– Christian Hoffmann, Stefan Esser –
Kaposi’s sarcoma (KS) is the most common malignancy in patients with HIV infection. In 1981, the simultaneous occurrence of KS with pneumocystis pneumonias in young MSM led to the first description of AIDS. This entity is designated after the Hungarian dermatologist Moritz Kaposi who had described well 100 years before for the first time the ”classical” KS. Classical KS predominantly occurs in elderly, but otherwise healthy people from the Eastern Mediterranean area. It affects often only the skin at the lower extremities and thereby, clearly differs from HIV-associated KS which will be the focus of the following chapter.
In contrast to classical KS, HIV-associated KS may affect all skin and mucous membranes. Lymph nodes and internal organs such as stomach, gut, lung or liver may also be involved. The progression of HIV-associated KS is very variable and reaches from small lesions, remaining stable for years, to extremely aggressive courses, in which rapid progression may lead to death within a few months.
Compared to the 1980’s and early 1990’s, when KS was one of the most common AIDS illnesses, prevalence of KS today is relatively low (Francesci 2010). Since the early years of AIDS epidemic, the incidence fell to less than a tenth (Grabar 2006, Simard 2011). In addition, the clinical course of KS has changed with the introduction of antiretroviral therapy. The refractory variants with an aggressive, devastating and often fatal course which were seen in the pre-HAART era have became a rarity today.
The cellular origin of the spindle cells (considered as the KS tumor cells) is still controversially discussed. Newer investigations suggested lymphatic, endothelial cells (Dupin 2006). Since 1994, it is well known that KS is induced by an infection with the human Herpesvirus 8 (HHV-8) or Kaposi sarcoma associated herpesvirus (KSHV). HHV-8 can be always detected in the tumor tissue, and the level of HHV-8-plasma viremia correlates quite well with KS progression (Laney 2007). In HIV-infected patients with KS, a significant HHV-8 viremia is frequently found (Marshall 2010). Transmission of HHV-8 occurs predominantly by saliva (Pauk 2000), but also sexually, vertically and via blood products (Pica 2008). In some regions, particularly in Italy and Central Africa, HHV-8 can be found in up to 50% of the general population. The exact role of HHV-8 in the KS pathogenesis is not clear. Infection with HHV-8 does not lead inevitably to KS. Interactions particularly with HIV-1 (Aoki 2004), possibly also with other viruses such as HHV-6 and HSV-1, changed signal transduction chains, an increased production of growth factors as well as cytokine dysregulations may play a role (McCormack 2005).
Among the HIV population, MSM are almost exclusively affected by KS; in HIV-infected women, children or hemophiliacs KS is a rare disease. An immune defect and/or low CD4 T cells promote emergence and growth of KS. However, severe immunodeficiency is not a prerequisite for the development of KS which is one of the few AIDS illnesses occurring in patients with a relatively preserved immune status. Approximately 29% of all patients, who participated in the US in the years 1996-2007 in KS studies, had more than 300 CD4 T cells/µl and a HIV plasma viremia below the detection limit (Krown 2008). In one study, the activation of the CD8 T cells correlated more strongly with the progression than the number of CD4 T cells (Stebbing 2006). Although uncommon, there are some cases of very aggressive progressions occurring only a few months after introduction of antiretroviral therapy. This so-called IRIS-associated KS often comes with rapid pulmonary lesions (Crane 2005). High HHV-8 and HIV viremia seem to be risk factors (Letang 2009).
Signs, symptoms and diagnosis
HIV-associated KS does not have a preferential pattern of localization. It can begin on any area of the skin, but may also appear on oral, genital, or ocular mucous membranes. Typical findings at manifestation are a few asymptomatic purple macules or nodules. These lesions have a predilection for distribution along relaxed skin tension lines. As mentioned above, the disease progression is very variable: the tumors can remain unchanged for months to years, or grow rapidly within a few weeks and disseminate. Rapid growth can lead to localized pain and a yellow-green discoloration of the area around the tumor as a result of hemorrhage. Further progression of the tumor can lead to central necrosis and ulceration. The tumors may bleed easily. Plaque-like and nodular KS lesions, often become confluent and can be accompanied by massive lymphoedema. In the oral cavity, the hard palate is frequently affected. Lesions begin with purplish erythema and progress to plaques and nodules that ulcerate easily. KS lesions may also involve the external genitalia including the foreskin and glans penis.
