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Information from PDQ -- for Health Professionals
Kaposi's sarcoma
208/01271
** GENERAL INFORMATION **
Kaposi's sarcoma (KS) was first described in 1872 by the Austro-Hungarian
dermatologist, Moritz Kaposi. From that time until the current human
immunodeficiency virus (HIV) disease epidemic identified with the Acquired
Immunodeficiency Syndrome (AIDS), KS remained a rare tumor. While most of the
cases seen in Europe and North America have occurred in elderly men of Italian
or Eastern European Jewish ancestry, the neoplasm also occurs in several other
distinct populations: young black African adult males, prepubescent children,
renal allograft recipients, and other patients receiving immunosuppressive
therapy. The disseminated, fulminant form of KS associated with HIV disease is
referred to as epidemic KS to distinguish it from the classic, African, and
transplant-related varieties of the neoplasm. In addition, KS has been
identified in homosexual men apart from the HIV disease epidemic.[1] Although
the histopathology of the different types of the Kaposi's tumor is essentially
identical in all of these groups, the clinical manifestations and course of the
disease differ dramatically.[2] A key piece to the puzzle of KS pathogenesis
was the 1994 discovery of a gamma herpes virus, human herpes virus type 8
(HHV-8), also known as Kaposi's sarcoma herpes virus.[3] HHV-8 was identified
in KS tissue biopsies from virtually all patients with classic, African,
transplant-related, and AIDS-associated KS, but was absent from non-involved
tissue.[4-7]
-- Classic Kaposi's sarcoma --
Considered a rare disease, classic KS occurs more often in males, with a ratio
of approximately 10 to 15 males to 1 female. In North Americans and Europeans,
the usual age at onset is between 50 and 70 years of age. Classic KS tumors
usually present with 1 or more asymptomatic red, purple, or brown patch,
plaque, or nodular skin lesions. The disease is often limited to single or
multiple lesions usually localized to 1 or both lower extremities, especially
involving the ankle and soles. Classic Kaposi's sarcoma most commonly runs a
relatively benign, indolent course for 10 to 15 years or more with slow
enlargement of the original tumors and the gradual development of additional
lesions. Venous stasis and lymphedema of the involved lower extremity are
frequent complications. In long-standing cases, systemic lesions can develop
along the gastrointestinal tract, in lymph nodes, and in other organs. These
visceral lesions are generally asymptomatic and are most often discovered only
at autopsy, although clinically, gastrointestinal bleeding can occur. Up to
one-third of the patients with classic KS develop a second primary malignancy,
most often non-Hodgkin's lymphoma.[8-10]
-- African Kaposi's sarcoma --
In the 1950s, KS was recognized as a relatively common neoplasm endemic in
native populations in equatorial Africa, comprising approximately 9% of all
cancers seen in Ugandan males. African KS is seen as either an indolent
neoplasm identical to the classic disease seen in Europe and North America or
as an aggressive disease with fungating and exophytic tumors that may invade
the subcutaneous and surrounding tissue including the underlying bone. In
Africa, both the indolent and locally more aggressive forms of KS occur with a
male to female ratio comparable to that observed with the classic KS tumor seen
in North America and Europe. In general, however, patients in Africa are
significantly younger than their European counterparts. A lymphadenopathic
form of KS is also seen in Africa, primarily in prepubescent children
(male:female ratio 3:1). In these cases, the generalized lymphadenopathy is
frequently associated with visceral organ involvement. The prognosis is very
poor, with a 100% fatality rate within 3 years.[11,12]
-- Immunosuppressive treatment-related Kaposi's sarcoma --
In 1969, the first case of KS in association with immunosuppression in a renal
transplant patient was described. Since that time a number of renal and other
organ allograft recipients receiving prednisone and azathioprine have developed
KS shortly after the onset of immunosuppressive therapy.[13] The incidence of
KS in immunosuppressed renal transplant recipients has been estimated at
between 150 and 200 times the expected incidence of this tumor in the general
population. The average time to develop KS after transplantation is about 16
months. Although the tumor in these iatrogenically immunosuppressed patients
often remains localized to the skin, widespread dissemination with
mucocutaneous or visceral organ involvement is common. In some cases, the KS
tumors have regressed as a result of reduction or changes in immunosuppressive
therapy. Clinical management of renal transplant patients who develop KS is
difficult and requires a balance between the risk of death from generalized KS
and the risk of graft rejection and complications of renal failure that may
occur if the immunosuppressive therapy is discontinued.
