542094
research-article2014
AORXXX10.1177/0003489414542094Annals of Otology, Rhinology & LaryngologyWatanabe et al
Article
Clear Cell Carcinoma of the Base of the Tongue: Case Report and Literature Review
Annals of Otology, Rhinology & Laryngology 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003489414542094 aor.sagepub.com
Kenichi Watanabe, MD, PhD1,2, Yuri Okumura, MD1, Ken Hashimoto, MD1, and Takashi Suzuki, MD, PhD3
Abstract Objective: Clear cell carcinoma (CCC) is a rare, low-grade malignant neoplasm of minor salivary glands. Clear cell carcinoma is composed of monomorphic clear cells that contain glycogen within a hyalinized stroma. The microscopic diagnosis can be challenging, and the treatment strategy has not been established. Methods: We report a case of a 56-year-old woman with CCC in the base of the tongue. A literature review, including 22 published cases and our case, was performed to clarify the clinical characteristics of CCC in the base of the tongue. Results: The exophytic tumor showed no infiltration to the neighboring tissues. She underwent a local excision en bloc transorally and is free of the disease 15 months after surgery. In our review of 23 cases of CCC in the base of the tongue, 21 cases received surgical excision for the purpose of the primary treatment modality. The fact that the distinctive features of restricted site-related symptoms and the rare presentation of pain emerged was similar to previously reported cases of CCC. A relatively good prognosis was still indicated. Conclusion: We reveal the features of the unusual occurrence of CCC in the base of the tongue and consider the appropriate surgical approach for primary treatment. Keywords clear cell carcinoma, CCC, base of the tongue, minor salivary gland tumor
Introduction Salivary gland tumors are uncommon and account for less than 0.3% of all malignancies and approximately 6% of all head and neck cancers.1 These tumors’ characteristics, including that they encompass a wide range of morphological diversity between different tumor types, can sometimes make the diagnosis difficult. Clear cell carcinoma (CCC) is a rare neoplasm that accounts for less than 1% of all salivary gland tumors.2 It is considered to be a low-grade malignant tumor composed predominantly of clear cells, and it lacks the features and characteristics of other salivary gland tumors. The most frequent site of occurrence of CCC is the minor salivary glands in the oral cavity. Because CCC arising in the base of the tongue is extremely rare, only 22 cases have been reported in the English literature since 1994. In this article, we present an additional case of CCC occurring in the base of the tongue and a literature review, and we describe therapeutic considerations.
Case Report A 56-year-old woman suffered from intermittent hemoptysis for a month. On otolaryngological consultation in a
regional hospital, a large mass on her tongue base was observed. After the transoral biopsy was performed, the patient was referred to our department. The local examination showed a mass covered by a slight hyperemic mucosa at the base of the tongue (Figures 1A and 1B). The mass was elastic, hard, and nontender. There was no induration of the attached tongue base tissue. She had no palpable neck lymph nodes. Although the mass caused her throat to narrow, she complained of no difficulty with swallowing and had no dyspnea. Her family had noticed her snoring beginning a few years ago. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 35 × 30 × 25 1
Department of Otolaryngology, Sendai Social Insurance Hospital, Sendai, Japan 2 Department of Otorhinolaryngology–Head and Neck Surgery, Tohoku University School of Medicine, Sendai, Japan 3 Department of Pathology and Histotechnology, Tohoku University School of Medicine, Sendai, Japan Corresponding Author: Kenichi Watanabe, MD, PhD, Department of Otorhinolaryngology–Head and Neck Surgery, Tohoku University School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai, 980-8574, Japan. Email: [email protected]
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Figure 1. (A) Endoscopic findings via the oral cavity of the tumor arising in the base of the tongue. (B) Endoscopic findings via the nasal cavity of the submucosal large tumor. The epiglottis (*) is slightly leaning backward because of the tumor.
Figure 2. (A) Axial computed tomography image of the neck with contrast medium revealing a 35 × 25 mm well-enhanced ovoid tumor originating from the base of the tongue. (B) Coronal T1-weighted magnetic resonance image with contrast medium showing a 30 × 25 mm well-enhanced tumor that occupies most of the pharyngeal cavity.
mm well-defined tumor occupying most of the pharyngeal lumen (Figures 2A and 2B). The tendency of infiltration to surrounding tissues could not be clearly observed on the imaging. There was no evidence of cervical lymphadenopathy. Because the histopathological diagnosis by previous biopsy revealed myoepithelioma, she underwent a local excision of the lesion orally under general anesthesia, with preparation for tracheostomy in the event of an emergency. After induction, nasotracheal intubation was performed. We first tried to use the laryngoscopic potassium titanyl
phosphate (KTP) laser method, but the mass was too large for us to clearly examine the site of occurrence through the rigid laryngoscope. We carried out the resection therapy by electrocautery with assistance in pulling out the tongue and depressing the base with a tongue blade. An en bloc resection, including some of the tonsillar tissue that attached to the site of the tumor, was accomplished with difficulty because of the narrow working space. The excised tumor was 36 × 30 × 28 mm in size, had a smooth surface, and was circumscribed. The total surgery time was 40 minutes, and
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Figure 3. (A) A section of the tumor demonstrates a monomorphous population of oval to polygonal cells with a clear cytoplasm among hyalinized stroma (hematoxylin and eosin stain, original magnification ×400). (B) Neoplastic cells are strongly positive immunohistochemically for cytokeratin AE1/AE3 (original magnification ×400). (C) Neoplastic cells are negative immunohistochemically for PAX8 (original magnification ×100).
