Large Malignant Fibrous Histiocytoma Treated with Hypofractionated Proton Beam Therapy and Local Hyperthermia.

Purpose
Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas. The standard treatment is adequate surgical resection; in addition, radiation therapy plays a major role in perioperative treatment in most cases. Herein, we report the case of a patient with a large MFH who was successfully treated with combined proton beam therapy (PBT) and local hyperthermia (LH).


Case Presentation
A 60-year-old man presented with a 6×4-cm mass on his left thigh. Histopathology and immunohistochemistry indicated MFH, and he refused limb amputation. He received treatment with PBT at a dose at 72 GyE in 18 fractions. To cover the entire large target lesion, we used a patch-field protocol. He also concurrently received 7 courses of LH. The combination therapy achieved long-term local control without severe acute or late toxicity during the 7-year follow-up period.


Conclusions
This case suggests that the combination of PBT and LH may be an option as a limb-preserving treatment for large inoperable MFH in the extremities.


Introduction
Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas (STSs). Its peak incidence is between the sixth and seventh decades of life, and it has a male predilection [1]. In adults, MFH most commonly arises in the deep soft tissues of the extremities (lower extremities 49%, upper extremities 19%) and the abdominal cavity or retroperitoneum (16%) [1]. Malignant fibrous histiocytoma involving the extremities generally presents as a painless, enlarging, multilobular mass over a period of months [2]. A multidisciplinary team is necessary for its optimal management, and surgical resection is the cornerstone of treatment. A complete resection, and, where possible, adequate resection margin, is the key to improving overall survival. Distant metastasis is significantly associated with a high mortality rate [3]. Therefore, amputation is often required in cases of extended disease in the extremities. Radiation therapy is mainly used as a perioperative treatment of bone and STSs (BSTSs), including MFH, to improve local control [4][5][6][7]. Particle therapy, especially carbon-ion radiation therapy (CIRT), may be a http://theijpt.org new choice for the treatment of BSTSs [8]. Local hyperthermia sensitizes tumor cells to radiation therapy. Some mechanisms of radiosensitization of local hyperthermia have been proposed including selective cytotoxicity to radioresistant S-phase cells and hypoxic cells and reduction of repair of radiation-induced DNA damage by inhibiting some molecules on the DNA damage response pathway [9][10][11].
We report the case of a 60-year-old man with a large MFH in his left thigh, treated with concurrent local hyperthermia (LH) and proton beam therapy (PBT), who obtained 7-year local control. In addition, he is ambulatory with his preserved left lower limb.

Case Presentation
A 60-year-old man without any significant past medical history was referred to an orthopedic doctor for a 634-cm mass on his left thigh. The disease was limited to the vastus intermedius. A biopsy of the mass demonstrated only an inflammatory change, suggesting proliferative mastitis. The patient underwent resection and the resected tissue also showed inflammatory changes without any malignancy, so he was thereafter observed as an outpatient.
Eleven months later, he presented with a progressively enlarging mass at the resected area. Magnetic resonance imaging (MRI) showed multiple diffusely extended lesions in the quadriceps femoris. The maximum diameter of the lesion was 15 cm or more. Biopsy of the mass indicated a lack of a specific line of differentiation, and immunohistochemistry was positive for CD34 and negative for muscle-specific actin, desmin, and S-100. There was no nuclear beta-catenin expression. These findings confirmed high-grade pleomorphic MFH and myxoid MFH ( Figure 1). Amputation of the left limb was proposed to obtain complete excision of the tumor, but he refused. He was referred to a radiation oncologist at the CIRT center, but owing to the extent of the tumor, he was ineligible for CIRT. The oncologist recommended PBT as an alternative treatment. The patient underwent neoadjuvant chemotherapy (3 courses of cisplatin plus doxorubicin) at another hospital, but the tumor showed shrinkage within the extent of ''stable disease'' according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and he was sent to our proton beam center for treatment.
On examination, indurated swelling was palpated on the left thigh. He did not have any history of left femur fracture or radiation therapy. Axial gadolinium-enhanced T1-weighted MRI revealed diffusely extended abnormal signals in the ventral muscles (from the vastus medialis to the vastus lateralis) of his thigh. The coronal image showed abnormal signal enhancement 20 cm in longitudinal length ( Figure 2). The 3-dimensional measurements of the tumor was 20.0 3 5.6 3 6.3 cm. Positron emission tomography (PET) showed an ill-defined mass with diffuse heterogeneous F-18 fluorodeoxyglucose (FDG) uptake in the left quadriceps femoris, with a maximum standard uptake value of 5.67. There was also an irregularly enhanced mass with intense FDG avidity in the fat tissues between the muscles, suggesting tumor invasion.
For PBT, a total dose of 72 GyE in 18 fractions for 5 weeks was delivered to the tumor site. The initial clinical target volume (CTV) was the muscle compartment of the front part of the thigh because of the local invasion into the muscle. To cover the length of the tumor, we used a patch-field protocol, which uses the combination of 2 isocentric fields, as described previously [12]. Although radiation dermatitis was grade 1 before 40 GyE, we included a 1-week break in treatment of both proton beam and LH after 40 GyE in 10 fractions because of concern of severe normal tissue reaction. From the 11th to the 15th fractions (from 44 to 60 GyE), the CTV was designed as the area of FDG accumulation and the area of contrast enhancement on MRI. Finally, from the 16th to the 18th fractions (from 64 to 72 GyE), the CTV was designed as the area of FDG accumulation ( Figure 3). The maximum dose to the bone was 70.9 GyE, and a mean dose was 21.6 GyE.
Local hyperthermia was administered to the tumor site by using the Thermotoron-RF8 (Yamamoto Vinita Co Ltd, Osaka, Japan) twice a week concurrent with PBT to obtain radiosensitization and intensify treatment effect. Hyperthermia was performed immediately after PBT, for a total of seven 60-minute sessions. The radiofrequency was set at a maximum of 900 W.
The patient tolerated the treatment without any severe complications. Three months later, PET revealed decrease of standardized uptake value (SUV) in tumor (SUVmax [1.5 hour] ¼ 3.24) compared with pre-PBT SUV (SUVmax [1.5 hour] ¼ 5.67). Nine months later, it revealed only faint accumulation of FDG caused by irradiation ( Figure 4). An MRI scan 6 months after PBT showed decreased signal intensity with STIR sequences and shrinkage of enhancement area, compared with pretreatment image (Figure 4). PET-Computed tomography (CT) 2 years after PBT revealed a neuroendocrine tumor in his pancreas, for which he underwent surgical resection. Seven years have passed without any recurrence or distant metastasis of MFH.
In terms of acute toxicity, he developed grade 2 radiation dermatitis (Common Terminology Criteria for Adverse Events version 4). He developed grade 1 localized edema, lymphedema, and telangiectasia; hyperpigmentation of the skin; and muscle contracture in the ventral muscles of his thigh. As of the last follow-up, he is ambulatory and on his feet without joint stiffness.

