565024

research-article2015

IJSXXX10.1177/1066896914565024International Journal of Surgical PathologyIshibashi et al

Case Report

Androgen Receptor–Positive Mucoepidermoid Carcinoma: Case Report and Literature Review

International Journal of Surgical Pathology 2015, Vol. 23(3) 243­–247 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914565024 ijs.sagepub.com

Kenichiro Ishibashi, DMD1,2, Yohei Ito, DMD1,2, Kana Fujii, DMD1, Ayako Masaki, MD, PhD1, Shintaro Beppu, MD1, Daisuke Kawakita, MD, PhD1, Kei Ijichi, MD, PhD1, Kazuo Shimozato, DMD, PhD2, and Hiroshi Inagaki, MD, PhD1

Abstract Androgen receptor (AR) is usually expressed in salivary duct carcinoma (SDC), but only infrequently in other carcinoma types including mucoepidermoid carcinoma (MEC). The clinicopathological characteristics of AR-positive MEC remain to be clarified. Here we report a case of AR-positive MEC. A 76-year-old man presented with a growing painless tumor of the right parotid. The resected tumor was a high-grade tumor with necroses. Since the tumor was positive for AR, GCDFP-15, and HER2, SDC was first suspected, but it was also positive for CK5/6 and P63, and negative for S-100 protein and α-smooth muscle actin. In addition, scattered mucous secreting tumor cells were found in the tumor nests, and they were positive for Alcian blue. A diagnosis of AR-positive MEC was finally made. The patient died of the tumor 5 years after the surgery. The present case may expand the histopathological spectrum of high-grade MEC. Keywords mucoepidermoid carcinoma, androgen receptor, GCDFP-15, HER2, and salivary duct carcinoma

Introduction

Clinical Summary

Mucoepidermoid carcinoma (MEC) is the most common malignancy of the salivary gland.1,2 Histologically, MEC is characterized by a combination of mucus-secreting, squamous, and intermediate cell types. Low-grade MECs are comprised predominantly of glandular elements and mucous secreting cells, while high-grade MEC consists largely of sheets or nests of squamoid and intermediate cells intermixed with smaller populations of mucous secreting cells.1,2 To make a correct diagnosis of highgrade MEC is sometimes difficult because of its similarity to other high-grade tumors including squamous cell carcinoma and salivary duct carcinoma (SDC).3,4 SDC is one of the most aggressive tumors of the salivary gland, and it usually shows consistent expression of androgen receptor (AR) as well as gross cystic disease fluid protein-15 (GCDFP-15) and HER2.3,5 Since rarely expressed in other tumor types, AR is often used as a useful immunohistochemical marker for the diagnosis of SDC.3-7 Here we report a high-grade MEC of the parotid gland that was positive for AR, GCDFP-15, and HER2.

A 76-year-old man presented with a 1-year history of an asymptomatic right parotid mass with a recent enlargement in size. His past medical history included hypothyroidism and chronic heart failure. He had no facial nerve dysfunction or constitutional symptoms. Radiologic examination showed a tumor of 15 mm × 7 mm in size and lymphadenopathy in the neck. Fine-needle aspiration cytology of the parotid tumor and an enlarged cervical lymph node showed malignant epithelial tumor involvement. He underwent a right superficial parotidectomy and radical neck dissection. While the parotid and neck lesions were well controlled after the surgery, lung tumor 1

Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 2 Aichi-Gakuin University School of Dentistry, Nagoya, Japan Corresponding Author: Hiroshi Inagaki, Department of Pathology and Molecular Diagnostics, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Email: [email protected]

244 metastasis was detected 3 years after the surgery. He refused treatment for the lung disease and died of the tumor 2 years after the detection of the lung metastasis.

Materials and Methods Pathological Analysis and Immunohistochemistry Sections were stained with hematoxylin and eosin (HE), periodic acid–Schiff (PAS), and Alcian blue. Immunohistochemistry was performed using the following antibodies: AR (AR441, BioGenex, San Ramon, CA), gross cystic disease fluid protein-15 (GCDFP-15; 23A3, Signet Laboratories, Dedham, MA), HER2 protein (polyclonal, Dako, Tokyo, Japan), S-100 protein (polyclonal, Dako), p63 (4A4, Dako), α-smooth muscle actin (SMA; 1A4, Dako), and Ki-67 (MIB-1, Dako).

Molecular Analysis Reverse transcription polymerase chain reaction (RT-PCR) for the CRTC1/3–MAML2 fusion transcripts was performed as previously described.8,9 Briefly, total RNA extracted from paraffin sections was subjected to an initial reverse transcription, followed by nested PCR amplification. As an internal control for RNA quality, ubiquitously expressed ACTB mRNA fragment was amplified. Fluorescence in situ hybridization (FISH) was also performed as previously described.10 Paraffin sections were deparaffinized and digested in a protease solution. After denaturation, sections were incubated with an MAML2 break-apart probe (ZytoVision, Bremerhaven, Germany) overnight. After posthybridization washing, sections were stained with diaminophenilindole and mounted.