the amount of intraoperative blood loss was small. Mild laryngeal edema occurred the day after surgery, and the patient had a favorable postoperative course. Microscopically, the parenchyma of the tumor was composed of atypical monomorphic ovoid to polygonal cells with abundant clear cytoplasm. The nuclei were slightly irregular with coarse chromatin (Figure 3A). The neoplastic cells were arranged in sheets or nests among hyalinizing fibrous stroma. The resection stump was in close proximity to the tumor but was negative. Periodic acid Schiff (PAS) staining showed intracytoplasmic glycogen. Immunohistochemical staining demonstrated that the tumor cells were positive for cytokeratin AE1/AE3 (Figure 3B) and negative for desmin, vimentin, smooth muscle actin (SMA), myoglobin, HMB-45, melan A, S-100, and CD10. Metastatic renal cell carcinoma could be excluded, because an additional staining with an antibody for PAX8 was
carried out to reveal a negative result (Figure 3C). A Ki-67 labeling index was 3% to 5%. The histopathological and immunohistochemical findings suggested CCC in the base of the tongue. After discharge, the patient received an abdominal ultrasound that revealed no renal mass. We performed fluorine-18 deoxyglucose positron emission tomography (FDG-PET), which showed no FDG uptake in a primary lesion, lymph node of the neck, or other regions. The patient is under close follow-up and is currently free from disease 15 months after surgery.
Discussion Since 1994 when Milchgrub et al3 described a series of 11 cases of a distinctive salivary gland tumor, this tumor has been reported under different names, such as hyalinizing
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clear cell carcinoma, clear cell adenocarcinoma, and clear cell carcinoma. The latest World Health Organization classification of salivary gland tumors published in 2005 uses the term “clear cell carcinoma not otherwise specified, CCC-NOS” as a separate entity.4 The microscopic diagnosis of CCC can be challenging because the spectrum of microscopic characteristics frequently overlaps with other salivary gland tumors that contain clear cells. The diagnosis of CCC can be a diagnosis of exclusion. The main distinctive microscopic feature of CCC is the presence of round to polygonal epithelial cells with a clear cytoplasm rich in glycogen, organized in trabeculae, cords, or solid nests surrounded by an abundant hyalinizing fibrocollagenous stroma.2,3,5-10 Clear cells can be found in a variety of salivary gland tumors, including benign tumors such as clear cell oncocytoma and clear cell myoepithelioma, malignant tumors such as mucoepidermoid carcinoma, epithelialmyoepithelial carcinoma, myoepithelial carcinoma, and acinic cell carcinoma, and some nonsalivary gland tumors such as some odontogenic carcinomas and metastatic renal cell carcinoma.3,5-7,9,11 The clear cytoplasm has been shown to contain abundant glycogen by PAS staining.3,5,9,12,13 The immunohistochemical pattern of the tumor is characterized by immunoreactivity for epithelial antigens including cytokeratin, cytokeratin CAM 5.2, and epithelial membrane antigen (EMA). Vimentin, S-100, SMA, muscle-specific actin, and calponin are not expressed.3,6,7,9,13-16 Positivity for CD10 antigen was used for differentiating CCC from metastatic renal cell carcinoma,9,11 but low specificities have been reviewed and recognized.17 Recently, PAX8, which belongs to the human paired box gene family, has been shown to be a more sensitive marker for the diagnosis of primary and metastatic renal cell carcinoma.17,18 We confirmed that metastatic renal cell carcinoma could be excluded to show the lack of staining for PAX8. The behavior of CCC has been assumed to be relatively indolent. It is a low-grade salivary gland malignancy3,9,13,15,16 with an expected good prognosis. One early review estimated the 10-year survival to be 90%.19 In a review of 85 cases of CCC of the head and neck regions, Casani et al13 reported that regional lymph node involvement and distant metastases were present in 15.3% and 4.7% of cases, respectively. O’Sullivan-Mejia et al9 reviewed 55 cases from 1994 to 2009, including 8 cases of their own, and they observed that 16.4% of cases had reported metastases to the regional lymph nodes or distant regions. In a case series and review of the literature by Solar et al,11 it was noted that 25% of cases reported in the literature had evidence of metastases; this rate was slightly higher than the rates reported by others. They concluded that CCC was less indolent than was previously believed and that careful observation of the neck was required. The most frequent site of CCC is the tongue and palate, which accounts for > 50% of tumors; it affects the minor salivary glands within the oral cavity.9,11,16 The occurrence of
