Version May 2024
INTRODUCTION — Kaposi sarcoma (KS) is an angioproliferative disorder that requires infection with human herpes virus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus (KSHV), for its development [1-3]. KS is classified into four types based on the clinical circumstances in which it develops: classic (the type originally described by Kaposi, which typically presents in middle or old age), endemic (several forms described in individuals from sub-Saharan Africa prior to the acquired immunodeficiency syndrome [AIDS] epidemic), iatrogenic (a type associated with immunosuppressive drug therapy, typically seen in renal allograft recipients), and AIDS associated (epidemic KS). The epidemiologic and clinical aspects of these four types of KS are compared in the table (table 1). Additionally, an increased number of cases of KS have been reported in men who have sex with men (MSM) without HIV infection [4]. While some have proposed that KS in MSM without HIV infection be recognized as a distinct fifth form of KS [5-8], one may argue that these individuals comprise a subset of classic KS, as the disease typically presents with relatively few lesions and takes an indolent course. (See "Primary care of gay men and men who have sex with men".)
This review will focus on the clinical presentation, staging, diagnosis, and treatment of classic KS. The epidemiology, risk factors, pathology, and molecular pathogenesis of classic KS are discussed elsewhere, as are AIDS-related KS and iatrogenic KS developing in the setting of immunosuppressive therapy. (See "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis" and "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis" and "AIDS-related Kaposi sarcoma: Staging and treatment" and "Malignancy after solid organ transplantation", section on 'Kaposi sarcoma'.)
CLINICAL FEATURES — Classic KS occurs most often in older males of Mediterranean or Central/Eastern European ancestry, in whom the lesions usually occur on the distal extremities, particularly the lower legs and feet (see "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis"). Initial lesions may occur in unusual cutaneous locations, however, in the absence of distal extremity involvement [9,10].
Skin lesions — Classic KS is characterized by the appearance of purplish, reddish blue, or dark brown/black macules, plaques, and nodules on the skin (picture 1A-C). Nodular lesions may ulcerate and bleed easily. The skin lesions range in size from very small to several centimeters in diameter, and they can remain unchanged for months to years, or grow rapidly within a few weeks and disseminate. (See 'Natural history' below.)
The dermatology literature contains reference to at least 10 different morphologic variants of the cutaneous lesions of KS, which are referred to as patch, plaque, nodular, lymphadenopathic (usually in African children), exophytic, infiltrative (the previous two in African adults with endemic KS), ecchymotic, telangiectatic, keloidal, and cavernous or lymphangioma-like variants [11]. Rare cases of apparently "classic" KS with cutaneous and lymphadenopathic features have been described in children outside Africa [12-16], in some cases associated with rare single-gene inborn errors of immunity without generalized immunodeficiency. The cavernous or lymphangioma-like variants are common in classic KS, particularly in the setting of chronic lymphedema. In this variant, lesions develop on the lower extremities that consist of compressible nodules that appear to be fluid-filled cysts. Histologically, lymphangioma-like KS consists of anastomosing networks of smaller, irregular, and compressible dilated lymphatics lined by flat and cytologically banal endothelial cells [17-19]. There are also additional descriptive categories, including hyperkeratotic (verrucous), micronodular, bullous, anaplastic, pyogenic granuloma-like [20], and intravascular KS variants [21].
There may be accompanying lymphedema of the affected extremity. The lymphedema is not generally associated with the presence of bulky regional nodal disease but, instead, is related to local dermal infiltration and/or dermal lymphatic involvement. (See "Clinical features and diagnosis of peripheral lymphedema" and "Clinical staging and conservative management of peripheral lymphedema".)
Extracutaneous involvement — During the course of the disease (rarely initially [22-24]), mucous membranes of the mouth and gastrointestinal tract, and regional lymph nodes may be affected. Gastrointestinal tract involvement is usually asymptomatic, but bleeding, diarrhea, protein-losing enteropathy, intussusception, and perforation have been reported [25,26]. In general, gastrointestinal tract/oral mucosal involvement is less common than with acquired immunodeficiency syndrome (AIDS)-related KS, affecting ≤10 percent of patients [27-29]. (See "AIDS-related Kaposi sarcoma: Staging and treatment".)
