Kaposi's sarcoma (KS) is a virally induced tumor most commonly appearing in the immunosuppressed. It is caused by infection with human herpesvirus-8, which in healthy individuals causes no symptoms. However, in patients with weakened immune systems, such as in HIV and organ transplant patients, the virus can proliferate leading to KS. Following the introduction of antiretroviral therapy (ART) for HIV and AIDS, the prevalence of AIDS-related KS has fallen, but it has begun to appear in subsets of patients on treatment. Treatments for KS vary depending on the cause of immunosuppression. In the case of HIV, ART is the first-line treatment, but other therapies are initiated based on tumor response. In transplant patients, primary treatment involves stopping or reducing immunosuppression and similarly advancing to other therapies based on response. This presents a dilemma in many cases where chemotherapy will reduce an already-weakened immune system or in strengthening an immune system in patients at risk for transplant rejection. This review will focus on summarizing the effects of immunosuppression in HIV-related (epidemic) and iatrogenically immunosuppressed transplant patients with KS and its etiology, pathophysiology, current treatments, and management along with novel therapies.
Kaposi's sarcoma (KS) is caused by infection with KS herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), a linear, double-stranded enveloped DNA virus, with its effect mainly seen on endothelial cells. It presents most commonly with skin lesions described as purple, brown, and red patches that progress to plaques to nodules. There are four commonly described subtypes of KS. The classic (sporadic) form is most prevalent in males over the age of 50 of European or Mediterranean descent that usually presents on the lower extremities. The endemic or African form is seen in sub-Saharan Africa, mostly in children suffering from chronic illness with substantial similarity to HIV-associated KS. The iatrogenic form is seen in patients on immunosuppressive drug therapy, typically transplant patients, again with similarities to endemic and HIV-associated KS. Finally, the epidemic form or AIDS-related KS is predominant in men who have sex with men (MSM) and arose after the HIV/AIDS epidemic in 1980.[2,3] KS has also been increasingly seen in a potential fifth patient subgroup containing MSM that are HIV seronegative with no identifiable immunodeficiency.
Etiology and Transmission of Kaposi's Sarcoma
KS is caused by HHV-8/KSHV which is found in all those who are affected. HHV-8 interferes with normal cellular function by invading and remaining latent inside the cells until switched to the lytic stage. Viral infection activates mammalian target of rapamycin (mTOR), thereby initiating mesenchymal differentiation and subsequent angiogenesis. It can maintain this through immunosuppression using the latency-associated nuclear antigen (LANA), an oncogenic protein that dysregulates various tumor suppressor pathways such as pRb and p53. It also blocks the expression of reactivation transcriptional activator thereby preventing lysis. It is mainly transmitted in the general population during childhood via saliva but can also be transmitted sexually, through blood transfusions, and by intravenous drug use. Seroprevalence of the general population varies widely but are highest in sub-Saharan Africa, with rates exceeding 50% and the Mediterranean between 3% and 20%.
Epidemiology/Risk Factors in Epidemic Subtype
KS is an AIDS-defining illness. The risk of an HIV-infected individual developing KS is 100,000 times greater than that of the general population. The incidence has since dropped with the introduction of antiretroviral therapy (ART), with a prevalence of 6% in a recent HIV-infected cohort after the introduction of ART. This sharp fall in the incidence of KS occurred around 1996 with the introduction of ART; however, with increasing drug resistance, those with AIDS are still at high risk.
There is a strong association with KS and immunosuppression, explaining why HIV-infected individuals are more at risk. A study measuring the CD4 T-cell counts and the risk of developing KS in patients with a new diagnosis of KS being treated with combined ART showed an inverse correlation. Low CD4 cell counts are, therefore, strongly associated with a higher incidence of KS. Overall, low CD4 cells, high HIV-1 viral loads, high circulating neopterin (a marker of cellular immune activation), and beta-2 microglobulin (an indicator of HIV progression) are strongly associated with KS.
However, the picture is not completely clear as a more recent study from 2016 found that, over time, KS can occur at higher CD4 counts with lower HIV RNA values. Improvements in ART access and earlier initiations of therapy are leading to an earlier suppression of HIV RNA and higher CD4 counts. This highlights the changing characteristics of KS manifesting in patients with HIV after immune recovery.
