Fulminant Kaposi’s Sarcoma Complicating Long-Term Corticosteroid Therapy

HERMES 0. KOOP, M.D. MARK HOLODNIY. M.D. ALAN F. LIST, M.D. Phoenix, Arizona

Prom the Department of Internal Medicine, Good Samaritan Medical Center, and the Section of Hematology-Oncology, Veterans Administration Medical Center, Phoenix, Arizona. Requests for reprints should be addressed to Dr. Alan F. List, Section of Hematology-Oncology (11 l), Veter- ans Administration Medical Center, 7th Street and Indian School Road, Phoenix, Arizona 85012. Manuscript received February 3, 1987, and accepted April 28, 1987.

Cutaneous Kaposi’s sarcoma occurs rarely in patients receiving lcq- term cortiiosteroid therapy. The case of a rapidly progressive form of Kaposi’s sarcoma occurring in a 29-year-old Palestinian woman with steroid-dependent Crohn’s disease and familial Mediterranean fever is reported. Despite~ an extensive transfusion history, serologic and viro- logic studies falled to demonstrate exposure to the human lmmunodefi- ciency virus. Serologic and virolo9ic evidence of concomitant cyto- megalovirus infection, however, suggests possible pathogenic features similar to the acquired immunodeficiency syndrome-related form of Kaposi’s sarcoma.

Kaposi’s sarcoma has been described with increasing frequency be- cause of its association with the acquired immunodeficiency syndrome (AIDS). This epidemic form of Kaposi’s sarcoma is readily distinguished from its sporadic counterpart by virtue of its clinical behavior, character- ized by early extracutaneous dissemination. Although patients treated with exogenous immunosuppressants demonstrate an increased risk for the development of Kaposi’s sarcoma, the disease is generally confined to the integument, with tumor regression often achieved simply by reduction or withdrawal of the offending immunosuppressive agents.

We report the case of a 29-year-old Palestinian woman with steroid- dependent Crohn’s disease and familial Mediterranean fever, who suc- cumbed to a rapidly progressive form of Kaposi’s sarcoma. Exposure to the human immunodeficiency virus was not demonstrable by serologic or virologic techniques. Serologic evidence for concomitant infection by cytomegalovirus, however, suggests possible pathogenic features simi- lar to the AIDS-related Kaposi’s sarcoma.

CASE REPORT

A 29-year-old Palestinian woman was hospitalized in June 1986, with a three-month history of painful, nodular, and violaceous skin lesions, local- ized to the medial aspects of the thighs, soles, and dorsum of the feet. Shotty inguinal adenopathy was present bilaterally. Biopsy of a skin lesion revealed Kaposi’s sarcoma. The results of liver function tests and chest radiography were unremarkable. Treatment was initiated with electron beam irradiation (800 rads) to the lower extremities, with marked regres- sion of the lesions.

The patient’s medical history was remarkable for Crohn’s disease (ste- roiddependent since 1982), type II familial Mediterranean fever, end-stage renal disease secondary to amyloidosis managed with chronic ambulatory peritoneal dialysis, seronegative symmetric inflammatory polyarthritis, ad- renal insufficiency, and transfusion-dependent anemia of 10 years’ dura- tlon, requiring monthly transfusions. Medications included prednisone (ta- pered from 30 mg to 7 mg per day), colchicine, metronidazole, piroxicam, and ranitidine. There was no history of multiple sexual partners or intrave- nous drug use.