tumors in the larynx or oropharynx is very rare.2,15 We summarize 22 cases of CCC occurring at the base of the tongue that have been published in case reports or series reports in the English literature since 1994 (Table 1).2,3,5-10,12-16,20-23 The clinical characteristics of all 23 cases, including our case, are examined. The mean age at diagnosis was 58.0 years (range, 32-81 years). Apart from 1 case with no sex information, there was a female-to-male ratio of 1:1 (11:11). The average greatest diameter in the tumor was 2.8 cm (range, 1.06.0 cm). The initial symptoms, in order of frequency, were dysphagia (41.1%), painless mass in the throat (29.4%), and foreign body sensation, pharyngeal pain, and hemoptysis (17.6%). Twenty-one cases (91.3%) received surgical excision for the purpose of the primary treatment modality. One of the other cases underwent radiation therapy and avoided surgery. Another case did not have a description of the treatment. Neck dissection with local resection was performed for approximately half of the operated patients. Radiotherapy pre/postoperatively or for first-line treatment was used for 5 cases, and no cases included chemotherapy. From the available description of the outcomes of 20 cases, the disease-specific survival rate at 2 years was calculated to be 89.7%, although the follow-up period was short. In this review, the distinctive features of restricted site-related symptoms and the rare presentation of pain emerged. This was similar to previously reported cases of CCC. The lesion in the base of the tongue was difficult to find, and the slow-growing, painless submucosal mass could lead to a possible delay in diagnosis. A relatively good prognosis was still indicated. These results reconfirm that CCC is a low-grade malignancy neoplasm. For the treatment of CCC, wide surgical margin excision of the primary tumor site is generally recommended, either with or without pre/postoperative radiotherapy.2,3,8,9,13,16,20 The surgical approach to the base of the tongue varies according to the size, location, and pathology of the tumor. There are technical difficulties of limited operative exposure and intricate neurovascular anatomic relationships that might result in significant morbidity, such as impaired speech, deglutition disorder, or aspiration. Detailed information regarding the surgical approaches to the primary lesions could be obtained from only half of the 21 cases of CCC who underwent surgery. A transmandibular approach was used for 4 cases, a suprahyoid pharyngotomy for 2, a transoral-transcervical approach for 2, a transoral approach for 2, and a lateral pharyngotomy for 1. The mandibulotomy approach can guarantee wide exposure of tumors of the base of the tongue. As a result of obtaining sufficient working space, the surgeon could take advantage of being able to decide the tumor resection range safely, can achieve hemostasis during the operation, and if necessary, can reconstruct the resulting local defect from the wide resection. This method has the possibility of causing some functional or cosmetic problems postoperatively. The lip-splitting might be associated with unfavorable
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Watanabe et al Table 1. Summary of Published Cases and Series of Clear Cell Carcinoma Occurring in the Base of the Tongue Since 1994. First Author (Year)
Clinical Symptoms (Multiple Allowed)
Age/Sex
Size, cma
Milchgrub (1994)
51/F
3.0
NA
48/M
2.0
NA
Rinaldo (1999)
42/F 77/M 39/F
1.5 2.5 NA
Milchgrub (2000)
32/M
2.5
Wang (2002) Balakrishnan (2002)
74/M 81/M 35/M
1.0 3.0 3.0
O’Regan (2004)
57/F
3.5
NA NA Pharyngeal pain, choking, foreign body sensation Cervical lymphadenopathy NA NA Painless mass, foreign body sensation Pharyngeal pain
Sicurella (2004)
69/NA
3.5
Suzuki (2006)
66/F
4.0
Uzochukwu (2007)
47/F
2.6
Lai (2008) Pujary (2008)
52/F 57/M
2.0 3.0
Yang (2008) O’Sullivan-Mejia (2009) Casani (2011)
58/M 65/F 59/F
Surgical Approach to Primary Lesion Total glossectomy and laryngopharyngectomy Wide local resection via mandibulotomy Wide local excision Wide local excision Excision
Treatments in Addition to Surgery
Follow-Up
Preoperative RT
DOD postop
No
NED at 18 mo
No Preoperative RT No
NED at 2 y DOC at 2 y NED at 6 y
NA
NA
NA
NA NA No
NA NED at 13 mo NED at 1 y
Postoperative RT
DOD at 10 mo
1.0 6.0 3.0
Operation Operation Transmandibular approach (reconstructed) Subtotal glossectomy, partial mandibulectomy (reconstructed) Dysphagia Middle pharyngotomy via suprahyoid Dysphagia, painless Transmandibular mass approach Dysphagia, Complete excision pharyngeal pain, hemoptysis Painless mass Complete resection Foreign body Suprahyoid approach sensation Painless mass Wide excision Dysphagia Wide excision Dysphagia Surgical excision
75/F
2.2
Hemoptysis
Masilamani (2011) Jin (2012)
73/M 61/M
3.0 3.0
Dysphagia Painless mass
Adil (2013)
59/M
T2
Dysphagia, otalgia
Transmandibular approach Laser excision No (RT was performed as primary treatment) Wide local excision via lateral pharyngotomy
No
NED at 1 y
No
NED at 21 mo
No
NED at 8 mo
No Postoperative RT
NED at 1 y NED at 18 mo
No No NA
NED at 10 y DOD at 26 mo NED at 1 y
No
NED at 18 mo
No (RT without surgery) No
NED at 1 y Recurrence at 10 mo NED at 1 y
Abbreviations: DOC, dead of other cause; DOD, dead of disease; F, female; M, male; NA, data not available; NED, no evidence of disease; RT, radiation therapy. a Size refers to the greatest dimension.
