ELSEVIERJournal of the European Academy of Dermatology and Venereology

8(1997) 245-250

Case report

The development of Kaposi's sarcoma during immunosuppressivetherapy for temporal arteritis

Lester F. Libow-'*, Susati L. Fraser\ Thomas J. CaseyS Richard James''

•'Department of Dermaiology. 67th Combat Support Hospiial. Josef-Se'ilz strasse 20. 97rJ76 Wiirztiurg. GermanyDeparlmeni of Internal Medicine. 67ih Combat Support Hospital. Wurzburg. Germany

''Department of Pathology. 67th Combai Support Hospital. Wurzburg. GermanyGullying Health Clinics, 67th Combat Support Hosp'ital. Wurzburg. Germany

Abstract

Background The appearance of Kaposi's sarcoma during iairogenic imrriLnosuppression for renal transplantation is wellknown. A growing number of patients undergoing immunosuppressive therapy for conditions other than organ transplantationhave also developed this neoplasm, and temporal arteritis is emerging as one of the more common of those conditions. Ca.se:We report a ca.se of Kaposi's sarcoma complicating cortico.stcroid therapy for temporal arteritis. summarize the previouslyreported cases and consider the possible association between these two disorders. Comiiisiotr. Although inconclusive from theavailable data, patients with temporal arteritis may be predisposed to iatrogenic Kaposi's sarcoma due to a shared antigenspecilic immune response. © 1997 Elsevier Science B.V.

Keywords: Kaposi's sarcoma; Temporal arteritis; Immunosupprcssion

1. Introduction

Kaposi's sarcoma (KS) has frequently beetireported to develop during combination immunosup-pressive therapy for renal transplant recipients [1.2].Less commonly. KS has developed in non-AIDS. non-transpiant recipient patients undergoing immunosup-pressive therapy for a variety of underlying condi-tions. Six of the 59 patients reported have hadtemporal arteritis as the underlying disorder [3,11-15|. We describe another patient whose immunosup-pressive therapy for temporal arteritis was compli-

* Corresponding ainhor. Tel.: +49 931 8043924;e-mail: i 00710.1317©>CompuServe.eom

cated by the development of KS and review thepreviously reported cases.

2. Case report

A 78 year old French Canadian male presented witha 3 week history of bilateral vision loss, headaches,right scalp tenderness, anorexia, weight loss andmyalgias. His past medical history was significantfor ocular hypertension treated with 0.5% titnololmaleate. and cervical degenerative joint disease. Hismother had developed blindness in her forties fromunknown causes. The physical examination wasremarkable for a weight of 49 kg. fixed and dilatedpupils, total blindness bilaterally with papillitis on

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246 LF. Ubow el al. /J. Eur. Acad. Dermatol. Venereol. 8 (1997) 245-250

Pig. I. Violaeeous nodules of Kaposi's sarcoma in a palieni with

temporal arteritis involving [he trunk (A), and upperexiremity (B).

funduscopic exam, a 'rock-hard* right temporal arteryand generalized muscle weakness. The remainder ofthe physical exam was unremarkable, with no mentionof skin lesions. Laboratory studies showed an erythro-cyte sedimentation rate (ESR) of 130 mm/h, hemoglo-bin of 11.1 g/d! and an alkaline phosphatase of 225 U/I. The patient was admitted and an unsuccessfulattempt made to biopsy the right temporal artery.Intravenous methylprednisolone (1 g every 12 h)was administered with improved myalgias but noreturn of vision.

The patient was discharged with diagnoses of tem-poral arteritis and polymyalgia rheumatica on oralprednisone (100 mg/day). Three months later he wasreferred to the Internal Medicine Clinic of this institu-tion for follow-up and steroid tapering. At that time hewas taking 20 mg of prednisone daily and had noted again in weight. His physical exam was notable for aweight of 59 kg. total blindness and a well-healedright temporal scar. No obvious cutaneous lesion.swere noted. The ESR was 42 mm/h and the hemoglo-

bin 14 g/dl. Prednisone dose was tapered to 20 and 10mg on alternate days. At follow-up 24 days later acutaneous exam revealed multiple 0.5-1.0 cm firm,non-tender, puiple to violaceous papules and nodulesinvolving the left upper back and proximal extremities(Fig. 1). The mucous membranes were uninvolved.The patient denied having similar lesions prior todeveloping temporal arteritis. His steroids weretapered further and he was referred to the dermatologyclinic.

