8. Grattan CE, Peachey RD, Boon A. Evidence for a role of local trauma in the pathogenesis of erosive pustular dermatosis of the scalp. Clin Exp Dermatol 1988; 13: 7-10. 9. Shahmoradi Z, Abtahi-Naeini B, Pourazizi M. Erosive pustular dermatosis of the scalp following hair transplantation. Adv Biomed Res 2014; 3: 176. 10. Hendriks AG, Keijsers RR, Seyger MM, van Erp PE, van de Kerkhof PC. Are newly discovered drivers of immune-mediated skin disorders expressed in normal skin regenerating from standardized surface injury? Dermatology 2014; 228: 255-60.
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Copyright © 2017 John Libbey Eurotext. Téléchargé par NYU LANGONE MED CTR SCH OF MED HEALTH SCIENCES LIBRARY le 15/03/2017.
doi:10.1684/ejd.2015.2528
Complete regression of melanoma skin metastases after electrochemotherapy plus ipilimumab treatment: an unusual clinical presentation Skin metastases represent a relatively frequent event in the natural history of melanoma, developing both in early and in late disease stages. Cutaneous or subcutaneous lesions arise in 15-20% of patients; almost 50% of subjects with metastatic disease have soft tissue metastases [1]. The treatment of these lesions is still a challenge: surgical excision and radiotherapy represent the standard treatments for isolated lesions, while melphalan and/or tumour necrosis factor limb perfusion is considered the standard of care for multiple lesions involving the entire extremity [2]. Electrochemotherapy (ECT) represents an effective therapeutic option, both for first-line treatment and in palliative settings, especially in painful and bleeding lesions [3, 4]. ECT, by means of brief and intense electric pulses, increases the cell membrane permeability to anticancer drugs (such as bleomycin and cisplatin) that normally scarcely penetrate into the cells. More recently, the novel systemic drugs approved in the treatment of advanced melanoma (e.g. the anti-CTLA-4, PD-1 /PD-1L blockers and the MAP kinase inhibitors) also showed a clinical benefit in the treatment of patients affected by cutaneous metastases [5]. Herein we describe a case of an advanced melanoma in which a sequential treatment with ECT plus ipilimumab induced a complete clinical response of multiple cutaneous metastases, with unusual vitiligo-like lesions as the final outcome. A 71-year-old Caucasian male had a prior excision of a pT2b malignant melanoma located on his left leg in December 2010; sentinel lymph-node biopsy resulted negative. After two years, he developed multiple bluish papulonodular metastatic lesions ranging from 0.5 to 1.5 cm, on the same limb (figure 1A). The clinical scenario was suggestive for in-transit melanoma metastases. FDG PET/CT scan confirmed the high metabolic activity and excluded visceral involvement. During an eight-month period, three ECT treatments were performed with 15mg/m2 intravenous bleomycin, using the Cliniporator TM device (IGEA Ltd, Carpi, Italy). Neither post-treatment complications nor peripheral nerves injuries, nor post-procedural pain were observed. Globally, 28 lesions were treated, with a partial response (figure 1B). The scheduled total body CT-scan, EJD, vol. 25, n◦ 3, May-June 2015
Figure 1. A) multiple bluish papulo-nodular metastatic lesions ranging from 0.5 to 1.5 cm in diameter on the left leg. B) cutaneous lesions after three ECT. C) Multiple vitiligo-like hypopigmented lesions on the sites of previous cutaneous metastases, persistent one year after the end of the ipilimumab treatment. D) post-inflammatory dermal melanosis at the histopathological analysis.