Epidemiology/Risk Factors in Iatrogenic Subtype
The risk of developing KS in solid organ transplant recipients is pronounced, but less than in AIDS, at 80–500 times greater than the general population. Being seropositive for HHV-8 before transplantation increases the risk by 23%–28% compared to being seronegative. It is also more prevalent in patients of Mediterranean, Jewish, Caribbean, African, or Arab descent, as in the classic form of KS. Patients undergoing transplantation are often on various immunosuppressive agents to prevent allograft rejection. KS typically presents between 13 and 21 months after transplantation.
Pathophysiology of Kaposi's Sarcoma
There are three main pathological states in KS lesions: the patch stage, plaque stage, and nodular stage. The patch stage is defined by spindle cell proliferation within irregular vessels lined by thin endothelial cells in the upper dermis. An infiltrate of extravasated red blood cells, chronic inflammatory cells, and hemosiderin-laden macrophages are frequently present. The plaque stage is characterized by spindle cell and vessel proliferation with more prominent spindle cell bundles, involving the dermis and extending into the subcutis. The inflammatory infiltrate is denser, with lymphocytes, plasma cells, and dendritic cells. In the nodular stage, the tumor is solid with well-defined nodules and large fascicles, containing spindle-shaped endothelial cell.[2,17]
Molecularly, KSHV activates the mTOR pathway, and the cells undergo mesenchymal differentiation causing vascular endothelial cells to transform and resemble lymphatic endothelium. HHV-8 infection alone is not enough to cause KS. It further requires some host immune dysfunction, as seen in HIV-positive and posttransplant patients. Immunosuppression and chronic inflammation allow HHV-8-infected cells to propagate. The growth of KS upregulates HHSV-8 gene products, affecting cellular proliferation, apoptosis, cytokine production, immune evasion, and angiogenesis. Around 25% of KSHV proteins have been shown to play a role in regulating aspects of the host immune system. The LANA-1, which causes p-53 binding and the suppression of apoptosis, is dominant among them and found in all forms of KSHV-associated malignancies such as Castleman disease and primary effusion lymphoma. Another protein named KSHV complement control protein aids viral entry and mediates viral evasion from the host's complement system. The transcription of KS-associated herpesvirus G protein-coupled receptor constitutively activates a series of transcription factors that induce the expression of growth factors, pro-inflammatory cytokines, vascular endothelial growth factor (VEGF), and other angiogenic factors. HHV-8 remains latent within cells, evading the host immune system until they can be induced to enter the lytic phase and produce intact virions.[2,18,19]
Clinical Presentation of Kaposi's Sarcoma
KS has been documented in almost every site in the body, but the skin, oral mucosa, lymph nodes, and visceral organs are the most commonly involved. The epidemic subtype of KS is generally more aggressive and can be attributed to HIV infection promoting HHV–8 replication. On the other hand, in patients receiving ART, the clinical presentation is substantially attenuated. The skin lesions in all forms of KS can be purple, red, or brown with plaque–like, papular, or nodular appearance and most often occur on the lower extremities, face, and oral cavity. See Figures 1 and 2 for examples of patches and nodular KS lesions.
The gastrointestinal (GI) tract is widely involved but is less prominent after the use of ART in HIV–related KS. GI lesions are often asymptomatic but may lead to bleeding, weight loss, nausea, vomiting, and other GI symptoms. GI symptoms as the first sign of KS in patients with HIV are uncommon, especially with no cutaneous lesions, but they have been reported.
Pulmonary involvement is also very common in AIDS-related KS and can involve the airways, pleura, parenchyma, and lymph nodes. It produces symptoms including dyspnea, cough, chest pain, and bronchospasm. Pulmonary involvement is more common in patients that have cutaneous presentations, but 15% of patients have no mucocutaneous lesions at diagnosis.[18,21] Rarely, the involvement of bone and skeletal muscle has been reported.
In patients with the iatrogenic form of KS posttransplantation, the presentation is typically cutaneous and mucosal. Visceral involvement in kidney transplant patients is rare, but it is more commonly seen in heart and lung transplantations that normally require greater immunosuppression to prevent rejection. This can explain the shorter survival rate of patients with KS postheart/lung transplantation. Interestingly, it is quite rare after allogeneic hemopoietic stem cell transplantations.
Treatment of Kaposi's Sarcoma
In posttransplant patients with KS, reduction or withdrawal of the immunosuppressive therapy is the first-line treatment. Naturally, this elevates the risk of acute organ rejection and failure and the possibility of recurrence if immunosuppressive therapy is restarted. The substitution of sirolimus, for others such as cyclosporine and tacrolimus, has shown KS regression without an increased risk of organ rejection. If the KS does not regress, treatment options are similar to the other forms of KS (except ART for HIV-related KS).
