Seattle Treatment Education Project (STEP) Perspective, Vol. 7, No. 1 - Spring 1995; A Publication of the Seattle Treat- ment Education Project, 127 Broadway E. Ste. 200, Seattle, WA 98102 * (206) 329-4857. Published 3 times a year
David M. Aboulafia, MD

Epidemiology and Pathogenesis

In 1872, Moritz Kaposi described slow-growing, blue-colored lesions on the lower extremities of elderly men of Eastern European descent. These tumors, now known as "classic" Kaposi's sarcoma, were rarely fatal. In central Africa an "endemic" form was described in the 1960s. There the disease may be indolent, although an aggressive lymphadenopathic variant (spreading to the lymph glands) occasionally is encountered. Kaposi's sarcoma in patients with acquired immunosuppression may be localized or widespread. In contrast, epidemic Kaposi's sarcoma seen among US male homosexuals often is progressive with frequent visceral involvement (spread to the internal organs).

The unique facets of Kaposi's sarcoma epidemiology must be accounted for in any model of its pathogenesis. These include the association of disease with sexually transmitted HIV but not parenterally acquired infection (IV drug use or blood transfusions), the male to female ratio of roughly 20:1, its rare appearance in individuals at risk for HIV infection but without detectable HIV, and its declining incidence among male homosexuals.

The Kaposi's sarcoma etiologic factor remains unknown although several viruses including cytomegalovirus, Epstein-Barr virus and hepatitis B virus have been previously linked to its pathogenesis. Human papillomavirus type 16 and more recently genetic sequences from an incompletely described human herpesvirus have been recovered from biopsied Kaposi's sarcoma lesions although their precise role will require additional study. Assuming the etiologic factor is transmitted via fecal-oral contamination during anal intercourse, the declining incidence of Kaposi's sarcoma among male homosexuals may be related to the gradual adoption of safer sex strategies which minimizes transmission. Kaposi's growth is accelerated by corticosteroids. Furthermore, endogenous dihydro-epiandersterone and testosterone levels may be higher in patients with HIV and Kaposi's sarcoma. Additional study of the metabolic effects of steroids on tumor growth may provide clues in explaining the importance of immune surveillance in inhibiting carcinogenesis and the male predominance of this tumor.

Kaposi's sarcoma is a multifocal, polyclonal, hyperplastic neoplasm. Unlike most solid tumors, it is not characterized by a primary local growth and eventual metastases (spread). Although the precise origin of Kaposi's sarcoma cells remains in doubt, cell lines express endothelial markers, suggesting the tumor develops from vascular or lymphatic endothelial cells. Both angiogenic growth factors and an altered progenitor cell appear to be key elements in Kaposi's sarcoma development.

Oncostatin M, a protein produced by activated T-cells, macrophages, and Kaposi's cells is the most potent Kaposi's sarcoma cell growth factor identified, and in-vitro, produces a morphologic change in endothelial cells to the spindle-shape characteristic of Kaposi's sarcoma cells. The HIV-tat protein also may have a direct effect on Kaposi's sarcoma cell generation, or it may induce the production of interleukin-6, a cytokine growth factor capable of stimulating tumor growth. Other Kaposi's sarcoma cell growth promoters include basic fibroblast growth factor, interleukin-1, and tumor necrosis factor. In concert with signals from the immune system and possible genetic and hormonal factors, endothelial cells, fibroblasts, macrophages, and lymphocytes may increase Kaposi's sarcoma growth. This multistep model of Kaposi's sarcoma pathogenesis is consistent with the hypothesis that Kaposi's sarcoma represents a proliferative disorder of mesenchymal cells in response to HIV and dysregulation of immune mediators from HIV infection, in conjunction with an unidentified infectious agent.

Clinical Manifestations

The clinical features of epidemic Kaposi's sarcoma differ markedly from those seen in classic, iatrogenic, and endemic forms (table I, page 11). AIDS-Kaposi's sarcoma tends to be multicentric. Some people may have small, innocuous-looking skin blemishes easily overlooked or rarely confused with benign nevi, or bacillary angiomatosis. Alternatively, large and confluent skin lesions manifested as red, purple, or brown patches, plaques, or nodules may be randomly scattered from head to toe. In some individuals, only a few lesions are apparent, and they remain unchanged for years; in others, lesions appear rapidly. In most people, new lesions develop gradually during a period of several weeks to months but may grow suddenly during periods of heightened immunosuppression.

Tumors of the head and neck and especially the tip of nose may cause substantial alterations in appearance. Lymphatic involvement may produce debilitating and cosmetically unacceptable edema (swelling), particularly in the periorbital area (around the eye), genitalia, and lower extremities. Foot and toe lesions are common and when present in addition to peripheral neuropathy, dementia, or compromised visual acuity the lesions are subject to trauma and superimposed fungal infections. Involvement of the airway, lungs or their lining, are ominous Kaposi's complications. Individuals may present with dyspnea (shortness of breath), bloody fluid in the lungs, and fevers. Alternatively, some people may be asymptomatic, but lymph node enlargement, or a spreading into the lung tissue or prominent spots on the chest x-ray should heighten clinical suspicion. Approximately 30% to 50% of people with cutaneous Kaposi's sarcoma may also have gastrointestinal involvement. Examination of the mouth and throat may uncover asymptomatic hard and soft palate lesions, which if allowed to grow, can interfere with eating or, rarely, cause airway obstruction. These tumors may be an uncommon cause of gastrointestinal bleeding or obstruction. Kaposi's sarcoma may involve almost all organs, but central nervous system involvement is sufficiently rare to be a reportable event.

