Report

Kaposi Sarcoma Associated with Human Immunodeficiency Virus Infection Dimas E. Hernandez, M.D., Jose Ricardo Perez, M.D., Jaime Wilder, M.D., and Rafael Muci, M.D.

Abstract: In the present study, 11 patients with epidemic Kaposi sarcoma wete evaluated; 55% wete In stage IV and 45% in stage 11; in addition, 75% had systemic symptoms, 89% had low total and T-lymphocyte counts, and all of them had not only low T-helper lymphocyte counts but also Thelpet/T-supptessor ratios. The majotity of patients (89%) had tow proliferative responses with phytohemaggiutinin (PHA). Nine patients were treated with: alpha-2 interferon (five patients), zidovudine (two patients), doxorubicin and zidovudine (one patient), and radiotherapy (one patient). There were only five patients with stable disease, three treated with alpha-2 interferon, one with doxorubicin, and one with doxorubicin plus azidothymidine. Two patients (one with doxorubicin and one with doxorubicin plus zidovudine) needed lithium to increase leukocyte and platelet counts. In May 1989, 73% of patients were dead (median survival 8 ±2 months). It is concluded that: (1) it is important to select the patients who have the best chance to improve with treatment; (2) the response with atpha2 interferon or monochemotherapy is low and there is no change in overall survival; (3) a low helper cell count, low Thelper/ T-suppressor ratio, and low proliferative response with mitogens are features of poor prognosis; (4) toxicity with treatment was acceptable; and (5) lithium increased neutrophil and platelet counts.

Kaposi sarcoma (KS) wasfirstdescribed as "idiopathic multiple pigmented sarcomas of the skin" by Moritz Kaposi in 1872. It is a rare tumor except in some African countries (Uganda, Zaire) where KS represents 9% of all registered tumors. Classical KS-affected individuals are older than 60 years, with Eastern European or Italian extraction. The lesions are localized in the legs and are treated principally with local radiotherapy or monocbemotherapy. Epidemic Kaposi sarcoma (EKS) began to be described in young homosexual men witb severe depression of cellular immunity in the spring of 1981. The cutaneous lesions are disseminated, affecting the head, neck. From the Department of Medicine, Hospital Vargas, and School of Medicine, Central University of Venezuela, Caracas, Venezuela. Address correspondence to: Dimas E. Hernandez, M.D., Ap. postal:75196, El Marques 1070-A, Caracas, Venezuela. February 1991, Vol. 30, No. 2

arms, and trunk, and mucosal and visceral involvement also is quite frequent.' EKS represents the initial presentation in 30% of all human immunodeficiency virus (HIV) group IVinfected patients.^ Overall survival is 18 months, although there are some reports of patients witb good survival beyond 2 years. ^ Therapy of EKS includes recombinant alpha-2 interferon, chemotherapy, or local radiotherapy. Any treatment decision has to balance the real benefits, because opportunistic infections are the first cause of morbidity and mortality in this group of patients.'* Patients and Methods • Between October 1985 and May 1989, 11 patients witb EKS from Hospital Vargas and Instituto Diagnostico (Caracas) were evaluated. All patients were homosexual or bisexual men, and had HIV-EIisa (-I-) and biopsyproven KS. A clinical staging scheme developed by Groopman' and Mitsuyasu* was used: I—limited cutaneous disease (less than ten lesions or a single anatomic region); II—disseminated cutaneous disease (more tban ten lesions or involvement of more than one anatomic region); III—visceral lesions (eg, lymph node or gastrointestinal tract); and IV—both cutaneous and visceral involvement or lung disease. For any given stage, A— without systemic symptoms; and B—with fever, prolonged for more than 2 weeks witb no evident infection and weight loss greater than 10% of usual body weight. Nine patients were treated witb: recombinant alpha-2 interferon (alpha-2 IFN), 10 to 30 million units/m^ three times per week (five patients), monochemotberapy with doxorubicin 20 mg/m^ every 2 weeks (two patients), doxorubicin at the same dose along with zidovudine (AZT) 200 mg PO every 4 bours (one patient), and radiotherapy to painful KS lesions on tbe soles of the feet (one patient). Tbe reasons for discontinuing treatment included progression of tbe disease, side eflects. and acquisition of an opportunistic infection. Lithium carbonate, 900 mg/ day was prescribed in two patients who were treated witb doxorubicin and doxorubicin plus AZT. A close follow-up was done on all patients, taking into account 109