A biopsy of a lesion from the left arm was per-formed. The histology showed a dermal lesion con-sisting predominantly of small slit-like vascularspaces, and occasional larger ectatic vessels separatedby stroma containing benign appearing spindle toovoid shaped cells (Fig. 2). The nuclei containedfinely granular evenly dispersed chromatin and anoccasional small nucieolus. Rare mitoses were pre-sent. Hemosiderin deposits and small numbers of lym-phocytes atid plasma cells were scattered throughoutthe lesion. Due to the presence of occasional epithe-lioid cells with apparent intracytoplasmic lumina andthe ectatic vessels, a diagnosis of spindle ceil heman-gioendothelioma was considered. However, themajority of histologic features, as well as the clinicalpresentation, were consistent with KS. Additionallaboratory studies included negative HIV and antinuc-lear antibody titers. normal protein electrophoresis,negative cytomegalovirus IgM titer and positive cyto-megalovirus IgG titer. Steroids were stopped 3months later. Over the subsequent 6 months the skin

Fig. 2. Small sHt-like vaseular spaces and predominantly spindleeell stroma are apparent. Exiravasated erythrocytcs are visible(hematoxylin and eosin 200 x ).

LF. Libow et al. / J. Eur. Acad. Dermaiol- Venereol- 8 (1997) 245-250 247

lesions completely resolved, his weight increased to66 kg and the ESR remained stable at 42 mm/h.

3. Discussion

The four clinical varieties of KS recognized areclassical KS seen in elderly men of Mediterraneanor Eastern European Jewish ancestry, endemic KSaffecting children and young adult males in sub-Saharan Africa, epidemic KS in patients with theacquired immunodeficiency syndrome and iatrogenicKS complicating immunosuppressive therapy [16].Patients on immunosuppressive therapy followingorgan transplantation comprise the majority of iatro-genic KS cases. While renal transplant recipients oncombination immunotherapy are generally felt to bemost at risk (an estitnated 0.4%), data from Europesuggests liver transplant recipients may have an equalor greater risk of developing this complication, espe-cially if they are chronic Hepatitis-B surface antigencarriers [171.

KS is being increasingly reported in patients under-going immunosuppressive therapy for a variety ofconditions other than organ transplantation, A recent

Table I

Diseases reported in assoeiation with iatrogenic Kaposi's sarcoma"

Lymphoma 129|Leukemia [3]Myeloma |3]Syslemie lupus erythematostis [3]Dermatomyositis | 3 |Polymyo.sitis | 3 |ldiopaihic ihrombocytopenic purpura [3]Wcgener's granulotnatosis [3]Uleerative colitis [61Pemphigus vulgaris [3]Aplastic anemia |29|Hemolytie anemia [31Asthma |3.8]Nephrotic syndrome |28|Polymyalgia rheumatica |28]Rhetimatoid iirlhritis |9,10]Temporal arteritis [3,11-15]Bullous pemphigoid (3.28)Tubercular pericarditis [7]Sjogren syndrome [31Sezary syndrome [3[Chronic obstructive lung disease [3]

'Modified from Ref. [161.

summary of such cases, along with several either notincluded or subsequently reported, bring the total to59 cases to date |3-15]. The underlying conditionsrequiring immunosuppression are varied includingboth autoimmune and non-autoimmune disorders, aswell as malignancies (Table I). Two conditionsappear to be emerging as disproportionally repre-sented: temporal arteritis and rheumatoid arthritismake up six and nine cases, respectively, and are cur-rently the two conditions most frequently associatedwith iatrogenic KS in non-transplant recipients.