Regression of KS during is not only indicated by size reduction of the lesions but also by colour changes from dark to bright red. However, some lesions may persist even lifelong. These often dirty-grey-brown to light brown hyperpigmentations are caused by hemosiderin deposits and, possibly, increased stimulation of melanocytes due to the inflammation. Lymphoedema can also persist over years.
Diagnosis of cutaneous KS is usually made based on clinical findings. However, in all inconclusive or questionable cases a histologic diagnosis (excision or incision) is recommended. Differential diagnosis includes other neoplasia such as cutaneous lymphomas or angiosarcoma, but also infectious diseases such as syphilis and bacillary angiomatosis. Histological findings include spindle-shaped cells with vascular channels lined by abnormal endothelial cells. Extravasated erythrocytes, hemosiderin, and fibrosis can often be seen.
In every case of KS, clinical staging procedures are recommended, including:
- Complete inspection (oral and genital mucous membranes!)
- Abdominal ultrasound
- Gastroduodenoscopy and coloscopy (both procedures obligatory when mucous membranes are involved)
- Chest radiography (exclusion of a pulmonary KS)
If KS is newly diagnosed in an HIV-infected patient who is naïve to antiretroviral therapy, ART should be initiated: In early KS stages additional chemotherapy is only required in 20% of cases (Bower 2009). In all patients on ART but without sufficient suppression of HIV plasma viremia, ART should be optimized. Treatment interruptions should be avoided (Silverberg 2007). With decreasing HIV plasma viremia and immune reconstitution, many KS lesions stabilize or even resolve completely without any specific treatment. In one Italian study on 22 consecutive, ART-naïve KS patients, the overall clinical response rate to ART only was 91%: 18 complete and 2 partial responses were achieved, and only two patients experienced disease progression. CR was sustained in all 18 patients (Cattelan 2005).
Animal and in vitro experiments have suggested a direct anti-proliferative effects of PIs (Sgadari 2002, Gantt 2011). However, there is no ART combination of choice for KS patients. PIs are not required necessarily as NNRTI-based regimens are also effective with regard to KS regression (Grabar 2006, Martinez 2006). With ART, there is also an improvement of the humoral response against HHV-8 (Sullivan 2010). ART interruptions should be avoided in patients with current or previous KS. In the SMART study, KS was among the most frequent AIDS-defining illnesses during treatment interruptions, in particular among patients with a history of KS (Silverberg 2007).
ART as the only therapy is not recommended in all cases. In patients with rapidly progressive disease, with KS-related symptoms, or with visceral disease, ART should be combined with cytotoxic chemotherapy. There are different options which will be discussed in the following.
Chemotherapy: should be considered in all patients with rapid progression of KS, with visceral involvement, lymphoedema or with persistant lesions during ART, especially in those with IRIS associated KS. Pegylated liposomal doxorubicin hydrochloride (Caelyx® or Doxil®) at a dosage of 20 mg/m² body surface is the treatment of choice (Di Trolio 2006). It has replaced older therapies such as the ABV regimen, a combination of adriamycine, bleomycine and vincristine. With Caelyx® complete remission rates of up to 80% are possible (Lichterfeld 2005). The infusions over 30-60 min every 2-3 weeks are ambulatory feasible and usually well tolerated. An antiemetic therapy is not necessary. Usually 6-8 cycles are required to achieve a good clinical response. Relapses during Caelyx® therapy occur rarely and particularly during the first year (Martin-Carbonero 2008). During treatment, myelotoxicity and cardiotoxicity of doxorubicin should be considered. Although the latter is rare and occurs only above cumulative doses of 450 mg, echocardiography (ejection fraction?) is recommend at the beginning of therapy as well as controls after six cycles. Another important side effect of Caelyx® is palmo-plantar erythrodysesthesia (PPE, “hand-foot-syndrome”), which becomes apparent as painful erythemas at hands and feet (Lorusso 2007). The incidence of PPE is increased in patients receiving Caelyx® compared with conventional doxorubicin.
