Dermatologic Therapy, Vol. ••, 2014, ••–•• Printed in the United States · All rights reserved
© 2014 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Classic Kaposi’s sarcoma treated with topical rapamycin Blanca Díaz-Ley, Emiliano Grillo, Luis Ríos-Buceta, John Paoli, Carmen Moreno, Sergio Vano-Galván & Pedro Jaén-Olasolo Department of Dermatology, Ramon y Cajal University Hospital, University of Alcalá, Madrid, Spain
ABSTRACT: Kaposi’s sarcoma (KS) is an angioproliferative disorder caused by human herpesvirus 8 (HHV-8). Current research efforts have focused on the study of the relative role of KSHV-encoded genes in Kaposi’s sarcomagenesis in order to identify novel mechanism-based therapies for patients suffering from this tumor. Although several viral genes have potential for KS pathogenesis, compelling data point to the KSHV-encoded G protein-coupled receptor (vGPCR) as a leading candidate viral gene for the initiation of KS. Interestingly, the oncogenic potential of vGPCR seems to correlate with its capacity to activate the mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin, the prototypical inhibitor of the mTOR signaling pathway, has recently emerged as an effective treatment for KS when administered orally. In this case report, we present an immunocompetent patient with KS lesions treated with topical rapamycin achieving clinical and histologic healing after 16 weeks of treatment. The topical application of rapamycin could be a novel therapeutic option for the treatment of KS. KEYWORDS: Kaposi’s sarcoma, rapamycin, treatment
Introduction Rapamycin (or sirolimus), the prototypical inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, has recently emerged as an active treatment for Kaposi’s sarcoma (KS) due to its ability to block the KS herpesvirus-encoded G protein-coupled receptor (vGPCR) oncogenesis in vitro and in vivo (1). Its effectiveness when administered orally has been demonstrated in the treatment of KS in renal transplant patients (2). However, as of yet, it has not been used topically in the treatment of localized lesions of KS. Herein, we Address correspondence and reprint requests to: Emiliano Grillo, MD, Researcher, Department of Dermatology, Ramon y Cajal University Hospital, University of Alcalá, Carretera Colmenar km 9.100, 28034 Madrid, Spain, or email: [email protected].
describe a 73-year-old HIV-negative man with localized classic or Mediterranean KS that regressed completely after 16 weeks of topical rapamycin therapy.
Case report A 73-year-old man examined at the Department of Dermatology of the Ramón y Cajal Hospital presented two purplish nodules on the first metatarsal of the right foot and on the external malleolus of the right ankle measuring 2.0 × 1.7 and 1 × 1 cm, respectively (FIG. 1). A punch biopsy of the larger lesion revealed a dermis packed with a fusiform cellular proliferation with areas of irregular cleft-like vascular channels lined by plump, slightly atypical and hyperchromatic endothelial cells compatible with KS (FIG. 2). Immunohistochemical staining
1
Díaz-Ley et al.
FIG. 1. (A) Purplish nodule measuring 2.0 × 1.7 cm located on the first metatarsal of the right foot. (A1) Pretreatment. (A2) Six weeks after treatment, the lesion has disappeared almost completely. (B1) Six weeks after treatment, the lesion has disappeared almost completely. (B) Bluish papule measuring 1 × 1 cm located on the external malleolus of the right ankle. (B1) Pretreatment. (B2) Six months after treatment, a hyperkeratotic lesion is observed with no evidence of recurrence.
FIG. 2. Histology of the larger lesion revealed a dermis packed with a fusiform cellular proliferation with areas of irregular cleft-like vascular channels lined by plump, slightly atypical, and hyperchromatic endothelial cells compatible with Kaposi’s sarcoma.