-- Epidemic Kaposi's sarcoma --
In 1981, a fulminant and disseminated form of KS in young homosexual or
bisexual men was first reported as part of an epidemic now known as AIDS.[14]
The etiology of AIDS is a T-cell lymphotropic retrovirus known as HIV. The
underlying immunologic deficiency that characterizes HIV disease is an acquired
profound disorder of cell-mediated immune functions. This immunologic
deficiency and immune dysregulation predisposes the host to a variety of
opportunistic infections and unusual neoplasms, especially KS. HIV itself may
play an indirect role in the development of KS.[15]
Approximately 95% of all the cases of epidemic KS in the United States have
been diagnosed in homosexual or bisexual men. In the past, approximately 26%
of all homosexual males with HIV disease presented with, or eventually
developed, KS during the course of their illness. By comparison, less than 3%
of all heterosexual intravenous drug users with HIV disease developed KS. The
proportion of HIV disease patients with KS has steadily decreased since the
epidemic was first identified in 1981.[16] About 48% of AIDS patients in 1981
had KS as their presenting AIDS diagnosis. By August 1987, the cumulative
proportion of AIDS patients with KS had diminished to less than 20%. The
introduction of highly active antiretroviral therapy (HAART) may delay or
prevent the emergence of drug-resistant HIV strains, profoundly decrease viral
load, lead to increased survival, and lessen the risk of opportunistic
infections.[17,18] The use of HAART might possibly be related to the
continuing downtrend (12%) in the incidence of KS as an AIDS-defining illness.
Epidemic KS is usually characterized by multifocal, widespread lesions at the
onset of illness.[19] These lesions may involve the skin; oral mucosa; lymph
nodes; and visceral organs, such as the gastrointestinal tract, lung, liver and
spleen. Most patients with HIV disease who present with the mucocutaneous
lesions of KS feel healthy and are usually free of systemic symptoms as
compared to those patients with HIV disease who first develop an opportunistic
infection. The sites of disease at presentation of epidemic KS are much more
varied than those seen in the other types of this neoplasm. In an early report
on the clinical manifestations of the disease, 49 patients were described.[19]
Eight percent had no skin involvement, 27% had localized or fewer than 5 skin
lesions, and 63% had innumerable skin lesions widely distributed over the skin
surface area. Sixty-one percent of the patients had generalized
lymphadenopathy at the time of the first examination. Four of these patients
who had generalized lymphadenopathy in the absence of skin lesions or
detectable visceral organ involvement at the time of presentation were found to
have biopsy-proven KS localized to the lymph nodes. In 45% of the patients
studied, KS lesions were found in 1 or more sites along the gastrointestinal
tract. Twenty-nine percent of the patients had either unexplained fever or
weight loss when first seen. Thus, while most patients present with skin
disease, KS involvement of lymph nodes or the gastrointestinal tract may
occasionally precede the appearance of the cutaneous lesions.
Eventually, almost all patients with epidemic KS develop disseminated disease.
Progression often proceeds in an orderly fashion from a few localized or
widespread mucocutaneous lesions to more numerous and generalized skin disease
with lymph node, gastrointestinal tract disease, and other organ involvement.
Pleuropulmonary KS is an ominous sign usually occurring late in the course of
the disease, especially in those patients whose death is directly attributed to
KS.[20] Most patients with epidemic KS die of 1 or more complicating
opportunistic infections.
-- Non-epidemic gay-related Kaposi's sarcoma --
There have been several reports documenting KS in homosexual men who
persistently have no evidence of HIV infection. These patients have an
indolent and cutaneous form of the disease, with new lesions appearing every
few years. Lesions occur most commonly on the extremities and genitalia but
can occur anywhere on the skin.[1] These cases may indicate the presence of
causal factors, other than HIV, that homosexual men may be exposed to due to
their lifestyle.