In August 2011, Janssen-Cilag reported shortage of Caelyx® (Doxil®) due to production delays at a contract manufacturer. Intermittent capacity constraints are expected for the remainder of 2011. The company advised doctors not to start new patients on the drug. An alternative may be liposomal daunorubicine (DaunoXome®) which, however, appears to be less effective than Caelyx® (Cooley 2007). Of note, non-liposomal and non-pegylated forms of doxorubicin are not bioequivalent.
Beside doxorubicine and daunorubicine, paclitaxel (Taxol®) is also effective in KS (Tulpule 2002, Dhillon 2005, Stebbing 2006, Cianfrocca 2010). However, paclitaxel is more myelotoxic and leads almost always to complete alopecia, often already during the first cycle (patient must be informed!). Paclitaxel should be used only, if KS lesions show progression during therapy with Caelyx® or when Caelyx® or DaunoXome® are not available. Docetaxel (Taxotere®) is also effective according to uncontrolled studies (Autier 2005, Lim 2005). It should be mentioned that there may exist significant interactions between the taxanes and ART (Bundow 2004).
For the treatment of doxorubicin refractory cases, beside taxanes, oral etoposide (Evans 2002), irinotecan (Vaccher 2005) and the ABV regimen mentioned above may be considered. According to a retrospective study from Kenya, even gemcitabine has promising activity in KS (Strother 2010).
Immunotherapy: With interferons (IFN) acceptable remission rates are reached. However, CR rates seem to be lower than with pegylated liposomal doxorubicin (Kreuter 2005). The effect mechanism of IFN is KS is not fully clarified. Apart from an immune modulating effect, IFN probably induce the apoptosis in KS-cells. It is important to note that the effectiveness depends on the immune status. In patients with more than 400 CD4 T cells/µl, remission rates during IFN are at least 45%, compared with only 7% in patients with less than 200 CD4 T cells/µl. There may be some other factors predicting response to IFN such as endogenous IFN levels, which are increased in the advanced stage of the HIV infection.
There are currently no standardized IFN treatment regimens. Due to the considerable side effects, a high dose treatment (up to 30 million I.U./day) is not commonly administered. Daily doses of 3-6 million I.U. subcutaneously are usually given. After remission (tumour growth stopped, tumours flattened, loss of purple colour, change to brownish colour), interferon dosing can be reduced to 3x/week. Remission can be expected after 6-8 weeks of treatment (often significantly later). There is no sufficient data on the use of the pegylated IFN for HIV-associated KS. However, there are some promising case report in AIDS patients (Van der Ende 2007, Ueno 2007) and in patients with classical KS (Di Lorenzo 2008).
Table 1: Specific therapies for KS when ART is not sufficient
Pegylated liposomal doxorubicine (Caelyx™ or Doxil™)
20 mg/m2 i.v. every 2 weeks
Treatment of choice, cave myelotoxicity, cardiotoxicity, hand-foot-syndrome
Liposomal daunorubicin (DaunoXone™)
40 mg/m2 i.v. every 2-3 weeks.
Slightly less effective than Caelyx™, seldom used during the past decade. However, as capacity constraints for Caelyx™ are expected for 2011/12, an important alternative
Interferon-a 2a (Roferon™)
3-6 x 106 I.E. s.c. or i.m.
3 x / week
Considerable side effects, less efficacy than with doxorubicin. Use only when CD4-T cells are >200/µl and limited disease
Pegylated Interferon-a 2b (PegIntron™)
50 µg s.c. weekly
Tolerability improved compared to conventional IFN-a (2a,b), but lack of data in AIDS-KS, Off Lable-Use!