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clinical response, toxicity, opportunistic infections, and survival. Response criteria were as follows: L Complete response was defined as an absence of clinically detectable disease and normalization of previous abnormal radiographic findings for lnore than 2 months. Any remaining pigmented lesion was be biopsied to demonstrate absence of viable tumor, 2, Partial response included a decrease in more than 50% of the original tumor burden, as measured by the sum of the bidirectional measurement of an indicator lesion and the total lesion number, 3, Mixed response included a decrease in tumor burden as measured by lesion size, number, pigmentation, or nodularity in less than 25% of lesions; there concomitantly might be up to a 25% increase in the total number of lesions. 4, Stable disease was defined as no measurable increase or decrease of lesions. 5, Progression was defined as more than a 25% increase in the sum of the bidirectional measurement of indicator lesions or more than a 25% increase in the number of new lesions."^ Survival was reported from the pathologic diagnosis of KS until death. Results Clinical Features (Fig. 1)

The patients' age range was 21 to 48 years (median age 30 years). The lesions were red-to-violaceous macules and papules, painful in 27% of subjects. Pain was the chief complaint in the patients with lymph node involvement and foot sole lesions. Fifty-five percent of individuals had gastrointestinal tract, lung, or lymph node involvement (stage IV), and 45% had cutaneous disseminated lesions (stage II). Systemic symptoms were reported in 75% of our series. In our group, KS was the initial presentation of HIV group IV infection in 82% of patients; 18% of them recovered from Pneumocystis carinii pneumonia (PCP). Immunologic Findings

Eighty-nine percent of patients showed low total and T-lymphocyte counts; T-suppressor lymphocyte count was low in 44% and normal in the remainder. All individuals had very low T-helper lymphocyte counts and T-helper/T-suppressor ratios. Eighty-six percent of patients showed low lymphocyte proliferative response with PHA (Table 1). Treatment

Two patients in stage II, one of them with B symptoms, and three patients in stage IV, two of them with B symptoms, were treated with increasing doses of alpha-2 IEN, 10-30 million units/m^ three times a week. All patients received at least 10 weeks of treat-

Figure 1, lntergluteal Kaposi sarcoma lesion,

ment. Three patients in stage IVB were treated with doxorubicin, 20 mg/m^ every 2 weeks, and one of them also received AZT 200 mg PO every 4 hours. All patients received at least six doxorubicin courses. One patient in stage IIB was treated with radiotherapy, 3,000 rads to painful lesions on soles. Eive patients had stable disease during treatment (three with alpha-2 IEN, one with doxorubicin, and one with doxorubicin plus AZT). There was disease progression in three patients during treatment (two with alpha-2 IEN and one with doxorubicin); these individuals were treated over the course of 1 to 1 'h months. Toxicity was mild and tolerable with alpha-2 IEN (Table 2); there was no hematologic or liver toxicity. Hematologic toxicity was remarkable with doxorubicin with or without AZT, with two patients requiring lithium carbonate to increase platelet and leukocyte counts in order to continue the treatment (Eigs. 2,3). Survivai and Cause of Death

By the end of May 1989, 73% of patients had died; median survival was 8 ± 2 months. The causes of death were opportunistic infections and neurologic disease in

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Kaposi Sarcoma with HIV Infection • Hernandez et al.

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Table 1. Immunologic Findings in Nine Patients with Kaposi Sarcoma

Patient No. 1 2 3 4 5 6 7 8 9

Total Lymphocytes

T Lymphocytes

T4

(u.1)

605 716 595 3,472 928 465 671 1,612 596

322 295 207 489 529 312

281 582 326

56 15 107 153 101 109 130 176 95

T8 (nO

Ratio of T4 to T8

171

0.32

150 237 945 307 150 274 282 485

0.1

PHA (cpm) 16,242 (C:57102) 1,762 (C:68924) 2,815 (C:45937) 8,317 (C:54630) 96,432 (C:94404) 3,181 (C:75417)

0.45 0.16 0.32 0.72 0.47 0.62 0.19

4,217 (C:46219)

PHA: phytohemaggiutinin; C: control. Normal counts: total lymphocytes, 2202 ± 648; T lymphocytes, 1434 ± 433; T4, 860 ± 257; T8, 407 ± 136; ratio T4/T8, 2.2 ± 0.4.

six patients, but KS was not directly related with this mortality. In two patients, the cause of death was unknown, and three patients are still alive 4 months after the pathologic diagnosis of KS (two in stage IIB and one in stage IVB).

