2019 NPB-14

This case was originally published in 2019. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 45-year-old man with a history of multiple prior surgical resections of skin lesions throughout his life presented with an area of induration on his left frontoparietal scalp, overlying the site of a ventriculoperitoneal shunt placed during childhood due to aqueductal stenosis. Imaging revealed a diffusely enhancing lesion with focal heterogeneous nodularity involving the skin and subcutaneous soft tissue. A wide local resection was performed.

Tissue Site
Skin and soft tissue of scalp

The whole slide image provided is an H&E-stained image of the scalp from a resection.

Malignant peripheral nerve sheath tumor (MPNST) is a rare neoplasm typically seen in the adult population. It accounts for approximately 5% of all soft tissue sarcomas. The diagnosis carries a poor prognosis with a five-year survival rate between 35% and 50%. The most common locations are the limbs, retroperitoneum, trunk, and head and neck. While 50% arise in the setting of neurofibromatosis type 1 (NF1), 10% present following radiation therapy and the rest are sporadic.

NF1 is an autosomal dominant hereditary tumor syndrome with significant clinical variability characterized by the presence of skin lesions (café au lait macules, axillary freckling), cutaneous and intraneural neurofibromas, gliomas and other tumors, as well as other abnormalities of development including aqueductal stenosis. MPNSTs occur approximately 10 years earlier in this population than in sporadic cases. Germline mutations in the NF1 gene located in chromosome 17q11 are the underlying etiology, and they can arise de novo in the absence of family history. Other hereditary tumor syndromes including neurofibromatosis type 2 and schwannomatosis are not typically associated with MPNST.

A spindle cell lesion of the subcutaneous soft tissue in a patient with NF1 (Image A) raises a differential diagnosis that includes diffuse neurofibroma, plexiform neurofibroma, and MPNST. The latter is characterized by a densely cellular spindle cell proliferation, frequently with fascicular or herringbone architecture (Image B), hyperchromatic nuclei with scant cytoplasm, perivascular cellular arrangement, necrosis, and frequent mitoses (Image C). Cutaneous neurofibromas can be diffuse (plaque-like) or localized (frequently pedunculated). They are typically well-differentiated proliferations of bland Schwann cells with intermixed nonneoplastic cells, frequently show myxoid matrix, and are rich in wavy collagen. Although degenerative nuclear atypia is possible, there is rarely significant mitotic activity. Plexiform neurofibroma, practically pathognomonic for NF1 when present in major nerve trunks, involves multiple nerve fascicles which appear grossly distended (“bag of worms”). Perineurioma and schwannoma are usually well-circumscribed benign tumors with perineurial onion-bulb morphology in the former and alternating cellular areas with nuclear palisading and loose areas with microcystic change in the latter. In the setting of NF1, MPNST frequently arises in association with a plexiform or intraneural neurofibroma, while association with a diffuse dermal neurofibroma is rare (Image B demonstrates features of neurofibroma on the right with transition to morphology of MPNST on the lower left).

In the absence of a precursor nerve sheath tumor or a history of neurofibromatosis, the differential diagnosis of MPNST versus other monophasic spindle cell tumors can prove challenging. Only between 30% and 70% of MPNSTs express neural-crest origin Schwann cell markers such as S100 and SOX10, with higher grade tumors showing less frequent positivity. In addition, these markers, even when positive, can be very focal. Some tumors with heterologous differentiation can aberrantly express markers of other cellular signatures, such as cytokeratins and desmin. When arising from a preexisting neurofibroma, loss of S100 expression can be seen in the malignant areas, while S100 positivity is maintained in the benign components (Image D).

Molecular alterations recently characterized in 70% to 90% of MPNST include coexisting inactivation of NF1 (neurofibromin) and CDKN2A in combination with inactivation of the polycomb repressive complex 2 (PRC2) via mutations in one of its components (embryonic ectoderm development EED1 or suppressor of zeste 12 SUZ12). PRC2 is physiologically responsible for trimethylation of the lysine at amino acid 27 of histone 3 (identified as H3K27me3), and it participates in global DNA methylation by interaction with DNA methyltransferases. The consequence of PRC2 inactivation is a decrease of H3K27me3, which can be assessed by IHC. Recent studies have demonstrated that loss of H3K27me3 immunoexpression, when complete (Image E), is a specific marker for MPNST, albeit its sensitivity is not as strong. The mosaic pattern (partial loss) of H3K27me3 immunoexpression is considered nonspecific. This is of particular interest in sporadic and radiation-induced cases, in which the complete loss of H3K27me3 is frequent and can establish a definitive answer in cases that otherwise are a diagnosis of exclusion. The presence of internal control positivity in endothelial and inflammatory cells is essential in the interpretation of this stain. Associated loss of neurofibromin by IHC further supports the diagnosis, representing a highly specific combination. Histological mimics such as monophasic synovial sarcoma, dedifferentiated liposarcoma, dermatofibrosarcoma protuberans, spindle cell melanoma, and others have consistently demonstrated retained H3K27me3 nuclear expression in multiple studies. Of note, epithelioid MPNST seems to represent a different morphological and genetic entity with characteristic loss of INI1 (SMARCB1) and retained H3K27me3 expression.

• MPNST is a rare malignant tumor of peripheral nerve, frequently associated with NF1.
• MPNST can arise de novo or in conjunction with a preexisting neurofibroma.
• MPNST commonly shows combined inactivation of NF1 and CDKN2A and loss of function mutations in components of PRC2, which lead to loss of trimethylation of lysine 27 in histone 3.
• Complete H3K27me3 loss by IHC is a reliable and specific biomarker for MPNST, albeit with limited sensitivity.

1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumours of the Central Nervous System. Revised 4th ed. Lyon, France: IARC; 2016:280-1.
2. Prieto-Granada CN, Wiesner T, Messina JL, et al. Loss of H3K27me3 expression is a highly sensitive marker for sporadic and radiation-induced MPNST. Am J Surg Pathol. 2016 Apr;40(4):479-89.
3. Rodriguez FJ, Giannini C, Spinner RJ, Perry A. Tumors of peripheral nerve. In: Perry A, Brat DJ, eds. Practical Surgical Neuropathology: A Diagnostic Approach. 2nd ed. Philadelphia: Elsevier; 2018:323-73.
4. Röhrich M, Koelsche C, Schrimpf D, et al. Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol. 2016 Jun;131(6):877-87.
5. Schaefer IM, Fletcher CD, Hornick JL. Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod Pathol. 2016 Jan;29(1):4-13.