Kaposi's Sarcoma Resolves After Sirolimus Therapy in a Patient With

OBSERVATION Kaposi’s Sarcoma Resolves After Sirolimus Therapy in a Patient With Pemphigus Vulgaris

Sarika Saggar, MD; Joshua A. Zeichner, MD; Tamu T. Brown, MD; Robert G. Phelps, MD; Steven R. Cohen, MD, MPH

Background: Iatrogenic Kaposi’s sarcoma (KS) has been well-controlled PV. Three months after the substitution reported in patients who use immunosuppressive regi- of methotrexate with sirolimus, the KS gradually re- mens for the treatment of autoimmune disorders, ma- solved. With the patient on a maintenance regimen of lignant neoplasms, and organ transplant rejection. How- sirolimus, in conjunction with low-dose prednisone and ever, iatrogenic KS in the setting of pemphigus vulgaris dapsone therapy, KS and PV have remained in remis- (PV) has been infrequently observed. The conventional sion, without further recurrence, during a 24-month fol- treatment strategy for iatrogenic KS has focused on re- low-up period. ducing immunosuppression, which carries a poor prognosis owing to a substantial risk for exacerbation of the Conclusion: The present case introduces a novel therapy primary disease. for this patient population, highlighting the efficacy of sirolimus in treating iatrogenic KS without sacrificing the Observations: A 49-year-old man developed KS on his immunosuppression necessary to maintain control of PV. wrist after 2 years of long-term immunosuppressive therapy with prednisone, methotrexate, and dapsone for Arch Dermatol. 2008;144(5):654-657

ATROGENIC KAPOSI’S SARCOMA therapy for PV. The substitution of siro- (KS) has been reported in pa- limus for methotrexate resulted in com- tients undergoing immunosup- plete clearance of the KS tumor. This case pressive therapies for autoim- demonstrates the efficacy of sirolimus as mune disorders, cancer, and a novel therapy for iatrogenic KS in a pa- Iorgan transplant rejection.1,2 It has been tient with PV. infrequently described in patients with pemphigus vulgaris (PV) as a complica- REPORT OF A CASE tion of long-term immunosuppression.3 The conventional treatment strategy for iat- The patient presented with oral erosions at rogenic KS has focused on reducing im- the age of 47 years. He was otherwise munosuppression, which carries a poor healthy, with a medical history of well- prognosis owing to the substantial risk for controlled psoriasis with topical therapy. His exacerbation of the primary disease.4 In the family history and a review of systems were last decade, a growing literature de- noncontributory. The findings of routine scribes the treatment of posttransplanta- histologic examination of a tongue biopsy tion KS with sirolimus-based regimens, specimen as well as the results of direct (in- while discontinuing the use of other im- tercellular pattern with IgG) and indirect (ti- munosuppressive agents.5,6 Unlike other ter, 1:80) immunofluorescence confirmed immunosuppressives, sirolimus, which is the diagnosis of PV. a relatively new drug, has shown antineo- Therapy was initiated with oral pred- plastic activity via antiangiogenic ef- nisone (60 mg/d), which led to clinical im- fects.5 We were unable to find any re- provement. After several weeks, intramus- Author Affiliations: Division of ports documenting the use of sirolimus for cular injections of gold sodium thiomalate Dermatology, Department of the treatment of iatrogenic KS in the set- (50 mg/wk) were added to the treatment Medicine, Albert Einstein ting of PV. regimen. During the next 3 months, as blis- College of Medicine, Bronx, tering activity ceased, the dosage of pred- New York (Drs Saggar, Brown, and Cohen); and Department of See also page 692 nisone therapy was gradually tapered to Dermatology, Mount Sinai 7.5 mg/d, and the frequency of gold in- Medical Center, New York, We describe a 49-year-old man who de- jections was decreased to monthly inter- New York (Drs Zeichner and veloped localized KS on his left forearm vals. After more than 1 year of a stable Phelps). during long-term immunosuppressive treatment regimen, new cutaneous blis-

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Figure 2. Poorly formed and jagged vessels dissect through collagen bundles and surround preexisting capillaries (hematoxylin-eosin, original magnification ϫ40).