Results Histopathology and Immunohistochemistry Microscopic examination showed infiltration of large polygonal epithelial cells with eosinophilic cytoplasm, in a large cystic pattern with frequent central necroses or in tumor nests with fibrous stroma (Figure 1A-C). Perineural and vascular tumor involvement was frequently observed. Occasionally, mucous secreting cells, which was positive for Alcian blue and negative for PAS, were found admixed in the tumor nests (Figure 1D). Immunohistochemically, tumor cells were positive for CK5/6 (Figure 1E), AR (Figure 1F), GCDFP-15 (Figure 1G), HER2 (Figure 1H), and P63, and negative for S-100 protein and α-SMA. MIB1 labeling index was scored high (40%).

International Journal of Surgical Pathology 23(3)

Molecular Analyses Total RNA was preserved as evidenced by RT-PCR for ACTB mRNA. An RT-PCR assay for CRTC1/3–MAML2 fusion showed no detectable PCR products. FISH analysis was performed using MAML2 break-apart probe on paraffin section. No split signals of the MAML2 gene were detected in the tumor nuclei.

Discussion AR expression in MEC is rare,11 and only 8 cases of AR-positive MEC including the present case have been reported in the English literature (Table 1).7,12,13 Although Ito et al commented that AR was expressed in 2 cases of high-grade MEC,7 clinicopathological features of AR-positive MECs are largely unknown, and the significance of AR expression in MEC remains to be clarified. Diagnosis of high-grade MEC is sometimes difficult, and SDC is one of the differential diagnoses when tumors form variable-sized, cystic, or solid nodules with frequent comedo-type necroses and show eosinophilic cytoplasm and frequent mitotic figures.3,5 In our case, in addition to these histological findings, the tumor was positive for AR, GCDFP-15, and HER2. To the best of our knowledge, an MEC case expressing AR, GCDFP-15, and HER2 has not been reported. From these histopathological and immunohistochemical findings, SDC was suspected first. However, the tumor was positive for CK5/6 and P63,4 and rare mucous secreting tumor cells were found and they were positive for Alcian blue, which is generally unreactive to SDC.3 Finally, a diagnosis of AR-positive MEC was made. Although CRTC1/3–MAML2 fusions were negative in our case, these gene fusions are usually negative for highgrade MEC. Experimentally, androgen may influence the expression of proto-oncogenes and apoptotic factors in the salivary tissues.14-16 It has been also suggested that AR may be associated with the mediation of an epidermal growth factor receptor and transforming growth factor-α autocrine pathway, similarly in the pathogenesis in prostatic carcinoma.17 However, prognostic significance of AR expression in SDC has not been established.18 The significance of AR expression in other malignant salivary gland tumors has been poorly clarified. Our AR-positive MEC case was a high-grade tumor and the patient died of the tumor 5 years after the surgery, suggesting that AR expression might be associated with unfavorable clinical outcome. Recently, beneficial effects of anti-AR agents against SDCs have been reported.19 Detection of AR expression may have a therapeutic significance not only in SDC but also in nonSDC tumors with AR expression.

Ishibashi et al

245

Figure 1.  (A-C) Histological findings show large cystic lesions with central necrosis and small tumor nodules with fibrous stroma. (D) Occasionally, mucous secreting tumor cells (arrows) with atypical nuclei are found. Mucous secreting tumor cells are positive for Alcian blue (inset). Immunohistochemically, the tumor cells are positive for CK5/6 (E), AR (F), GCDFP-15 (G), and HER2 (H).

246

International Journal of Surgical Pathology 23(3)

Table 1.  Androgen Receptor-Positive Mucoepidermoid Carcinoma. Age Case (years) 1 2 3 4 5 6 7 8

ND ND ND ND ND ND ND 76

Sex Male Female ND ND ND ND ND Male

Primary Tumor Tumor Site Size (mm) Histology ND ND ND ND ND ND ND Protid

ND ND ND ND ND ND ND 15

ND ND High grade High grade ND ND ND High grade

Nodal Distant Follow-Up Treatment Metastasis Metastasis (years) Outcome ND ND ND ND ND ND ND Surgery

ND ND ND ND ND ND ND Yes

ND ND ND ND ND ND ND No

ND ND ND ND ND ND ND 5

ND ND ND ND ND ND ND DOD

Comment

Reference

ND 12 ND 12 ND 7 ND 7 ND 13 ND 13 ND 13 MAML2 gene split Present case (−), GCDFP-15 (+), HER2 (+)

Abbreviations: ND, not described; DOD, died of disease.

In this report, we described a case of AR-positive highgrade MEC of the parotid gland. The present case may expand the clinicopathological spectrum of MEC. Further study is needed to clarify the clinicopathological significance and molecular mechanism of AR expression in MEC. Authors’ Note This study was approved by the ethics review board at the Nagoya City University and conformed to the provisions of the Declaration of Helsinki.