ART, previously called highly active ART and combination ART (cART), is the standard of treatment and is used virtually in all patients with AIDS-related KS. The CD4 cells usually recover in two phases after the initiation of ART. In the redistribution phase, an increase in the circulating memory T-cells originating from the lymphoid tissue is seen. Months later, in the repopulation phase, naïve T-cells are produced improving the overall immunity, and this is when the regression of KS is usually observed.[26,27]
Many studies have documented clear reductions in the incidence of KS since the introduction of ART. One study showed that ART-era KS patients survived longer with a 79% 1-year survival rate, compared to 59% in pre-ART patients. ART-era patients were also less likely to be diagnosed with other opportunistic infections. Treatment beyond ART is based on the extent of disease, speed of tumor growth, CD4+ T-cell count, and HIV-1 viral load.
Local symptomatic therapy can be started if there are limited disease-causing symptoms, but it does not prevent the development of new lesions elsewhere. Vinblastine is the most widely used intralesional agent. Systemic chemotherapy is used in the presence of extensive cutaneous disease, visceral involvement, and unresponsive KS. Radiotherapy has also been effectively used for localized forms. Liposomal doxorubicin and daunorubicin (anthracyclines) are the first-line chemotherapy agents due to their increased uptake, longer half-life, and lower toxicity.
Utilizing a stage-stratified approach where patients with skin-limited disease are treated with ART alone and patients with lymphedema or visceral involvement are treated with ART plus liposomal anthracycline chemotherapy has been effective. It results in high survival and decreases exposure of patients in early-stage KS to chemotherapy. Paclitaxel can be used in combination with ART instead of liposomal anthracyclines. Although it has more toxic potential, it can be used safely in the treatment of advanced and previously treated AIDS-related KS, especially in patients not responding to anthracyclines.
Often used in the iatrogenically immunosuppressed and patients with HIV, corticosteroid therapy has been associated with worsening preexisting KS and in the induction of KS. In these patients, the KS lesions may regress after the withdrawal of steroids.
A more recent study focused on immunotherapy with nivolumab and pembrolizumab and the use of checkpoint inhibitors. In these HIV-infected patients, the CD8+ T-cells have an impaired ability to produce cytokines and surveillance for malignancy. This in part appears to be due to increased PD-1 expression which may lower their ability for immune surveillance and contribute to the overall susceptibility of patients with HIV to KS. This overexpression offers a target for PD-1 inhibitors. Indeed, this study found a high response rate in HIV-related KS patients to PD-1 checkpoint blockade without significant toxicity. Nine patients were treated with PD-1 blockade, six had partial remission, and one had complete remission. Another report had similar results in two non-HIV-associated endemic KS cases treated with nivolumab, the so-called “significant partial response” with the ability to withdraw opioids from both patients who were previously opioid dependent to ambulate.
Pazopanib, a multitargeted receptor tyrosine kinase inhibitor, inhibits angiogenic pathways by inhibiting VEGFs. It was relatively well tolerated and demonstrated an excellent response in a single case of classic KS. This study highlights the importance of VEGF signaling in KS and offers a new target pathway that needs to be investigated with a formal clinical trial.
One ongoing clinical trial is looking into identifying biological and clinical subsets within the HIV-associated KS population in order to create a composite score specifically for KS, leading to more relevant treatment strategies for each patient. Another current trial is comparing the effectiveness of bleomycin and vincristine in the longitudinal quality of life of patients with HIV-associated KS.
KS demonstrates a complex interplay of immunoevasion by a virus and the development of tumors in the immunosuppressed. Regardless of transplant patients with iatrogenically weakened immune systems, chronically ill or malnourished in the endemic form, elderly Mediterraneans, or the HIV infected, a component of weakened immunity is ever present. Novel therapies including targeted therapies such as immune checkpoint blockade and tyrosine kinase inhibition have shown promise. While still rare in the developed world, the cases which do exist are often recalcitrant with treatment refractory to many traditional therapies. Cytotoxic chemotherapies are used in those where immune restoration is insufficient but often has significant toxicity and less than durable responses. In patients with weakened immune systems, chemotherapy often serves to further weaken their immune systems, placing them at even higher risk for infection. While in the early stages of study, targeted therapy has shown promise, an ongoing prospective trial of combined nivolumab and ipilimumab in HIV-related malignancies may elucidate the role of targeted therapy in these groups.
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