January 2023 – Bone and Soft Tissue

EWSR1::PATZ1-rearranged sarcoma.

Malignant mesenchymal tumors harboring EWSR1::PATZ1 gene fusions are currently classified by the WHO as “round cell sarcomas with EWSR1-non-ETS fusions.” The majority of tumors harboring EWSR1::PATZ1 gene fusions share common morphologic features, including relatively bland cytology, low mitotic activity, and absent necrosis; however, a minor percentage of tumors can show unusual morphology, high mitotic activity, or necrosis. Although they occur commonly in the torso, they may also occur in other regions, such as the leg and head and neck region. They display an unusual immunoprofile, with co-expression of epithelial, skeletal muscle, and nerve sheath-associated antigens. So far, only a limited number of cases have been reported with short follow-up, which makes judgement of clinical behavior somewhat difficult; however, preliminary studies suggest that these tumors may behave in a somewhat indolent fashion after complete excision.

Desmoplastic small round cell tumor: This is an uncommon tumor, usually occurring in the abdominal cavity of young male patients. By histology they are characterized by nests, sheets, and cords of relatively monomorphic cells intervened by abundant desmoplastic fibrous stroma. Mitoses and necrosis are very common. These tumors stain diffusely for keratin and desmin, while they are usually negative for GFAP and S100. The most common fusion identified in these tumors is EWSR1::WT1.

Alveolar rhabdomyosarcoma: This sarcoma is a high-grade malignant neoplasm presenting predominantly in the head and neck region or the extremities of adolescents and young adults. Histologically, it shows a highly cellular tumor composed of nests and sheets of primitive-appearing rounded cells separated by variably prominent fibrous septae, often forming an alveolar-like (pseudoalveolar) spaces. The lesional cells usually have scant cytoplasm and rhabdomyoblasts may be seen. By immunohistochemistry, these tumors show usually diffuse desmin, myogenin, and MYOD1 expression, occasional keratin positive cells and variable expression for neuroendocrine markers. Molecular testing reveals a fusion between FOXO1 and PAX3 or PAX7 in the majority of cases. 

Ewing sarcoma: This tumor presents as a small, round, blue cell tumor and might histologically be the most similar neoplasm to EWSR1::PATZ. In fact, previously some of these new tumors were likely classified as Ewing sarcoma before we had fusion testing. Histologically, Ewing sarcoma shows a uniform population of small, round, blue cells with abundant vacuolated cytoplasm secondary to deposition of glycogen. Necrosis is fairly common and may present in a peritheliomatous pattern characterized by a sheath of viable tumor cells closely surrounding central vessels. These tumors are highlighted diffusely by CD99 in a membranous fashion; FLI1 and NKX2.2 are usually positive, too. Focal keratin staining is seen in about a third of cases. The most classic fusion of Ewing sarcoma is EWSR1::FLI1; however, EWSR1::ERG or other rearrangements between members of the FET family (most commonly EWSR1, also FUS, TAF15) with the ETS family (FLI1, ERG, ETV1, ETV4 and FEV) may occur. 

References

1. Michal M, Rubin BP, Agaimy A, et al. EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers. Mod Pathol. 2021;34(4):770–785. 
   https://doi.org/10.1038/s41379-020-00684-8
2. Bridge JA, Sumegi J, Druta M, Bui MM, Henderson-Jackson E, Linos K, Baker M, Walko CM, Millis S, Brohl AS. Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma. Mod Pathol. 2019 Nov;32(11):1593-1604. doi:10.1038/s41379-019-0301-1. Epub 2019 Jun 12. PMID: 31189996.