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放射治療與腫瘤學 Therapeut Radiol Oncol 2016; 23(2): 129-135 129 CarCinosarComa ex PleomorPhiC adenoma of the Parotid Gland: a Case rePort Chun-Chieh Wu1, Ying-Hsiang Chou1,2, Yu-Ting Wang3, Yueh-Chun Lee1,4, Hsien-Chun Tseng1,5 Department of Radiation Oncology1, Department of Pathology3, Chung Shan Medical University Hospital School of Medical Imaging and Radiological Sciences2, Institute of Medicine4, School of Medicine5, Chung Shan Medical University Pleomorphic adenoma of the parotid gland is the most common tumor of the salivary glands. Although very rare, this tumor can undergo malignant transformation, resulting in carcinosarcoma ex pleomorphic adenoma, which possesses the characteristics of both carcinoma and sarcoma. In the literature, the number of such cases is very low and the treatment outcomes are varied. Surgery remains the primary local treatment. Radiotherapy may be added to enhance local-regional control. Here, we present a 45-year-old male who underwent surgical removal of pleomorphic adenoma of the right parotid gland twice. He was eventually diagnosed with carcinosarcoma ex pleomorphic adenoma. Treatment consisted of superficial parotidectomy and adjuvant concurrent chemoradiation with weekly cisplatin and a radiation dose of 66 Gy. After 30 weeks of follow-up, no disease recurrence or distant metastasis was observed. [Therapeut Radiol Oncol 2016; 23(2): 129-135 ] DOI: 10.6316/TRO/201623(2)129 Key words: Carcinosarcoma, Pleomorphic adenoma, Parotid gland, Radiotherapy introdUCtion Pleomorphic adenoma is the most common benign tumor of the salivary glands. Only about 3-4% of these tumors undergo malignant change [19]. Malignant transformation of pleomorphic adenoma follows 3 patterns: carcinoma ex pleomorphic adenoma, metastasizing benign pleomorphic adenoma and carcinosarcoma ex pleomorphic adenoma, with the latter 2 being extremely rare [11]. Carcinosarcoma is also called t r ue malig nant mixed t u mor. By def i nition, carcinosarcoma is composed of both epithel ial (ca rci nomatou s) a nd mesenchy mal (sarcomatous) components. It mainly occurs in the elderly; mean age at diagnosis is 58 years with similar prevalence in both sexes. It usually arises in the major salivary glands with associated symptoms of swelling, pain and facial palsy. The clinical behavior of carcinosarcoma is aggressive and the tumor growth is rapid. The prognosis of carcinosarcoma is poor with a mean survival of 2.5 to 3.6 years [6]. Since carcinosarcoma ex pleomorphic adenoma over salivary glands is very rare, there is no consensus in terms of the treatment protocol globally. Here, we present a case of carcinosarcoma ex pleomorphic adenoma over right parotid gland treated with superficial Received: 2015, 11, 30. Accepted: 2016, 1, 11. Address reprint request to: Hsien-Chun Tseng, MD. Ph.D., Department of Radiation Oncology, Chung Shan Medical University Hospital., No.110, Sec.1, Jianguo N. Rd., Taichung City 40201, Taiwan, R.O.C. 06_129-135_RAC吳俊玠E.indd 129 2016/6/13 下午 12:11:43 130 Carcinosarcoma ex Pleomorphic Adenoma of the Parotid Gland parotidectomy and adjuvant concurrent chemoradiotherapy. The current literature regarding the treatment options and prognosis of this disease was reviewed. Case rePort In August 2009, a 45-year-old male presented with the chief complaint of a fixed mass with swelling sensation over the right parotid region at our hospital. Neither facial palsy nor facial numbness was noted at that time. After tumor removal by a surgeon, pleomorphic adenoma was diagnosed (Fig 1A). In March 2012, another episode of painful swollen mass over the right parotid region occurred and he received repeat surgical excision. Recurrent (A) (D) (B) pleomorphic adenoma was diagnosed. During regular follow-up after the second surgery, residual tumor over the right parotid gland was