Acknowledgments YI and KI contributed equally to this work. The authors thank Mrs Takeo Sakakibara and Hisashi Takino for their excellent technical assistance.

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. Goode RK, El-Naggar AK. Mucoepidermoid carcinoma. In: Barnes EL, Eveson JW, Reichart P, Sidransky D, eds. Pathology and Genetics of Head and Neck Tumours. WHO Classification of Tumours. Lyon, France: IARC Press; 2005:219-220. 2. Ellis GL, Aculair PL. Mucoepidermoid carcinoma. In: Ellis GL, Aculair PL, eds. Tumours of the Salivary Glands. AFIP Atlas of Tumor Pathology. Annapolis, MD: ARP Press; 2008:173-192. 3. Ellis GL, Aculair PL. Salivary duct carcinoma. In: Ellis GL, Aculair PL, eds. Tumours of the Salivary Glands. AFIP Atlas of Tumor Pathology. Annapolis, MD: ARP Press; 2008:322-331.

4. Butler RT, Spector ME, Thomas D, McDaniel AS, McHugh JB. An immunohistochemical panel for reliable differentiation of salivary duct carcinoma and mucoepidermoid carcinoma. Head Neck Pathol. 2014;8:133-140. 5. Brandwein-Gensler MS, Skálová A, Nagao T. Salivary duct carcinoma. In: Barnes EL, Eveson JW, Reichart P, Sidransky D, eds. Pathology and Genetics of Head and Neck Tumours. WHO Classification of Tumours. Lyon, France: IARC Press; 2005:236-237. 6. Sygut D, Bień S, Ziółkowska M, Sporny S. Immunohistochemical expression of androgen receptor in salivary gland cancers. Pol J Pathol. 2008;59:205-210. 7. Ito FA, Ito K, Coletta RD, Vargas PA, Lopes MA. Immunohistochemical study of androgen, estrogen and progesterone receptors in salivary gland tumors. Braz Oral Res. 2009;23:393-398. 8. Okabe M, Miyabe S, Nagatsuka H, et al. MECT1-MAML2 fusion transcript defines a favorable subset of mucoepidermoid carcinoma. Clin Cancer Res. 2006;12:3902-3907. 9. Nakayama T, Miyabe S, Okabe M, et al. Clinicopathological significance of the CRTC3-MAML2 fusion transcript in mucoepidermoid carcinoma. Mod Pathol. 2009;22: 1575-1581. 10. Noda H, Okumura Y, Nakayama T, et al. Clinicopathological significance of MAML2 gene split in mucoepidermoid carcinoma. Cancer Sci. 2013;104:85-92. 11. Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol. 2006;24:2673-2678. 12. Nasser SM, Faquin WC, Dayal Y. Expression of androgen, estrogen, and progesterone receptors in salivary gland tumors. Frequent expression of androgen receptor in a subset of malignant salivary gland tumors. Am J Clin Pathol. 2003;119:801-806. 13. Cros J, Sbidian E, Hans S, et al. Expression and mutational status of treatment-relevant targets and key oncogenes in 123 malignant salivary gland tumours. Ann Oncol. 2013;24:2624-2629. 14. Quarmby VE, Beckman WC Jr, Wilson EM, French FS. Androgen regulation of c-myc messenger ribonucleic acid levels in rat ventral prostate. Mol Endocrinol. 1987;1: 865-874.

Ishibashi et al 15. Berchem GJ, Bosseler M, Sugars LY, Voeller HJ, Zeitlin S, Gelmann EP. Androgens induce resistance to bcl-2-mediated apoptosis in LNCaP prostate cancer cells. Cancer Res. 1995;55:735-738. 16. Toda I, Wickham LA, Sullivan DA. Gender and androgen treatment influence the expression of proto-oncogenes and apoptotic factors in lacrimal and salivary tissues of MRL/lpr mice. Clin Immunol Immunopathol. 1998;77:59-71. 17. Fan CY, Melhem MF, Hosal AS, Grandis JR, Barnes EL. Expression of androgen receptor, epidermal growth factor receptor, and transforming growth factor alpha in salivary

247 duct carcinoma. Arch Otolaryngol Head Neck Surg. 2001;127:1075-1079. 18. Williams MD, Roberts D, Blumenschein GR, et al. Differential expression of hormonal and growth factor receptors in salivary duct carcinomas: biologic significance and potential role in therapeutic stratification of patients. Am J Surg Pathol. 2007;31:1645-1652. 19. Jaspers HC, Verbist BM, Schoffelen R, et al. Androgen receptor-positive salivary duct carcinoma: a disease entity with promising new treatment options. J Clin Oncol. 2011;29:e473-e476.

Copyright of International Journal of Surgical Pathology is the property of Sage Publications Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

Androgen receptor-positive mucoepidermoid carcinoma: case report and literature review.

Androgen receptor (AR) is usually expressed in salivary duct carcinoma (SDC), but only infrequently in other carcinoma types including mucoepidermoid ...
439KB Sizes 2 Downloads 12 Views