Table I: Clinical Features of Kaposis's Sarcoma ____________________________________________________________________

Clinical Type Population Characteristics Course ---- ---------- --------------- -------

Classic 50-80-year Typically confined Median survival old men of to lower 13 years Mediterranean extremities or Jewish heritage

Endemic 25-40-year old Localized cutaneous Indolent; black men of lesions in the lymphadenopathic African majority variant more heritage aggressive and fatal within 2-8 years

Iatrogenic Patients with May be localized or May regress with organ widespread with with restoration transplants, systemic of immuno- autoimmune involvements competence; disorders fatal in approx 30%

Epidemic Patients with Disseminated Indolent or (AIDS- acquired immune tumors with aggressive related) deficiency frequent visceral syndrome; organ involvement primarily homosexuals ---------------------------------------------------------------

Clinical Evaluation

Initial evaluation of a person with Kaposi's sarcoma includes a physical examination with particular attention given to the skin, rectal and oral cavities, a chest x-ray, and if necessary, confirmed by biopsy. People with presumed pulmonary Kaposi's sarcoma undergo bronchoscopic evaluation; a biopsy is rarely required as the clinical appearance is characteristic. Symptomatic gastrointestinal involvement is best evaluated by endoscopy with biopsy of suspicious lesions. Routine blood tests, including serum albumin, cholesterol, and CD4+ T lymphocyte count, help divide patients into good or poor prognosis groups. Immunologic status, tumor size, fever, night sweats, weight loss, diarrhea, and history of prior opportunistic infections are important prognostic variables that are incorporated into the AIDS Clinical Trials Group (ACTG) classification scheme (table II, page 12). Specifically, the ACTG recommends a standardized format for detailing the extent of Kaposi's sarcoma lesions on initial and subsequent evaluation. Response definitions include assessment of lesion size and tumor-associated swelling in addition to the more traditional method of recording the number and size of lesions. ____________________________________________________________

Table II: Proposed staging classification for HIV-related Kaposi's Sarcoma _____________________________________________________________

Good Risk Poor Risk (all the following must apply) (if any of the following apply) ------------------------------ --------------------------------

Tumor (T) Confined to skin and/or lymph Tumor-associated edema or nodes and/or minimal oral ulcerations; extensive oral disease. [a] disease; gastrointestinal disease; disease in other non-nodal visceral

Immunue System (I) CD4+ T Lymphocytes <200 cells/æl CD4+ T lymphocytes >200 cells/æl

Systemic Illness (S) History of OI and/or oral No history of OI or oral candidiasis; candidiasis; no "B" symptoms "B" symptoms present; [b] Karnofsky performance Karnofsky performance status<70%; status >70% other HIV-related illness

---------------------------------------------------------------- a Minimal oral disease is non-nodular HIV-KS confined to the palate.

b "B" symptoms: unexplained fever, night sweats, greater than 10% involuntary weight loss, or diarrhea persisting more than two weeks

OI=opportunistic infection ________________________________________________________________

Treatment

Epidemic Kaposi's sarcoma is not a curable malignancy, and with the exception of chemotherapy for pulmonary Kaposi's sarcoma, no data have shown treatment improves survival. Consequently, immediate therapeutic intervention for Kaposi's sarcoma often is not necessary at diagnosis, although most AIDS-Kaposi's sarcoma persons will require some form of symptom relieveing treatment during the course of their disease (table III, page 12). Reasons to consider initiating therapy without delay include the presence of life-threatening disease, symptomatic disease, and cosmetically unacceptable lesions.

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Table III: Treatment options for AIDS-related Kaposi's Sarcoma _____________________________________________________________

Extent of Disease Recommendations ------------------ ---------------- Minimal Disease Cutaneous, asymptomatic, Observation, antiretrovirals, stable or slowly progressive investigational agents

Locally symptomatic Radiotherapy

Local cosmesis Liquid nitrogen cryotherapy Intralesional vinblastine Radiotherapy

Widespread Symptomatic Pulmonary Doxorubicin (Adriamycin)- bleomycin-vincristine (ABV)

Severe extremity edema Bleomycin-vincristine (BV) ±Doxorubicin or Etoposide Radiotherapy

Rapidly progressive but Interferon with zidovudine but not life threatening (if CD4+ T cell>200/ l) Vincristine/vinblastine or Vincristine/bleomycin

Cytopenic patients Vincristine and/or bleomycin or combination chemotherapy with hematopoietic growth factors

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Small, localized lesions of limited number may be observed or treated with regional therapy including intralesional vinblastine and topical liquid nitrogen. In contrast to other soft tissue tumors, Kaposi's sarcoma responds to modest doses of radiation therapy. Radiation is especially useful in treating tumors complicated by swelling involving the extremities and area around the eyes. Painful lesions on the sole of the foot and those on the conjunctiva, nose, ear, and genitalia may also be well managed with radiotherapy. However, palliation is usually temporary, and tumors may recur in previously treated sites within a few months. Further, HIV-infected persons have heightened susceptibility to radiation-induced mucositis, and oral and rectal lesions are probably best managed by other methods. Additional complications of radiotherapy for cutaneous Kaposi's sarcoma include skin irritation and ulcers, hair loss, and pigmentary changes.

