Hemorrhagic Kaposi sarcoma. Successful treatment with IFN‐α

ARTICLE

Auteur(s) : Konstantinos BASSIOUKAS¹_, Aikaterini ZIOGA²_, Markus HANTSCHKE³_, George KLOUVAS⁴_, John HATZIS¹

¹ Department of Skin and Venereal Diseases, Medical School, University of Ioannina, 45110 Ioannina, Greece
² Department of Histopathology, University Hospital of Ioannina, Ioannina, Greece
³ Dermatopathologische Gemeinschaftspraxis, Friedrichshafen, Germany
⁴ Department of Oncology, University Hospital of Ioannina, Ioannina, Greece

Article accepted 07/10/2003

Kaposi sarcoma (KS) is an interesting angioproliferative disorder. Many unanswered questions remain however, regarding its origin, pathogenesis, malignancy and epidemiology although its cause is believed to be HHV-8 [1-3].
The diagnosis of KS can sometimes be difficult because of an atypical clinical picture [4-6].
We present a patient with an unusual haemorrhagic classic KS treated successfully with recombinant Interferon α-2b (IFN α-2b).

Case report

A 76-year-old woman was presented to our clinic with blue violaceous hemorrhagic, cyst-like lesions scattered and confluent in plaques on the extremities.
Physical examination revealed multiple, vascular, cyst-like lesions about 1 to 2 cm in diameter, varying in size and forming plaques on the lower legs and feet. The lesions on the lower extremities were easily indented by a human finger and returned to their previous hemispheric nodular appearance in 10 to 15 seconds. On puncture they bled confirming their vascular nature. There was no pulse sensed. In addition, the lesions flattened with diascopy and their brown-violaceous appearance remained constant. Macules and papules were also present on the dorsal area of the hands (Fig. 1a, b). No lesions were evident in the oral cavity, nose or on the genitalia. The lesions were first noticed by the patient 2 years previously and had over that period become progressively more aggravated in appearance. The initial symptoms were edema and the presence of bluish-violet macules that slowly developed into nodular cysts which later formed into plaques. The patient had no accompanying lymphadenopathy, no varicose veins, weight loss, fever or malaise but only mild pain and pruritus associated with the lesions. Personal and family medical histories were negative.
Full blood count, and routine hematological and biochemical tests were within normal limits except Erythrocyte Sedimentation Rate: 55 mm/h, Hemoglobulin: 10 gr/100 ml and Hematocrit: 35%. Urinalysis, prothrombin time, partial thromboplastin time, serum immunoglobulin levels and C3, C4 were normal. Antinuclear antibodies were negative. Markers for hepatitis B and C were negative. Human immunodeficiency virus antibodies were negative. Gastroduodenoscopy and colonoscopy were negative. Liver ultrasound revealed a lesion of 1 cm diameter in the left lobe of the liver. Liver scanning tomography showed that this lesion was a hemangioma.
The histopathologic examination of specimens from skin lesions showed:
a) From the hand: Interweaving bands of spindle-shaped cells with a prominent feature of neoplastic proliferated lymph channels (factor VIII negative). Extravasation of erythrocytes was also observed, as well as inflammatory cells, lymphocytes and plasma cells. Epidermis was normal with mild hyperkeratosis (Fig. 2).
b) From the leg: In the reticular dermis lymphatic-like channels were observed, lined with endothelial cells without nuclear atypia. Some of them were around the separated collagen bundles or around a sweat coil. There was a mild inflammatory infiltrate with many lymphocytes and plasma cells without deposits of hemosiderin.
By PCR assay Kaposi sarcoma associated Herpes Virus (KSHV) Human Herpes Virus 8 (HHV = 8) DNA could be detected (Fig. 3). The presence of DNA able to be amplified was proved by PCR using primers specific for factor V. By sequencing of the KSHV/HHV-8 PCR product an identity of 97% to Kaposi sarcoma associated herpes virus (KSHV/HHV-8) could be found.
The patient was treated with recombinant Interferon α-2b (3,000,000 IU) subcutaneously, 3 times weekly for 6 months and twice weekly as maintenance dose for 14 months with excellent response. During treatment no side effects, either systemic or local, were noticed except for a brief flu-like syndrome.
The response to the treatment was obvious from the first month. Fourteen months later, complete healing of the lesions was observed with no recurrence in a 7½ year follow up (Fig. 4). Moreover emollients and sometimes corticosteroid creams were applied locally to control the pruritus.

