Myxofibrosarcoma with epithelioid morphology: A clinicopathological study of 44 cases with emphasis on differential diagnosis

AIMS: Epithelioid myxofibrosarcoma (eMFS) is an aggressive morphological variant associated with high rates of local recurrence and metastatic disease. The clinicopathological understanding of this disease is currently limited to a few small case-series. METHODS AND RESULTS: We reviewed 44 cases of eMFS and classified them based on the presence of focal (< 50%) or diffuse (> 50%) epithelioid morphology and Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade. The patients (28 males; 16 females) had a median age of 71 years (range = 14-90 years). The proximal extremity was the most common site (n = 21), followed by the trunk (n = 11), distal extremity (n = nine) and head/neck (n = two). Of cases with known depth of involvement (n = 41), 39 involved the subcutis, one was limited to the dermis and one limited to the skeletal muscle. Most cases (n = 34, 77%) demonstrated diffuse (> 50%) epithelioid morphology and were FNCLCC grade 3 (n = 29, 66%). Follow-up data were available for 22 patients. Two developed local recurrence and 10 developed metastases, frequently to regional lymph nodes. All metastatic tumours had a primary lesion with diffuse epithelioid morphology (P = 0.09). There was no association between grade and recurrent or metastatic disease (P = 0.67 and 0.90, respectively). Three cases initially diagnosed as eMFS, one in the neck and two in the axilla, were found to have NRAS Q61R mutations and a high tumour mutation burden and/or ultraviolet (UV)-light DNA mutational signature. CONCLUSIONS: These findings suggest that UV-driven malignancies (including melanoma or sarcomatoid squamous cell carcinoma) may histologically mimic eMFS and should be considered in cases of eMFS presenting at atypical anatomical sites.