References:
1. Friedman-Kien AE, Saltzman BR, Cao Y, et al.: Kaposi's sarcoma in
HIV-negative homosexual men. Lancet 335(8682): 168-169, 1990.
2. Safai B: Kaposi's sarcoma and acquired immunodeficiency syndrome. In:
DeVita VT, Hellman S, Rosenberg S, eds.: AIDS: Etiology, Diagnosis,
Treatment and Prevention. 4th ed., Philadelphia: Lippincott-Raven
Publishers, 1997, pp 295-318.
3. Chang Y, Cesarman E, Pessin MS, et al.: Identification of
herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.
Science 266(5192): 1865-1869, 1994.
4. Moore PS, Chang Y: Detection of herpesvirus-like DNA sequences in
Kaposi's sarcoma in patients with and those without HIV infection. New
England Journal of Medicine 332(18): 1181-1185, 1995.
5. Su IJ, Hsu YS, Chang YC, et al.: Herpesvirus-like DNA sequence in
Kaposi's sarcoma from AIDS and non-AIDS patients in Taiwan. Lancet
345(8951): 722-723, 1995.
6. Gao SJ, Kingsley L, Li M, et al.: KSHV antibodies among Americans,
Italians and Ugandans with and without Kaposi's sarcoma. Nature
Medicine 2(8): 925-928, 1996.
7. Chang Y, Ziegler J, Wabinga H, et al.: Kaposi's sarcoma-associated
herpesvirus and Kaposi's sarcoma in Africa. Archives of Internal
Medicine 156(2): 202-204, 1996.
8. Safai B, Good RA: Kaposi's sarcoma: a review and recent developments.
Clinical Bulletin 10(2): 62-69, 1980.
9. Reynolds WA, Winkelmann RK, Soule EH: Kaposi's sarcoma: a
clinicopathologic study with particular reference to its relationship to
the reticuloendothelial system. Medicine 44(5): 419-443, 1965.
10. Safai B, Mike V, Giraldo G, et al.: Association of Kaposi's sarcoma with
second primary malignancies: possible etiopathogenic implications.
Cancer 45(6): 1472-1479, 1980.
11. Taylor JF, Templeton AC, Vogel CL, et al.: Kaposi's sarcoma in Uganda: a
clinicopathological study. International Journal of Cancer 8(1):
122-135, 1971.
12. Templeton AC, Bhana D: Prognosis in Kaposi's sarcoma. Journal of the
National Cancer Institute 55(6): 1301-1304, 1975.
13. Penn I: Kaposi's sarcoma in organ transplant recipients: report of 20
cases. Transplantation 27(1): 8-11, 1979.
14. Kaposi's sarcoma and pneumocystis pneumonia among homosexual men: New
York City and California. Morbidity and Mortality Weekly Report 30(25):
305-308, 1981.
15. Vogel J, Hinrichs SH, Reynolds RK, et al.: The HIV tat gene induces
dermal lesions resembling Kaposi's sarcoma in transgenic mice. Nature
335(6191): 606-611, 1988.
16. Selik RM, Starcher ET, Curran JW: Opportunistic diseases reported in AIDS
patients: frequencies, associations, and trends. AIDS 1(3): 175-182,
1987.
17. Flexner C: HIV-protease inhibitors. New England Journal of Medicine
338(18): 1281-1292, 1998.
18. Palella FJ, Delaney KM, Moorman AC, et al.: Declining morbidity and
mortality among patients with advanced human immunodeficiency virus
infection. New England Journal of Medicine 338(13): 853-860, 1998.
19. Krigel RL, Laubenstein LJ, Muggia FM: Kaposi's sarcoma: a new staging
classification. Cancer Treatment Reports 67(6): 531-534, 1983.
20. Gill PS, Akil B, Colletti P, et al.: Pulmonary Kaposi's sarcoma: clinical
findings and results of therapy. American Journal of Medicine 87(1):
57-61, 1989.
** STAGE INFORMATION **
The staging evaluation of patients with classic Kaposi's sarcoma (KS) should be
individualized. The advanced age of most of these patients, localized nature
of the tumor, rarity of visceral involvement, and usually indolent course of
the disease should temper the extent of the evaluation. A careful examination
of the skin and lymph nodes is sufficient in most cases. For those unusual
patients with rapidly progressive tumor or signs or symptoms of visceral
involvement, appropriate evaluation is indicated. There is no universally
accepted classification for epidemic KS. Staging schemes have been proposed
that incorporate laboratory parameters as well as clinical features. Since
most patients with epidemic KS do not die from the disease itself, it is
apparent that factors besides tumor burden are involved in survival.
