Development of vitiligo during melanoma treatment with a novel survivin inhibitor: a case report and review of the literature
Abstract
Background The development of vitiligo has been associated with an improved clinical response in melanoma patients.
Methods We report a case of vitiligo associated with a novel antisurvivin drug and review the literature to determine the pathogenesis of vitiligo occurring during melanoma treatment.
Results A 78-year-old man with stage IV malignant melanoma developed vitiligo after the first therapeutic cycle of a novel antisurvivin drug. Although his vitiligo remained static, his melanoma continued to progress and he died in 8 months. A review of the literature demonstrates a relationship between vitiligo development and improved clinical response in many melanoma cases treated with immunotherapy;
however, the relationship may depend on the type of treatment.
Conclusions Understanding complex immune responses in vitiliginous skin and melanoma sites is important in order to interpret the development of vitiligo occurring during melanoma treatment.
Introduction
The development of vitiligo in melanoma patients is con- sidered to be the result of the immune-mediated destruction of melanocytes. Previous studies have suggested that vitiligo is associated with an improved prognosis in melanoma patients.1–13 We report herein a case of vitiligo associated with a novel antisurvivin therapy. Despite the development of vitiligo, the patient experienced melanoma progression during treatment.
Case Report
A 78-year-old man with no personal or family history of malignant melanoma presented with a suprapubic skin lesion in December 2005. The lesion had been present since the 1y70s, but had grown rapidly over the past few months. Excisional biopsy demonstrated malignant melanoma with ulceration and a Breslow depth greater than 5 mm. An abdominal computed tomography (CT) scan revealed multiple enlarged inguinal nodes. He was treated by wide local excision with concurrent sentinel lymph node biopsy in February 2006. Two sentinel nodes from the left and one node from the right groin were positive for metastatic melanoma. The patient declined to undergo lymph node dissection because of complications from the sentinel lymph node biopsy. In June 2006, the patient developed bony metastases and pelvic lymph node metastases, and was enrolled in a phase II clinical trial of the antisurvivin drug YM-155 (Astellas Pharma Inc., Deerfield, Illinois, US). Informed consent was obtained from the patient for its use. Several days after the first therapeutic cycle, consist- ing of a 168-h continuous infusion of YM-155 (4.8 mg/m2/day), the patient rapidly developed depigmentation on his hands extending to his arms (Fig. 1). Biopsy specimens demonstrated perivascular lymphocytic infiltrates and mild exocytosis in the peripheral area of depigmentation and a complete absence of melanocyte/melanoma-associated antigen recognized by T cells (MART-1)-positive melanocytes in the center of depigmentation (Fig. 2). The patient completed two cycles of YM-155 treatment, 3 weeks apart, without systemic adverse effects. A CT scan in August 2006 revealed a lung nodule and scattered retroperitoneal lesions consistent with interval progression of metastatic disease. YM-155 was discontinued and temozolomide was started in September 2006. Although the vitiligo remained unchanged, malignant melanoma continued to progress and the patient died in February 2007.
Discussion
Recent strategies for the treatment of melanoma have focused on inhibitors that block molecular pathways vital to the proliferation and survival of melanoma.14,15 This treatment strategy differs from immunotherapy which aims to augment immune-mediated destruction of melanoma by effector cells.
