Case r e port K E Y WORDS Kaposi's sarcoma, human herpesvirus 8 Kaposi 's sarcoma and herpesvirus 8 D-issemiflllted cUlSsic Kaposi's sarcoma associated with human herpesvirus 8 irif ectwn. Case report M. Poljački, V. Duran, M. Matic, Z. Gajinov, S. Stojanovic and N. Vranješ SuMMARY Authors report a case of disseminated form of classic Kaposi's sarcoma case, in which presence of DNA sequences of human herpesvirus 8 has been confirmed. Viral DNA was identified with nested PCR method in tissue sam ples of skin and tumor of left submandibular region. Detected sequences corresponded to amplicone of 160 base pairs. In accordance with previous literature reports, these results confirm the possible etiopathogenetic role of Human herpesvirus 8 in classic Kaposi's sarcoma development. Introduction Kaposi's sarcoma (KS) is a multicentric malignancy, which apart from skin can affect various interna! or- gans. It became a significant medica! and dermatovene- rological problem after 1981 when it's association with AIDS was observed. Previously quite rare, tumor was then noted in 35% of AIDS patients in USA (1) . Moritz Kaposi described it for the first time in 1872 and named "idiopathic, multiple , pigmented sarcoma" (2). KS is characterized by proliferation of vascular endothelial and lymphoreticular cells; it is rather reactive than neo- plastic. The disease is important due to possible multi- centric involvement of interna! organs that is a cause of death in most cases. On the basis of clinical and epide- miological features, four types ofKS can be recognized: classic, endemic (African), iatrogenic and epidemic (AIDS related). Classic KS with the greatest frequency occurs in Europe and North Arnerica, among the eld- erly male of Mediterranean or Eastern European descent (3). Etiology and pathogenesis of KS is not clear yet. Recent findings ofHurnan herpesvims 8 (HHV-8) DNA sequences in tumor lesions and peripheral blood mono- nuclear cells of patients with all forrns ofKS, today shed a different light on the possible etiopathogenetic mecha- nisrn ofthe disease (4,5) . Case report 65 years old male patient was refereed to the Clinic for Dermatovenereology of the Clinical Centre of Novi Acta Dermatoven APA Vol 10, 2001, No 3 - ----- ---- --------- --- ------------ 93 Kaposi's sarcoma and herpesvirus 8 Sad, because of progression of livid-red nodule on the skin of upper and lower limbs, face , neck, trunk, palms and soles. During the 10 years of clisease the patient never consu ltecl a physician. The skin lesions appeared on the right upper arm. Examination revealed numer- ous nodes, 1 to 10 cm in diameter, distributecl mostly on upper and lower limbs, palms and soles (Figures 1, 2). Solitary lesions were present on the face, neck and trunk (Figure 3) . On the hard palate mucosa , livid macules were observed, and in the left submandibular region a tumor large asa male fist (Figure 4). All lesions were indolent; except for plantar which were verrucous and accompaniecl by edema. In his youth he had pul- monary tuberculosis, and in the past 12 years only car- diac medications were taken. Laboratory examinations were within normal limits for ESR, total blood count, urine analysis, renal and he- patic functions ; serology for HIV, Hepatitis B virus , Hepatitis C virus, and Epstein-Barr virus were negative. X-ray examination ofthe lung and gastrointestinal tract, irigographia and ultrasound examination of hepato- biliary system, spleen, kidneys, urine bladder and pros- tate were normal, and exclucled dissemination of dis- ease. Otorinolaryngologic examination was within nor- mal range. Ultrasound examination of the tumor in left submandibular region revealed infiltration , w ith hypo- echogenic zones w ithin it. Cardiologic examination re- Figure 1. Multiple nodes on upper limbs Figure 2. Verrucous and nodular lesions on feet Figure 3. Nodular lesions on head and neck C ase r e port 