Extensive or rapidly progressive disease, particularly that involving internal organs, requires a more aggressive systemic approach. Single and combination chemotherapy consisting of vinca alkaloids, anthracyclines, and bleomycin are active against Kaposi's sarcoma and produce response rates varying from 25% to 80%. Vincristine, vinblastine, and bleomycin are often favored initially because they are well tolerated and less likely to produce profound bone marrow suppression or hair loss. However, caution must be exercised when using vincristine because of the high incidence of peripheral neuropathy in people living with AIDS. Etoposide and doxorubicin are used when disease progresses and, at relatively low doses, are associated with acceptable bone marrow suppression although hair loss is invariable. Interferon-a produces objective response rates of 25% to 50% when used as a single agent, although high doses are often required and poorly tolerated. The best responses are generally seen in patients with CD4+ T lymphocytes greater than 200/ml and without prior AIDS-related symptoms. When coupled with zidovudine (AZT), lower doses of interferon may be used with response rates similar to those achieved with single agent, higher dose interferon. Nonetheless, dose-related side effects may still be severe and include malaise, fever, headache, myalgia (muscle aches), bone marrow suppression, and hepatitis. Flu-like symptoms can often be lessened by instructing patients to take injections before sleep and taking acetaminophen (Tylenol) every 4 to 6 hours. Within one to two weeks, fevers and muscle aches decrease. The addition of white and red blood cell growth factors and other antiretroviral agents may preserve bone marrow and immune function, and are often incorporated into treatment regimens.

New therapies undergoing clinical evaluation for Kaposi's sarcoma include human chorionic gonadotropin ("hCG") inhibitors of Kaposi's sarcoma HIV-induced cytokine cascade (e.g., anti-TNF antibodies) and novel anti-blood vessel growth factors. Dessicated shark cartilage is one such product, although initial results have not shown, at least in its current preparation, that it has significant anti-tumor benefits.

Liposomal encapsulated doxorubicin (Doxil-SLc) is another new drug that is proving to be a very valuable addition to the list of anti-tumor drugs. It is given as an injection every three weeks. What distinguishes it from standard doxorubicin is the lack of significant side effects such hair loss, nausea, or mucositis. To date, approximately 30 patients have been treated with this drug at Virginia Mason, in Seattle, on a research protocol and most likely it will receive FDA approval within the next few months.

Newer yet is LGD 1069, a drug which is just beginning to enter into the clinical arena. The drug is a derivative of retinoic acid, and when applied directly on the Kaposi's sarcoma lesions, may cause tumor shrinkage. For more information regarding this compound, please call Julie Deszo, RN at (206) 223-6611.

Dr. Aboulafia is the Attending Hematologist/Oncologist for Virginia Mason Medical Center. He is also a Clinical Assiciate Professor, University of Washington and the Medical Director for Bailey Boushay House, Seattle.

SELECTED REFERENCES

1. Chang Y, Cesarman E, Pessin MS, et al: Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994;266:1865-9.

2. Beral V, Peterman TA, Berkelman RL, et al. Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990;335:123-8.

3. Krown SE, Metroka C, Wernz JC: Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response and staging criteria. J Clin Oncol 1989; 7:1201-7.

4. Ensoli B, Barilari G, Gallo RC: Pathogenesis of AIDS-associated Kaposi's sarcoma. Hematol Oncol Clin North Am 1991; 5:281-95.

5. Miles SA, Martinez-Maza O, Rezai A, et al. Oncostatin M as a potent mitogen for AIDS-Kaposi's sarcoma-derived cells. Science 1992; 255:1432-4.

6. Gill PS, Akil B, Colletti P, et al. Pulmonary Kaposi's sarcoma: clinical findings and results of therapy. Am J Med 1989; 87:57-61.

7. Krown SE, Gold JW, Niedzwiecki D, et al. Interferon-alpha with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi's sarcoma associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1990; 112:812-821.

8. Kahn J, Northfelt D, Volberding P: Chemotherapy for AIDS-associated Kaposi's sarcoma. Oncology 1991; 5:57-63.

9. Krown SE, Paredes J, Bundow D, et al: Interferon-a, zidovudine, and granulocyte-macrophage colony stimulating factor: a phase I AIDS clinical trial group study on patients with Kaposi's sarcoma associated with AIDS. J Clin Oncol 1992;10:1344-1351.

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