2020 NPB-13

This case was originally published in 2020. 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.

The patient is a 16-year-old boy who presented with trismus and left-sided facial pain. Imaging revealed a large, sharply-circumscribed, smooth-bordered, heterogeneously-enhancing, T2-bright mass within the left infratemporal fossa. The mass was resected.

Tissue Site
Left infratemporal fossa

The whole slide image provided is an H&E-stained slide from the left infratemporal fossa mass resection.

The diagnosis is spindle cell/sclerosing rhabdomyosarcoma (SRMS), initially considered a subtype of embryonal rhabdomyosarcoma until the 2013 World Health Organization (WHO) classification, when it was fully recognized as a distinct entity. Most rhabdomyosarcomas (RMS) occur in young people, with an annual incidence of 4.3 per million people younger than 20 years. They tend to involve characteristic anatomic sites, as described below, but may be found anywhere, including within the CNS. Four major types are recognized by the 2013 WHO classification of soft tissue tumors: embryonal, alveolar, pleomorphic, and spindle cell/sclerosing.

Of the other RMS subtypes, embryonal RMS is the most common, and may involve head and neck sites. The spectrum of cells in embryonal RMS emulate various stages of development in embryonal skeletal muscle, with very primitive stellate cells containing sparse cytoplasm on one end of the spectrum and brightly-eosinophilic strap-shaped cells with cytoplasmic cross-striations and peripheral nuclei at the other end. Rhabdomyoblasts occupy the middle of the spectrum and have eosinophilic cytoplasm and eccentric, oval nuclei with central nucleoli. Botryoid variants are grossly polypoid and microscopically display a dense layer of neoplastic cells abutting an epithelial surface forming a so-called cambium layer. Rare tumors may have features of both embryonal RMS and spindle cell/sclerosing RMS. Embryonal RMS frequently shows aneuploidy with chromosomal gains and losses; alterations of RAS family genes (HRAS, NRAS, KRAS) and mutations in FGFR4, PIK3CA, NF1, and FBXW7 may also be seen.

Alveolar RMS generally occurs in the extremities of children and young adults and is highly cellular with a monomorphous population of primitive cells with round nuclei. Most cases show the gene fusion PAX3-FOXO1 or PAX7-FOXO1, but rare cases with a PAX3-NCOA2 gene fusion have also been described.

Pleomorphic RMS is typically a disease involving the extremities of adults. Prominent cytologic pleomorphism and its distinctive clinical characteristics generally exclude this subtype of RMS from the differential diagnosis of a spindle cell neoplasm of the head and neck in an adolescent, as in this case.

Spindle cell/sclerosing rhabdomyosarcoma (SRMS) is defined as a spindle cell neoplasm of children and adults that displays skeletal muscle differentiation by IHC. It accounts for anywhere from 3% to 10% of RMS and commonly involves head and neck sites (Image A), the paratesticular region, or extremities. The spindle cell pattern was described in the early 1990’s and consists of elongated spindle cells arranged in a fascicular or storiform pattern (Image B and Image C). The sclerosing pattern was subsequently described and is characterized by prominent hyaline sclerosis and a pseudovascular growth pattern. The WHO classification recognizes a histologic spectrum between the spindle cell and sclerosing patterns but incorporates them in a single combined category. Male patients outnumber female patients by a ratio of up to 6:1. IHC for desmin (Image D) and myoD1 (Image E) generally show diffuse, strong immunoreactivity, while myogenin IHC may be focal (Image F). Focal S100 and cytokeratin immunoreactivity can occur.

Three molecular subgroups of SRMS have been described: tumors with NCOA2 and VGLL2 fusions (either with each other or with other partners, and often occurring in infantile or congenital cases), tumors with a MYOD1 mutation (in adult and pediatric cases), and tumors without recurrent genetic abnormalities.

While IHC markers of skeletal muscle are present in all types of RMS, myogenin IHC is typically focal in embryonal, pleomorphic, and SRMS (as noted in the current case); by contrast, myogenin IHC is diffusely positive in alveolar RMS.

The differential diagnosis of SRMS is broad and includes other spindle cell neoplasms. Fibrous meningioma involving the skull base may have a similar appearance but lacks skeletal muscle markers and is instead immunoreactive for EMA and SSTR2A. Schwannoma may also resemble SRMS but should display strong, diffuse S100 and SOX10 immunoreactivity. IHC for STAT6 can help exclude solitary fibrous tumor, which is characterized by nuclear STAT6 immunoreactivity. Leiomyosarcoma has an overlapping lHC profile with SRMS: it is typically positive for SMA, desmin, and h-caldesmon, but it lacks myoD1 or myogenin immunoreactivity. Hyalinized or matrix-rich areas may be present in SRMS and sometimes prompt consideration of other types of sarcoma, including osteosarcoma, chondrosarcoma, or angiosarcoma.

• Spindle cell neoplasms involving the skull base have a broad differential diagnosis, including peripheral nerve sheath tumors, meningioma, solitary fibrous tumor/hemangiopericytoma, and rare sarcomas, including SRMS.
• Judicious use of IHC or other ancillary testing is recommended to establish the diagnosis, particularly in young people.
• SRMS was formerly considered a variant of embryonal RMS, but has distinctive clinical, morphological, and molecular alterations, including NCOA2 and VGLL2 fusions (often occurring in infantile or congenital cases) and MYOD1 mutations (in adult and pediatric cases).

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