Discussion The diversity of clinical presentations is one of the main features of KS associated with HIV group IV infection; additionally, prognosis and treatment modalities are complicated by the frequency of opportunistic infections in these patients. Similar to other series,^ our group included young homosexual or bisexual men with disseminated red-to-violaceous macules and papules. They were usually asymptomatic, except for the painful oral or sole lesions; nodal involvement produced lymphedema and pain. In three patients only was pain reported, two of them with oral lesions, the remainder with soles involved. The nose tip was a unique location observed by us in only 27% of patients. The hard palate, one of the most common involved areas, was reported in all stage IV patients.^ Inguinoscrotal and intergluteal locations are very unusual, and were seen in just one patient. The advanced form of the disease was the most fre-

quent presentation (55% stage IV) with mucosal, gastrointestinal tract, lung, or lymph node involvement; most of these patients had B symptoms. The latter clinical findings constitute a poor prognosis in our series. KS is the initial presentation in 30% of individuals with HIV group IV infection, and this frequency has remained very constant since 1981.^ In Venezuela, however, Guzman et al.^ found only 12% with KS as a presenting feature. Two patients had PCP before developing KS lesions; this information is not defined clearly in the literature but it is considered to be a low-frequency event.^ Lymph node involvement was reported in 47% of patients by Safai et al.-'; in our series, one patient showed mediastinal and retroperitoneal nodal involvement. Pulmonary KS is the cause of death in only 27% of patients'""; in our series, there was one patient with lung nodules with a biopsy outcome of KS, but this did not contribute to cause of death. Patients with EKS showed profound alteration of cellular immunity. T-

Table 2. Toxicity of Alpha-2 Interferon in Five Patients with Kaposi Sarcoma

Symptoms

No. of Patients

Fatigue Headache Chills Myalgias Nausea Vomiting Fever

5

3 5 4 4

0

1

2

Weeks of Ulhium

Figure 2. Effect of lithium carhonate on neutrophil counts in two patients with Kaposi sarcoma treated with doxorubicin (—) and doxorubicin plus zidovudine (—I—).

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1

2

Weeks of Lithium

Figure 3, Effect of lithium carbonate on platelet counts in two patients with Kaposi sarcoma treated with doxorubicin (—) and doxorubicin + zidovudine (—h—),

helper cell counts and T-helper/T-suppressor ratios were decreased, and lymphocyte proliferative response with PHA also was low. Classical KS, in heterosexual men, did not show any depression of cellular immunity. Our data are similar to those previously reported.'^ Treatment efficacy in KS patients is quite difficult to evaluate because of the high frequency of opportunistic infections; therefore, the decision to start treatment should take into account the general conditions of the patients. We decided to treat five KS patients, without previous history of opportunistic infections and rapid-growing lesions, with alpha-2 IFN (two in stage 11, three in stage IV). Only three patients had stable disease (60%), although previous reports have shown 30-50% objective (complete and partial) response with high doses of alpha-2 IFN (30 million units/m^),"'^'^'" as compared with the low response in our group. The explanation of these data lies with the bad prognosis features of our series: low T-helper cell counts, low lymphocyte proliferative responses, B symptoms, and advanced lesions.^''' Single-agent or combination chemotherapy also is reported to be efficacious in palliative management of KS but there is concern regarding the increased rate of development of opportunistic infections with prolonged leukopenia. For this reason, it is justifiable to treat with chemotherapy patients with advanced visceral or pulmonary disease and patients who got over an opportunistic infection. We treated two patients with doxorubicin and one with doxorubicin plus AZT. The clinical response was poor, and stabilization was the only therapeutic outcome; better response rates have been published with vinblastine (25% objective responses and 50% stable disease)."' We think that this low clinical response is due to the bad prognosis features in our series and to the limited number of individuals.

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Toxicity with alpha-2 IFN was tolerable and it was not necessary to omit or decrease any dose, but acetaminophen was prescribed simultaneously during the treatment. Toxicity was similar to that previously reported except for hematologic and hepatic toxicity, which was not marked in our series.^'^'** Lithium carbonate was used in two patients treated with doxorubicin and doxorubicin plus AZT to overcome low platelet or leukocyte counts. Lithium has been shown to reverse neutropenia and thrombocytopenia in patients receiving myelosuppressive therapy. In addition, lithium may help reduce infection and leukopenia during systemic chemotherapy." Lithium is able to inhibit adenyl cyclase and decrease intracellular cAMP levels, which increases lymphocyte interleukin-1 (IL-1). Because IL-1 is an important regulatory protein in colony-stimulating factor (GM-CSF) production, lithium augments GM-CSF in lymphocytes.^"-^' Lithium has been used recently to reverse neutropenia and thrombocytopenia in HIV-infected patients treated with KLlP Our patients showed improvement of platelet and neutrophil counts without any serious adverse reactions. Overall survival was low (8 ± 2 months) compared with other series.^'^^ This probably was related to the clinical and laboratory features previously described, and although there are some reports in the literature of 50% objective responses, there is no clear evidence of overall survival increase. Drug Names alpha-2 interferon: Intron doxorubicin: Adriamycin azidothymidine: Retrovir

Acknowledgment Mauricio Goihman-Yahr, M,D,, reviewed the manuseript.