2
showed expression of human herpesvirus 8 (HHV8). The immunocompetent patient tested negative for both HIV 1 and HIV 2. Our patient had previously received topical imiquimod (3) applied daily for 3 months, and twice per day for another 3 months. Despite this, the lesions grew in size. The patient had previously rejected the possibility of other treatment options such as radiotherapy or surgery. Rapamycin was therefore considered as a therapeutic possibility for our patient as it had shown an antitumoral and antiangiogenic effect, and as its oral administration had been effective for the treatment of cutaneous KS tumors related to immunosuppression (4). Systemic exposure to rapamycin may have caused undesirable adverse events in this healthy although aged patient. However, we hypothesized that the topical application of rapamycin could be a novel, practical, and safe therapeutic option for the treatment of this patient’s KS. Rapamycin was delivered topically as a 0.5% ointment considering its effect on angiofibromas and psoriasis when tested as an off-label therapy
Kaposi’s sarcoma treated with topical rapamycin
(5,6). The 0.5% rapamycin ointment was prepared by crushing 50 tablets of rapamycin (Rapamune® Pfizer Inc., New York, NY, USA; Sirolimus 2 mg) in a vertical laminar flow hood. The crushed tablets were then filtered to obtain a fine powder. Finally, mineral oil was added to form a paste and the process was completed with petrolatum until we finally had 20 g of ointment. The ointment was stored at room temperature and protected from light. The hospital’s ethics committee approved the compassionate use of the drug. Fully informed written consent was obtained. The patient was treated with one application of 0.5% rapamycin ointment every 12 hours for 16 weeks. Follow-up was performed every 2 weeks. A second biopsy obtained from the same area as used for the diagnostic one (lesion 1) was performed 16 weeks after treatment. Treatment outcome was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECISTGuidelines) (7) and by histological confirmation. The patient’s KS lesions decreased in size and volume gradually. There was a greater acceleration in the decline of both lesions between 6 and 8 weeks after initiation of therapy. The treatment was well tolerated by the patient, experiencing only slight itching after administration of the product during the first weeks of treatment, which gradually disappeared. The biopsy performed after treatment showed a fibrotic dermis with sparse hemosiderophages while no tumor cells were observed (FIG. 3). Consequently, we believe that the patient achieved
FIG. 3. Skin biopsy of the larger lesion after 16 weeks of treatment. The histology showed a fibrotic scarring reaction with sparse hemosiderophages in the dermis. There was no evidence of vascular tumor proliferation.
clinical and histologic healing of both lesions. After 2 years of follow-up we have not detected recurrences. For safety issues, an ethylenediaminetetraacetic acid blood sample was obtained after 6 and 16 weeks of treatment. Sirolimus plasma levels were determined using a chemiluminescent microparticle enzyme immunoassay (Abbott ARCHITECT®, Abbott Park, IL, USA). Blood levels of sirolimus were below the limit of detection (
© 2014 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Classic Kaposi’s sarcoma treated with topical rapamycin Blanca Díaz-Ley, Emiliano Grillo, Luis Ríos-Buceta, John Paoli, Carmen Moreno, Sergio Vano-Galván & Pedro Jaén-Olasolo Department of Dermatology, Ramon y Cajal University Hospital, University of Alcalá, Madrid, Spain
ABSTRACT: Kaposi’s sarcoma (KS) is an angioproliferative disorder caused by human herpesvirus 8 (HHV-8). Current research efforts have focused on the study of the relative role of KSHV-encoded genes in Kaposi’s sarcomagenesis in order to identify novel mechanism-based therapies for patients suffering from this tumor. Although several viral genes have potential for KS pathogenesis, compelling data point to the KSHV-encoded G protein-coupled receptor (vGPCR) as a leading candidate viral gene for the initiation of KS. Interestingly, the oncogenic potential of vGPCR seems to correlate with its capacity to activate the mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin, the prototypical inhibitor of the mTOR signaling pathway, has recently emerged as an effective treatment for KS when administered orally. In this case report, we present an immunocompetent patient with KS lesions treated with topical rapamycin achieving clinical and histologic healing after 16 weeks of treatment. The topical application of rapamycin could be a novel therapeutic option for the treatment of KS. KEYWORDS: Kaposi’s sarcoma, rapamycin, treatment
Introduction Rapamycin (or sirolimus), the prototypical inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, has recently emerged as an active treatment for Kaposi’s sarcoma (KS) due to its ability to block the KS herpesvirus-encoded G protein-coupled receptor (vGPCR) oncogenesis in vitro and in vivo (1). Its effectiveness when administered orally has been demonstrated in the treatment of KS in renal transplant patients (2). However, as of yet, it has not been used topically in the treatment of localized lesions of KS. Herein, we Address correspondence and reprint requests to: Emiliano Grillo, MD, Researcher, Department of Dermatology, Ramon y Cajal University Hospital, University of Alcalá, Carretera Colmenar km 9.100, 28034 Madrid, Spain, or email: [email protected].
describe a 73-year-old HIV-negative man with localized classic or Mediterranean KS that regressed completely after 16 weeks of topical rapamycin therapy.