Pertinent laboratory data included a normal total lymphocyte number (1 ,400/mm3; normal range, 1,200 to 3,900/mm3). Quantitation of

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T-lymphocyte subsets by indirect fluorescent antibody techniques yielded the following results: helper T-lympho- cytes (OKT4) 490/mm3 (52 percent), suppressor T-lympho- cytes (OKT8) 445/mm3 (48 percent), and OKT4:OKT8 ratio 1.1 (normal range, 1.0 to 2.2). Reactions to intradermal antigens (purified protein derivative, cocci, and Candida control) were negative. Quantitation of serum immunoglob- ulin levels revealed a normal level of IgG (713 mg/dl; normal range, 650 to 1,500 mg/dl), and decreased IgA (59 mg/dl; normal range, 75 to 300 mg/dl) and IgM levels (66 mg/dl; normal range, 75 to 300 mg/dl). The results of serologic tests for syphilis, hepatitis A virus, and hepatitis B virus were negative. IgG antibody to cytomegalovirus was detectable at a titer greater than 1:2,048, and results of urine culture for cytomegalovirus were positive. Presence of antibody to human immunodeficiency virus was not de- monstrable using enzyme-linked immunosorbent assay (ELISA) or Western blot analysis. Results of blood cultures for human immunodeficiency virus remained negative at eight weeks of incubation.

One month later, the patient was readmitted with recur- rence of tumor nodules on the thighs and feet, progressive inguinal adenopathy, and an ulcerating foot lesion. Biopsy of the ulcer revealed Kaposi’s sarcoma. Electron beam irradiation was resumed, but was terminated after only three fractions (600 rads) with the development of a small bowel obstruction. A partial small bowel resection was performed that revealed submusooal involvement of the jejunum, the bowel mesentery, and the abdominal wall by Kaposi’s sarcoma. Evidence of active Crohn’s disease was limited to the distal ileum. After a stormy and brief postoper- ative course, the patient died. Permission for postmortem examination was refused.

COMMENTS

Kaposi’s sarcoma occurs with increased frequency in a variety of altered immune states [l-7]. in renal allograft recipients treated with exogenous immunosuppressants [2] and in rare cases of Kaposi’s sarcoma arising during long-term corticosteroid administration [3-61, the disease is generally confined to the integument, often regressing upon withdrawal of the immunosuppressive agents. The epidemic or aggressive form of Kaposi’s sarcoma in this country has been limited almost exclusively to patients with AIDS or with serologic evidence of human immuno- deficiency virus infection [8]. In some patients with “pre- AIDS,” steroid therapy may unmask the expression of Kaposi’s sarcoma and AIDS. Kaposi’s sarcoma devel- oped in the patient we describe during long-term predni- sone therapy for Crohn’s disease, but she demonstrated a rapidly progressive course with early lymph node and visceral metastases. Although the patient was at risk for

human immunodeficiency virus exposure by virtue of her extensive transfusion history, antibody to the retrovirus was not demonstrable by ELISA or Western blot tech- niques, and attempts to culture human immunodeficiency virus were unsuccessful.

Defects in immunoreguiation are thought to represent an essential element in the pathogenesis of Kaposi’s sarcoma in patients with altered immune states. In pa- tients with the epidemic form of Kaposi’s sarcoma in particular, profound impairment of cellular immunity is almost uniformly encountered [9]. Quantitation of T-lym- phocyte subsets and heiper:suppressor T-ceil ratios in our patient revealed that values were within the normal range. We cannot exclude, however, the possibility of functional defects in cellular immunity attributable to prednisone or prior transfusions. Indeed, the cutaneous anergy in our patient suggests this possibility. Deficient suppressor T- cell activity has been reported in patients with familial Mediterranean fever [ 10,l I] and active inflammatory bowel disease [ 12,131.

Sporadic reports of epidemic Kaposi’s sarcoma in patients without evidence of human immunodeficiency virus infection and with normal measurable immune pa- rameters suggest that factors other than immune impair- ment per se may be operative [ 14,151. Recently, cyto- megalovirus has been implicated in the pathogenesis of the AIDS-related form of Kaposi’s sarcoma on the basis of viral antigen expression or detection of cytomegaiovi- rus genome in tumor extracts [ 161. Although these studies were not performed in the current case, our patient dem- onstrated a high-titer serologic response to cytomegalovi- rus (1:2,048) and virus was recovered from urine cul- tures, suggesting ongoing cytomegaiovirus infection.

