Kaposi’s sarcoma (KS) was the earliest and most visible manifestation of HIV infection when it was first described. In 1981, the Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report published an article about the unusual occurrence of KS and Pneumocystis carinii pneumonitis (PCP, later Pneumocystis jirovecii pneumonitis [PJP]), which is generally accepted as the first description of what came to be known as acquired immune deficiency syndrome (AIDS). There are four distinct KS variants: the classical or sporadic form, the endemic African form, the iatrogenic immunosuppression-related form, and the epidemic or human immunodeficiency virus (HIV)-related form.
KS is a malignancy of vascular endothelial cells and the result of co-infection with human herpes virus type 8 (HHV-8) (alternatively referred to as Kaposi’s sarcoma-associated herpes virus KSHV). HHV-8 has also been associated with primary effusion non-Hodgkin lymphoma and multicentric Castleman disease. There is some evidence that circulating growth factors, such as basic fibroblast growth factor and numerous cytokines (including interleukin 1, tumour necrosis factor and interleukin-6) also play a role in the pathogenesis of HIV-related KS.
The clinical KS variants are now thought to represent different manifestations of the same pathological process. Studies using increasingly specific and sensitive assays of HHV8 antibodies have shown that the prevalence of HHV-8 infection matches the rate of KS in different populations. Low rates (0.2-10%) have been demonstrated in the general populations of the USA Asia and many parts of Europe; high levels (50% or higher) occur in central Africa, and intermediate levels in Mediterranean countries. The background rate of HHV-8 prevalence in patients with HIV infection differs considerably according to the mode of transmission of HIV infection. Rates are high for males who have acquired HIV infection through male-to-male sexual transmission and low for those who have acquired HIV through intravenous drug use, blood or factor concentrate infusion, or heterosexual contact. Current debate still surrounds the exact nature of transmission of this virus. However, there is general agreement that, in endemic areas transmission occurs through saliva similar to the transmission of Epstein Barr virus, whereas in epidemic KS, sexual transmission is thought to be the major mode of transmission. The exact sexual activity which leads to acquisition of HHV-8 is not yet determined, although HHV-8 has been detected in both the saliva and semen of people with HHV-8 infection. Transmission has also been documented following organ transplantation. The risk of transmission via blood products is thought to be low, particularly for highly refined plasma products. The development of new KS after autologous bone marrow transplant is thought to originate from the cellular products necessary as clinical support through the transplant process rather than the immunosuppressive effects of the induction process.
Clinical presentations Immune-deficient people
Primary infection with HHV-8 appears to be asymptomatic. Immunosuppression is a cofactor for the development of disease in most patients. KS generally manifests as pigmented lesions involving the skin or the mucous membranes lining the mouth, nose, eye and anus. Skin lesions occur as plaques, patches or nodules. These are reddish or purple in fair-skinned people and bluish or brown in darker-skinned people. Although the skin lesions are usually painless, they can cause painful swelling, particularly when the lower limbs are affected. Internal organs may also be affected, with the gastrointestinal tract and the lung most commonly involved. Lymph node disease is also common. Nausea, vomiting and bleeding may occur with gastrointestinal tract involvement, and shortness of breath with lung involvement.
The clinical presentation of KS differs according to the KS variant. Epidemic KS occurs commonly in advanced immunosuppression, but may occur at any CD4 T lymphocyte (CD4) cell count. Presentation usually features multiple skin lesions often occurring in the lines of skin cleavage (Langer’s lines) – a phenomenon not seen in other KS variants. These skin lesions may rapidly multiply and progress to involve internal organs. The classical form of KS presents as skin lesions in localised clusters on the lower extremities and usually runs an indolent course over several years, with those affected usually dying from other causes. There is an association, however, with another primary malignancy, and clinicians should consider the possibility of other malignancies in individuals with KS lesions. Endemic African KS and iatrogenic immunosuppression-related KS usually present as skin lesions. These generally remain localised to the skin, but may spread in some patients and affect other organs. A particularly aggressive lymphadenopathic form of endemic KS occurs in young children and is rapidly fatal.
KS-associated immune reconstitution inflammatory syndrome Control of HIV replication usually leads to stabilisation or regression of KS disease in most patients. A paradoxical immune and inflammatory reaction brought about by the improvement in immune status on combination antiretroviral therapy (cART) occurs occasionally resulting in the development of KS-associated immune reconstitution inflammatory syndrome (KS-IRIS). Such KS may require a short course of systemic chemotherapy.
In a patient with HIV or risk factors for HIV, the diagnosis of KS should be considered for any skin lesion. However, diagnosis should rarely be made on appearance alone. Even the most experienced clinician will sometimes be fooled by a lesion mimicking the classical appearance of KS and, for this reason, the diagnosis is best confirmed by a punch biopsy and histopathological examination of the biopsy. The differential diagnosis of KS includes vascular lesions such as purpura, necrotising vasculitis, haemangiomas, angiokeratoma and venous lakes; inflammatory lesions such as pityriasis rosea, granuloma annulare, erythema multiforme, lichen planus and pyogenic granulomas; naevi, malignant melanomas and other cutaneous tumours such as basal cell carcinomas and mycosis fungoides. Other infective causes, such as secondary syphilis and bacillary angiomatosis, should always be considered.