suspected. The patient refused further surgical intervention, but agreed to follow up MRI every 3 months. The residual tumor grew into an 8-cm mass. Physical examination revealed a firm mass with local swelling, without tenderness, facial palsy, or facial numbness. CT scan demonstrated a 69 x 47 x 58 mm, lobulated, cystic lesion within the superficial lobe of the right parotid gland, as well as regional subcutaneous fat stranding. Under the impression of residual pleomorphic adenoma with progression, right superficial parotidectomy was carried out. The pathology report revealed (C) (E) Fig 1. The histological features of R’t parotid tumors in this 45 years old male. (A) Benign pleomorphic adenoma: It composed of ductal cells, myoepithelial cells and fibrous to chondroid stroma. (H&E; x 40) (B) Carcinosarcoma: The tumor reveals a biphasic appearance composed of an epithelial component (arrow) with variably sized nests and an intervening spindle cell component (split arrow). (H&E; x 100) (C) Malignant epithelial component: Enlarged right parotid gland (69 x 47 x 58 mm) with large lobulated cystic lesion (within superficial lobe) and relatively mild regional subcutaneous fat stranding. (H&E; x 100) (D) Malignant sarcomatous component: It displays pleomorphic spindle or fusiform cells set in variably collagenized stroma or myxoid stroma. (H&E; x 200) (E) CK (AE1/AE3) immunostaining: The epithelial component is positive for CK and negative for sarcomatous components (H&E; x 100) 06_129-135_RAC吳俊玠E.indd 130 2016/6/13 下午 12:11:44 Carcinosarcoma ex Pleomorphic Adenoma of the Parotid Gland carcinosarcoma ex pleomorphic adenoma, intermediate grade (G2), measuring 4.5 x 4.0 x 3.2 cm. The surgical margins were 1 mm and negative for lymphovascular or perineural invasion. The diagnosis of carcinosarcoma was based on the biphasic population of epithelial and mesenchymal cells, as well as the immuneprofiles (Fig 1B-D). The tumor was positive for cytokeratin (CK), P16, S100, vimentin and negative for CK5/6, P63, Desmin, HK, CK14, CD34, Calponin, Myogenin (Fig 1E). The pathological staging was pT3Nx. No cancer survey was conducted prior to the surgery. PET-CT was arranged post-operatively for staging work-up. No abnormal hypermetabolic foci consistent with regional lymph node metastases or distant metastases were identified. Although radical parotidectomy was indicated for malignant parotid tumor with close margin, the patient refused reoperation. After providing a thorough explanation to the patient, he received adjuvant concurrent chemoradiotherapy (CCRT). The regimen for chemotherapy was weekly cisplatin (Kemoplat) 35mg/m 2 for 6 cycles. Radiotherapy was delivered with a 6 MV linear accelerator by photon beam using intensity-modulated radiotherapy (IMRT) techniques (Elekta Synergy®) once per day, 5 fractions per week. The radiation fields included the initial tumor bed as clinical target volume-medium (CTV-M) and ipsilateral submandibular nodes, upper jugular nodes, middle jugular nodes, retropharyngeal nodes and parotid node group as clinical target volume-low (CTV-L). The clinical target volumes were expanded by 3mm to create planning target volumes PTV-M and PTV-L. The PTV-M received 66 Gy in 33 fractions and the PTV-L received 50.4 Gy in 28 fractions. Treatment planning was carried out with Philips’ Pinnacle 3 RTP system version 9.0. Cone-beam computed tomography was used for daily position correction. During CCRT, acute treatment-related sequelae included 06_129-135_RAC吳俊玠E.indd 131 131 grade 1 radiation dermatitis and pharyngitis according to RTOG criteria. The patient received regular follow-up after CCRT with complete physical examination at every visit and MRI every three months. Abdominal ultrasonography and chest X-ray were also performed every 6 months. The patient was followed up for 30 weeks after CCRT with no evidence of tumor