rounded by hemorrhagic papules was observed on the distal portion of the left forearm (Figure 1A). As- sumed to be a new, possibly vegetative lesion of PV, it was treated for 2 months with an increased dose of prednisone (15 mg/d) and intralesional triamcinalone (10 mg/ mL). The unusual morphological appearance of the new lesion and the recalcitrant genital blistering led to the ini- C tiation of rituximab therapy (1000 mg), which was ad- ministered intravenously on days 1 and 15. When the patch on the patient’s wrist unexpectedly continued to thicken into a firm hemorrhagic annular plaque after the rituximab infusions, a trephine biopsy specimen was ob- tained for routine histologic analysis and direct immunofluorescence. Microscopic examination revealed a proliferation of small vessels around preexisting capillaries throughout the dermis. The vessels had a jagged and irregular out- line with a slitlike appearance that dissected diffusely through the collagen bundles. The endothelial cells lin- ing the vessels were thin and attenuated, without sig- Figure 1. A, Kaposi’s sarcoma (KS) plaque on the distal portion of the left nificant atypia. Both the vessels and the preexisting cap- wrist before sirolimus therapy; B, flattened KS plaque 1 month after initiation of sirolimus therapy; and C, site of KS plaque 3 to 4 months after initiation of illaries were frequently associated with a scattered sirolimus therapy. lymphoplasmacytic infiltrate. The findings were consid- ered diagnostic of patch-stage KS (Figure 2). No im- munopathologic features were detected on direct immu- ters developed on the patient’s extremities and genita- nofluorescence, with negative staining for IgG, IgM, IgA, lia. The dosage of prednisone therapy was transiently in- complement, and fibrinogen. Serologic tests were nega- creased to 20 mg/d, and oral methotrexate (7.5 mg/wk tive for human immunodeficiency virus. in 3 divided doses of 2.5 mg every 12 hours) was added Once the diagnosis of KS was established, cryosur- to the regimen. The dosage of methotrexate therapy was gery was initiated with liquid nitrogen spray for a dura- gradually increased to a weekly regimen of 12.5 mg in 3 tion of 60 seconds. Methotrexate therapy was discontin- divided doses (5 mg, 5 mg, and 2.5 mg) every 12 hours. ued in an effort to reduce immunosuppression. Treatment An excellent clinical response was achieved for 6 months. with prednisone (15 mg/d), dapsone (50 mg/d), and in- The recurrence of new blisters prompted the addition of tramuscular gold sodium thiomalate (50 mg/mo) was con- dapsone (50 mg/d) to the regimen. The patient contin- tinued. After 1 month of observation, palpation of the ued to experience low-grade blistering of the genitalia with KS lesion revealed increasing induration, and new pem- a regimen of prednisone (7.5 mg/d), methotrexate (12.5 phigus blisters were evident on the genitalia. In the ab- mg/wk in 3 divided doses every 12 hours), dapsone (50 sence of a response to both cryosurgery and rituximab mg/d), and intramuscular injections of gold sodium thio- therapy, a decision was made to initiate a trial of oral siro- malate (50 mg/wk). limus (Rapamune) (2 mg/d). Mild blistering of the genitalia persisted for more than During the first month of sirolimus therapy, dramatic 12 months, when a new, isolated erythematous patch sur- involution of the KS plaque was observed (Figure 1B). The