performed three months after the last ECT session, revealed multiple liver and adrenal glands metastases. Thus ipilimumab treatment at the standard dose of 3 mg/kg was administered; no immune-related adverse events were reported. One month after the end of the anti CTLA-4 treatment we observed a progressive reduction in diameter, thickness and pigmentation of the cutaneous lesions; vitiligo areas became visible around the ECT treated lesions. A complete (visceral and cutaneous) response was confirmed by a PET/CT scan. Two skin biopsies in the site of prior metastatic lesions revealed only a post-inflammatory dermal melanosis (figure 1C). One year later the patient still has a durable complete response with multiple vitiligo-like hypo-pigmented lesions (figure 1D). Melanoma is an immunogenic cancer characterized by the presence of tumor-infiltrating lymphocytes that justify the clinical responses to immunotherapy. Tumor-associated antigens (TAAs), recognized by autologous antibodies and T-cells and capable of inducing tumor-directed immune responses, were identified in melanoma earlier than in other tumors. Studies of the nature of these interactions led to the development of many immunotherapeutic strategies; one immunotherapeutic anti-CTLA-4 agent, ipilimumab, was recently approved for the treatment of metastatic melanoma [5]. Roux et al. demonstrated that, after ECT antigen-presenting cells are recruited in the treated area, the expression of toll-like receptor 9 is up-regulated [6]. A recent study by Gerlini et al. [7] provides the rationale for combining ECT with dendritic cell (DC) activation protocols in a clinical setting. Their results confirm that ECT produces an inflammatory infiltrate with a high number of DCs and that cell-death induced by ECT releases TAAs [8]. DC recruitment and TAA availability are two essential factors in systemic antitumor immunity. More recent findings suggest that the combination of ECT with immunotherapy may produce an effective immune response for systemic tumor control [9]. In our case, the onset of vitiligo-like lesions, developed exclusively around the site of previous ECT, might suggest the presence of an enhanced localized immune-activation, as a consequence of increased TAA liberation on ECT
271
Copyright © 2017 John Libbey Eurotext. Téléchargé par NYU LANGONE MED CTR SCH OF MED HEALTH SCIENCES LIBRARY le 15/03/2017.
treated lesions. On the basis of this observation, even if the role of ipilimumab alone cannot be excluded, we postulate a combined role of ECT and ipilimumab and suggest that the complete response observed may be expression of an abscopal effect, similar to that observed in other therapeutic associations involving ipilimumab and radiotherapy [10]. If these observations are confirmed on larger clinical studies, the local response triggered by ECT might be used to enhance a systemic response in advanced melanoma patients treated with ipilimumab. Disclosure. Financial support: none. Conflict of interest: none. Department of Medical Sciences, University of Turin v. Cherasco 23, 10126, Torino, Italy a both
authors contributed equally to this paper.
Matteo BRIZIOa Paolo FAVAa Chiara ASTRUA Giovanni CAVALIERE Paola SAVOIA
1. Savoia P, Fava P, Nardò T, Osella-Abate S, Quaglino P, Bernengo MG. Skin metastases of malignant melanoma: a clinical and prognostic survey. Melanoma Res 2009; 19: 321-6. 2. Hayes AJ, Clark MA, Harries M, Thomas JM. Management of in-transit metastases from cutaneous malignant melanoma. Br J Surg 2004; 91: 673-82. 3. Möller MG, Salwa S, Soden DM, O’Sullivan GC. Electrochemotherapy as an adjunct or alternative to other treatments for unresectable or in-transit melanoma. Expert Rev Anticancer Ther 2009; 9: 1611-30. 4. Quaglino P, Mortera C, Osella-Abate S, et al. Electrochemotherapy with intravenous bleomycin in the local treatment of skin melanoma metastases. Ann Surg Oncol 2008; 15: 2215-22. 5. Palathinkal DM, Sharma TR, Koon HB, Bordeaux JS. Current systemic therapies for melanoma. Dermatol Surg 2014; 40: 948-63. 6. Roux S, Bernat C, Al-Sakere B, et al. Tumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responses. Cancer Immunol Immunother 2008; 57: 1291-300. 7. Gerlini G, Di Gennaro P, Borgognoni L. Enhancing antimelanoma immunity by electrochemotherapy and in vivo dendritic- cell activation. Oncoimmunology 2012; 1: 1655-7. 8. Quaglino P, Osella-Abate S, Marenco F, et al. FoxP3 expression on melanoma cells is related to early visceral spreading in melanoma patients treated by electrochemotherapy. Pigment Cell Melanoma Res 2011; 24: 734-6. 9. Queirolo P, Marincola F, Spagnolo F. Electrochemotherapy for the management of melanoma skin metastasis: a review of the literature and possible combinations with immunotherapy. Arch Dermatol Res 2014; 306: 521-6. 10. Stamell EF, Wolchok JD, Gnjatic S, Lee NY, Brownell I. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys 2013; 85: 293-5. doi:10.1684/ejd.2015.2522