The conventions used to stage KS and the methods used to evaluate the benefits
of KS treatment have been evolving for over a decade in response to changes in
the treatment of HIV and in recognition of deficiencies in standard tumor
assessment. The clinical course of KS, the selection of treatment, and
response to treatment are heavily influenced by the degree of underlying immune
dysfunction and opportunistic infections.
The AIDS Clinical Trials Group (ACTG) Oncology Committee has published criteria
for the evaluation of epidemic KS.[1] This staging system incorporates
measures of extent of disease, severity of immunodeficiency, and presence of
systemic symptoms. As shown below, the ACTG criteria categorizes extent of
tumor as localized or disseminated, CD4 cell number as high or low, and
systemic illness as absent or present. A subsequent prospective analysis of
294 patients entered on ACTG trials for KS between 1989 and 1995 showed that
each of the tumor, immune system, and systemic illness (TIS) variables was
independently associated with survival.[2] Multivariate analysis showed that
immune system impairment was the most important single predictor of survival.
In patients with relatively high CD4 counts, tumor stage was predictive. A CD4
count of 150 cells per cubic millimeter may be a better discriminator than the
published cut off of 200 cells per cubic millimeter. A study is in progress to
determine if viral load adds predictive information. It is important to note
that none of the prior studies were conducted at a time when highly active
antiretroviral therapy (HAART) was readily available. The impact of HAART on
survival in KS will require continued assessment.
===============================================================================
AIDS Clinical Trials Group staging classification
Good Risk (0) Poor Risk (1)
(All of the following) (Any of the following)
Tumor (T) Confined to skin Tumor-associated
and/or lymph nodes edema or ulceration
and/or minimal oral Extensive oral KS
disease* Gastrointestinal KS
KS in other non-nodal
viscera
Immune system (I) CD4 cells >/= 200/microL CD4 cells <200 per
cubic millimeter
Systemic illness (S) No history of OI or History of OI
thrush and/or thrush
No "B" symptoms** "B" symptoms
Performance status present
>/= 70 (Karnofsky) Performance status
<70
Other HIV-related
illness (e.g.,
neurological disease,
lymphoma)
*minimal oral disease is non-nodular KS confined to the palate
**"B" symptoms are unexplained fever, night sweats, greater than 10%
involuntary weight loss, or diarrhea persisting more than 2 weeks.
===============================================================================
References:
1. Krown SE, Metroka C, Wernz JC: Kaposi's sarcoma in the acquired immune
deficiency syndrome: a proposal for uniform evaluation, response, and
staging criteria. Journal of Clinical Oncology 7(9): 1201-1207, 1989.
2. Krown SE, Testa MA, et al., for the AIDS Clinical Trials Group Oncology
Committee: AIDS-related Kaposi's sarcoma: prospective validation of the
AIDS Clinical Trials Group staging classification. Journal of Clinical
Oncology 15(9): 3085-3092, 1997.
** CLASSIC KAPOSI'S SARCOMA **
Classic Kaposi's sarcoma usually is limited to the skin and has an indolent
course. Patients with this tumor are predisposed to the development of a
second primary malignancy, and the treating physician should consider this
factor when arranging a schedule of follow-up for the patient.
Equivalent standard treatment options:
Solitary lesions:
1. Radiation therapy: For solitary lesions or lesions of limited extent,
modest doses of radiation applied to the lesions themselves with a limited
margin provide excellent control of disease in the treated area. Usually
superficial radiation beams, such as electron beams, are used. Disease
recurrence in adjacent, untreated skin is said to be common by some authors if
only involved field radiation therapy is used. These authors claim better cure
rates when extended field radiation is used instead.[1,2]
A. low-voltage (100 kv) photon radiation: 800 to 1,000 cGy as a single-dose
or 1,500 to 2,000 cGy over 1 week, for solitary lesions control nearly
100% of local disease but recurrence in adjacent areas is common.
