Hiroyuki Hanakawa, Nobuya Monden, Kaori Hashimoto, Aiko Oka, Isao Nozaki, Norihiro Teramoto, Susumu Kawamura
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1 Accepted Manuscript Radiation-induced laryngeal angiosarcoma: Case report Hiroyuki Hanakawa, Nobuya Monden, Kaori Hashimoto, Aiko Oka, Isao Nozaki, Norihiro Teramoto, Susumu Kawamura PII: S (18) DOI: /j.xocr Reference: XOCR 64 To appear in: Otolaryngology Case Reports Received Date: 12 January 2018 Revised Date: 25 February 2018 Accepted Date: 12 March 2018 Please cite this article as: Hanakawa H, Monden N, Hashimoto K, Oka A, Nozaki I, Teramoto N, Kawamura S, Radiation-induced laryngeal angiosarcoma: Case report, Otolaryngology Case Reports (2018), doi: /j.xocr This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
2 1 Radiation-Induced Laryngeal Angiosarcoma: Case Report Authors: Hiroyuki Hanakawa, MD, PhD, 1 Nobuya Monden, MD, PhD, 1 Kaori Hashimoto, MD, 1 Aiko Oka, MD, 1 Isao Nozaki, MD, PhD, 2 Norihiro Teramoto, MD, PhD, 3 Susumu Kawamura, MD 4 Affiliations: 1 Department of Head and Neck Surgery, Shikoku Cancer Center, 160, Minami-umemoto Kou, Matsuyama, , Japan. 2 Department of Surgery, Shikoku Cancer Center, 160, Minami-umemoto Kou, Matsuyama, , Japan. 3 Department of Pathology, Shikoku Cancer Center, 160, Minami-umemoto Kou, Matsuyama, , Japan. 4 Department of Plastic Surgery, Shikoku Cancer Center, 160, Minami-umemoto Kou, Matsuyama, , Japan.
3 2 Abstract: Head and neck angiosarcoma (AS) is extremely rare. We report the fourth case report of radiation-induced laryngeal AS. The patient is a 73-year-old man with a past medical history of radiation treatment for hypopharyngeal cancer. Laryngoscopy revealed a huge mass with a necrotic lesion in the larynx and pharynx. Biopsy showed AS. We performed radical resection. The pathological diagnosis was AS. 32 months after surgery, the patient died by local relapse. The patient spent over 2 years without relapse. We consider radical surgery as the first-line treatment for radiation-induced laryngeal AS.
4 3 Introduction Angiosarcoma (AS) is a relatively rare tumor that accounts for only 2% of all sarcomas [1]. Surgery is the main form of treatment for head and neck AS, but overall survival is low. Acquiring a wide resection margin for head and neck lesions is difficult. Although irradiation may lead to the development of AS, radiation-induced laryngeal AS has been reported in only three cases [2, 3, 4]. This is the fourth case report.
5 4 Case Presentation The patient is a 73-year-old man with a past medical history of hypopharyngeal cancer (cstage 2, T2N0M0, pathology; squamous cell carcinoma). He had undergone radiation treatment with 2 Gray (Gy) fractions to a total dose of 58 Gy. Routine follow-up examinations (at least once a year) showed that the patient remained disease-free over 15years. However, he presented at our hospital in respiratory distress. Laryngoscopy at this visit revealed a huge mass with a necrotic lesion in the larynx and pharynx (Figure 1). Biopsy showed AS. Because he had already received radiation treatment, surgical resection was regarded as the only curative treatment. After obtaining informed consent, we performed radical resection and reconstruction with free jejunal graft. Therefore, we resected the tumor as follows: (1) nasopharynx; (2) oropharynx (included soft palate, lateral wall, posterior wall, and base of tongue); (3) tongue; (4) larynx and hypopharynx; (5) cervical esophagus (Figure 2). Bilateral neck dissection was also performed. A free jejunal graft was opened on the oral side and sutured to the nasopharynx and oral cavity floor.
6 5 The tumor was diagnosed as AS histologically (Figure 3). The axial tumor size was approximately 7 cm. The solid part of the tumor containing irregular and anastomosing vascular spaces lined and/or filled with sarcoma cells under nonneoplastic squamous epithelia of the pharynx and larynx. Immunohistochemically, the sarcoma cells were negative for cytokeratin AE 1/3 (dako, Glustopp) and positive for CD31 (dako, Clone JC70A) and CD34 (dako, Clone QBEnd10). The p53/d07 was wild typic, and the MIB-1 labeling index was about 20%. Although no sarcoma cells were found at the edges of the resected specimen, the risk of relapse was high because of its extremely high invasivity. We proposed adjuvant chemotherapy, which the patient and his family refused. He was transferred to other hospital. He had local relapse (details unknown) 29 months after surgery and died 3 months later.
