Oral Leiomyosarcoma or Low-Grade Myofibrosarcoma: Report of a Challenging Differential Diagnosis ^†

Soft tissue spindle cell neoplasms represent less than 1% of all malignancies [1]. The pathological definitive diagnosis is challenging due to the presence of atypical histopathological and immunohistochemical (IHC) features; in more than one-third of cases the assessment of the surgical specimen allows to refine the first diagnosis from incisional biopsy.

A 31-year-old woman was referred for a painful ulcerated fast-growing swelling on the right posterior palate, with palpable cervical lymphadenopathy (Figure 1). Her past medical history is notable for thyroid and breast carcinomas. Incisional biopsy showed atypical spindle cell proliferation arranged in fascicles, with wavy nuclei and prominent nucleoli, low mitotic activity and no necrosis. IHC just demonstrated low positivity for smooth muscle actin; pan-cytokeratin, desmin, S100, CD34, CD31, CD10, ß-catenin were not found. These features were suggestive for a low-grade myofibrosarcoma (LGMS). Imaging (MRI, PET/CT, CT) showed a local spread to pterygopalatine and infratemporal fossa and regional node involvement. Neoadjuvant chemotherapy (epirubicin + ifosfamide) was performed before wide surgical resection. Assessment of the surgical specimen highlighted positive IHC for caldesmon protein leading to a final diagnosis of leiomyosarcoma (LMS). On account of multiple tumours, a NGS multi-gene panel testing including PTEN, BRCA1, BRCA2, TP53, ATM and CHEK2 was performed. ATM heterozygous mutations in exon 24 and CHECK2 homozygous mutation in exon 4 were found.

LMS represents approximately 3% to 10% of H&N sarcomas [2]. The common morphological pattern includes broad fascicles of spindle cells with blunt ended, brightly eosinophilic cytoplasm, cigar-shaped nuclei and occasional perinuclear vacuoles. LMS normally shows positive IHC for mesenchymal smooth muscle antigens, while desmin is variably positive. IHC for S-100 protein, epithelial, neurofilaments, factor VIII–related and angiosarcoma is usually negative. Different tumours with myofibroblastic origin and LMS share similar morphological and IHC patterns making the differential diagnosis challenging. LGMS, whose definition was revised in 2013, originates from myofibroblasts, mesenchymal spindle-shaped cells with ultrastructural features of fibroblasts and smooth-muscle cells. In LGMS, malignant myofibroblasts differ from LMS for palely eosinophilic cytoplasm and sometimes round-shaped or vescicular nuclei with indentations and small indistinct nucleoli. IHC staining shows variable positive reactions for actin and/or desmin; heavy positivity to caldesmone is more rarely observed when compared to smooth muscle cells. Wide surgical resection with clear margins is the mainstay management for oral LMS, with a five-year survival rate of 55%. Local recurrences are frequent and distant metastases occur especially in lungs. Other than this, LMS arising from the oral cavity has a high rate of regional involvement. Sometimes sarcomas occur in heritable cancer predisposition syndromes: recent studies reported multiple genes involved in the development of LMS, among which ATM and CHEK2. Genetic studies could lead to novel therapies: to date AKT/MTOR pathways seem to be the most promising potential therapeutic targets especially in high-grade LMS.