aesthetic results or disfiguring scars, and the osteotomy might induce malocclusion, wound healing problems, and temporomandibular joint pain.24 The suprahyoid pharyngotomy procedure creates an entrance into the pharynx through the vallecula. Primary closure without the use of flaps for reconstruction can be easily handled. Although this technique provides excellent
functional and cosmetic outcomes for localized tumors, a major complication in this technique is underestimating the size of the tumor25; lateral or anterior extension of the tumor might be inadequately exposed, which could possibly result in cutting into the tumor. The transoral approach is used even for small tumors that are localized or exophytic. This approach is less
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invasive to the patient and causes some difficulties in accessing the area and a chance of bleeding and tumor spillage. There were some reports that a transoral midline glossotomy results in better surgical exposure of the lesion.26 Recently, several groups have developed transoral laser microsurgery (TLM), which mainly uses a carbon dioxide laser, for tumors in the base of the tongue. Steiner et al27 achieved a 5-year local control rate of 85% in a group of 48 cases (T stage classification was T1, 1; T2, 12; T3, 7; and T4, 28) of squamous cell carcinoma (SCC) in the base of the tongue using TLM and postoperative radiotherapy. Grant et al28 reported a 5-year local control rate of 90% for their 59 cases (T1, 16; T2, 23; T3, 12; and T4, 8). From the aspect of functional outcomes, 98% of patients receiving TLM experienced little to no change in swallowing function, and 70% retained normal speech.29 Their results were almost comparable to the results of Steiner et al,27 who achieved 92% normal swallowing and 88% understandable speech. They concluded that TLM offers an acceptable treatment approach in terms of oncologic and functional results when it is used as the primary surgical therapy for selected patients with SCC of the tongue base.27-29 There have been no reports to date of a case of CCC in the base of the tongue, but we estimate that the indolent behavior of the tumor as localized, slow-growing, or exophytic makes the tumor suitable for TLM. On the conditions that the tumor could be adequately exposed through bivalve laryngopharyngoscope,27,28 favorable local control would be expected, and this might maintain the quality of life related to swallowing or speech for patients with CCC. In our case, a negative surgical stump was observed, though the margins were small, and swelling of the lymph nodes in the neck was not detected on the images. Instead of additional surgery or postoperative radiotherapy, the patient has been carefully observed with yearly PET-CT. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Ries LAG, Hankey BF, Miller BA, Hartman AM, Edwards BK. Cancer Statistics Review, 1973-88. Bethesda, MD: National Cancer Institute; 1991. 2. Balakrishnan R, Nayak DR, Pillai S, Rao L. Hyalinizing clear cell carcinoma of the base of the tongue. J Laryngol Otol. 2002;116:851-853. 3. Milchgrub S, Gnepp DR, Vuitch F, Delgado R, AlboresSaavedra J. Hyalinizing clear cell carcinoma of salivary gland. Am J Surg Pathol. 1994;18:74-82.
4. Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization Classification of Tumors: Pathology and Genetics of the Head and Neck Tumours. Lyon, France: IARC Press; 2005. 5. Milchgrub S, Vuitch F, Saboorian MH, Hameed A, Wu H, Albores-Saavedra J. Hyalinizing clear-cell carcinoma of salivary glands in fine-needle aspiration. Diagn Cytopathol. 2000;23:333-337. 6. Wang B, Brandwein M, Gordon R, Robinson R, Urken M, Zarbo RJ. Primary salivary clear cell tumors—a diagnostic approach: a clinicopathologic and immunohistochemical study of 20 patients with clear cell carcinoma, clear cell myoepithelial carcinoma, and epithelial-myoepithelial carcinoma. Arch Pathol Lab Med. 2002;126:676-685. 7. Sicurella F, Gregorio A, Stival P, Brenna A. Clear cell carcinoma of minor salivary gland of the tongue. Acta Otorhinolaryngol Ital. 2004;24:157-160. 8. Suzuki H, Katoh A, Udaka T, et al. Hyalinizing clear cell carcinoma arising from the base of the tongue. Acta Otolaryngol. 2006;126:653-656. 9. O’Sullivan-Mejia ED, Massey HD, Faquin WC, Powers CN. Hyalinizing clear cell carcinoma: report of eight cases and a review of literature. Head Neck Pathol. 2009;3:179-185. 10. Adil E, Setabutr D, Mikesell K, Goldenberg D. Hyalinizing clear cell adenocarcinoma of the oropharynx. Head Neck. 2013;35:E184-E186. 11. Solar AA, Schmidt BL, Jordan RC. Hyalinizing clear cell carcinoma: case series and comprehensive review of the literature. Cancer. 2009;115:75-83. 12. O’Regan E, Shandilya M, Gnepp DR, Timon C, Toner M. Hyalinizing clear cell carcinoma of salivary gland: an aggressive variant. Oral Oncol. 2004;40:348-352. 13. Casani AP, Marchetti M, Seccia V, Fontanini G, Filice ME, Muscatello L. Clear cell adenocarcinoma of the base of the tongue: a case report and review of the literature. Ear Nose Throat J. 2011;90:E9-E16. 14. Lai G, Nemolato S, Lecca S, Parodo G, Medda C, Faa G. The role of immunohistochemistry in the diagnosis of hyalinizing clear cell carcinoma of the minor salivary gland: a case report. Eur J Histochem. 2008;52:251-254. 15. Pujary K, Rangarajan S, Nayak DR, Balakrishnan R, Ramakrishnan V. Hyalinizing clear cell carcinoma of the base of tongue. Int J Oral Maxillofac Surg. 2008;37:93-96. 16. Yang S, Zhang J, Chen X, Wang L, Xie F. Clear cell carcinoma, not otherwise specified, of salivary glands: a clinicopathologic study of 4 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:712-720. 17. Sangoi AR, Karamchandani J, Kim J, Pai RK, McKenney JK. The use of immunohistochemistry in the diagnosis of metastatic clear cell renal cell carcinoma: a review of PAX8, PAX-2, hKIM-1, RCCma, and CD10. Adv Anat Pathol. 2010;17:377-393. 18. Ozcan A, de la Roza G, Ro JY, Shen SS, Truong LD. PAX2 and PAX8 expression in primary and metastatic renal tumors: a comprehensive comparison. Arch Pathol Lab Med. 2012;136:1541-1551. 19. Maiorano E, Altini M, Favia G. Clear cell tumors of the salivary glands, jaws, and oral mucosa. Semin Diagn Pathol. 1997;14:203-212.