7 6 Discussion Among all malignant tumors, AS occurring in head and neck lesion is rare. It appears most commonly on the scalp and facial skin. Its pathological features are (1) growth of aberrant and polymorphic endothelial cells and (2) irregular and anastomosing vascular spaces [2]. Its differential diagnosis includes other sarcomas, lymphomas, malignant melanoma, and poorly differentiated carcinoma. Immunohistochemical studies are useful for the diagnosis. CD31 and CD34 are often used as vascular endothelium markers. CD31 is a good marker with high sensitivity and specificity, and most ASs are positive for CD31. CD34 is inferior to CD31 regarding both sensitivity and specificity. Epithelial markers (e.g., cytokeratin AE1/3) are generally negative [2]. The actual incidence of laryngeal AS is unknown. Only 14 well-documented and histologically confirmed cases have been reported in the English-language literature [2]. Laryngeal AS mainly arises from the supraglottis, followed by the glottis and subglottis [2, 3, 4]. In this case, the tumor location seemed to be the supraglottis. AS is caused by chronic stimulation, such as irradiation. The criteria for a radiation-induced malignancy are as follows: (1) The site of origin must be within the field of previous radiation. (2) The patient should have received a significant amount of radiation therapy (>25 Gy). (3) An interval of at least 3 5 years must elapse between
8 7 the time of irradiation and the development of the sarcoma. (4) The second primary cancer must be histologically different from the primary neoplasm 2, 3. In our case, the larynx, pharynx and whole neck were included in the primary irradiation field and had received 58 Gy. An interval between the last cancer (hypopharyngeal cancer) and the AS was 16 years. The primary cancer had been squamous cell carcinoma. There have been only three cases of radiation-induced laryngeal AS that fully matched the above criteria [2, 3, 4]. Our case the fourth case is the most widespread and underwent the widest resection among the four. The prognosis of AS is poor, with a 5-year survival of 22-33% [2]. Also, the larger the tumor, the worse is the prognosis [3]. Although surgery with a wide margin is a well-known treatment for AS, standard therapy is still undecided. The usefulness of systemic chemotherapy with the paclitaxel has been reported [5], but there are no reported randomized controlled trials. Radiotherapy is also a well-known treatment for AS, but there is no adaptation for radiation-induced laryngeal AS because of the history of radiotherapy. The three prior cases were undergone surgery, as did our patient. Surgery for radiation-induced laryngeal AS, however, is problematic because of the tumor s unclear edges and the difficulty of dissection caused by radiation associated adhesion. Although wide surgical margin is needed, it is difficult to keep a wide margin
9 8 for head and neck lesions because there are many important organs in this area. In fact, all past cases and our case had a local relapse.
10 9 Conclusions The patient spent without recurrence over 2 years after surgery. We consider surgical resection with wide margins as the first-line treatment for radiation-induced laryngeal AS.
11 10 Acknowledgment Nothing to declare Conflict of Interest Nothing to declare
12 11 References; [1] Coindre JM, et al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91: [2] Dowdall JR, et al. A case of radiation-induced multifocal laryngeal angiosarcoma presenting as a diagnostic dilemma. Case Rep Otolaryngol. 2012: [3] Miura K, Kum Y, Han G, and Tsutsui Y. Radiation-induced laryngeal angiosarcoma after cervical tuberculosis and squamous cell carcinoma: case report and review of the literature. Pathol Int. 2003;53: [4] Thomas RL. Non-epithelial tumours of the larynx. J Laryngol Otol. 1979;93: [5] Penel N, et al. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008;26:
13 12 Figure legends Figure 1. Left: A dark red irregular lesion with necrosis was seen in epiglottis (*) and posterior pharyngeal wall (**). Right: An irregular lesion was also seen in whole larynx (*; epiglottis, #; arytenoid). Figure 2. (A) After total pharyngolaryngectomy and neck esophageal resection with bi-lateral selective neck dissection. (B) After total glossectomy with resection from nasopharynx to oropharynx. (C) After radical resection. Nasopharynx (single arrow), the posterior edge of hard palate (double arrows) and prevertebral muscles ( ) were seen. (D) The extracted specimen. The tumor involved from the nasopharynx to the esophagus with an ulcer on the tongue floor (arrow). Figure 3: Microscopic findings of the angiosarcoma. The sarcoma formed ill-defined lesions containing irregular and anastomosing lumens [hematoxylin-eosin, low magnification] (A). The lumens were lined or filled with angiosarcoma cells [hematoxylin-eosin, high magnification] (B). The angiosarcoma was positive for anti-cd31 (C) and negative for cytoketatin AE 1/3 (D).
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17 Ethical Statement This study is a retrospective and noninvasive case report, and we got written informed consent from patient. And we also abide by the Helsinki Declaration.
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