Discussion
We treated a patient with MFH by using PBT and LH. From this case, we experienced 2 important clinical issues. The first is that the combination of PBT and LH achieved long-term local control for the treatment of MFH of the extremity. The mainstay of the treatment of BSTSs, including MFH, is surgery. Radiation therapy is mainly administered as perioperative treatment [8].
In PBT, the particle beam stops at a specific depth in the body that corresponds to its energy, the so-called Bragg peak. The particle beam is delivered to the target, where it takes the shape of the tumor [13]. As a result, the radiation is concentrated within the target without increasing the dose of radiation to the surrounding normal tissue. For soft tissue tumors, particle therapies make it possible to prevent irradiation to the healthy limb, bone, and joints.
Carbon-ion radiation therapy for BSTSs of the extremities has been shown to achieve good local control, most likely owing to the high biological interactions [14][15][16][17]. Sugahara et al [18] reported the promising results of a phase I/II trial of CIRT for localized primary sarcomas of the extremities. They evaluated 17 cases of localized primary or recurrent BSTSs of the extremities (3 osteosarcomas, 2 liposarcomas, 2 synovial sarcomas, 2 rhabdomyosarcomas, 2 pleomorphic sarcomas, 1 MFH, and 5 others; there were 9 cases of primary disease and 8 of recurrent disease) that underwent CIRT between April 2000 and May 2010. The local control rate at 5 years was 76%. Our patient was thought to be unfit for CIRT because of the large size of the tumor, and instead underwent PBT. While the biological effects of protons are almost identical to those of photons, the relative biological effectiveness of protons is considered to be 1.1 [19]. Malignant fibrous histiocytoma is considered to be a radioresistant tumor, which may have high ability to repair DNA damage, so hypofractionation is one of the choices for increasing cytotoxicity by radiation therapy. For the purpose of strengthening the treatment intensity of low linear energy transfer radiation, we decided to administer LH, which is known to sensitize tumor cells to radiation therapy [20]. Some mechanisms have been suggested for this thermal-sensitizing effect [21]. It has also been reported that hyperthermia exhibits radiobiological features similar to those of high linear energy transfer radiation, like CIRT [22].
The second important clinical issue is that the function of the lower extremity was preserved with the conformal treatment plan with care for anatomic compartments. This patient has been ambulatory after our treatment for more than 7 years without bone fracture, joint stiffness, or edema. The risk of bone fracture is related to the radiation dose and the volume of irradiated bone [23]. Dickie et al [23] examined the incidence of radiation-induced bone fractures in 691 patients with lower extremity STS, and found that patients who received a maximum dose of 64 Gy to the bone and a mean dose of 45 Gy were more likely to develop bone fractures than those who received a maximum dose of 59 Gy and a mean dose of 37 Gy. The field size is also a predictive factor of fibrosis and joint stiffness, and is marginally predictive of edema [24,25]. In this patient, we considered the anatomic component, and finally used a technique to shrink the radiation field according to the expected tumor cell density. This patient did not develop severe dermatitis. Skin toxicity is a possible complication of local hyperthermia treatment. During the treatment, cooling reflux water in the water bag attached to the hyperthermia machine prevented the temperature of skin from rising too much, while heating the tumor. Additionally, an empirical 1-week break in the radiation treatment might have contributed to decreasing the late toxicity of the radiation treatment.
In conclusion, we experienced a case of large MFH of the extremity that was treated with the combination of PBT and LH. We were able to preserve the patient's lower leg, and 7 years have passed with good local control. This suggests that the combination of these treatment modalities can be a new treatment option for MFH of the extremities to obtain long-term local control with normal limb function.

ADDITIONAL INFORMATION AND DECLARATIONS
Conflicts of Interest: The authors have no relevant conflicts of interest to disclose. Funding: This work was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan. Ethical Approval: All patient data have been collected under an institutional review board (IRB)-approved protocol.