sive ulcerative lesions on the posterior aspects of both legs, which reportedly appeared some weeks before and had since rapidly extended. The lesions, which were very painful, had first developed as multiple erythematoviolaceous plaques which later became deeply ulcerated, showing irregular margins and a seropurulent bed. The patient suffered from severe psoriasis, for which he had been under infliximab intravenous therapy for the last 4 years. The last infliximab administration was performed in June 2013. He also suffered from moderate hypertension, treated with oral olmesartan. Family history was positive for psoriasis but negative for other skin or auto-immune disorders. Culture and PCR examinations for bacteria, fungi and mycobacteria, performed from lesional skin swabs as well as from biopsies, were negative. Histologic examination showed necrosis of the epidermis and massive neutrophilic dermal infiltration (figure 1A).The diagnosis of pyoderma gangrenosum (PG) was made. Infliximab was discontinued and the patient was treated with symptomatic drugs to ease the pain. The lesions started to heal spontaneously, with considerable improvement after 3 weeks (figures 1B,C), and complete resolution after another 4 weeks. In September 2013 the patient was switched to ustekinumab subcutaneous injections. Presently, after 10 months of follow-up, the psoriasis is under control and no recurrence of PG has been observed. To the best of our knowledge this is the first case of PG arising under infliximab therapy in a psoriatic patient. Three similar cases have been reported in individuals receiving infliximab for ulcerative colitis or rheumatoid arthritis. In these cases infliximab therapy had been initiated a few months before. In the first case, affected by ulcerative colitis, PG developed in the peristomal region, probably favored by persistent trauma generated by colostomy, and was treated with oral corticosteroids and topical tacrolimus [1]. In the second case infliximab had first been used to treat ulcerative colitis (with poor results) and then reintroduced after total colectomy. Following the second infusion at week 2, PG developed. Infliximab was discontinued. The lesions improved with oral cyclosporin A [2]. In the third case, the patient was affected by RA and besides infliximab he was also receiving methotrexate and methylprednisolone. Infliximab and methotrexate were stopped and the lesions regressed with methylprednisolone and cyclosporin A. The patient resumed biologic treatment with etanercept and developed a recurrence when the steroids were tapered [3]. In our case infliximab therapy had been initiated 4 years before. However, the absence of other confounding drugs,
A
B
C
Late paradoxical development of pyoderma gangrenosum in a psoriasis patient treated with infliximab In July 2013 a 43-year-old Caucasian man presented to our outpatient Dermatology clinic with multiple exten-
272
Figure 1. A) Histologic aspect. Note the intense inflammation with extensive neutrophilic infiltration and exocytosis. B, C) Ulcerative lesions affecting the posterior aspects of the legs (B: left, C: right), 5 weeks after the last infliximab administration. EJD, vol. 25, n◦ 3, May-June 2015
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B
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Copyright © 2017 John Libbey Eurotext. Téléchargé par NYU LANGONE MED CTR SCH OF MED HEALTH SCIENCES LIBRARY le 15/03/2017.
doi:10.1684/ejd.2015.2528
Complete regression of melanoma skin metastases after electrochemotherapy plus ipilimumab treatment: an unusual clinical presentation Skin metastases represent a relatively frequent event in the natural history of melanoma, developing both in early and in late disease stages. Cutaneous or subcutaneous lesions arise in 15-20% of patients; almost 50% of subjects with metastatic disease have soft tissue metastases [1]. The treatment of these lesions is still a challenge: surgical excision and radiotherapy represent the standard treatments for isolated lesions, while melphalan and/or tumour necrosis factor limb perfusion is considered the standard of care for multiple lesions involving the entire extremity [2]. Electrochemotherapy (ECT) represents an effective therapeutic option, both for first-line treatment and in palliative settings, especially in painful and bleeding lesions [3, 4]. ECT, by means of brief and intense electric pulses, increases the cell membrane permeability to anticancer drugs (such as bleomycin and cisplatin) that normally scarcely penetrate into the cells. More recently, the novel systemic drugs approved in the treatment of advanced melanoma (e.g. the anti-CTLA-4, PD-1 /PD-1L blockers and the MAP kinase inhibitors) also showed a clinical benefit in the treatment of patients affected by cutaneous metastases [5]. Herein we describe a case of an advanced melanoma in which a sequential treatment with ECT plus ipilimumab induced a complete clinical response of multiple cutaneous metastases, with unusual vitiligo-like lesions as the final outcome. A 71-year-old Caucasian male had a prior excision of a pT2b malignant melanoma located on his left leg in December 2010; sentinel lymph-node biopsy resulted negative. After two years, he developed multiple bluish papulonodular metastatic lesions ranging from 0.5 to 1.5 cm, on the same limb (figure 1A). The clinical scenario was suggestive for in-transit melanoma metastases. FDG PET/CT scan confirmed the high metabolic activity and excluded visceral involvement. During an eight-month period, three ECT treatments were performed with 15mg/m2 intravenous bleomycin, using the Cliniporator TM device (IGEA Ltd, Carpi, Italy). Neither post-treatment complications nor peripheral nerves injuries, nor post-procedural pain were observed. Globally, 28 lesions were treated, with a partial response (figure 1B). The scheduled total body CT-scan, EJD, vol. 25, n◦ 3, May-June 2015
Figure 1. A) multiple bluish papulo-nodular metastatic lesions ranging from 0.5 to 1.5 cm in diameter on the left leg. B) cutaneous lesions after three ECT. C) Multiple vitiligo-like hypopigmented lesions on the sites of previous cutaneous metastases, persistent one year after the end of the ipilimumab treatment. D) post-inflammatory dermal melanosis at the histopathological analysis.
