Primary oral leiomyosarcoma of the maxillary bone and sinus: case report and up-to-date review of literature

eiomyosarcoma (LMS) is a mesenchymal malignancy of mooth muscle, which accounts for 1%--4% of head and neck arcomas.1,2 The involvement of the oral cavity is considered xtremely rare.1 Due to the lack of smooth muscle tissue in he oral cavity, it has been suggested that LMS arise from mooth muscle cells of the blood vessel walls, circumvallate apillae of the tongue, neuromuscular bundles, myoepthelial cells or pluripotent undifferentiated mesenchymal ells.1,3,4 Clinically, sarcomas of the oral cavity show nonspecific igns and symptoms and can appear as primary tumors, adiation-associated tumors or metastatic tumors.1,4,5 iopsy, histological examination and immunohistochemical taining are mandatory to achieve a definitive diagnosis.1,5 The aim of this study was to report a case of maxillary MS and to perform a review of literature including papers escribing LMS of the oral cavity.


Introduction
Leiomyosarcoma (LMS) is a mesenchymal malignancy of smooth muscle, which accounts for 1%---4% of head and neck sarcomas. 1,2 The involvement of the oral cavity is considered extremely rare. 1 Due to the lack of smooth muscle tissue in the oral cavity, it has been suggested that LMS arise from smooth muscle cells of the blood vessel walls, circumvallate papillae of the tongue, neuromuscular bundles, myoepithelial cells or pluripotent undifferentiated mesenchymal cells. 1,3,4 Clinically, sarcomas of the oral cavity show nonspecific signs and symptoms and can appear as primary tumors, radiation-associated tumors or metastatic tumors. 1,4,5 Biopsy, histological examination and immunohistochemical staining are mandatory to achieve a definitive diagnosis. 1,5 The aim of this study was to report a case of maxillary LMS and to perform a review of literature including papers describing LMS of the oral cavity.

Figure 2
Wide maxillary osteolytic lesion associated with dental root resorption and involvement of the right maxillary sinus: orthopantomography (a), axial CT (b), 3D reconstruction (c) and PET (d) images.

Case report and literature review
A 67-year-old man presented at the oral medicine department for oral growing-mass, which caused difficult in feeding and speaking. The patient reported the first occurrence of a small swelling on the premaxilla's palatal side approximately three months before, but he did not seek medical care due to the COVID-19 pandemic lockdown. He reported sporadic bleeding episodes and progressive increasing of lesion's dimensions up to our observation. The clinical history was negative for systemic diseases and drug intake.
At the clinical examination, the patient showed impairment in speaking, due to a large painless brownish-reddish mass, which appeared bilobular and firm at palpation.
The lesion had a total longitudinal size of 6 cm, it was extended at the buccal side of the premaxilla, covering the hard palate, and incorporating the teeth (Fig. 1). Orthopantomography and CT revealed a wide area of osteolysis of the maxillary and palatal bones, which bilaterally involved the nasal fossa and the right maxillary sinus and caused the dental root resorption (Fig. 2). Putative clinical diagnosis included mesenchymal tumors, Kaposi's Sarcoma, hematologic or bone malignancies. 7---9 Multiple incisional biopsies led to the histopathological diagnosis of high-grade leiomyosarcoma. Immunohistochemical profile of the lesion was positive for smooth-muscle-actin and muscle-specific antigen (HHF-35), shows minor-degree expression for desmin and was negative for S-100 protein (Fig. 3). Positron emission tomography showed large enhanc-

Figure 3
Hematoxylin and eosin stains show, under the oral epithelium, a sarcomatous proliferation characterized by fascicles of medium/large size spindle cells with abundant eosinophilic cytoplasm and well-defined cell borders (A). The nuclei are spindle or oval with mild to marked atypia. Both typical and atypical mitotic activity is easily found together a mild lymphocytic infiltrate without necrosis. Immunochemistry shows diffuse expression of smooth muscle actin (B) and HHF35 (C), and desmin (D) at a minor degree. Table 1 Reported cases of oral primary leiomyosarcomas in the last two decades, excluding three manuscripts for which the full text was not available and the immunohistochemical details were not provided in the abstract (modified from). 3

