To the Editor: In their review of Kaposi's sarcoma, Drs. Antmanand Chang (April 6 issue)1 thoroughly discuss the therapeuticoptions for advanced and aggressive Kaposi's sarcoma and concludethat "all the drugs studied so far have clinically significantsystemic side effects." Treatment options for cases of lesssevere disease were omitted from the discussion by Antman andChang.
Until recently, the treatment of less severe cutaneous Kaposi'ssarcoma has been limited to the destructive approaches of cryotherapywith liquid nitrogen and intralesional vinblastine. Althougheffective in the treatment of individual cutaneous lesions ofKaposi's sarcoma, these approaches are painful and cause scarring.
An advance in treatment was the development of 1 percent alitretinoingel.2,3,4,5 Alitretinoin (9-cis-retinoic acid) is a retinoidpanagonist, since the compound binds to all six known retinoidreceptors (retinoic acid receptor , ß, and and retinoidX receptor , ß, and ). The long-term use of retinoidsas antiproliferative agents is well established in dermatology.One percent alitretinoin gel is the only topical agent approvedby the Food and Drug Administration for AIDS-related Kaposi'ssarcoma.
As investigators in clinical trials of 1 percent alitretinoingel, we have found that this medication represents an additionto the armamentarium of safe and well-tolerated outpatient treatmentsfor limited cutaneous Kaposi's sarcoma. It represents the onlypatient-approved therapy for Kaposi's sarcoma whose side effectsare limited to reactions at the application sites.
Ken Washenik, M.D., Ph.D. Lesley Clark-Loeser, M.D. Alvin Friedman-Kien,M.D. New York University School of Medicine New York, NY 10016
Editor's note: The Department of Dermatology at New York UniversitySchool of Medicine has received funding to perform clinicaltrials of 1 percent alitretinoin gel, and Drs. Washenik andFriedman-Kien have served as consultants to Ligand Pharmaceuticals(the manufacturer of 1 percent alitretinoin gel), have receivedspeakers' fees from the company, or both.
References
Antman K, Chang Y. Kaposi's sarcoma. N Engl J Med 2000;342:1027-1038. [Free Full Text]
Clark-Loeser L, Friedman-Kien A, Washenik K. Alitretinoin gel for the topical treatment of AIDS-related Kaposi's sarcoma. Today's Ther Trends 1999;17:289-302.
Bodsworth N, International Panretin Gel KS Study Group. Topical 9-cis-retinoic acid (Panretin) gel as treatment of cutaneous AIDS-related Kaposi's sarcoma: interim results of an international, placebo-controlled trial (ALRT 1057-503). Presented at the 12th World AIDS Conference, Geneva, June 28–July 3, 1998.
Krown SE. Clinical overview: issues in Kaposi's sarcoma therapeutics. In: Journal of the National Cancer Institute. Monograph 23. Bethesda, Md.: National Cancer Institute, 1998:59-63.
Walmsley S, Northfelt DW, Melosky B, Conant M, Friedman-Kien AE, Wagner B. Treatment of AIDS-related cutaneous Kaposi's sarcoma with topical alitretinoin (9-cis-retinoic acid) gel. J Acquir Immune Defic Syndr 1999;22:235-246.
To the Editor: In their timely review of Kaposi's sarcoma, Antmanand Chang mention that commercial preparations of human chorionicgonadotropin may provide some therapeutic benefit in this disease.Clinical-grade preparations of human chorionic gonadotropinare derived from the urine of pregnant women and hence containa mixture of biologic contaminants. These preparations are heterogeneousbecause of the various methods of urine conservation, extraction,and purification used.1 We have recently found that in somecommercial preparations available in Belgium (Pregnyl, Organon,Oss, the Netherlands), substances extracted together with thehuman chorionic gonadotropin dimer stimulate the growth of Kaposi'ssarcoma–derived cells.2 We therefore suggest the cautioususe of preparations of human chorionic gonadotropin in clinicalpractice.
