Abstract
Sinonasal mucosal melanomas (SNMM) of the head and neck regions are rare and aggressive malignancies. Although they can affect patients of any ethnicity, they are more numerous in Chinese patients. The diagnosis and treatment of these tumors can be challenging. Recent studies have reported that Sox10 is a sensitive melanocytic marker for cutaneous melanoma (Nonaka et al. in Am J Surg Pathol 32:1291–1298, 2008). In addition, a CD117 (c-kit) gene mutation has been identified in cutaneous melanomas, indicating that there may be potential therapeutic benefits of tyrosine kinase inhibitors, such as Imatinib. The purpose of this study was to detect and test the immunohistochemical expression of Sox10 and c-kit in mucosal melanomas (MM) arising in the nasal cavities of Chinese patients. Twenty eight patients with mucosal melanomas of the nasal cavity were treated in two major hospitals in China. All cases had been locally diagnosed as primary SNMM. We confirmed all diagnoses with positive immunohistochemical stains for S100 and HMB-45. Additionally, automated immunohistochemistry was performed using a goat polyclonal Sox10 antibody and a monoclonal c-kit antibody counterstained using a standard avidin–biotin complex method. Immunohistochemical positive expression of Sox10 was defined by nuclear stain; and positivity for c-kit resulted in a distinct membranous staining. The extent of nuclear positivity for Sox10 and membranous stain for c-kit was graded by 4 board certified pathologists as follows: 1+, 1–25 % of positive tumor cells; 2+, 25–50 %; 3+, 50–75 %; and 4+, ≥75 %. Sox10 nuclear expression was found in all cases (100 %), with 4+ staining in 26 out of 28 cases (92.8 %) and 3+ staining in two cases with (7.1 %). The overall positivity for S100 staining was 23 out of 28 (82.1 %), with 1+ staining in 10 cases, 2+ staining in 6 cases, 3+ staining in 7 cases, and no staining in 5 cases. The sensitivity and intensity of Sox10 immunohistochemistry were both higher than with S100 immunohistochemistry. Immunopositivity of membranous stain for c-kit (CD117) was seen in 24 out of 28 cases (85.7 %), including 6 tumors that were 4+, eight that were 3+, six that were 2+, and four that showed 1+ staining. Our results demonstrate that Sox10 is a sensitive marker for SNMM and it may possess diagnostic value in addition to that of S100 protein. The expression of c-kit in the majority of MMs suggests that it may be useful in the assessment of these tumors for potential treatment with tyrosine kinase inhibitors.
Similar content being viewed by others
References
Nonaka D, Chiriboda L, Rubin BP. SOX10: a pan-schwannian and melanocytic marker. Am J Surg Pathol. 2008;32:1291–8.
Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol. 2003;27:594–611.
Younes MN, Myers JN. Melanoma of the head and neck: current concepts in staging, diagnosis, and management. Surg Oncol Clin N Am. 2004;13:201–29.
Penel N, Mallet Y, Mirabel X, et al. Primary mucosal melanoma of head and neck: prognostic value of clear margins. Laryngoscope. 2006;116:993–5.
Meleti M. leemans CR, de Bree R, et al. Head and neck mucosal melanoma: experience with 42 patients, with emphasis on the role of postoperative radiotherapy. Head Neck. 2008;30:1543–51.
Pandey M, Mathew A, Iype EM, et al. Primary malignant mucosal melanoma of the head and neck region: pooled analysis of 60 published cases from India and review of literature. Eur J Cancer Prev. 2002;11:3–10.
Papaspyrou G, Garbe C, Schadendorf D, et al. Mucosal melanomas of the head and neck: new aspects of the clinical outcome, molecular pathology, and treatment with c-kit inhibitors. Melanoma Res. 2011;21:475–82.
Gershon TR, Oppenhermer O, Chin SS, et al. Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation. Neoplasia. 2005;7:575–84.
Potterf SB, Mollaaghababa R, Hou L, et al. Analysis of SOX10 function in neural crest-derived melanocyte development: SOX10-dependent transcriptional control of dopachrome tautomerase. Dev. Biol. 2001;237:245–57.
Kordes U, Cheng YC, Scotting PJ. Sox group E gene expression distinguishes different types and maturational stages of glial cells in developing chick and mouse. Brain Res Dev Brain Res. 2005;157:209–13.
Kelsch RN. Sorting out SOX10 functions in neural crest development. BioEssays. 2006;28:788.
Ramos-Herberth FI, Karamchandani J, Kim J, et al. SOX10 immunostaining distinguishes desmoplastic melanoma from excision scar. J Cutan Pathol. 2001;37:944–52.
Blochin E, Nonaka D. Diagnostic value of Sox10 immunohistochemical staining for the detection of metastatic melanoma in sentinel lymph nodes. Histopathology. 2009;55:626–8.
Jennings C, Kim J. Identification of Nodal Metastases in Melanoma Using Sox-10. Am J Dermatopathol. 2011;33:474–82.
Rivera RS, Nagatsuka H, Gunduz M, et al. c-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma. Virchows Arch. 2008;452:27–32.
Lennartsson J, Blume-Jensen P, Hermanson M, et al. Phosphorylation of Shc by Src family kinases is necessary for stem cell factor receptor/c-kit mediated activation of Ras/MAP kinase pathway and c-fos induction. Oncogen. 1999;18:5546–53.
Lin SC, Liu CL, Wang TI, et al. Clinical implication of C-kit gene mutation in patients with large gastrointestinal stromal tumors. J Gastroenterol Hepatol. 2006;21:1604–8.
Handolias D, Hamilton AL, Salemi R, et al. Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT. Br J Cancer. 2010;102:1219–23.