recurrence. disCUssion Clinical features About half of salivary gland tumors are pleomorphic adenomas, which are also called benign mixed tumors [15]. The most common site for pleomorphic adenoma is the superficial lobe of the parotid gland. The choice of treatment for parotid pleomorphic adenoma is superficial parotidectomy, which reduces the risk of recurrence to less than 5%. Other surgical techniques, such as simple enucleation, result in a 20-45% local recurrence rate. Total parotidectomy, a more extensive procedure, does not further reduce recurrence rate, but does increase the rates of facial nerve dysfunction and other complications [9]. Carcinoma ex pleomorphic adenoma is defined as a carcinoma arising from a primary (de novo) or recurrent benign pleomorphic adenoma [14]. This indicates that there is a malignant transformation component within pleomorphic adenoma. The frequency of malignant transfor mation increases with increasing time interval between tumor diagnosis and treatment. Harada et al. reported that risk of malignant change increases from 1.5% for a 5-year interval between tumor diagnosis and treatment to about 9.5% for a 15-year interval [8]. Our patient experienced his first episode of pleomorphic adenoma in 2009. Six years later, the tumor underwent malignant transformation. Carcinosarcoma ex pleomorphic adenoma 2016/6/13 下午 12:11:44 132 Carcinosarcoma ex Pleomorphic Adenoma of the Parotid Gland is a rare entity, resulting from the malignant transformation of pleomorphic adenoma. It accounts for one third to one half of all salivary gland carcinosarcomas, with the remaining being carcinosarcoma de novo [12]. Salivary gland carcinosarcoma is a very rare tumor, which only accounts for 0.4% of all malignant salivary gland neoplasms and 0.04-0.16% of all salivary gland tumors [6]. Sixty-seven percent of salivary gland carcinosarcomas occur in the parotid glands, 19% in the submandibular glands, and 14% in the soft palate. By definition, carcinosarcoma is composed of both epithelial (carcinomatous) and mesenchymal (sarcomatous) components. The most common types of carcinoma components are adenocarcinoma, undifferentiated carcinoma and squamous cell carcinoma. In addition, the most common sarcomatous components are chondrosarcoma and osteosarcoma followed by fibrosarcoma [21]. The differences in the above in terms of histology, such as prognosis or survival, are not well known due to the rarity of these types of tumors. In our case, the carcinomatous type was squamous cell carcinoma with variably sized nests and intervening spindle cell components. Two thirds of patients develop local recurrence while about half develop distant metastases. Metastasis to the lung is the most common [13, 16]. Peterson et al. reviewed 31 malignant parotid mixed tumors and found that tumor stage, local extension, existence of facial palsy and tumor grade are important prognostic factors [17]. In our case, the mass grew rapidly to 8 centimeters within a year, indicating the malignant behavior of the tumor. However, no distant metastasis was found during the systemic work-up. This case was only followed up for 30 weeks, and the disease prognosis may be poor. Distant metastasis should be taken into consideration during posttreatment follow-up. 06_129-135_RAC吳俊玠E.indd 132 Diagnosis The term carcinosarcoma ex pleomorphic adenoma is based on the demonstration of both true malignant epithelial and mesenchymal components within the pleomorphic adenoma. The immunochemical panel of this tumor varies. While the carcinomatous component is usually positive for CK and epithelial membrane antigen (EMA), the sarcomatous component is usually positive for vimentin and S100 [16]. However, in very poorly differentiated tumors, only focal or weak staining of CK or EMA is observed. In our case, the tumor was positive for CK in carcinomatous component and positive