Thierry Simonart, M.D. Jean-Paul Van Vooren, M.D. Sylvain Meuris,M.D. Erasme University Hospital B-1070 Brussels, Belgium
References
Nagy AM, Meuris S, Robyn C. Inventory of the molecular heterogeneity of purified human chorionic gonadotropin preparations as revealed by immunoelectrotransfer. Med Sci Res 1989;17:771-3.
Simonart T, Hermans P, Van Vooren JP, Meuris S. Paradoxical pro-Kaposi's sarcoma activity of preparations of human chorionic gonadotropin. Blood 1999;94:376-377. [Free Full Text]
To the Editor: In their article, Antman and Chang underscoredthe role of Kaposi's sarcoma–associated herpesvirus (KSHV),also called human herpesvirus 8 (HHV-8),1 in the developmentof body-cavity lymphomas, Kaposi's sarcoma, and multicentricCastleman's disease. Multicentric Castleman's disease is a systemiclymphoproliferative disorder characterized by angiofollicularlymphoid proliferation causing fever, lymphadenopathy, hepatosplenomegaly,and rash. This uncommon, non-neoplastic disease is associatedwith an increased risk of Kaposi's sarcoma and lymphoid cancers.2In addition, both Kaposi's sarcoma and multicentric Castleman'sdisease are characterized by vascular hyperplasia, dysregulationof the immune system, and increased plasma levels of interleukin-6.2,3We recently cared for a patient who had HHV-8 infection associatedwith multicentric Castleman's disease and Kaposi's sarcoma.
In June 1999, a 54-year-old man began to notice low-grade feverin the evening, lymph-node enlargement, and weakness. A lymph-nodebiopsy showed B follicles with Castleman-like features and proliferationof Kaposi's sarcoma in the same lymph node (Figure 1A); otherhistological features of the lymph node are shown in Figure 1B,1C, and 1D. The patient was negative for human immunodeficiencyvirus but strongly positive for KSHV antibody (titer, 1:10,000),with a high level of KSHV viremia in mononuclear cells. He diedtwo weeks later with hepatic coma.
Panel A shows B follicles with Castleman-like features (arrow) and proliferation of Kaposi's sarcoma (asterisk) (hematoxylin and eosin, x10). Panel B shows Castleman-like features: a B follicle with onionskin modifications, increased vascularization, and a reduction in the number of centrofollicular cells; pronounced plasmacytosis is evident in the follicular area (Giemsa, x25). Panel C shows Kaposi's sarcoma fusiform cells, arranged in fascicles, delineating slit-like vascular spaces containing erythrocytes (hematoxylin and eosin, x25). Panel D shows strong expression of factor VIII by the neoplastic cells of Kaposi's sarcoma (streptavidin–biotin–peroxidase method, x25).
Our findings underscore the association among KSHV, Kaposi'ssarcoma, and multicentric Castleman's disease. The associationof multicentric Castleman's disease with Kaposi's sarcoma andthe finding of some features common to both diseases led usto search for HHV-8 sequences in samples of multicentric Castleman'sdisease. In fact, HHV-8 DNA sequences have been demonstratedin a substantial percentage of cases of multicentric Castleman'sdisease.2 It is not known whether the KSHV-positive plasmablasticor immunoblastic cells in multicentric Castleman's disease area feature of KSHV-negative multicentric Castleman's diseaseor whether the plasmablastic variant of this disease is specificallyassociated with KSHV.2,4 The importance of this case is relatedto the simultaneous presence of these two diseases in the samelymph node and the association with KSHV infection. This uncommonfinding is another piece of evidence of the close link amongKSHV, Kaposi's sarcoma, and multicentric Castleman's disease.