94 ------------------ --- - -------- -----Acta Dermatoven APA Vol 10, 2001, No 3 Case report Figure 4. Bluish macules on hard palate Figure 5. Numerous vascular spaces in middle dermis surrounded with spindle cells and sparse lymphocytes. Dermal collagen and elastin fibers and also fibers between them are homogenized and hyalinized. Acta Dermatoven APA Vol 10, 2001, No 3 Kaposi's sarcoma and herpesvirus 8 vealed a cardiac decompensation. Pathohistology of the skin lesions (2 samples) and the submandibular tumor confirmed the diagnosis of KS (Figure 5). With nested PCR method in all 3 lesions HHV-8 DNA sequences were detected, corresponding to 160 base pairs amplicone (Figure 6). Due to dissemination of lesions the onco- logic consultant recommended polychemiotherapy, which should have to be institutecl in Clinic for Hema- tology. Discussion Classic KS is a form of disease, which in most cases has a relatively benign course. Usually it is character- ized with slow growing benign tumors localized on clis- tal portions of lower limbs. On rare occasions the dis- ease can have aggressive behavior with disseminated skin lesions and involvement of interna! organs (6). Dissemination of skin lesions usually follows their uni- lateral primary localization (2). Changes of oral mucosa are frequent in KS patients, especially on hard palate or in proximity of molar teeth. Rarely it can be the first manifestation of the disease (1,2). Similar to oral mu- cosa lesions, KS changes can affect pharyngeal, laryn- geal of oesophageal mucosa (7). Classic KS can be seen most frequently in Israel, among Jews, Italians, and Greeks but also in people of Eastern-European and Northern-American ancest1y (8 , 9). Histological features of classic KS are not different from other forms of dis- ease (3, 10). Usually it appears between the fifth and sixth decades of life , in Africans even earlier, in third or fourth decade, more frequently in males (3). Data about male to female ratio are different, severa! reports claims 10: 1 male to female ratio, while others claim a signifi- cantly lower number 3: 1 (2, 3). Development and course of disease , clinical and histhologic features in our pa- tient led to diagnosis of disseminated form of classic KS, without the involvement of interna! organs. Nega- tive HIV serology, normal laboratory findings, and ab- sence of immunosuppressive drugs in patient's history confirmed the diagnosis of classic form of the disease. Coexistence of other malignancies weren't proved in this patient. In the literature reports about possible as- sociations of KS and other tumors , especially lympho- proliferative diseases exist (3, 9, 11). Lymphedema on lower limbs, as a consequence of small lymph vessel obstruction, was observed in our patients too , with pre- dominant localization on feet , with numerous nocles and verrucous lesions. Verrucous aspect of the feet, KS lesions in some cases resembling common warts (1) , have been described previously. 95 Kaposi 's sarcoma and herpesvirus 8 Finding of HHV-8 DNA sequences in KS lesions is in accordance with recent reports about viral presence in classic and other forms of disease. Chang et al. in 1994 for the first tirne , using PCR method, have con- firmed DNA vira! sequences in tissue samples of HIV associated KS (5). Later studies confirmed Chang's re- search, and detected HHV-8 DNA sequences in lesions of classic, endemic and iatrogenic form of KS (12 , 13, 14, 15 , 16). These results assume the possible etiopa- thogenetic role of this virus in clevelopment of ali forms of disease, particularly because viral presence was con- firmed in other lymphoproliferative disorders, such as body cavities lymphomas or Castelmann clisease, which are often, but not obligatory HIV related (16). Conclusion Finding ofHHV-8 DNA sequences in cutaneous and extracutaneous lesions of classic KS is a further confir- mation of the hypothesis suggesting t~e possible etiopathogenetic role of HHV-8 in KS development, independently from the HIV infection. Figure 6. Nested PCR analysis of HHV8 DNA in tissue specimens of classic KS Column 1: DNA marker O 17 4; Column 2 and 3: speci men of tumorous skin lesion; Column 4: positive control (DNA extracted from positive specimen); Column 5: specimen from extracu- taneous lesion; Column 6: HHV8 negative contr_ol (DNA extracted from negative sample); Column 7 and 8: empty laboratory dish. R v J' L' -R 1=' "' ' { -.. 