SMARCB1 gene inactivation resulting in SMARCB1 loss by immunohistochemistry is observed in approximately 75% of cases. They rarely have genetic alterations in the neurofibromin (NF1), p16/p15 (CDKN2A/CDKN2B), and PRC2 pathways.

When the tumor arises in a nerve, there is a fusiform enlargement of the nerve. In patients with NF1, a tumor can be seen usually in association with a plexiform neurofibroma. MPNSTs are usually > 5 cm at the time of diagnosis and have a tan-white, fleshy cut surface, often with areas of hemorrhage and necrosis.

Tumors are typically composed of fascicles of spindle-shaped cells, often with a hemangiopericytoma-like vascular pattern, and alternating hypercellular and hypocellular areas (tapestry appearance). There are often areas of geographical necrosis and conspicuous mitotic figures. The cells are spindle or serpentine in shape, with hyperchromatic nuclei and pale wavy cytoplasm. MPNST may occasionally show extensive pleomorphism, simulating an undifferentiated pleomorphic sarcoma. Perivascular accentuation of tumor cells may be seen; in those areas, the cells frequently become plumper. Heterologous differentiation, such as skeletal muscle, bone, cartilage, and blood vessels, is seen in about 15% of tumors. A malignant triton tumor is an MPNST with skeletal muscle differentiation. Glandular differentiation, with or without mucin production, is rarely seen (glandular MPNST); almost all of these tumors arise in patients with NF1. When involving a large nerve, the neoplastic cells may track along the nerve bundles. In NF1-related MPNST arising in a pre-existent neurofibroma, the distinction between a low-grade MPNST and an atypical neurofibroma / atypical neurofibromatous neoplasm of uncertain biological potential is often problematic, especially on small biopsies. Recently, diagnostic criteria to distinguish these tumors from other types of NF1-associated nerve sheath tumors have been established.

Epithelioid MPNST is a rare subtype of MPNST (< 5% of the tumors) that is composed of plump, epithelioid cells with abundant eosinophilic cytoplasm, sometimes embedded in an abundant extracellular myxoid or hyalinized matrix and typically demonstrating a lobulated growth pattern. Although rare, this subtype of MPNST is the most common type to arise ex-schwannoma. Epithelioid MPNST is not associated with NF1. Immunohistochemically, MPNST may be positive for S100 (< 50% of tumors), SOX10 (< 70%), and GFAP (20–30%). Importantly, staining for S100 and SOX10 is patchy or focal. Diffuse staining for S100 or SOX10 is not usually compatible with the diagnosis of conventional MPNST. Complete loss of staining for H3K27me3 may be helpful in the diagnosis of MPNST, with high-grade tumors (and radiation-induced MPNST) showing more-frequent loss than low-grade tumors. The heterologous components (e.g., skeletal muscle differentiation or angiosarcomatous areas) stain for appropriate markers. The glands in glandular MPNST show positive staining for keratin and CEA and may be positive for neuroendocrine markers. Unlike conventional MPNSTs, epithelioid MPNSTs show strong and diffuse staining for S100 and SOX10, in the absence of melanoma markers. They retain expression of H3K27me3 and most show loss of SMARCB1 expression. Epithelioid MPNST may also be positive for keratin.

Not clinically relevant

MPNST is an aggressive tumor with a poor prognosis. Truncal location, tumor size > 5 cm, local recurrence, and high-grade morphology are all adverse prognostic factors; patients with NF1-associated MPNST appear to have a worse prognosis than patients with sporadic tumors. Malignant triton tumors are particularly aggressive.

Not clinically relevant

Essential: sarcoma arising from a nerve or pre-existing nerve sheath tumor or in a patient with NF1; tumors with a spindle fascicular growth, geographical necrosis, and often a limited degree of nuclear pleomorphism; in the sporadic setting, diagnosis is most often based on the identification of Schwann cell differentiation (S100/SOX10 focal positivity) and/or loss of H3K27me3 expression in a soft tissue mass; heterologous elements in a sarcoma should suggest MPNST; epithelioid MPNSTs occur outside the NF1 setting and often show diffuse S100 and SOX10 positivity and loss of SMARCB1 expression.