for S100 and vimentin in sarcomatous component. The malignant transformation of pleomorphic adenoma is quite difficult to identify on imaging studies. Both CT and MRI are used in the evaluation of head and neck tumors. MRI is widely accepted due to its imaging quality with respect to the soft tissue. In parotid regions, MRI can detect suspected deep lobe involvement and depict tumor extent more accurately. CT, on the contrary, has the benefit of detecting calcification within the salivary glands. Fan et al. reported using CT scan to identify calcification of the parotid mass, which is most frequently seen in parotid pleomorphic adenoma when compared with mucoepidermoid carcinomas, schwannomas and venous malformations [4]. The malignant features of parotid carcinosarcoma, studied by Gogas et al., include ill-defined margins and irregular rim enhancement on CT images [7]. In contrast, Som et al. consider MRI a more accurate tool for predicting malignant potential of parotid tumors. On T2-weighted images, a low to intermediate signal correlates with 73% accuracy in predicting a high-cellular malignant tumor, while thick irregular rim enhancement suggests possible malignancy [19]. In our case, both MRI and CT images revealed a heterogeneous mass with irregular 2016/6/13 下午 12:11:44 Carcinosarcoma ex Pleomorphic Adenoma of the Parotid Gland rim enhancement and ill-defined margin (Fig 2A, Fig 2B). T2-weighted MRI performed in January 2014 showed a 4-cm irregularly shaped parotid mass with multiple small cysts and mild subcutaneous fat infiltration. Eight months later, follow up CT revealed 7-cm enlarged parotid mass with irregular rim enhancement and subcutaneous infiltration. During this short interval, the mass grew by 3 cm in diameter with more obvious infiltration to adjacent tissue. Therefore, malignancy was suspected. 133 Due to the rarity of carcinosarcoma ex pleomorphic adenoma, the treatment strategy va r ies. Wide su rgical excision is most commonly accepted as the primary treatment [18]. Ishikura et al. reported a case of right parotid carcinosarcoma ex pleomorphic adenoma. Initially, mild pain and facial palsy were noted. Treatment included parotidectomy and ipsilateral radical neck dissection. The tumor measured 2.5-cm with histology of undifferentiated carcinoma and poorly differentiated adenocarcinoma with chondrosarcoma and osteosarcoma. There was no lymph node metastasis. After surgery, adjuvant RT (60 Gy) and chemotherapy were applied. The patient showed no recurrence or metastasis after a 17-month follow-up [10]. Patnayak et al. reported another case of parotid carcinosarcoma ex pleomorphic adenoma presenting with facial palsy and treated with total parotidectomy only. The histology of the tumor was ductal type adenocarcinoma with malignant spindle cell tumor and chondrosarcomatus component. No lymph nodes were involved. Adjuvant RT was applied. After 2 years of follow-up, no evidence of disease recurrence was noted [16]. Anamaria et al. presented another carcinosarcoma of the parotid gland, treated with radical surgery and post-operative radiotherapy. However, the patient died 13 months later due to lung metastasis [1]. In this modern era of cancer treatment, multidisciplinary treatment is to be considered due to rapid growth and trend toward metastasis. In our case, the rationale for adjuvant radiotherapy was to decrease the risk of local recurrence after inadequate surgery (superficial parotidectomy) with close margin. (A) (B) Treatment strategies Fig 2. (A) Neck MRI with T2-weighted image, Irregular heterogenous enlarged right parotid gland with multiple cystic lesions and mild infiltration to adjacent tissue. (B) Neck CT with contrast enhancement, Enlarged rim enhanced right parotid gland (69 x 47 x 58 mm) with large lobulated cystic lesion (within superficial lobe) and relatively mild regional subcutaneous fat stranding. 