Mucosal melanoma of the head and neck is a rare and aggressive tumor entity with a poor prognosis. The standard treatment is radical tumor resection, with or without adjuvant radiation, where conventional chemotherapies in advanced stage or recurrent diseases have shown little benefit. Overexpression of the programmed cell death ligand 1 (PD-L1) is a common feature in human cancer. Although PD-L1 is an acknowledged prognostic biomarker for dismal prognosis in other tumors of the head and neck, expression and clinical relevance of PD-L1 in mucosal melanoma have not been addressed so far. We assessed PD-L1 expression using immunohistochemical staining in 23 tumor samples from patients with primary mucosal melanoma and correlated expression status with clinicopathological and outcome data. Tumors were derived from the nasal cavity (43.5%), nasal sinuses (43.5%), and the conjunctiva (13%). All patients had undergone surgery; 39% of all patients received adjuvant radiation and 13% were administered systemic interferon therapy. The probability of 1- and 5-year overall survival was 87 and 34.8%, respectively. The mean overall survival was 51 months and the mean recurrence-free survival was 23 months. Immunohistochemical staining showed PD-L1 expression in 13% (3/23) of mucosal melanoma. In contrast, prominent PD-L1 staining was detected in 100% of tissue sections from a control group of cutaneous melanoma (n=9). PD-L1 expression in mucosal melanoma was not correlated with age, sex, nor anatomical localization of the tumor. Interestingly, patients with PD-L1-positive mucosal melanoma had a significantly longer recurrence-free survival (P=0.026). In contrast to cutaneous melanoma and some other malignancies, a relevant PD-L1 overexpression in mucosal melanoma could not be confirmed.
BackgroundMolecular mechanisms of intrinsic or acquired radioresistance serve as critical barrier for curative therapy of head and neck squamous cell carcinoma (HNSCC) and remain a major obstacle for progression-free and disease-specific survival.MethodsHNSCC cell lines were treated with a protocol of fractionated irradiation (IR, 4× 2Gy) alone or in combination with antagonists of estrogen receptor signaling and viability was determined by a colony-forming assay (CFA). Expression of submaxillary gland androgen-regulated protein 3A (SMR3A) and estrogen receptor 2 (ESR2) were assessed in tumor cells in vitro by RQ-PCR, Western blot analysis and immunofluorescence staining, and by immunohistochemical staining of tissue microarrays containing tumor sections from patients with oropharyngeal squamous cell carcinoma (OPSCC), which were treated by definitive or adjuvant radiotherapy. Subgroups with distinct SMR3A and ESR2 expression patterns were correlated with clinical parameters and survival outcome including multivariable analysis.ResultsFractionated irradiation (IR) revealed an accumulation of tumor cells with prominent SMR3A expression, which was accompanied by an up-regulation of the estrogen receptor 2 (ESR2). ESR2-dependent regulation of SMR3A was supported by induced expression after stimulation with estradiol (E2), which was impaired by co-treatment with 4-Hydroxytamoxifen (TAM) or Fulvestrant, respectively. Both drugs significantly sensitized FaDu cells to fractionated IR as determined by a CFA and accelerated apoptosis. These data suggest a critical role of ESR2 in radioresistance and that SMR3A might serve as a surrogate marker for active ESR2 signaling. In line with this assumption, ESR2-positive oropharyngeal squamous cell carcinoma (OPSCC) with high SMR3A expression had an unfavorable progression-free and disease-specific survival as compared to those tumors with low SMR3A expression.ConclusionsIn summary, our findings provide compelling experimental evidence that HNSCC with SMR3A and ESR2 co-expression have a higher risk for treatment failure and these patients might benefit from clinically well-established drugs targeting estrogen receptor signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0496-2) contains supplementary material, which is available to authorized users.
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