Antonino Mazzone, M.D. Elena Ottini, M.D. Marco Paulli, M.D. Istituto di Ricovero e Cura a Carattere Scientifico S. MatteoHospital 27100 Pavia, Italy
References
Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994;266:1865-1869. [Free Full Text]
Parravicini C, Chandran B, Corbellino M, et al. Differential viral protein expression in Kaposi's sarcoma-associated herpesvirus-infected diseases: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Am J Pathol 2000;156:743-749. [Free Full Text]
Mazzucchelli I, Vezzoli M, Ottini E, Paulli M, Boveri E, Mazzone A. A complex immunodeficiency: idiopathic CD4+ T-lymphocytopenia and hypogammaglobulinemia associated with HHV8 infection, Kaposi's sarcoma and gastric cancer. Haematologica 1999;84:378-380. [Free Full Text]
Belec L, Mohamed AS, Authier FJ, et al. Human herpesvirus 8 infection in patients with POEMS syndrome-associated multicentric Castleman's disease. Blood 1999;93:3643-3653. [Free Full Text]
The authors reply:
To the Editor: Dr. Washenik and colleagues write that "treatmentoptions for cases of less severe disease were omitted from thediscussion" and that "until recently, the treatment of lesssevere cutaneous Kaposi's sarcoma has been limited to the destructiveapproaches of cryotherapy with liquid nitrogen and intralesionalvinblastine." Actually, we extensively discussed treatmentsfor patients with indolent or limited lesions, for which excisionalsurgical biopsy and even observation are totally appropriate.Radiation, particularly electron-beam radiation, was describedin some detail, as were single-agent chemotherapy and oral etoposide.Retinoids (differentiating agents), including 9-cis-retinoicacid, were also described as having activity against Kaposi'ssarcoma. Washenik and colleagues point out that 9-cis-retinoicacid in a gel form can also be effective in managing cutaneousAIDS-related Kaposi's sarcoma.
We certainly agree with Simonart and colleagues that human chorionicgonadotropin should be used with caution. Since we includedthe discussion of human chorionic gonadotropin in the sectionon experimental therapies, we clearly meant that the hormoneshould be used only in a clinical trial and not in clinicalpractice.
Kaposi's sarcoma was first described in 1872 by Moritz Kaposi,and Castleman's disease was described exactly one century laterby Benjamin Castleman and colleagues.1 Since 1972, numerouspatients with concurrent or sequential cases of Kaposi's sarcomaand Castleman's disease have been described, leading to speculationabout a common or shared pathogenesis.
Along with other investigators,2,3,4 Mazzone and colleagueshave clearly documented the simultaneous occurrence of Kaposi'ssarcoma and Castleman's disease in the same lymph node. However,although both Kaposi's sarcoma and a subgroup of cases of Castleman'sdisease are caused by KSHV, the mechanisms underlying the developmentof these two lesions are likely to be very different. The virusin the two disorders demonstrates distinct, tissue-specificpatterns of gene expression.5 One of the critical factors inthe development of Castleman's disease is the abnormal expressionof interleukin-6, whether of cellular or viral origin, whereasviral interleukin-6 is not expressed at all in Kaposi's sarcomaspindle cells.
Karen Antman, M.D. Yuan Chang, M.D. Columbia University Collegeof Physicians and Surgeons New York, NY 10032
References
Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer 1972;29:670-683. [CrossRef][Medline]
Xerri L, Guigou V, Lepidi H, Horschowski N, Lejeune C, Hassoun J. Lymphadenopathic tumor exhibiting intermingled features of Kaposi's sarcoma, malignant lymphoma, and angiofollicular hyperplasia. Arch Pathol Lab Med 1991;115:1162-1166. [Medline]
Gerald W, Kostianovsky M, Rosai J. Development of vascular neoplasia in Castleman's disease: report of seven cases. Am J Surg Pathol 1990;14:603-614. [Medline]
Rywlin AM, Rosen L, Cabello B. Coexistence of Castleman's disease and Kaposi's sarcoma: report of a case and a speculation. Am J Dermatopathol 1983;5:277-281. [Medline]
Parravicini C, Chandran B, Corbellino M, et al. Differential viral protein expression in Kaposi's sarcoma-associated herpesvirus-infected diseases: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Am J Pathol 2000;156:743-749.
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