100 mg/m² i.v. every 2 weeks or
135 mg/m2 i.v. every 3 weeks
Cave neutropenia, peripheral neuropathy, allergic reactions, alopecia
Off Lable-Use! Caution with ART-interactions
Local therapy: is well-tolerated and less costly. Many different methods are used depending on the size and location of tumors: cosmetic camouflage, cryosurgery, intralesional injections of vinca alkaloids or interferons, soft x-ray radiation, electron beam therapy, cobalt radiation (fractionated) or Imiquimod (Celestin Schartz 2008). Compressive therapy with elastic stockings is an important strategy for the treatment of KS associated lymphoedema (Brambilla 2006).
KS is a strikingly radiosensitive tumor (Becker 2006). Superficial macular or plaque-like KS lesions respond well to daily doses of 4-5 Gy (total dose 20-30 Gy, fractionated 3x/week) of soft x-ray radiation. In the case of large KS lesions with oedema, radiation with fast electron beams (5 x 2 Gy per week, total dose 40 Gy) is recommended.
As KS is a multifocal systemic disease, surgical treatment is limited to excisional biopsies for diagnosis and palliative removal of small tumors in cosmetically disturbing areas. Since tumors often extend further into the surroundings than is clinically visible and local trauma can lead to new tumors (Koebner phenomenon), local and regional recurrences can be expected. These can be prevented by radiation therapy: in order to reach the tumor cells spreading along the vascular channels, the field of radiation should be extended 0.5-1.0 cm beyond the edges of the tumor.
New therapeutic approaches: With regards to the KS pathogenesis, several new therapies have been suggested such as virustatic agents, cytokines and inhibitors of angiogenesis. They will be discussed briefly.
· Valgancyclovir – promising approach as this antiviral agent significantly reduces the frequency and quantity of HHV-8 replication. This was recently shown by a randomized trial (Casper 2008). Better tolerability than foscarnet which had been discussed in the 90’s. However, there are no data on clinical efficacy in AIDS-KS published to date. As HHV-8 is involved in early steps of the KS pathogenesis, it is questionable if valgancyclovir has any effect on manifest lesions. In patients with classical KS, the drug remained inefficient (Krown 2011).
· Interleukin-12 – high response rates in a phase II study, in which this cytokine was combined with liposomal doxorubicin (Little 2007). No randomized studies.
· Sirolimus (and everolimus) – new immunosuppressive agents used in the transplantation setting. Good response rates in uncontrolled studies on HIV negative renal transplant recipients with KS (Stallone 2005, Campistol 2007). It is postulated that these drugs inhibit tumour angiogenesis through impaired vascular endothelium growth factor production.
· Bevacizumab – an early study of this VEGF-antibody showed moderate response rates in 31% of 17 HIV-infected patients with KS progression on ART (Uldrick 2010). A study on combination with liposomal doxorubicine is ongoing.
· Imatinib (Glivec®) – activation of the platelet-derived growth factor (PDGF) and c-kit receptors has been proposed as important in mediating the growth of AIDS- KS. Treatment with the PDGF receptor/c-kit inhibitor, imatinib mesylate, resulted in clinical and histologic regression of cutaneous KS lesions in 5/10 patients within 4 weeks (Koon 2005).
· Sorafenib (Nexavar®) – is an oral Raf kinase inhibitor, approved for the treatment of advanced renal cancer. Case reports on KS (Ardavanis 2008). Phase I studies are underway.
· Matrix metalloproteinases (MMPs) – are involved in tumour metastasis and are overexpressed in Kaposi’s sarcoma (KS) cells. MMP inhibitors such as COL-3 have shown activity in a phase II study on patients with advanced KS (Dezube 2006). However, clinical response rates were at best moderate with 41%. The most common adverse events were photosensitivity and rash. Encouraging phase II study with topical halofuginone (Koon 2011).
· Retinoid compounds (tretinoin, isotretinoin, acitretin) – may inhibit the proliferation of KS cells. Many studies on different formulations have been conducted (Duvic 2000, Bodsworth 2001, Bernstein 2002, Aboulafia 2003). However, efficacy is only moderate. Thus, retinoids will face a difficult path attaining approval for treatment of KS.
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