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Watanabe et al 20. Rinaldo A, McLaren KM, Boccato P, Maran AG. Hyalinizing clear cell carcinoma of the oral cavity and of the parotid gland. ORL J Otorhinolaryngol Relat Spec. 1999;61:48-51. 21. Uzochukwu NO, Shrier DA, Lapoint RJ. Clear cell carcinoma of the base of the tongue: MR imaging findings. AJNR Am J Neuroradiol. 2007;28:127-128. 22. Masilamani S, Rao S, Chirakkal P, Kumar AR. Hyalinizing clear cell carcinoma of the base of tongue: a distinct and rare entity. Indian J Pathol Microbiol. 2011;54:167-169. 23. Jin R, Craddock KJ, Irish JC, Perez-Ordonez B, Weinreb I. Recurrent hyalinizing clear cell carcinoma of the base of tongue with high-grade transformation and EWSR1 gene rearrangement by FISH. Head Neck Pathol. 2012;6:389394. 24. Agrawal A, Wenig BL. Resection of cancer of the tongue base and tonsil via the transhyoid approach. Laryngoscope. 2000;110:1802-1806.
25. Ying YL, Zimmer LA, Myers EN. Base of tongue schwannoma: a case report. Laryngoscope. 2006;116:1284-1287. 26. Jones JE, Healy GB. Transoral surgical management of lesions of the base of the tongue. Arch Otolaryngol Head Neck Surg. 1992;118:1350-1352. 27. Steiner W, Fierek O, Ambrosch P, Hommerich CP, Kron M. Transoral laser microsurgery for squamous cell carcinoma of the base of the tongue. Arch Otolaryngol Head Neck Surg. 2003;129:36-43. 28. Grant DG, Salassa JR, Hinni ML, Pearson BW, Perry WC. Carcinoma of the tongue base treated by transoral laser microsurgery, part one: untreated tumors, a prospective analysis of oncologic and functional outcomes. Laryngoscope. 2006;116:2150-2155. 29. Camp AA, Fundakowski C, Petruzzelli GJ, Emami B. Functional and oncologic results following transoral laser microsurgical excision of base of tongue carcinoma. Otolaryngol Head Neck Surg. 2009;141:66-69.
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research-article2014
AORXXX10.1177/0003489414542094Annals of Otology, Rhinology & LaryngologyWatanabe et al
Article
Clear Cell Carcinoma of the Base of the Tongue: Case Report and Literature Review
Annals of Otology, Rhinology & Laryngology 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003489414542094 aor.sagepub.com
Kenichi Watanabe, MD, PhD1,2, Yuri Okumura, MD1, Ken Hashimoto, MD1, and Takashi Suzuki, MD, PhD3
Abstract Objective: Clear cell carcinoma (CCC) is a rare, low-grade malignant neoplasm of minor salivary glands. Clear cell carcinoma is composed of monomorphic clear cells that contain glycogen within a hyalinized stroma. The microscopic diagnosis can be challenging, and the treatment strategy has not been established. Methods: We report a case of a 56-year-old woman with CCC in the base of the tongue. A literature review, including 22 published cases and our case, was performed to clarify the clinical characteristics of CCC in the base of the tongue. Results: The exophytic tumor showed no infiltration to the neighboring tissues. She underwent a local excision en bloc transorally and is free of the disease 15 months after surgery. In our review of 23 cases of CCC in the base of the tongue, 21 cases received surgical excision for the purpose of the primary treatment modality. The fact that the distinctive features of restricted site-related symptoms and the rare presentation of pain emerged was similar to previously reported cases of CCC. A relatively good prognosis was still indicated. Conclusion: We reveal the features of the unusual occurrence of CCC in the base of the tongue and consider the appropriate surgical approach for primary treatment. Keywords clear cell carcinoma, CCC, base of the tongue, minor salivary gland tumor
Introduction Salivary gland tumors are uncommon and account for less than 0.3% of all malignancies and approximately 6% of all head and neck cancers.1 These tumors’ characteristics, including that they encompass a wide range of morphological diversity between different tumor types, can sometimes make the diagnosis difficult. Clear cell carcinoma (CCC) is a rare neoplasm that accounts for less than 1% of all salivary gland tumors.2 It is considered to be a low-grade malignant tumor composed predominantly of clear cells, and it lacks the features and characteristics of other salivary gland tumors. The most frequent site of occurrence of CCC is the minor salivary glands in the oral cavity. Because CCC arising in the base of the tongue is extremely rare, only 22 cases have been reported in the English literature since 1994. In this article, we present an additional case of CCC occurring in the base of the tongue and a literature review, and we describe therapeutic considerations.