The six previously reported patients who haveeither developed or experienced dissemination ofKS while undergoing immunosuppressive therapyfor temporal arteritis, along with the current case,are summarized in Table 2. There are four femalesand two males (sex not stated in one case), of varyingethnic backgrounds. Their median age is 70 (range45-79 years), and two of the seven were known tohave pre-existing KS lesions. None had associatedconditions with the exception of one patient (currentcase) who had coexistent polymyalgia rheumatica. Allwere taking corticosteroids and one had also receivedazathioprine for treatment of the temporal arteritis.The mean time from the initiation of immunosuppres-sive therapy to the appearance (or dissemination) ofKS was 11 months. Antibodies to cytomegaloviruswere found in two cases, a negative assay for HIVwas reported in three of the seven and indicators ofboth humoral and T-cell immunodeficiency (cuta-neous anergy, reduced T4/T8 ratio and transientimmunoglobulin deficiency) reported in one. Whilefive out of seven had generalized involvement, thelower extremities were involved in all cases andwere the site of the pre existing KS lesions in twopatients. Five of the seven patients experienced eitherpartial or complete regression of their KS lesions ontapering or withdrawal of immunosuppressive ther-apy, and one was treated with vincristine and radio-therapy.

We considered current views regarding the patho-genesis of temporal arteritis and KS in an attempt todetermine if patients with temporal arteritis are pre-disposed fo this complication of immunosuppression.While the etiology of temporal arteritis is unknown,evidence supports an autoimmune pathogenesis, spe-cifically a T-cell response to an altered tissue antigen.Degenerated or calcified internal elastic lamina.

248 LF. Ubow ei al- /J. Eur. Acad. Dermatol. Venereol- 8 (1997) 245-250

Table 2

Iatrogenic Kaposi's sarcoma and temporal arteritis

Age

79

70

70

74

69

45

78

Sex

Female

Female

NR

Female

Male

Female

Male

Ethnic origin

Ashkenazi Jew

Armenian

Italian

Spanish

Italian

Spanish

f-renchCanadian

TX

Prednisone.azathinprinePrednisone

Corticosteroid

Prednisone

Prednisone

Prednisone

Prednisone

LAB

HIV/NR

HIV/NRANA/ncgRF/neg

HIV/neg

HIV/neg

HIV/NRCMV/posIgG/decIgM/decT4/T8/dccANA/negcutaneotisanergyHl.AB8/DR3HIV/NR

HiV/ncgCMV/posANA/neg

Delay'

l.'i months

5 months

12 months

2 months

3 months

3 years

5 months

Sites

Lower extremity

••Lefl ankle, leftwrist, hands, lips.neck. back.righl thighFeet thenupperextremitiesand trunk'rightanklelowerextremitiesRighl anklethen lowerextremitieshands andforearms

Face, chest.back, armshands, legs

Baek.proximalextremities

Course

Partial resolulion withsteroid reductionAll excepi leftankle lesionresolved withsteroid redtictionNRsteroidsconlintied

Completeresoltition withsteroidreductionLesions persistedwith continuedhigh doseprednisone

Stabilized withsteroidreduction, partialregression withvinerisline andradiotherapyCompleteresolution withsteroidwithdrawal

Ref.

[3]

[I3i

[11]

[12]

[15]

[141

Currentcase

•"Time from initiation of immunosuppressive therapy to appearance or dissemination of KS.Preexisting KS lesion: NR, not reported; CMV, cytomegalovirus: neg, negative; pos. positive: dec, decreased.

smootli muscle ce]]s and endothelia] ceUs are consid-ered potentia] antigenic targets [ 18J. Solar damage haslong been considered a precipitating event in thedevelopment of temporal arteritis but recently thisview has been questioned [191. The acute onset oftemporal arteritis, along with the intense developmentof acute phase reactants, has suggested a role for an asyet unidentified infectious agent. Temporal arteritis ismost commonly seen in individuals over the age of 50from Northern Europe or areas of the United Stateswith a similar ethnic origin []9]. Women are affectedmore often than men [19J. Genetic markers liave

shown an increased frequency of HLA-DR4, an asso-ciation it shares with polymyalgia rheumatica andrheumatoid arthritis [20.21].