B. electron beam therapy: 400 cGy once weekly for 6 to 8 consecutive weeks
with a 4 to 6 MeV electron beam. Ports should include the entire skin
surface 15 cm above the lesion.
2. Surgical excision may be of benefit in some patients with small, superficial
lesions but local recurrence is likely to be a problem. However, multiple
small excisions can be performed over the years and achieve good disease
control.
Widespread skin disease:
1. Radiation therapy: Modest doses are effective in controlling disease. The
type of radiation (that is, photon vs. electron) and fields used must be
tailored to suit the distribution of disease in the individual patient. Nisce
et al. have recommended extended field electron beam radiation therapy. For
disease limited to areas distal to the knee, subtotal skin electron beam
radiation therapy directed to skin below the umbilicus has been recommended.
Total skin electron beam radiation therapy has been recommended for disease
that extends above the knee.
Electron beam radiation used in this manner gave long-term results superior to
those obtained with radiation of successive individual lesions given as they
appeared.[2]
electron beam therapy: 400 cGy once weekly for 6 to 8 consecutive weeks,
subtotal or total skin radiation for extensive disease.
2. Chemotherapy: Because classic Kaposi's sarcoma is such a rare disease in
the United States and is usually treated initially with radiation therapy, few
patients have been treated with chemotherapy and no randomized, prospective
trials have compared 1 agent to another. Several authors have used
single-agent vinblastine at a weekly dose of approximately 0.1 mg/kg.[3-6]
Almost all the patients had "good" to "excellent" response. In most cases,
patients required prolonged courses of therapy, up to several years, to
maintain a partial response. Doses of vinblastine were titrated in individual
patients to maintain a WBC count above approximately 3000. Follow-up after
completion of therapy was not presented.
Odom et al. treated 1 patient repeatedly with intralesional injections of 0.25
to 0.50 mg of vincristine with complete disappearance of the treated lesion.[7]
Multiple courses of therapy were required because of recurrence of disease in
untreated areas.
Lymph node and gastrointestinal tract involvement:
1. Chemotherapy: Several of the patients mentioned previously under the
section dealing with chemotherapy of widespread skin disease also had lymph
node and GI tract involvement. The disease in these sites also responded to
vinblastine. No studies are otherwise available to address the treatment of
visceral classic Kaposi's sarcoma specifically.
2. Local radiation therapy may be added to chemotherapy if individual lesions
require urgent therapy.
References:
1. Hamilton CR, Cummings BJ, Harwood AR: Radiotherapy of Kaposi's sarcoma.
International Journal of Radiation Oncology, Biology, Physics 12(11):
1931-1935, 1986.
2. Nisce LZ, Safai B, Poussin-Rosillo H: Once weekly total and subtotal skin
electron beam therapy for Kaposi's sarcoma. Cancer 47(4): 640-644,
1981.
3. Solan AJ, Greenwald ES, Silvay O: Long-term complete remissions of
Kaposi's sarcoma with vinblastine therapy. Cancer 47(4): 637-639, 1981.
4. Tucker SB, Winkelmann RK: Treatment of Kaposi's sarcoma with vinblastine.
Archives of Dermatology 112(7): 958-961, 1976.
5. Scott WP, Voight JA: Kaposi's sarcoma: management with
vincaleukoblastine. Cancer 19(4): 557-564, 1966.
6. Klein E, Schwartz RA, Laor Y, et al.: Treatment of Kaposi's sarcoma with
vinblastine. Cancer 45(3): 427-431, 1980.
7. Odom RB, Goette DK: Treatment of cutaneous Kaposi's sarcoma with
intralesional vincristine. Archives of Dermatology 114(11): 1693-1694,
1978.
** IMMUNOSUPPRESSIVE TREATMENT RELATED KAPOSI'S SARCOMA **
Some patients with Kaposi's sarcoma have noted spontaneous and lasting
remissions following discontinuation of immunosuppressive therapy. If
immunosuppressive therapy is not critical in the management of the patient, its
discontinuation is a reasonable first step in these patients.
Standard treatment options:
1. Discontinue immunosuppressive therapy (often results in tumor regression).
This option is critically important in patients who are receiving
immunosuppressive drugs as in the case of certain transplant patients.