Case Report A 56-year-old woman suffered from intermittent hemoptysis for a month. On otolaryngological consultation in a
regional hospital, a large mass on her tongue base was observed. After the transoral biopsy was performed, the patient was referred to our department. The local examination showed a mass covered by a slight hyperemic mucosa at the base of the tongue (Figures 1A and 1B). The mass was elastic, hard, and nontender. There was no induration of the attached tongue base tissue. She had no palpable neck lymph nodes. Although the mass caused her throat to narrow, she complained of no difficulty with swallowing and had no dyspnea. Her family had noticed her snoring beginning a few years ago. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 35 × 30 × 25 1
Department of Otolaryngology, Sendai Social Insurance Hospital, Sendai, Japan 2 Department of Otorhinolaryngology–Head and Neck Surgery, Tohoku University School of Medicine, Sendai, Japan 3 Department of Pathology and Histotechnology, Tohoku University School of Medicine, Sendai, Japan Corresponding Author: Kenichi Watanabe, MD, PhD, Department of Otorhinolaryngology–Head and Neck Surgery, Tohoku University School of Medicine, 1-1 Seiryomachi, Aoba-ku, Sendai, 980-8574, Japan. Email: [email protected]
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Figure 1. (A) Endoscopic findings via the oral cavity of the tumor arising in the base of the tongue. (B) Endoscopic findings via the nasal cavity of the submucosal large tumor. The epiglottis (*) is slightly leaning backward because of the tumor.
Figure 2. (A) Axial computed tomography image of the neck with contrast medium revealing a 35 × 25 mm well-enhanced ovoid tumor originating from the base of the tongue. (B) Coronal T1-weighted magnetic resonance image with contrast medium showing a 30 × 25 mm well-enhanced tumor that occupies most of the pharyngeal cavity.
mm well-defined tumor occupying most of the pharyngeal lumen (Figures 2A and 2B). The tendency of infiltration to surrounding tissues could not be clearly observed on the imaging. There was no evidence of cervical lymphadenopathy. Because the histopathological diagnosis by previous biopsy revealed myoepithelioma, she underwent a local excision of the lesion orally under general anesthesia, with preparation for tracheostomy in the event of an emergency. After induction, nasotracheal intubation was performed. We first tried to use the laryngoscopic potassium titanyl
phosphate (KTP) laser method, but the mass was too large for us to clearly examine the site of occurrence through the rigid laryngoscope. We carried out the resection therapy by electrocautery with assistance in pulling out the tongue and depressing the base with a tongue blade. An en bloc resection, including some of the tonsillar tissue that attached to the site of the tumor, was accomplished with difficulty because of the narrow working space. The excised tumor was 36 × 30 × 28 mm in size, had a smooth surface, and was circumscribed. The total surgery time was 40 minutes, and
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Figure 3. (A) A section of the tumor demonstrates a monomorphous population of oval to polygonal cells with a clear cytoplasm among hyalinized stroma (hematoxylin and eosin stain, original magnification ×400). (B) Neoplastic cells are strongly positive immunohistochemically for cytokeratin AE1/AE3 (original magnification ×400). (C) Neoplastic cells are negative immunohistochemically for PAX8 (original magnification ×100).
the amount of intraoperative blood loss was small. Mild laryngeal edema occurred the day after surgery, and the patient had a favorable postoperative course. Microscopically, the parenchyma of the tumor was composed of atypical monomorphic ovoid to polygonal cells with abundant clear cytoplasm. The nuclei were slightly irregular with coarse chromatin (Figure 3A). The neoplastic cells were arranged in sheets or nests among hyalinizing fibrous stroma. The resection stump was in close proximity to the tumor but was negative. Periodic acid Schiff (PAS) staining showed intracytoplasmic glycogen. Immunohistochemical staining demonstrated that the tumor cells were positive for cytokeratin AE1/AE3 (Figure 3B) and negative for desmin, vimentin, smooth muscle actin (SMA), myoglobin, HMB-45, melan A, S-100, and CD10. Metastatic renal cell carcinoma could be excluded, because an additional staining with an antibody for PAX8 was
carried out to reveal a negative result (Figure 3C). A Ki-67 labeling index was 3% to 5%. The histopathological and immunohistochemical findings suggested CCC in the base of the tongue. After discharge, the patient received an abdominal ultrasound that revealed no renal mass. We performed fluorine-18 deoxyglucose positron emission tomography (FDG-PET), which showed no FDG uptake in a primary lesion, lymph node of the neck, or other regions. The patient is under close follow-up and is currently free from disease 15 months after surgery.