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 lesion decreased in size and thickness until it was virtu- tients with PV than in transplant recipients, which may ally imperceptible by month 3 (Figure 1C). The cutane- account for the lower frequency of KS in this group.8 Also, ous blistering also diminished shortly after the sirolimus in PV, the lower doses of immunosuppressive drugs at therapy was initiated. Maintenance therapy with oral siro- the onset of KS is a likely explanation for the milder clini- limus (2 mg/d) was not associated with recurrent or new cal course; however, higher doses often lead to a more KS lesions during the next 2 years. As the underlying PV fulminant picture.1,15 remained in complete remission, gold therapy was dis- Recent case studies have revealed that sirolimus is an continued approximately 1 year after the sirolimus therapy effective therapy for iatrogenic KS among transplant re- was initiated. No adverse events have been noted on a regi- cipients, while maintaining adequate immunosuppres- men of prednisone (5 mg/d), dapsone (50 mg/d), and siro- sion.5,6,16 Sirolimus is a macrolide antibiotic, with im- limus (2 mg/d). munosuppressive, antiproliferative, and antiangiogenic properties, indicated for the prevention of organ rejection, specifically renal transplantation.5,17 It has been COMMENT found to have antitumor effects by inhibiting mTOR (mammalian target of rapamycin), a protein that is in- Moriz Kaposi7 first described KS in 1872 under the name tegral to cell cycle progression, restoring the pro- idiopathic multiple pigmented sarcoma. Four clinical vari- grammed cell death mechanism and slowing the growth ants of KS are now recognized: classic, endemic, AIDS- of established vascularized tumors.11,12 Also, it blocks associated, and iatrogenic.8 The cutaneous morphologi- lymphocytic proliferation by inhibiting the response to cal appearance ranges from bluish red macules or papules interleukin 2.18 In contrast, calcineurin inhibitors, such to patches or plaques; lesions can become nodular or in- as tacrolimus and cyclosporine, function as immuno- filtrative and disseminate to visceral organs. suppressives predominantly by inhibiting the produc- The relationship between immunosuppression and KS tion of interleukin 2. was first reported in the organ transplant population in The antitumor effects of sirolimus have been demon- the 1960s.9 The advent of new immunosuppressive agents, strated in both in vitro and in vivo studies, using animal and their long-term use at high doses, has increased the models. One study showed that while cyclosporine pro- risk for the development of transplant-associated KS (128- moted tumor growth, normal immunosuppressive to 500-fold as compared with the general population).5,10,11 doses of sirolimus controlled the growth of established Also, iatrogenic KS has been observed in patients receiv- tumors and inhibited metastatic growth and angiogen- ing immunosuppressive drugs for lymphomas, multiple esis in mouse models.19 As the production of vascular myeloma, and autoimmune diseases.3 As all variants of endothelial growth factor (VEGF) and activation of KS have been linked to infection with human herpesvi- VEGF receptors have been implicated in the develop- rus 8, the pathogenesis of iatrogenic KS has been related ment of KS, it is noteworthy that the mechanism of siro- to the permissive effect of immunosuppressive therapy limus causes a decrease in the production of VEGF and on human herpesvirus 8 infection or reactivation.12 inhibits the extent of stimulation of endothelial cells in The prognosis associated with iatrogenic KS corre- response to VEGF.5,19 lates with the extent of disease. One-year survival rates Case series have extended this research to human vary substantially among patients with cutaneous (90%) subjects via reports of the clinical efficacy of sirolimus or visceral (70%) involvement.11 The standard therapy therapy in human transplant recipients.5,6,16 Two re- for iatrogenic KS—withdrawal of immunosuppressive mo- ports found that transplant recipients with biopsy- dalities—often produces a partial to complete regres- proved KS experienced regression of the tumors several sion through immune reconstitution and natural hu- months after calcineurin inhibitor therapy was replaced man herpesvirus 8 suppression.4 However, even after with a sirolimus-based regimen.5,6 Both studies demon- reduced immunosuppression, there is still substantial mor- strated that effective levels of immunosuppression were tality from KS, as well as the risk for exacerbation of the maintained to prevent organ rejection. Moreover, over a primary disease. 5-year follow-up period, sirolimus therapy was shown Pemphigus vulgaris is a chronic autoimmune disor- to prevent the onset of iatrogenic KS in kidney trans- der of the skin and mucous membranes. Systemic corti- plant recipients when compared with patients receiving costeroids with adjuvant immunosuppressive or anti- cyclosporine.16 Minor adverse cutaneous events associ- inflammatory agents are the mainstay of treatment. ated with sirolimus therapy include acnelike eruptions, Untreated PV is often fatal because of susceptibility to edema, and nail disorders.20 infections as well as fluid and electrolyte disturbances.13 A thorough review of the current literature revealed However, long-term immunosuppression may lead to no previous description of sirolimus therapy for iatro- complications such as infection and secondary neo- genic KS in the setting of PV. Our patient developed plasms as a result of impaired immune surveillance.14 We localized, cutaneous KS after 2 years of immunosup- describe a case of iatrogenic KS that developed in the set- pressive therapy for PV. His tumor did not improve ting of immunosuppressive therapy for PV. after the dosage of immunosuppressive therapy was To date, 10 cases of KS have been reported in asso- reduced. Complete cessation of immunosuppression ciation with immunosuppressive therapy for PV; 5 of these was not an option based on the clinical activity of his cases were fatal within 1 year of KS diagnosis, despite the PV. Therefore, sirolimus was chosen as an adjunct reduction of immunosuppressive regimens.3 Typically, medication based on published data regarding its effi- immunosuppressive medication doses are lower in pa- cacy in treating iatrogenic KS. After sirolimus was

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 added to the patient’s regimen, his KS lesion resolved REFERENCES completely, without exacerbation of the PV. It seems important to emphasize that intractable blistering dur- 1. Trattner A, Hodak E, David M, Sandbank M. The appearance of Kaposi sarcoma ing concomitant prednisone, dapsone, methotrexate, during corticosteroid therapy. Cancer. 1993;72(5):1779-1783. and intramuscular gold therapy resolved promptly after 2. Cathomas G, Tamm M, McGandy C, et al. Transplantation-associated malignancies. Transplantation. 1997;64(1):175-178. sirolimus was introduced to the regimen. No further 3. Avalos-Peralta P, Herrera A, Rıós-Martıń JJ, Pe´rez-Bernal AM, Moreno-Ramı´rez blistering has occurred during an observation period of D, Camacho F. 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