Discussion

Kaposi sarcoma has been classified in 4 main types (classic, African, AIDS-related and KS in immunocompromised patients) [1, 7].
Classic KS is a sporadic disease that usually affects older males of Mediterranean or Jewish descent. The clinical appearance consists of blue-black nodules on the extremities, more often the lower extremities. This type of KS was the only one recognized until 1950 and usually has a mild course [1, 7].
Classic KS must be differentiated from many other diseases with benign or malignant vascular proliferations such as: acroangiodermatitis [8], pseudo-Kaposi in chronic venous insufficiency and in congenital or acquired fistulas [8-10], lymphangiosarcoma [11], acquired progressive lymphangioma [12], benign lymphangioendothelioma [13, 14], intravascular papillary hyperplasia [15], penicillamine dermatopathy with lympangiectasias [16], ecchymothic patches [5], targetoid haemosiderotic haemangioma [17], stasis contact dermatitis, dermatofibroma and lupus erythematosus [4] and metastatic cancer [18].
The differential diagnosis in our case (cyst-like or varices-like lesions confluent in plaques) was difficult at the beginning because such an atypical picture is rare in the literature. In one reference [6] the authors had a typical KS with atypical histologic examination, but in our case the clinical appearance was atypical and only from the location of the lesions could the possibility of KS be considered. Thus, the present case represents a peculiar form of classic KS «lymphangioma-like» subtype of classic KS, as has previously been described [6, 19, 20]. As our patient was a woman of Mediterranean descent with negative HIV antibodies and without immunosuppression, we considered it as classic KS.
The biopsy from the left hand was compatible with KS whereas from the leg was not diagnostic (absence of spindle cells). This type of KS presents histopathologic difficulties in diagnosis as has been mentioned by other authors [19, 20].
HHV-8 is regarded as a major infective co-factor for the development of KS in the presence of specific immune anomalies [21]. In our case, Kaposi sarcoma associated Herpes Virus (KSHV/HHV-8) has been detected by PCR assay, confirming the diagnosis of classic KS.
IFNα has given good results in the treatment of classic KS [21-25]. Our patient with this peculiar form of KS also had an excellent response to IFN α-2b treatment (Fig. 3) after 14 months which is near to the meantime mentioned in the literature. We suppose that interferon alpha was effective in our case, because of its antiviral, antiproliferative and immunomodulatory properties [25].
We could not perform PCR analysis after the treatment because the patient refused further investigation. Nevertheless, some cases have been reported with persistence of the virus after a successful treatment with IFN-α [26, 27].
Our patient, in a 7½ year follow-up, still has no signs of recurrence and to our knowledge this is the longest period of such a course. n

References

1. Kaloterakis A, Stratigos J, Filiotou A, Kaloterakis M, Hatzakis A, Hadjiyiannis St. Mediterranean Kaposi's sarcoma: Risk factors. Hellen Dermatol Venereol Rev 1995; 6(2): 96-106.

2. Moore PS, Chang Y. Detection of herpes virus-like sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med 1995; 332: 1181-5.

3. Kemeni L, Gyulai R, Kiss M, Nagy F, Dobozy A. Kaposi's sarcoma associated herpesvirus/human herpesvirus 8: A new virus in human pathology. J Am Acad Dermatol 1997; 37: 107-13.

4. Blumenfeld W, Egbert BM, Sagebiel RW. Differential diagnosis of Kaposi's sarcoma. Arch Pathol Lab Med 1985; 109: 123-7.

5. Schartz RA, Spicer MS, Thomas I, Janniger CK, Clark Lambert W. Ecchymotic Kaposi's Sarcoma. Cutis 1995; 56: 104-6.

6. Gange RW, Wilson-Jones E. Lymphangioma like Kaposi's Sarcoma. A report of three cases. Br J Dermatol 1979; 100: 327-34.

7. Pietter WW. The incidence of second malignancies in subsets of Kaposi's sarcoma. J Am Acad Dermatol 1987; 16: 855-61.

8. Rashkovsky I, Gilead L, Schamroth J, Leibovici V. Acro-angiodermatitis: Review of the literature and report of a case. Acta Derm Venereol (Stockh.) 1995; 75: 475-8.