performed three months after the last ECT session, revealed multiple liver and adrenal glands metastases. Thus ipilimumab treatment at the standard dose of 3 mg/kg was administered; no immune-related adverse events were reported. One month after the end of the anti CTLA-4 treatment we observed a progressive reduction in diameter, thickness and pigmentation of the cutaneous lesions; vitiligo areas became visible around the ECT treated lesions. A complete (visceral and cutaneous) response was confirmed by a PET/CT scan. Two skin biopsies in the site of prior metastatic lesions revealed only a post-inflammatory dermal melanosis (figure 1C). One year later the patient still has a durable complete response with multiple vitiligo-like hypo-pigmented lesions (figure 1D). Melanoma is an immunogenic cancer characterized by the presence of tumor-infiltrating lymphocytes that justify the clinical responses to immunotherapy. Tumor-associated antigens (TAAs), recognized by autologous antibodies and T-cells and capable of inducing tumor-directed immune responses, were identified in melanoma earlier than in other tumors. Studies of the nature of these interactions led to the development of many immunotherapeutic strategies; one immunotherapeutic anti-CTLA-4 agent, ipilimumab, was recently approved for the treatment of metastatic melanoma [5]. Roux et al. demonstrated that, after ECT antigen-presenting cells are recruited in the treated area, the expression of toll-like receptor 9 is up-regulated [6]. A recent study by Gerlini et al. [7] provides the rationale for combining ECT with dendritic cell (DC) activation protocols in a clinical setting. Their results confirm that ECT produces an inflammatory infiltrate with a high number of DCs and that cell-death induced by ECT releases TAAs [8]. DC recruitment and TAA availability are two essential factors in systemic antitumor immunity. More recent findings suggest that the combination of ECT with immunotherapy may produce an effective immune response for systemic tumor control [9]. In our case, the onset of vitiligo-like lesions, developed exclusively around the site of previous ECT, might suggest the presence of an enhanced localized immune-activation, as a consequence of increased TAA liberation on ECT
271
Copyright © 2017 John Libbey Eurotext. Téléchargé par NYU LANGONE MED CTR SCH OF MED HEALTH SCIENCES LIBRARY le 15/03/2017.
treated lesions. On the basis of this observation, even if the role of ipilimumab alone cannot be excluded, we postulate a combined role of ECT and ipilimumab and suggest that the complete response observed may be expression of an abscopal effect, similar to that observed in other therapeutic associations involving ipilimumab and radiotherapy [10]. If these observations are confirmed on larger clinical studies, the local response triggered by ECT might be used to enhance a systemic response in advanced melanoma patients treated with ipilimumab. Disclosure. Financial support: none. Conflict of interest: none. Department of Medical Sciences, University of Turin v. Cherasco 23, 10126, Torino, Italy a both
authors contributed equally to this paper.