06_129-135_RAC吳俊玠E.indd 133 2016/6/13 下午 12:11:45 134 Carcinosarcoma ex Pleomorphic Adenoma of the Parotid Gland Carrillo et al. has reported that patients with poor risk factors could benefit from postoperative RT including high-grade tumors, facial nerve palsy, advanced stage lesions, positive surgical margins and/or older age [3]. Fu et al. reported postoperative RT may reduce local recurrence rate from 54 to 14 percent for patients having microscopic disease present at or close to the surgical margin [5]. Based on the evidence of head and neck squamous cell carcinoma (HNSCC), the rationale for adding chemotherapy to radiotherapy was enhancing locoregional control therefore decreasing risk of distant metastases. Bernier et al. reported 334 patients with stage III/IV HNSCC postoperatively randomized to post-op RT (66 Gy in 33 fractions) vs. post-op chemoradiation with high dose cisplatin (100 mg/m 2 on days 1, 22, 43) showed improve 5-year overall survival from 40 to 53 percent, 5-year disease-free survival from 36 to 47 percent and 5-year locoregional control from 69 to 82 percent [2]. In conclusion, here we present a right side carcinosarcoma ex pleomorphic adenoma, t reated w it h super f icial pa rot idectomy followed by CCRT with weekly cisplatin. After a 30-week follow-up, no recurrence or distant metastasis was found. Longer follow-up time is needed to ensure the treatment outcome. refferenCes 1. Anamaria M, Stan C, Alin HN, et al: True malignant mixed tumor (carcinosarcoma) of the parotid gland: case report. TMJ 2010; 60(4): 338-342. 2. Bernier J, Domenge C, Ozsahin M, et al: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004; 350(19): 1945-1952. 3. Carrillo JF, Vázquez R, Ramírez-Ortega MC, Cano A, Ochoa-Carrillo FJ, OñateOcaña LF: Multivariate prediction of the 06_129-135_RAC吳俊玠E.indd 134 probability of recurrence in patients with carcinoma of the parotid gland. Cancer 2007; 109 (10): 2043-2051. 4. Fan KF, Connor SE, Macbean AD, Langdon JD: MRI findings of carcinosarcoma in the parotid gland. Oral Oncology 2006; 42(3): 323-326. 5. Fu KK, Leibel SA, Levine ML, et al: Carcinoma of the major and minor salivary glands: analysis of treatment results and sites and causes of failures. Cancer 1977; 40: 2882. 6. Gnepp DR: Malignant mixed tumor of the salivary glands: a review. Pathol Annu 1993; 28: 279-328. 7. Gogas J, Markopoulos C, Karydakis V, Gogas G, Delladetsima J: Carcinosarcoma of the submandibular salivary gland. Eur J Surg Oncol 1999; 25: 333-335. 8. 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The Internet Journal of 135 Oncology 2008; 5(1): 1-7. 17. Peterson D, Overgaard J, Søgaard H, Elbrønd O, Overgaard M: Malignant parotid tumors in 110 consecutive patients: treatment results and prognosis. Laryngoscope 1992; 102(9): 1064-1069. 18. Pons Y, Alves A, Clément P, Conessa C: Salivary duct carcinoma of the parotid. Eur Ann Otorhinolaryngol Head Neck Dis 2011; 128(4): 194-196. 19. Seifert G, Sobin LH: Histological Typing of Salivary Gland Tumours, 2nd edn, SpringerVerlag, Berlin, 1991. 20. Som PM, Biller HF: High-grade malignancies of the parotid gland: identification with MR imaging. Radiology 1989; 173 (3): 823-826. 21. Tanahashi J, Daa T, Kashima K: Carcinosarcoma ex recurrent pleomorphic adenoma of the submandibular gland. APMIS 2007; 115(6): 789-794. 腮腺上皮肉瘤合併多形性腺瘤:病例報告 吳俊玠 1 周英香 1,2 王昱婷 3 李岳駿 1,4 曾顯群 1,5 中山醫學大學附設醫院 放射腫瘤科 1 病理科 3 中山醫學大學 醫學影像暨放射科學系 2 醫學研究所 4 醫學系 5 腮腺的多形性腺瘤是唾液腺中最常見的良性腫瘤 ,其中有非常少數會轉變為惡性腫瘤 ,而 轉變為惡性腫瘤中 ,轉化為上皮肉瘤是非常罕見的案例 。上皮肉瘤顧名思義是同時具備上皮 癌 ,以及肉瘤的特徵 。在過去文獻報導中個案數相當低 ,並且沒有一致的治療方針 。手術切 除仍是目前治療的主要方式 ,而術後的放射線治療則可以增進其局部控制率 。本篇病歷報告提 出一位 45 歲男性 ,在接受兩次切除右側腮腺多型性腺瘤之後,復發了多型性腺瘤合併上皮肉 瘤 。我們給予手術表淺腮腺切除之後 ,術後執行了同步化學治療合併放射線治療 ,使用每周 cisplatin 的輸注以及 66 Gy 的放射線治療 。病人追蹤 30 周 ,情況良好 ,沒有復發或轉移的現 象。 [ 放射治療與腫瘤學 2016; 23(2): 129-135 ] 關鍵詞:上皮肉瘤 、多型性腺瘤 、腮腺 、放射線治療 06_129-135_RAC吳俊玠E.indd 135 2016/6/13 下午 12:11:45