Examples of such inhibitors include the multikinase inhibitor sorafenib, ras inhibitors, mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, antiapoptosis inhibitors, and vascular endothelial growth factor (VEGF) inhibitors. YM-155 is a small molecule that selectively inhibits survivin antiapoptotic activity in tumor cells, resulting in an induction of tumor cell apoptosis.16 Survivin, a member of the inhibitor of apoptosis gene family, is expressed during fetal development, but is undetectable in most normal terminally differentiated tissues.17 It is overexpressed in many human cancers, and its expression in tumors is associated with a more aggressive phenotype, shorter survival times, and a decreased response to chemotherapy.18 Our patient developed vitiligo during treatment with YM-155. This is the first report of vitiligo in a melanoma patient treated with a survivin inhibitor. The temporal relationship between the initiation of treatment and subsequent loss of pigmentation suggests that melano- cytes were destroyed by YM-155 treatment, either directly or indirectly. Melanocytes do not express survivin,1y and YM-155 has little direct effect on normal cells that do not express survivin, making the possibility of a direct effect by YM-155 unlikely. Vitiligo-like skin changes have been reported in melanoma patients, mostly during immunotherapy for metastatic melanoma.1–13 Although YM-155 is not an immuno- therapy, histologic and immunohistologic findings suggest the immune-mediated destruction of melanocytes in vitiliginous skin. Sensitization to antigens shared by melanocytes and melanoma cells may have occurred during treatment. Survivin is expressed in many cancers, including melanoma tumors, but the amount and intensity of survivin expression in melanoma is variable.20,21 It is postulated that survivin was overexpressed in a portion of metastatic melanoma tumors in our patient, and that YM-155 treatment induced apoptotic cell death in a subpopulation of melanoma cells, consistent with the poor clinical response. Subsequently, macrophages phagocytosing apoptotic melanoma cells induced the activation of cytotoxic T cells directed to antigens shared by melanocytes and melanoma cells, leading to immune-mediated destruction of melanocytes in the skin via antigen recognition.
Previous studies have suggested that the development of vitiligo during melanoma therapy is associated with a better clinical response.1–13 We have analyzed the reported cases of vitiligo occurring during melanoma treatment and have summarized the results (Table 1).3–13,22–25 All cases other than ours received immunologic treatment, such as cytokines or vaccines. In the study by Richards et al.,3 77% and 23% of metastatic melanoma patients who developed vitiligo during immunochemotherapy showed objective tumor regression and stable disease, respectively, whereas 21% and 35% of patients who did not develop vitiligo showed partial response and progressive disease, respectively. Boasberg et al.5 reported enhanced survival in metastatic melanoma patients who developed vitiligo with immunochemotherapy. Gogas et al.7 recently demonstrated a correlation between the induction of autoimmunity and the improvement of survival during adjuvant treatment with interferon -2b. In contrast, Tsao et al.22 reported three melanoma cases with associated vitiligo, all of whom experienced disease progression during gp100/MART-1-transduced dendritic cell vaccine for melanoma. Poor clinical response was also observed in our patient, despite the development of vitiligo during antisur- vivin treatment.
Several mechanisms could explain why vitiligo development in the skin is not associated with antitumor responses at tumor sites in some cases. In contrast with normal melanocytes, melanoma cells are heterogeneous in the expression of tumor/ self-antigens and major histocompatibility complex (MHC) class I molecules,26,27 and cells that do not express antigens or MHC class I molecules can escape cytotoxicity by T cells. Furthermore, an immunosuppressive tumor microenviron- ment may develop via the induction of immunosuppressive cytokines, regulatory T cells, myeloid-derived suppressor cells, and plasmacytoid dendritic cells.28 Such an immunosuppressive tumor microenvironment could suppress immunodestruction at tumor sites, but not within normal skin. In addition, some treatments may alter immune responses directly. For example, activated memory T cells may become a target of antisurvivin treatment because of their expression of survivin.2y,30
Nonetheless, the review of the literature reveals a relationship between vitiligo development and improved clinical responses in many reported cases. Although the series considered herein may suffer from reporting bias, the analysis suggests that the relationship may depend on the type of treatment. Cases that show a relationship between vitiligo development and an improved clinical response may generate strong immunos- timulatory responses to counteract an immunosuppressive tumor microenvironment and reverse tumor resistance. Alternatively, cases that do not show a strong correlation between vitiligo development and an improved clinical response may generate less immunostimulation at tumor sites. As new therapies, including antisurvivin therapy, become prevalent in clinical use to treat melanomas, an understanding of the complex immune responses in vitiliginous skin and melanoma sites will be important to interpret the development of vitiligo during Sepantronium melanoma treatment.