Discussion Since 1994 when Milchgrub et al3 described a series of 11 cases of a distinctive salivary gland tumor, this tumor has been reported under different names, such as hyalinizing
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clear cell carcinoma, clear cell adenocarcinoma, and clear cell carcinoma. The latest World Health Organization classification of salivary gland tumors published in 2005 uses the term “clear cell carcinoma not otherwise specified, CCC-NOS” as a separate entity.4 The microscopic diagnosis of CCC can be challenging because the spectrum of microscopic characteristics frequently overlaps with other salivary gland tumors that contain clear cells. The diagnosis of CCC can be a diagnosis of exclusion. The main distinctive microscopic feature of CCC is the presence of round to polygonal epithelial cells with a clear cytoplasm rich in glycogen, organized in trabeculae, cords, or solid nests surrounded by an abundant hyalinizing fibrocollagenous stroma.2,3,5-10 Clear cells can be found in a variety of salivary gland tumors, including benign tumors such as clear cell oncocytoma and clear cell myoepithelioma, malignant tumors such as mucoepidermoid carcinoma, epithelialmyoepithelial carcinoma, myoepithelial carcinoma, and acinic cell carcinoma, and some nonsalivary gland tumors such as some odontogenic carcinomas and metastatic renal cell carcinoma.3,5-7,9,11 The clear cytoplasm has been shown to contain abundant glycogen by PAS staining.3,5,9,12,13 The immunohistochemical pattern of the tumor is characterized by immunoreactivity for epithelial antigens including cytokeratin, cytokeratin CAM 5.2, and epithelial membrane antigen (EMA). Vimentin, S-100, SMA, muscle-specific actin, and calponin are not expressed.3,6,7,9,13-16 Positivity for CD10 antigen was used for differentiating CCC from metastatic renal cell carcinoma,9,11 but low specificities have been reviewed and recognized.17 Recently, PAX8, which belongs to the human paired box gene family, has been shown to be a more sensitive marker for the diagnosis of primary and metastatic renal cell carcinoma.17,18 We confirmed that metastatic renal cell carcinoma could be excluded to show the lack of staining for PAX8. The behavior of CCC has been assumed to be relatively indolent. It is a low-grade salivary gland malignancy3,9,13,15,16 with an expected good prognosis. One early review estimated the 10-year survival to be 90%.19 In a review of 85 cases of CCC of the head and neck regions, Casani et al13 reported that regional lymph node involvement and distant metastases were present in 15.3% and 4.7% of cases, respectively. O’Sullivan-Mejia et al9 reviewed 55 cases from 1994 to 2009, including 8 cases of their own, and they observed that 16.4% of cases had reported metastases to the regional lymph nodes or distant regions. In a case series and review of the literature by Solar et al,11 it was noted that 25% of cases reported in the literature had evidence of metastases; this rate was slightly higher than the rates reported by others. They concluded that CCC was less indolent than was previously believed and that careful observation of the neck was required. The most frequent site of CCC is the tongue and palate, which accounts for > 50% of tumors; it affects the minor salivary glands within the oral cavity.9,11,16 The occurrence of
tumors in the larynx or oropharynx is very rare.2,15 We summarize 22 cases of CCC occurring at the base of the tongue that have been published in case reports or series reports in the English literature since 1994 (Table 1).2,3,5-10,12-16,20-23 The clinical characteristics of all 23 cases, including our case, are examined. The mean age at diagnosis was 58.0 years (range, 32-81 years). Apart from 1 case with no sex information, there was a female-to-male ratio of 1:1 (11:11). The average greatest diameter in the tumor was 2.8 cm (range, 1.06.0 cm). The initial symptoms, in order of frequency, were dysphagia (41.1%), painless mass in the throat (29.4%), and foreign body sensation, pharyngeal pain, and hemoptysis (17.6%). Twenty-one cases (91.3%) received surgical excision for the purpose of the primary treatment modality. One of the other cases underwent radiation therapy and avoided surgery. Another case did not have a description of the treatment. Neck dissection with local resection was performed for approximately half of the operated patients. Radiotherapy pre/postoperatively or for first-line treatment was used for 5 cases, and no cases included chemotherapy. From the available description of the outcomes of 20 cases, the disease-specific survival rate at 2 years was calculated to be 89.7%, although the follow-up period was short. In this review, the distinctive features of restricted site-related symptoms and the rare presentation of pain emerged. This was similar to previously reported cases of CCC. The lesion in the base of the tongue was difficult to find, and the slow-growing, painless submucosal mass could lead to a possible delay in diagnosis. A relatively good prognosis was still indicated. These results reconfirm that CCC is a low-grade malignancy neoplasm. For the treatment of CCC, wide surgical margin excision of the primary tumor site is generally recommended, either with or without pre/postoperative radiotherapy.2,3,8,9,13,16,20 The surgical approach to the base of the tongue varies according to the size, location, and pathology of the tumor. There are technical difficulties of limited operative exposure and intricate neurovascular anatomic relationships that might result in significant morbidity, such as impaired speech, deglutition disorder, or aspiration. Detailed information regarding the surgical approaches to the primary lesions could be obtained from only half of the 21 cases of CCC who underwent surgery. A transmandibular approach was used for 4 cases, a suprahyoid pharyngotomy for 2, a transoral-transcervical approach for 2, a transoral approach for 2, and a lateral pharyngotomy for 1. The mandibulotomy approach can guarantee wide exposure of tumors of the base of the tongue. As a result of obtaining sufficient working space, the surgeon could take advantage of being able to decide the tumor resection range safely, can achieve hemostasis during the operation, and if necessary, can reconstruct the resulting local defect from the wide resection. This method has the possibility of causing some functional or cosmetic problems postoperatively. The lip-splitting might be associated with unfavorable
