Ⅰ. INTRODUCTION

McCune-Albright syndrome (MAS) is a sporadic disease accompanied by fibrous dysplasia (FD) of bone, café-au-lait skin pigmentation, and/or hyperfunctioning endocrinopathies.¹⁾ If a patient has more than two symptoms, MAS can be diagnosed clinically. Some articles paraphrased MAS into fibrous dysplasia/McCune-Albright syndrome (FD/MAS) synonymously.²⁾ FD can rarely undergo malignant transformation.^1,3,4) Similarly, in patients with MAS, a few cases of FD showing sarcomatous change have been reported.

Here, we report an additional secondary osteosarcoma arising in the right mandible in a 41-year-old female patient with FD/MAS. In addition, the results of our literature review on malignant transformation in patients with FD/MAS will be described.

Ⅱ. Case report

A 41-year-old female patient was referred to our hospital for surgical treatment of a mandibular mass. At the age of 5 years, she was diagnosed as MAS while examining for vaginal bleeding due to precocious puberty. At the age of 19, she underwent cosmetic contouring surgery for FD of the mandible. Nine months before her visit to our hospital, she presented at another hospital with a rapidly growing swelling in the right mandible. Contrast-enhanced computed tomography and magnetic resonance imaging confirmed a mass with buccolingual expansion in the mandible, initially affected by FD (Fig. 1). The growing mass invaded the masseter area with a periosteal reaction on the lateral side of the ramus, suggesting malignancy. An incisional biopsy was done, and a diagnosis of spindle cell sarcoma of soft tissue was made. Neoadjuvant concurrent chemoradiotherapy (CCRT) was considered as the first-line treatment; she received radiation therapy (45 Gy in 25 fractions and 21.6 Gy in 12 fractions) concurrently with chemotherapy using etopside, ifosfamide, mensa, and cisplatin. Although the size of the lesion had slightly decreased during the CCRT period, the growth of the tumor was identified in the lingual area of the mandible 5 months after completion of CCRT (Fig. 2). Therefore, surgical resection was performed immediately at the Department of Oral and Maxillofacial Surgery in our hospital.

Gross examination showed a heterogeneous, white and yellow solid mass with focal necrotic change. The center of the tumor was located in the mandibular ramus, and the tumor extended to the masseter and medial pterygoid muscles (Fig. 3).

Microscopically, necrosis of tumor cells probably due to CCRT was primarily observed in the center, rather than the periphery, of the lesion and accounted for approximately 50% of the total examined area. In contrast, sheets of residual viable tumor cells were identified in the lateral and medial soft tissue areas with a lobular growth pattern. Tumor cells were not only tightly packed but also loosely arranged in a myxoid stroma (Fig. 4A). Tumor cells consisted mainly of spindle cells. Osteoid formation and chondroblastic differentiation of tumor cells were focally detected (Fig. 4B and C). Immunohistochemically, CD68 was positive in the malignant spindle cells (Fig. 4D), whereas CD31, desmin, and smooth muscle actin were all negative. S-100 was only expressed in the lobules of chondroblastic cells. Ki-67 was positive in 40-50% of tumor cells. Taken together, a final diagnosis was made as secondary osteosarcoma arising from FD, which could be histologically classified as fibroblastic osteosarcoma.

After surgery, the patient has received adjuvant chemotherapy with a new combination of adriamycin and cisplatin until the submission of this paper.

Ⅲ. Discussion

Fibrous dysplasia rarely shows sarcomatous transformation. The incidence of malignant transformation in FD/MAS has been reported as 4%, which is much higher than that of FD without MAS (0.5-1%).^5,6) As a result of our literature review, a total 16 cases of malignant transformation have been reported in patients with FD/MAS (Table 1).^6-17) The clinicopathologic features of the reviewed cases are summarized in Table 2. The age of onset of the syndrome ranged from 0 to 19 years, with the mean age of 7.6 years. The average age of initial presentation of sarcoma was 28.6 years, ranging from 8 to 51 years. There was no predominance of gender (M:F ratio = 1:1.1), as reported in a previous study on malignant transformation of fibrous dysplasia by Ruggieri et al.⁵⁾ Most of the malignancies occurred in the craniofacial bones (n=13; 76%), including the mandible (n=5), maxilla (n=5), skull base (n=1), calvarium (n=1), and orbit (n=1). This tendency to occur in the craniofacial region seems to be related to the fact that these bones are the most common sites for FD.¹⁾ Clinically, swelling was the most frequent symptom of malignant transformation in FD/MAS, followed by pain and vision loss. The most common histologic type of malignancies was osteosarcoma (n=14), followed by chondrosarcoma (n=2).

The most common syndrome-associated symptom in the reviewed cases included polyostotic FD in addition to café-au-lait spots, precocious puberty, hyperthyroidism, and growth hormone excess. Precocious puberty was more common in women (M:F=1:7), consistent with a previous study on patients with FD/MAS.⁴⁾ However, a male predominance was found for hyperthyroidism and growth hormone excess. Among these symptoms, it was suggested that growth hormone excess could be a risk factor for malignant transformation.¹⁸⁾

Although initially diagnosed as spindle cell sarcoma arising in soft tissue at another hospital, the final diagnosis of secondary osteosarcoma arising from fibrous dysplasia was rendered in our case after mass resection. Our case showed poor response to CCRT, which has been used as neoadjuvant therapy for soft tissue sarcoma.¹⁹⁾ Because of misdiagnosis made initially, radiotherapy which is not recommended as neoadjuvant therapy for osteosarcoma was applied, ²⁰⁾ indicating that accurate diagnosis is important in making treatment decision. According to a study of treatment for malignant transformation of craniofacial fibrous dysplasia,²¹⁾ aggressive surgery is recommended for better prognosis.

Of the 14 cases of secondary osteosarcoma in MAS with available survival data, 6 patients were alive, while 8 had died all within 1 year. Compared with these cases, patients with primary osteosarcoma of the jaws or malignant transformation of craniofacial FD without MAS generally showed longer survival times.^{21, 22)} The 12-month survival rate in malignancy arising in craniofacial FD was 67.5%,²¹⁾ and the 5-year survival rate in patient with conventional osteosarcoma of the jaws was 66.8%,²²⁾ both of which were even higher than the 1-year survival rate (42.9%) in FD/MAS patients with secondary osteosarcoma. The cause of death in FD/MAS patients with secondary osteosarcoma of the head and neck was mainly lung metastasis (3/4; 75%). In contrast, death in conventional osteosarcoma of the jaw results more often from uncontrolled local lesion than from distant metastases.²³⁾ Therefore, FD/MAS patients with secondary osteosarcoma may show a worse prognosis than patients with primary osteosarcoma or secondary osteosarcoma arising in FD without MAS. However, there is a limitation in the number of the relevant cases, which requires additional reports regarding the treatment and outcome.