9. Goldblum OM, Kraus E, Bronner AK. Pseudo-Kaposi's sarcoma of the hand associated with an acquired iatrogenic arteriovenous fistula. Arch Dermatol 1985; 121: 1038-40.

10. Koppel RA, Marrogi AJ, Fishman SJ. Unilateral pseudo-Kaposi's sarcoma (Bluefarb-Stewart type). Cutis 1994; 54: 257-60.

11. Mackie RM. Soft Tissue Tumors. In: Champion RH, Burton JL, Ebling FJG, eds. Rook/Wilkinson/Ebling Textbook of Dermatology, 5^th Edition, Blackwell Scientific Publications, 1992: 2073-92.

12. Zhu W-Y, Penneys NS, Reyes B, Khatib Z and Schachner L. Acquired progressive lymphangioma. J Am Acad Dermatol 1991; 24(5): 813-5.

13. Mehregan DR, Mehregan AH, Mehregan DA. Benign lymphangioendothelioma: report of 2 cases. J Cutan Pathol 1992; 19: 502-5.

14. Scott Herron G, Rouse RV, Kosek JC, Smoller BR and Egbert BM. Benign lymphangioendothelioma. J Am Acad Dermatol 1994; 31: 362-8.

15. Reed CN, Cooper RH, Swerlick RA. Intravascular papillary endothelial hyperplasia (multiple lesions simulating Kaposi's sarcoma). J Am Acad Dermatol 1984; 10: 110-3.

16. Goldstein JB, Scott McNutt N, Hambrick GW Jr, Hsu A. Penicillamine dermatopathy with lymphangiectases. A clinical, immunohistologic and ultrastructural study. Arch Dermatol 1989; 125: 92-7.

17. Santa Cruz DJ, Aronberg J. Targetoid hemosiderotic hemangioma. J Am Acad Dermatol 1988; 19: 550-8.

18. Adler MJ, Beckstead J, White CR. Angiomatoid Melanoma: A case of metastatic melanoma mimicking a vascular malignancy. Am J Dermatopathol 1997; 19: 606-9.

19. Ronchese D, Kern AB. Lymphangiona-like tumors in Kaposi's sarcoma. AMA Arch Dermatol 1957; 75: 418-27.

20. Masia IM, Mugoni MG, Massarevlli G, Rovasio S, Cottoni G. Lymphangioma like pattern and anaplastic evolution in a case of classic Kaposi's sarcoma. J Eur Acad Dermatol Venereol 1997; 9: 181-4.

21. Rubegni P, Cuccia A, Sbano B, Miracco C, Pacenti L, Fimiani M. Disseminated Mediterranean Kaposi Sarcoma treated with low-dose recombinant interferon-alpha-2α J Am Acad Dermatol 2003; 48: 148-9.

22. Tsampaos D, Georgiou S, Kapranos N, Georgala S, Zografaki Ch, Stratigos A, Koutselini H and Berger H. Systemische therapie des klassischen Kaposi-Sarcomes mit Interferon alpha-2b. H + G 1994; 69(11): 754-8.

23. Costa da Cunha CS, Lebbe C, Rybojad M, Ferchal F, Rabian C, Vignon-Pennamen MD, Calvo F, Morel P. Long term follow-up of non-HIV Kaposi's sarcoma treated with low-dose recombinant interferon-alpha 2b. Arch Dermatol 1996; 132: 285-90.

24. Somos S, Farkas B. Immunomodulatory treatment with low-dose interferon-alpha and oral retinoic acid in lymphangioma-like Kaposi's sarcoma. Anticancer Res 2000; 20: 541-5.

25. Kirkwood J. Cancer immunotherapy: the interferon-alpha experience. Semin Oncol 2002; 29 (Suppl.7): 18-26.

26. Deihmann M, Thome M, Jackel A, Utermann S, Bock M, Walmann V, Naher H. Non-human immunodeficiency virus Kaposi's sarcoma can be effectively treated with low-dose interferon-alpha despite the persistence of herpes virus-8. Br J Dermatol, 1998; 139: 1052-4.

27. Pfrommer C, Tebbe B, Tidona CA, Wolfer U, Krengel S, Zeichardt H, Zouboulis CC, Orfanos CE. Progressive HHV-8-positive classic Kaposi's sarcoma: rapid response to interferon alpha-2a but persistence of HHV-8 DNA sequences in lesional skin. Br J Dermatol, 1998; 139: 516-9.