Matteo BRIZIOa Paolo FAVAa Chiara ASTRUA Giovanni CAVALIERE Paola SAVOIA
1. Savoia P, Fava P, Nardò T, Osella-Abate S, Quaglino P, Bernengo MG. Skin metastases of malignant melanoma: a clinical and prognostic survey. Melanoma Res 2009; 19: 321-6. 2. Hayes AJ, Clark MA, Harries M, Thomas JM. Management of in-transit metastases from cutaneous malignant melanoma. Br J Surg 2004; 91: 673-82. 3. Möller MG, Salwa S, Soden DM, O’Sullivan GC. Electrochemotherapy as an adjunct or alternative to other treatments for unresectable or in-transit melanoma. Expert Rev Anticancer Ther 2009; 9: 1611-30. 4. Quaglino P, Mortera C, Osella-Abate S, et al. Electrochemotherapy with intravenous bleomycin in the local treatment of skin melanoma metastases. Ann Surg Oncol 2008; 15: 2215-22. 5. Palathinkal DM, Sharma TR, Koon HB, Bordeaux JS. Current systemic therapies for melanoma. Dermatol Surg 2014; 40: 948-63. 6. Roux S, Bernat C, Al-Sakere B, et al. Tumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responses. Cancer Immunol Immunother 2008; 57: 1291-300. 7. Gerlini G, Di Gennaro P, Borgognoni L. Enhancing antimelanoma immunity by electrochemotherapy and in vivo dendritic- cell activation. Oncoimmunology 2012; 1: 1655-7. 8. Quaglino P, Osella-Abate S, Marenco F, et al. FoxP3 expression on melanoma cells is related to early visceral spreading in melanoma patients treated by electrochemotherapy. Pigment Cell Melanoma Res 2011; 24: 734-6. 9. Queirolo P, Marincola F, Spagnolo F. Electrochemotherapy for the management of melanoma skin metastasis: a review of the literature and possible combinations with immunotherapy. Arch Dermatol Res 2014; 306: 521-6. 10. Stamell EF, Wolchok JD, Gnjatic S, Lee NY, Brownell I. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys 2013; 85: 293-5. doi:10.1684/ejd.2015.2522
sive ulcerative lesions on the posterior aspects of both legs, which reportedly appeared some weeks before and had since rapidly extended. The lesions, which were very painful, had first developed as multiple erythematoviolaceous plaques which later became deeply ulcerated, showing irregular margins and a seropurulent bed. The patient suffered from severe psoriasis, for which he had been under infliximab intravenous therapy for the last 4 years. The last infliximab administration was performed in June 2013. He also suffered from moderate hypertension, treated with oral olmesartan. Family history was positive for psoriasis but negative for other skin or auto-immune disorders. Culture and PCR examinations for bacteria, fungi and mycobacteria, performed from lesional skin swabs as well as from biopsies, were negative. Histologic examination showed necrosis of the epidermis and massive neutrophilic dermal infiltration (figure 1A).The diagnosis of pyoderma gangrenosum (PG) was made. Infliximab was discontinued and the patient was treated with symptomatic drugs to ease the pain. The lesions started to heal spontaneously, with considerable improvement after 3 weeks (figures 1B,C), and complete resolution after another 4 weeks. In September 2013 the patient was switched to ustekinumab subcutaneous injections. Presently, after 10 months of follow-up, the psoriasis is under control and no recurrence of PG has been observed. To the best of our knowledge this is the first case of PG arising under infliximab therapy in a psoriatic patient. Three similar cases have been reported in individuals receiving infliximab for ulcerative colitis or rheumatoid arthritis. In these cases infliximab therapy had been initiated a few months before. In the first case, affected by ulcerative colitis, PG developed in the peristomal region, probably favored by persistent trauma generated by colostomy, and was treated with oral corticosteroids and topical tacrolimus [1]. In the second case infliximab had first been used to treat ulcerative colitis (with poor results) and then reintroduced after total colectomy. Following the second infusion at week 2, PG developed. Infliximab was discontinued. The lesions improved with oral cyclosporin A [2]. In the third case, the patient was affected by RA and besides infliximab he was also receiving methotrexate and methylprednisolone. Infliximab and methotrexate were stopped and the lesions regressed with methylprednisolone and cyclosporin A. The patient resumed biologic treatment with etanercept and developed a recurrence when the steroids were tapered [3]. In our case infliximab therapy had been initiated 4 years before. However, the absence of other confounding drugs,
A
B
C
Late paradoxical development of pyoderma gangrenosum in a psoriasis patient treated with infliximab In July 2013 a 43-year-old Caucasian man presented to our outpatient Dermatology clinic with multiple exten-
272
Figure 1. A) Histologic aspect. Note the intense inflammation with extensive neutrophilic infiltration and exocytosis. B, C) Ulcerative lesions affecting the posterior aspects of the legs (B: left, C: right), 5 weeks after the last infliximab administration. EJD, vol. 25, n◦ 3, May-June 2015