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Watanabe et al Table 1. Summary of Published Cases and Series of Clear Cell Carcinoma Occurring in the Base of the Tongue Since 1994. First Author (Year)
Clinical Symptoms (Multiple Allowed)
Age/Sex
Size, cma
Milchgrub (1994)
51/F
3.0
NA
48/M
2.0
NA
Rinaldo (1999)
42/F 77/M 39/F
1.5 2.5 NA
Milchgrub (2000)
32/M
2.5
Wang (2002) Balakrishnan (2002)
74/M 81/M 35/M
1.0 3.0 3.0
O’Regan (2004)
57/F
3.5
NA NA Pharyngeal pain, choking, foreign body sensation Cervical lymphadenopathy NA NA Painless mass, foreign body sensation Pharyngeal pain
Sicurella (2004)
69/NA
3.5
Suzuki (2006)
66/F
4.0
Uzochukwu (2007)
47/F
2.6
Lai (2008) Pujary (2008)
52/F 57/M
2.0 3.0
Yang (2008) O’Sullivan-Mejia (2009) Casani (2011)
58/M 65/F 59/F
Surgical Approach to Primary Lesion Total glossectomy and laryngopharyngectomy Wide local resection via mandibulotomy Wide local excision Wide local excision Excision
Treatments in Addition to Surgery
Follow-Up
Preoperative RT
DOD postop
No
NED at 18 mo
No Preoperative RT No
NED at 2 y DOC at 2 y NED at 6 y
NA
NA
NA
NA NA No
NA NED at 13 mo NED at 1 y
Postoperative RT
DOD at 10 mo
1.0 6.0 3.0
Operation Operation Transmandibular approach (reconstructed) Subtotal glossectomy, partial mandibulectomy (reconstructed) Dysphagia Middle pharyngotomy via suprahyoid Dysphagia, painless Transmandibular mass approach Dysphagia, Complete excision pharyngeal pain, hemoptysis Painless mass Complete resection Foreign body Suprahyoid approach sensation Painless mass Wide excision Dysphagia Wide excision Dysphagia Surgical excision
75/F
2.2
Hemoptysis
Masilamani (2011) Jin (2012)
73/M 61/M
3.0 3.0
Dysphagia Painless mass
Adil (2013)
59/M
T2
Dysphagia, otalgia
Transmandibular approach Laser excision No (RT was performed as primary treatment) Wide local excision via lateral pharyngotomy
No
NED at 1 y
No
NED at 21 mo
No
NED at 8 mo
No Postoperative RT
NED at 1 y NED at 18 mo
No No NA
NED at 10 y DOD at 26 mo NED at 1 y
No
NED at 18 mo
No (RT without surgery) No
NED at 1 y Recurrence at 10 mo NED at 1 y
Abbreviations: DOC, dead of other cause; DOD, dead of disease; F, female; M, male; NA, data not available; NED, no evidence of disease; RT, radiation therapy. a Size refers to the greatest dimension.
aesthetic results or disfiguring scars, and the osteotomy might induce malocclusion, wound healing problems, and temporomandibular joint pain.24 The suprahyoid pharyngotomy procedure creates an entrance into the pharynx through the vallecula. Primary closure without the use of flaps for reconstruction can be easily handled. Although this technique provides excellent
functional and cosmetic outcomes for localized tumors, a major complication in this technique is underestimating the size of the tumor25; lateral or anterior extension of the tumor might be inadequately exposed, which could possibly result in cutting into the tumor. The transoral approach is used even for small tumors that are localized or exophytic. This approach is less
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Annals of Otology, Rhinology & Laryngology
invasive to the patient and causes some difficulties in accessing the area and a chance of bleeding and tumor spillage. There were some reports that a transoral midline glossotomy results in better surgical exposure of the lesion.26 Recently, several groups have developed transoral laser microsurgery (TLM), which mainly uses a carbon dioxide laser, for tumors in the base of the tongue. Steiner et al27 achieved a 5-year local control rate of 85% in a group of 48 cases (T stage classification was T1, 1; T2, 12; T3, 7; and T4, 28) of squamous cell carcinoma (SCC) in the base of the tongue using TLM and postoperative radiotherapy. Grant et al28 reported a 5-year local control rate of 90% for their 59 cases (T1, 16; T2, 23; T3, 12; and T4, 8). From the aspect of functional outcomes, 98% of patients receiving TLM experienced little to no change in swallowing function, and 70% retained normal speech.29 Their results were almost comparable to the results of Steiner et al,27 who achieved 92% normal swallowing and 88% understandable speech. They concluded that TLM offers an acceptable treatment approach in terms of oncologic and functional results when it is used as the primary surgical therapy for selected patients with SCC of the tongue base.27-29 There have been no reports to date of a case of CCC in the base of the tongue, but we estimate that the indolent behavior of the tumor as localized, slow-growing, or exophytic makes the tumor suitable for TLM. On the conditions that the tumor could be adequately exposed through bivalve laryngopharyngoscope,27,28 favorable local control would be expected, and this might maintain the quality of life related to swallowing or speech for patients with CCC. In our case, a negative surgical stump was observed, though the margins were small, and swelling of the lymph nodes in the neck was not detected on the images. Instead of additional surgery or postoperative radiotherapy, the patient has been carefully observed with yearly PET-CT. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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