As in temporal arteritis, the pathogenesis of KS isa]so not ]inown. Debate has focused particularly onhistogenesis and the question of whether KS repre-sents a hyperplasia rather than a true malignancy.Vascular, lymphatic and undifferentiated stem ceUshave all been proposed as the cell of origin, eachwith supporting evidence [16,22,23]. Argumentsfavoring the placement of KS as a non-malignanthyperplasia have been well summarized and include

LF. Eibow el al. / J. Eur- Acad. Dermatol. Venereol. 8 (1997) 245-250 249

its association with iatrogenic immunosuppression.the tendency toward partial or complete regressionfollowing withdrawal of immunosuppression and itsmultifocal character [16,24]. The role of infectiousagents in the etiology of KS has also received con-siderable attention with cytomegalovirus and arecently identified human Herpesvirus prominentamong those implicated [16,2,^.26]. Genetic factorsclearly appear to play a role in at least the c]assical,African and iatrogenic forms of the disease. ClassicalKS is associated with an increased frequency of HLA-DR5 [ 16|. Clustering of KS among the Black popula-tion in Eastern Africa, and the discrepancy betweenthe incidence in that group compared to Caucasians inthe same region, supports the role of heredity in theendemic form, although no HLA association has yetbeen found [27]. Groups most at risk for iatrogenic KS(both transplant and non transplant) overlap withpopulations predisposed to classical KS. Of non-trans-plant cases summarized by Trattner et al., 16 out of 22(for whom data were available) belonged to ethnicgroups susceptible to classical KS and six of their10 cases were Ashkenazi Jews [3]. Like classicalKS, males make up the majority of iatrogenic cases(male/fema]e ratio, 2:1).

Of the seven patients with temporal arteritis whodeveloped iatrogenic KS, three belonged to ethnicgroups known to be at risk for classical KS (Italian,Ashkenazi Jew), and two of the remaining four hadpre-existing KS lesions. Whi]e six of the seven werein age groups at risk for both disorders, the fema]epredominance (four of six for whom sex is known)favors a predisposition for tempora] arteritis. Thecoexistence of polymyalgia rheumatica with temporalarteritis in our case, while not uncommon, is note-worthy in that variants of the HLA-DR4 haplotypeappear to impart a susceptibility not only for thosetwo disorders but for rheumatoid arthritis as well,latrogenic KS has also been reported in associationwith polymyalgia rheumatica alone [28]. Of the casessummarized here, genetic analysis revealed HLA-B8/DR3 in the one patient (see Table 2) for whom thosedata were reported.

Theories concerning the mechanism of KS induc-tion following immunosuppression have centeredmainly on perturbations of the immune system(coupled with altered immune responses due to anunderlying autoimmune disease when present), lead-

ing to a breakdown in immunologic surveillance.Activation of oncogenic viruses or other cofactorsmay then transform dedifferentiated endothelial ceUsinto KS cells with altered growth factor requirementsand the ability to secrete autocrine and/or paracrinegrowth factors [ 16]. The majority of patients placedon immunosuppressive therapy, nonetheless, do notdevelop KS, leading many investigators to invoke agenetic predisposition in the development of this neo-plasm. The patients reported here support the cur-rently held view that iatrogenic KS occurs ingenetically defined groups similar to classic KS.Whether patients with temporal arteritis are particu-larly predisposed cannot be determined from the smallnumber of cases reported to date and the limited infor-mation available. The finding of positive cytomegalo-virus titers in two of the seven patients is interestingand we look forward to the study of similar patientsfor infection with KS associated human Herpesvirus.It is unlikely that these viruses alone render patientswith temporal arteritis particularly susceptible toiatrogenic KS, as there is no reason to presume thatthey as a group are more prone to these infections thanany other. If patients with tempora] arteritis do turnout to be unique]y susceptible to iatrogenic KS, amore plausible exp]anation may reside in sharedHLA dictated antigen-specific immune responses tooncogenic, possibly infectious cofactors.

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