In conclusion, cutaneous Kaposi’s sarcoma represents an exceedingly rare complication of long-term corticoste- roid administration. We describe a case of fulminant Kaposi’s sarcoma in a patient with steroid-dependent Crohn’s disease and familial Mediterranean fever. Viro- logic and serologic evidence of concomitant cytomegalo- virus infection in the presence of otherwise normal im- mune parameters suggests possible pathogenic features similar to the AIDS-related form of Kaposi’s sarcoma.

ACKNOWLEDGMENT

Culture for human immunodeficiency virus was per- formed by the Centers of Disease Control in Atlanta, Georgia. The manuscript was prepared by Mrs. Joni Spra- dling. We are grateful for their assistance.

REFERENCES

1. Safai B, Mike V, Giraldo G, Beth E, Good RA: Association of 2. Harwood AR, Osoba D, Hofstader SL, et al: Kaposi’s sarco- Kaposi’s sarcoma with second primary malignancies: ma in recipients of renal transplants. Am J Med 1979; 67: possible etiopathogenic implications. Cancer 1960; 45: 759-765. 1472-1479. 3. Klepp 0, Dahl 0, Stenwig JT: Association of Kaposi’s sarco-

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ma and prior immunosuppressive therapy. Cancer 1978; 42: 2626-2630.

4. Leung F, Fam AG, Osoba D: Kaposi’s sarcoma complicating corticosteroid therapy for temporal arteritis. Am J Med 1981; 71: 320-322.

5. Hoshaw RA, Schwartz RA: Kaposi’s sarcoma after lmmuno- suppressive therapy with prednisone. Arch Dermatol 1980; 116: 1280-1282.

6. Schulhafer EP, Grossman ME, Fagin G, Bell KE: Steroid- induced Kaposi’s sarcoma ih a patient with pre-AIDS. Am J Med 1987; 82: 313-317.

7. Snyder !?A, Schwartz RA: Telangiectatic Kaposi’s sarcoma: occurrence in a patient with thymoma and myasthenia gravis receiving long-term immunosuppressive therapy. Arch Dermatol 1982; 118: 1020-1021.

8. Fauci AS, Masur H, Gelmann EP, Markham PD, Hahn BH, Lane HC: The acquired immunodeficiency syndrome: an update. Ann Intern Med 1985; 102: 800-813.

9. Friedman-Kien AE, Laubenstein LJ, Rubinstein P, et al: Dis- seminated Kaposi’s sarcoma in homosexual men. Ann Intern Med 1982; 96: 693-700.

10. Melamed I, Shemer Y, Zakuth V, Tzehoval E, Pras M, Spirer Z: The immune system in familial Mediterranean fever.

Clin Exp lmmunol 1983; 53: 659-662. 11. Schlesinger M, llfeld D, Handzel ZT, et al: Effect of colchi-

tine on immunoregulatory abnormalities in familial Medi- terranean fever. Clin Exp lmmunol 1983; 54: 73-79.

12. Godin NJ, Sachar DB, Winchester R, Simon C, Janowitz HD: Loss of suppressor T-cells in active inflammatory bowel disease. Gut 1984; 25: 743-747.

13. Auer IO, Roder A, Frohlich J: Immune status in Crohn’s disease. VI. lmmunoregulation evaluated by multiple, dis- tinct T-suppressor cell assays of lymphocyte prolifera- tion, and by enumeration of immunoregulatory T-lym- phocyte subsets. Gastroenterology 1984; 86: 1531- 1543.

14. Marquart K-H, Oehlschlaegel G, Engst R: Disseminated Ka- posi’s sarcoma that is not associated with acquired im- munodeficiency syndrome in a bisexual man. Arch Pathol Lab Med 1986; 110: 346-347.

15. Mannucci PM, Quattrone P, Matturri L: Kaposi’s sarcoma without human immunodeficiency virus antibody in a he- mophiliac. Ann Intern Med 1986; 105: 466.

16. Drew WL, Miner RC, Ziegler JL, et al: Cytomegalovirus and Kaposi’s sarcoma in young homosexual men. Lancet 1982; II: 125-127.

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