Clifton N. Harrison l, Bradley PJ, Jones NS. Malignant melanoma of nasal cavity and paranasal sinuses: report 24 patients and literature review. J Laryngol Otol. 2011;125:479–85.
Mori W. Geographic pathology of malignant melanoma in Japan. In: McGovem VJ, Russell P, editors. Pigment cell mechanism in pigmentation, vol. 1. Basel: Karger; 1973. p. 246–54.
Shah JP, Huvos AG, Strong EW. Mucosal melanomas of the head and neck. Am J Surg. 1977;134:531–5.
Chang AE, Karnell LH, Menck HR. The National Cancer Data Base Report on cutaneous and non cutaneous melanoma. A summary of 84,836 cases from the past decade. Cancer. 1998;83:1664–78.
Wagner M, Morris CG, Werning JW, et al. Mucosal melanoma of the head and neck. Am J Clin Oncol. 2008;31:43–8.
Patrick RJ, Fenske NA, Messina JL. Primary mucosal melanoma. J Am Academy Dermatol. 2007;56:828–34.
Morris LG, Wen YH, Nonaka D, et al. melanocytic marker in immunohistochemical evaluation of primary mucosal melanoma of the head and neck. Head Neck. 2008;30:771–5.
Jiao Z, Zhang ZG, Hornyak TJ, et al. Dopachrome tautomerase (Dct) regulates neural progenitor cell proliferation. Dev Biol. 2006;296:396–408.
Prasad ML, Jungbluth AA, Iversen K, Huvos AG, Busam KJ. Expression of melanocytic differentiation markers in malignant melanomas of the oral and sinonasal mucosa. Am J Surg Pathol. 2001;25:782–7.
Yu CH, Chen HH, Jeng YM, et al. HMB-45 may be a more sensitive marker than S100 or Melan-A for immunohistochemical diagnosis of primary oral and nasal mucosa melanomas. J Oral Pathol Med. 2005;34:540–5.
Shin J, Vincent JG, Cuda JD, et al. Sox10 is expressed in primary melanocytic neoplasms of various histologies but not in fibrohistiocytic proliferations and histiocytoses. J Am Acad Dermatol. 2012; Feb 9. [Epub ahead of print]. PMID:22325460.
Went PT, Dirnhofer S, Bundi M, et al. Prevalence of KIT expression in human tumors. J Clin Oncol. 2004;22:4514–22.
Willmore-Payne C, Holden JA, Tripp S, et al. Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. Hum Pathol. 2005;36:486–93.
Willmore-Payne C, Holden JA, Hirshowitz S, et al. BRAF and c-kit gene copy number in mutation-positive malignant melanoma. Hum Pathol. 2006;37:520–7.
Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melamoma. J Clin Oncol. 2006;24:4340–6.
Antonescu CR, Busam KJ, Francone TD, et al. L567P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer. 2007;121:257–64.
Beadling C, Jacobson-Dunlop E, Hodi FS, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14:6821–8.
Satzger I, Schaefer T, Kuettler U, et al. Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas. Br J Cancer. 2008;99:2065–9.
Ashida A, Takata M, Murata H, et al. Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas. Int J Cancer. 2009;124:862–8.
Torres-Cabala CA, Wang WL, Trent J, et al. Correlation between KIT expression and KIT mutation in melanoma: a study of 173 cases with emphasis on the acral-lentiginous/mucosal type. Mod Pathol. 2009;22:1446–56.
Woodman SE, Davies MA. Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. Biochem Pharmacol. 2010;80:568–74.
Chute DJ, Cousar JB, Mills SE. Anorectal malignant melanoma: morphologic and immunohistochemical features. Am J Clin Pathol. 2006;126:93–100.
Alexis BJ, Martinez AE, Lutzky J. An immunohistochemical evaluation of c-kit (CD117) expression in malignant melanoma, and results of imatinib mesylate (Gleevec) therapy in three patients. Melanoma Res. 2005;15:283–5.
Medina JE, Ferlito A, Pellitteri PK, et al. Current management of mucosal melanoma of the head and neck. J Surg Oncol. 2003;83:116–22.
Patel SG, Prasad ML, Escrig M, et al. Primary mucosal malignant melanoma of the head and neck. Head Neck. 2002;24:247–57.
Gavriel H, McArthur G, Sizeland A, et al. Review: mucosal melanoma of the head and neck. Melanoma Res. 2011;21:257–66.
Fiorentini G, Rossi S, Lanzanova G, et al. Tyrosine Kinase inhibitor imatinib mesylate as an anticancer agent for advanced ocular melanoma expressing immunohistochemical C-KIT (CD117): preliminary results of a compassionate use clinical trail. J Exp Clin Cancer Res. 2003;22:17–20.
Ivan D, Niveiro M, Diwan AH, et al. Analysis of protein tyrosine kinases expression in the melanoma metastases of patients treated with Imatinib Mesylate (STI571, Gleevec). J Cutan Pathol. 2006;33:280–5.
Lefevre G, Glotin AL, Calipel A, et al. Roles of stem cell factor/c-kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis. J Biol Chem. 2004;279:31769–79.
Acknowledgments
The authors thank Dr. M. J. Klein for his advice in the preparation of this manuscript. This study is funded by NIH/NCRR 1UL1RR029893-01.
Conflict of Interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Dr. Herman Yee deceased.
Rights and permissions
About this article
Cite this article
Liu, H.G., Kong, M.X., Yao, Q. et al. Expression of Sox10 and c-kit in Sinonasal Mucosal Melanomas Arising in the Chinese Population. Head and Neck Pathol 6, 401–408 (2012). https://doi.org/10.1007/s12105-012-0375-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12105-012-0375-2