1.., s·, r ..... 1 .r ..1 .L1..11 ~ --~ -"~ l. Farthing CH, Brown S, Staughton RCD. A color Atlas of AIDS and HIV Disease. 2nd edn. Roche, Basel 1988; 59-73. 2. Rappersberger K, Stingl G, Wolff K. Kaposi 's Sarcoma. In: Fitzpatrick TB, Eisen AZ, Wolf K, Freedberg IM, Austen ME editors. Dermatology in general medicine. New York: Me Graw-Hill, 1996: 1195-205. 3. Braverman IM. Skin Signs of Systemic Disease 3rd edn, W.D. Saunders Company, Philadelphia London, Toronto, Montreal, Sydney, Tokyo, 1998. 121-31. 4. Moore P, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and those without HIV infection. N EnglJ Meds 1995; 332: 1181-5. 5. Chang Y, Cesarman E, Pessin MS. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994: 266: 1865-9. 6. Sarobe JM, Pibernat RM, Cabrerizo LMP, de Diego UA, Foraster FC. Classical Kaposi sarcoma of aggres- sive course. Rev Clin Wsp. 1998; 198 (2): 95-8. 7. Schiff NF, Annino DJ, Woo P, Shapshay SM. Kaposi's sarcoma of the larynx. Ann Oto! Rhinol Laryngol 1997; 106: 563-7. 8. Digiovana JJ, Safai B. Kaposi's sarcoma : a retrospective study of 90 cases with particular emphasis on the familial occurrence, ethnic background and prevalence of other diseases. AmJ Med 1981; 71: 779- 82 . 9. Weissmann A, LinnS, Weltfrined S, Friedman- Birnbaum R. Epidemiological study of classic Kaposi's sarcoma: a retrospective review of 125 cases from Northern Israel. J Eu Acad Dermatol Venereol 2000; 14: 91-5. Case report 96 --- -------------------------------Acta Dermatoven APA Vol 10, 2001, No 3 Kaposi 's sarcoma and herpesvirus 8 AUTHORS' ADDRESSES 10. Wahman A, Melnick SL, Rhame FS. The epidemiology of classic, African and immunosuppressed Kaposi's sarcoma. Epidemiol Rev 1991; 13: 178-99. 11. Pitte WW. The incidence of second malignancies in subsets of Kaposi's sarcoma. J Am acad Dermatol 1987; 16: 855-61. 12. Boshoff C, Whitby D, Hatziionnnou T, Fisher C, van der WaltJ, Hatzakis A, Weiss R. et al. Kaposi's- sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma. Lancet 345; 1043-44. 13. Dupin N, Grandadam M, Calvez V, Gorin I, Aubin JT, Havard Set al. Herpesvirus-like DNA sequences in patients with Mediterranean Kaposi 's sarcoma. Lancet 345; 761-2. 14. Rady P, Yen A, Martin RW, Nedelcu I, Hughes TK and Tyring SK. Herpesvirus-lik DNA sequences in classic Kaposi's sarcoma. J Med Virol 1995; 47: 179-83. 15. Papaziasis KT, Bo ura P, Fouks P, Dimitriadis KA. Corticosteroid-induced Kaposi's sarcoma in a patient with systemic lupus erythematosus. Arch On colo 2000; 8 ( 4): 181-2. 16. AmbroziakJA, Blackbourn DJ, Herndier BG, Glogan RG. Gullet]H, Me Donald AR et al. Herpes-like sequences in HIV-infected and uninfected Kaposi's sarcoma. Science. 1995; 268: 58-3. 17. Cesarman E, Chang Y, Moore P, SaidJW, Knowles DM. Kaposi sarcoma- associated herpes-like DNA sequences in AIDS-related body-cavity- based lymphomas. New EngJ Medc. 1995; 332: (18).1186-91. Mirjana Poljacki, MD, PhD, projessor oj dermatology, Chairman oj the Dept. oj Dermatology, Glinica! Centre Novi Sad, Hajduk Veljkova 1-3, 21000 Novi Sad, Yugoslavia, e-mail: cojans@eunet.yu Verica Duran, MD, PhD, projessor oj dermatology, same address Milan Matic, MD, MSc, same address Zorica Gajinov, MD, MSc, same address Slobodan Stojanovi6, MD, PhD, projessor oj dermatology, same address Nenad Vranješ, MD, same address Case report 98 - ----------- --------- ------ - ----Acta Dermatoven APA Vol 10, 2001, No 3