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Kaposi Sarcoma with HIV Infection • Hernandez et al.

6. Mitsuyasu RT. Kaposi's sarcoma in the acquired immunodefieieney syndrome. Infect Dis Med Clin North Am. 1988;2:511523. 7. Penn I. Kaposi's sarcoma in immunosuppressed patients. J Clin Lab Immunol. 1983;12:l-10. 8. Center for Disease Control. Kaposi's sarcoma and Pneumocy.'itis cartnit pneumonia among homosexual men. MMWR. I981;25:305-308. 9. Guzman M, Murillo J, Hernandez D, et al. Estudio de 58 pacientes con SIDA, atendidos en dos hospitales de Caracas. Gaceta Mediea de Caracas. 1988;46:73-79. 10. Gill PS, Akil B, Colletti P. Pulmonary Kaposi's sarcoma: clinical findings and result of therapy. Am J Med. 1989;87:57-61. 11. Meduri GU, Stover DE. Lee M. et al. Pulmonary Kaposi's sarcoma in the aequired immunodefieieney syndrome: clinical radiographic and pathologic manifestations. Am J Med. 1986;81:11-18. 12. Stahl RE, Friedman-Kien A, Dubin R, et al. Immunologic abnormalities in homosexual men: relationship to Kaposi's sarcoma. Am J Med. 1982 73:171-178. 13. Mitsuyasu RT, Volberding PA, Jacobs A, et al. High dose alpha-2 recombinant interferon in the therapy of epidemie Kaposi's sarcoma in AIDS (abstract). Proe Am Soc Clin Oneol. 1984;3:5L 14. Volberding PA, Mitsuyasu RT. Reeombinant interferon alpha in the treatment of acquired immunodeficiency syndrome-related Kaposi's sarcoma. Semin Oneol. 1985;12(suppl 5)'.2-6.

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15. Mitsuyasu RT, Taylor HMG, Glaspy G, et al. Heterogeneity of epidemie Kaposi's sarcoma. Caneer. 1986;57:1657-1661. 16. Volberding PA, Abrams DI. Conant M, et al. Vinblastine therapy for Kaposi's sarcoma in the acquired immunodeficiency syndrome. Ann Intern Med. 1985; 103:335-338. 17. Hernandez DE. Nuevas perspectivas en immunoterapia. Archivo Venezolano Farmaeologia Terapeutiea. I984;3:86-90. 18. Gutterman JU, Eine S, Quesada J, et al. Recombinant leukocyte A interferon: pharmacokineties, single-dose toleranee and biologic effects in cancer patients. Ann Intern Med. 1982;96:549556. 19. Lyman GH. Williams CC, Preston D. The use of lithium carbonate to reduce infeetions and leukopenia during systemie chemotherapy. N EngI J Med. I98O;3O2:257-26O. 20. Groopman JE, Mitsuyasu RT, DeLeo MJ, et al. Effeet of reeombinant human granuloeyte-maerophage colony stimulating factor on myelopoiesis in the acquired immunodefieieney syndrome. N EngI J Med. 1987;317:418-419. 21. Gelfand EW, Dosch HM, Hastings D, et al. Lithium: a modulator of eyelie AMP-dependent events in lymphocytes. Seience. 1979:203:365-366. 22. Roberts DE, Berman SM. Nakasato S, et al. Efifeet of lithium carbonate on zidovudine associated neutropenia in the aequired immunodefieieney syndrome. Am J Med. 1988:85:428-431. 23. Gelman EP, Longo D, Lane HC, et al. Combination chemotherapy of disseminated Kaposi's sarcoma in patients with acquired immunodeficiency syndrome. Am J Med. 1987;82:456-462.

"Aunt Augusta," Edward M. Shapiro, M.D., Pasadena, TX, Oil painting—third place, American Academy of Dermatology Art Exhibit, San Francisco, CA, 1989, Photograph courtesy of Dermik Laboratories, Inc,

Kaposi sarcoma associated with human immunodeficiency virus infection.

In the present study, 11 patients with epidemic Kaposi sarcoma were evaluated; 55% were in stage IV and 45% in stage II; in addition, 75% had systemic...
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