Case report A 73-year-old man examined at the Department of Dermatology of the Ramón y Cajal Hospital presented two purplish nodules on the first metatarsal of the right foot and on the external malleolus of the right ankle measuring 2.0 × 1.7 and 1 × 1 cm, respectively (FIG. 1). A punch biopsy of the larger lesion revealed a dermis packed with a fusiform cellular proliferation with areas of irregular cleft-like vascular channels lined by plump, slightly atypical and hyperchromatic endothelial cells compatible with KS (FIG. 2). Immunohistochemical staining
1
Díaz-Ley et al.
FIG. 1. (A) Purplish nodule measuring 2.0 × 1.7 cm located on the first metatarsal of the right foot. (A1) Pretreatment. (A2) Six weeks after treatment, the lesion has disappeared almost completely. (B1) Six weeks after treatment, the lesion has disappeared almost completely. (B) Bluish papule measuring 1 × 1 cm located on the external malleolus of the right ankle. (B1) Pretreatment. (B2) Six months after treatment, a hyperkeratotic lesion is observed with no evidence of recurrence.
FIG. 2. Histology of the larger lesion revealed a dermis packed with a fusiform cellular proliferation with areas of irregular cleft-like vascular channels lined by plump, slightly atypical, and hyperchromatic endothelial cells compatible with Kaposi’s sarcoma.
2
showed expression of human herpesvirus 8 (HHV8). The immunocompetent patient tested negative for both HIV 1 and HIV 2. Our patient had previously received topical imiquimod (3) applied daily for 3 months, and twice per day for another 3 months. Despite this, the lesions grew in size. The patient had previously rejected the possibility of other treatment options such as radiotherapy or surgery. Rapamycin was therefore considered as a therapeutic possibility for our patient as it had shown an antitumoral and antiangiogenic effect, and as its oral administration had been effective for the treatment of cutaneous KS tumors related to immunosuppression (4). Systemic exposure to rapamycin may have caused undesirable adverse events in this healthy although aged patient. However, we hypothesized that the topical application of rapamycin could be a novel, practical, and safe therapeutic option for the treatment of this patient’s KS. Rapamycin was delivered topically as a 0.5% ointment considering its effect on angiofibromas and psoriasis when tested as an off-label therapy
Kaposi’s sarcoma treated with topical rapamycin
(5,6). The 0.5% rapamycin ointment was prepared by crushing 50 tablets of rapamycin (Rapamune® Pfizer Inc., New York, NY, USA; Sirolimus 2 mg) in a vertical laminar flow hood. The crushed tablets were then filtered to obtain a fine powder. Finally, mineral oil was added to form a paste and the process was completed with petrolatum until we finally had 20 g of ointment. The ointment was stored at room temperature and protected from light. The hospital’s ethics committee approved the compassionate use of the drug. Fully informed written consent was obtained. The patient was treated with one application of 0.5% rapamycin ointment every 12 hours for 16 weeks. Follow-up was performed every 2 weeks. A second biopsy obtained from the same area as used for the diagnostic one (lesion 1) was performed 16 weeks after treatment. Treatment outcome was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECISTGuidelines) (7) and by histological confirmation. The patient’s KS lesions decreased in size and volume gradually. There was a greater acceleration in the decline of both lesions between 6 and 8 weeks after initiation of therapy. The treatment was well tolerated by the patient, experiencing only slight itching after administration of the product during the first weeks of treatment, which gradually disappeared. The biopsy performed after treatment showed a fibrotic dermis with sparse hemosiderophages while no tumor cells were observed (FIG. 3). Consequently, we believe that the patient achieved
FIG. 3. Skin biopsy of the larger lesion after 16 weeks of treatment. The histology showed a fibrotic scarring reaction with sparse hemosiderophages in the dermis. There was no evidence of vascular tumor proliferation.
clinical and histologic healing of both lesions. After 2 years of follow-up we have not detected recurrences. For safety issues, an ethylenediaminetetraacetic acid blood sample was obtained after 6 and 16 weeks of treatment. Sirolimus plasma levels were determined using a chemiluminescent microparticle enzyme immunoassay (Abbott ARCHITECT®, Abbott Park, IL, USA). Blood levels of sirolimus were below the limit of detection (