2. Radiation therapy (for disease limited to skin).[1-4]
3. Chemotherapy, single or multiple drug: Most systemic chemotherapy trials in
Kaposi's sarcoma patients have been carried out in the African and epidemic
varieties. See the section on treatment of epidemic Kaposi's sarcoma. The
applicability of the results of these trials to Kaposi's sarcoma in
immunosuppressed patients is unknown.
References:
1. Cohen L: Dose, time, and volume parameters in irradiation therapy of
Kaposi's sarcoma. British Journal of Radiology 35(415): 485-488, 1962.
2. Hamilton CR, Cummings BJ, Harwood AR: Radiotherapy of Kaposi's sarcoma.
International Journal of Radiation Oncology, Biology, Physics 12(11):
1931-1935, 1986.
3. Lo TC, Salzman FA, Smedal MI, et al.: Radiotherapy for Kaposi's sarcoma.
Cancer 45(4): 684-687, 1980.
4. Nisce LZ, Safai B, Poussin-Rosillo H: Once weekly total and subtotal skin
electron beam therapy for Kaposi's sarcoma. Cancer 47(4): 640-644,
1981.
** EPIDEMIC KAPOSI'S SARCOMA **
Treatment may result in a disappearance or reduction in size of specific skin
lesions and thereby alleviate the discomfort associated with the chronic edema
and ulcerations that often accompany multiple skin tumors seen on the lower
extremities and in control of symptoms associated with mucosal or visceral
lesions. There are no data, however, to show that treatment improves
survival.[1] In addition to anti-tumor treatment, essential components of an
optimal Kaposi's sarcoma (KS) treatment strategy include antiretroviral
treatment, prophylaxis for opportunistic infections, and rapid recognition and
treatment of intercurrent infections.
-- Local modalities --
Small localized lesions of KS may be treated by electrode siccation and
curettage cryotherapy or by surgical excision. KS tumors are also generally
very responsive to local radiation therapy, and excellent palliation has been
obtained with doses not much higher than 2,000 cGy.[2,3] One report
demonstrated a greater than 90% response rate with a median time to progression
of 21 months. Although no difference in response was noted with a variety of
fractionation regimens, a single fraction of 8 Gy is indicated for cutaneous
lesions and is associated with significantly fewer severe reactions.[4]
Radiation therapy is generally reserved to treat localized areas of the skin
and oral cavity. It is less often used to control pulmonary, gastrointestinal
tract, or other sites of KS lesions. Localized palatal KS lesions have also
been effectively treated with intralesional injections of vinblastine.[5]
-- Chemotherapy --
In epidemic KS, the already profoundly depressed immunologic status of the host
limits the therapeutic usefulness of systemic chemotherapy. Systemic
chemotherapy studies in epidemic KS have used as single agents or in
combinations doxorubicin, bleomycin, vinblastine, vincristine, and etoposide as
shown below.[6-10] The wide variation in response rates may reflect patient
selection and heterogeneity of the criteria used to evaluate response rather
than a significant difference in chemosensitivities.
Although a wide variety of single and combination drug regimens is available,
the current standard for first-line therapy uses one of the FDA-approved
liposomal anthracyclines. Liposomal encapsulation prolongs the circulating
half-life of the anthracyclines, increases drug concentration in the tumor, and
modifies the toxic effects profile.[11-14] Randomized, multicenter trials
showed an improvement in response rate and a more favorable toxic effects
profile compared to the combination of doxorubicin, bleomycin, and vincristine
(ABV) or bleomycin and vincristine (BV).[15-17]
Pegylated liposomal doxorubicin (PLD) (Doxil), at a dose of 20 milligrams per
square meter, was compared to a combination of bleomycin, at 15 units per
square meter, and vincristine, at 2 milligrams, in 241 patients. Both regimens
were administered by intravenous infusion every 3 weeks for 6 cycles. The
overall response to PLD was 58.7% versus 23.3% for the BV combination (p<.001).
Treatment with BV was associated with a higher incidence of peripheral
neuropathy (p<.001), whereas PLD was more commonly associated with neutropenia,
which resulted in the delay of treatment in some patients (p
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