The histological features of KS parallel the clinical appearance of the lesion. In the nodular form a well-circumscribed, non-encapsulated nodule is seen comprising tightly packed spindle cells. These cells form a vascular-slit pattern with extravasated erythrocytes. In the patch and plaque forms, the spindle cells are less tightly packed and form cleft-like arrangements between collagen bundles at all levels of the dermis. Haemosiderin-laden macrophages are seen in all types. In early lesions, spindle cells may be relatively few, but a striking perivascular infiltrate of plasma cells is often present. The histological appearance of KS may be easily confused with other conditions and should be assessed by an experienced pathologist.
Serological assays confirm past or current infection with HHV-8 and have little clinical utility in the diagnosis of KS. The potential relationship of HHV-8 viral load to the development or progression of KS is poorly understood and requires further investigation.
Therapies used to treat classical KS have proven effective in both endemic and epidemic forms of the disease. The response in epidemic KS is often less durable. In the vast majority of cases of epidemic KS, control of HIV replication itself through effective cART will lead to quiescence of KS disease, and regression of lesions already present.
There are, however, some circumstances when consideration should be given to immediate initiation of specific KS therapy. For example, extensive cutaneous disease and lesions causing discomfort or significant cosmetic problems. Examples include lesions on the face, over a joint, in the oropharynx or visceral lesions, or skin and nodal lesions in the groin or axilla causing lymphoedema.
A variety of local and systemic treatment options exist for KS. There are few definitive KS treatment guidelines so management is recommended in consultation with an expert.
Local treatments include radiotherapy and intralesional injections of chemotherapy. Intralesional chemotherapy is rarely used because of side-effects and the difficulties of administration. Radiotherapy to one area may be effective but needs to be reserved for urgent cases where systemic therapy is either inappropriate or has failed. The long-term side-effects of radiotherapy to lymph node draining areas in particular the groin need to be considered. Lymphoedema may be avoided or less severe if systemic therapy is used.
Systemic treatment in addition to cART may be necessary. Cytotoxic chemotherapy forms the mainstay of this approach. Better efficacy and less toxicity have made liposomal doxorubicin or daunorubicin the most useful single agents used to treat HIV-related KS. If required, they are generally given at a dose of 20 mg/m2 every 2 weeks with or without granulocyte colony stimulating factor (G-CSF) support. The treatment tends to be well tolerated with the main side-effects related to neutropenic sepsis. Hypersensitivity reactions during the infusion occur in about 5% of people, as with most liposomal compounds. The hand-foot syndrome is relatively common in non-HIV patients treated for metastatic breast or ovarian cancer but much less common in those treated for KS who are HIV positive. Cardiomyopathy, neuropathy and alopecia are rare. There are six randomised trials using single agent liposomal anthracyclines as a comparator versus alternative combinations and the single agent had superior overall response rates of about 80% and duration of response at 30 weeks. Quality of life was also better in the liposomal anthracyclines group. In one small study, the combination of cART and liposomal anthracyclines had a superior response rate to cART alone in a highly selected series of patients.
Paclitaxel, at a low dose of 100-135 mg/m2 every 2 to 3 weeks, is associated with response rates of around 71%. In patients who have failed other KS therapy, the response rate to paclitaxel is reduced to about 60%. Unfortunately the studies were not controlled for the use of cART. Side-effects include myelosuppression and neuropathy. Hypersensitivity is usually abrogated by the use of dexamethasone before infusion. Combination chemotherapy therapy regimes using doxorubicin, bleomycin and vincristine (ABV) are generally only appropriate when the two first-line agents are not available. Interferon alpha or beta have activity against KS, but can be toxic so are essentially outmoded therapies in the Australian setting.
New and experimental therapy
A variety of promising KS-specific agents such as retinoic acid were in development before the widespread introduction of cART. Retinoic acid inhibits interleukin (IL-6) production, an important cofactor in the pathogenesis of KS. There is evidence that anti-angiogenic agents such as thalidomide, matrix metalloproteinase inhibitors and imatinib have activity against HIV-related KS.
Antiviral agents such as ganciclovir and foscarnet may prevent the development of, or treat, KS in patients receiving them for cytomegalovirus infection. Trials of many of these agents have been abandoned because of the dramatic decline in the incidence of KS, leading to difficulties in trial recruitment and therefore evaluation of the efficacy of treatment.
Studies examining both progression and survival in epidemic KS in the pre-cART era found that progression of KS is best determined by markers of KS severity, whereas survival is best determined by markers of immunodeficiency (previous and concomitant opportunistic infections and low CD4 cell count). Even in the pre-cART era, fewer than 10% of AIDS patients with KS died as a direct consequence of their KS. In the post-cART era, it is generally understood that cART itself improves the outlook of those with KS - complicating HIV infection. If KS is rapidly progressive or symptomatic, systemic chemotherapy with, or followed immediately by, cART is indicated. The mainstay of systemic therapy is liposomal anthracyclines followed by paclitaxel as salvage. Other therapies are not often necessary but could include interferon, not often used because of its toxicities, or angiogenesis inhibitors such as thalidomide as occasionally referred to in case reports.
KS is not a curable condition. It tends to run a waxing and waning course reflecting the status of the immune system in the natural history of HIV disease progression and treatment. It is not uncommon for patients to require intermittent systemic treatment for years. They tend to re-respond to the same treatments although resistance to treatment can develop necessitating second and subsequent lines of therapy.
There is a paucity of randomised trial evidence evaluating the use of systemic therapies and cART. It is thought that protease inhibitor -containing regimens are not more superior to non- protease inhibitor -containing regimens.
The best prophylaxis for KS is treatment that restores immune function such as cART. Chemotherapy is not used prophylactically.