Author(s)
Year of publication  ing maxillary lesion (SUV max 15.8), and few areas, putatively inflammatory, localized at the esophagus and mediastinum (SUV max 2.2) (Fig. 2). Because of the patient's good systemic condition (ECOG Performance Status scale grade 1), two cycles of neo-adjuvant chemotherapy with ifosfamide, doxorubicin and mesna were performed, before surgery, with subsequent reduction of tumour's size. Total maxil-lectomy (with free resection margins) followed by cervical lymphadenectomy and reconstruction with fibula-free flap was performed (Fig. 4). After surgical resection, the patient received three further cycles of doxorubicin and dacarbazine, as adjuvant chemotherapy. The patient is currently on follow-up and, eight-months after surgery, he does not show clinical or radiological signs of recurrence (Fig. 4).   (Table 2).

Discussion
Leiomyosarcoma is a malignant tumor of smooth muscle derivation which account for 5%---10% of all soft tissue sarcomas. 3,10 LMS frequently affects the retro-peritoneal region, the uterus and the gastrointestinal tract. 1,11 Oral LMS are extremely rare, accounting for 0.64% of all LMS and for 5.7% of head and neck LMS. 5,11 The jawbones appear the most frequently affected oral sites (70% of cases) followed by tongue, buccal mucosa, soft palate, upper lip and floor of the mouth, 1,5,11,12 although a recent systematic review, which reported published case of intra-oral LMS up to 2017, found that soft tissues were more frequently involved than bone. 3 Oral LMS can occur at any age, commonly in the 5---7 th decades, with similar gender incidence rate (M:F, 11:9). 3,11 Clinically, it appears as a growing mass, painless and firm, which infiltrate the surrounding tissues with no pathognomonic signs. 1,3 Due to its rarity, oral LMS can be misdiagnosed with other common benign lesions before biopsy. 11 Moreover, due to overlapping histological features between different types of head and neck sarcomas, this lesion could be also misclassified for other more common spindle cell tumors of the oral cavity. 3,5,13 For this reason, histological examination associated with immunohistochemical confirmation is mandatory to obtain a definitive diagnosis of oral LMS. 1,3,11,13 Surgical resection with tumour-free margins is widely accepted as the treatment of choice for oral LMS. 1,3,5,11 In cases where the anatomical location of tumor does not allow radical surgical intervention, radiotherapy and administration of neoadjuvant/adjuvant chemotherapy may improve survival time and decrease or delay the recurrence rate. 1,2,11 However, no standard of care is still available. 2 The prognosis for oral LMS is poor, associated with a high rate of recurrence (42% for high-grade LMS within 2 years from surgery) and regional or distant metastasis. 1,2,5 Unfavorable clinical course is related to several factors, such as delayed diagnosis, tumor size (larger than 4 cm), histopathological high-grade (poorly-differentiated), site (bone involvement and extension into paranasal sinuses), lymphatic or hematogenous dissemination, positive surgical margins. 1---3,5 The estimated 5-years survival rate for primary oral LMS range from 55% to 61%. 1,12,14 Periodic follow-up examinations are mandatory for an early diagnosis of any signs of recurrence. 1,2,11 In the case presented above, the delayed diagnosis is associated with an increased size of the tumor and a subsequent more aggressive surgical intervention; it is not possible to establish how much the delayed diagnosis could have influenced the prognosis for the patient. However, on our experience during the first months of COVID pandemic, patients were often more scared of contracting COVID-infection in the hospital rather than their neoplastic disease. 15

Conclusion
Even if extremely rare, LMS should be considered in the differential diagnosis of oral growing-mass. Early diagnosis and treatment are essential to reduce the risk of recurrence and guarantee better prognosis. Periodic follow-up examinations are mandatory to identify early any signs of recurrence. 1,2,11 Due to the rarity of oral LMS further studies are necessary to better characterize this disease.

Institution's ethics committee
Institution's ethics committee approval is not required for the case report.
The study was conducted in compliance with the recognized international standards, including the principles of the Declaration of Helsinki.

Patient's informed consent
Data and samples were collected under patient's informed written consent, guaranteeing anonymity.

Funding
The authors received no specific funding for this work. No funds, grants, or other support were received.