However, in one report, an extraordinary 82 percent of Greek patients (71 of 87) with biopsy-proven classic KS who were investigated with upper gastrointestinal endoscopy had gastrointestinal lesions; all 71 had stomach lesions, 19 had esophageal lesions, 8 had lesions of the proximal duodenum, and 2 had both esophageal and duodenal lesions [30]. Although this finding could be interpreted as suggesting the need for screening endoscopy in patients with newly diagnosed classic KS, it also supports the view that the presence of asymptomatic gastrointestinal involvement probably has little effect on prognosis. In practice, routine endoscopy is not performed in people diagnosed with classic KS who do not have symptoms referable to the gastrointestinal tract.
Regional nodal involvement is relatively uncommon, and it is rarely bulky. Nodal involvement was reported in 15 percent of 66 Greek patients with classic KS in one study [27]. The presence of nodal disease probably does not worsen overall prognosis, although this has been demonstrated in AIDS-related KS, not classic KS. Rare cases of isolated lymph node involvement with classic KS have been described [31].
Involvement of visceral organs other than the lining of the alimentary tract (eg, lung, liver, bone, bone marrow) is extremely rare [27,32-34].
Natural history — In most cases, classic KS has a chronic, indolent course, and it rarely influences survival. Given the affected age group, death from unrelated causes is more common [35-37]. As an example, in a series of 438 American patients with classic KS who were followed for an average of 4.8 years, 24 percent died of second malignancies, 22 percent died of other medical conditions, and only 2 percent died of widespread disease [38].
Yet, the disease occasionally has an acute onset and a rapidly progressive course, or previously indolent disease can undergo sudden worsening, leading to disability and even death [35,36,39,40]. In fact, Kaposi's original 1872 paper described the disease as "incurable and deadly," stating that "the disease leads to death, and it does so within a short period of two to three years" [41].
DIAGNOSIS AND STAGING — The diagnosis of classic KS is usually suspected based on the appearance of the characteristic lesions (purplish, reddish blue, or dark brown/black patches, plaques, or nodules) and their distribution (on the skin, most often of the lower extremities).
Differential diagnosis — In the lower extremity, the lesions can be mistaken for the skin lesions of peripheral vascular disease, a condition that is common in the older adult patients who are at greatest risk for classic KS. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)
Other lesions that may mimic the appearance of classic KS include bacillary angiomatosis and other infections, angiosarcoma, and benign vascular lesions, such as hemangiomas.
Bacillary angiomatosis is caused by the Bartonella species, a slow-growing, fastidious, gram-negative bacillus, and is readily treated with antibiotic therapy. The skin lesions of bacillary angiomatosis usually appear as numerous, small, red to purple papules that may gradually expand into large pedunculated lesions or nodules that may become friable. The rash may be associated with symptoms such as fever, chills, malaise, headache, and anorexia. Sporothrix schenckii (sporotrichosis) and Mycobacterium marinum skin infections could also be confused with the nodular form of KS. (See "Bartonella quintana infections: Clinical features, diagnosis, and treatment" and "Clinical features and diagnosis of sporotrichosis" and "Epidemiology of nontuberculous mycobacterial infections".)
A variety of less common dermatologic lesions may also be mistaken for classic KS [11].
Biopsy — Biopsy is required for definitive diagnosis. In addition to observing typical histologic features on standard microscopy, polymerase chain reaction can be performed on the skin lesions to detect amplified human herpes virus 8 (HHV-8) DNA sequences, and immunohistochemical staining of biopsy specimens can also be performed to detect the presence of HHV-8 latency-associated nuclear antigen (LANA-1) within the spindle cells, thus confirming the diagnosis. (See "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis".)
Radiographic evaluation — Asymptomatic patients with classic KS rarely require radiographic evaluation of the affected extremity because of the chronic, usually indolent course. Screening for distant organ involvement is not needed due to the low frequency of radiographically evident metastatic disease. When present, mucosal involvement of the gastrointestinal tract is not generally visible on radiographic studies. As noted above, patients with symptoms referable to the gastrointestinal tract should be considered for endoscopy to evaluate for visceral mucosal involvement. In the absence of symptoms, we do not routinely work patients up for visceral disease based on the status of the cutaneous disease.
Staging — In contrast to acquired immunodeficiency syndrome (AIDS)-related KS, there is no commonly used or universally agreed upon staging system for classic KS. (See "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Staging system'.)
The most recent American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system for soft tissue sarcomas of the extremity and trunk specifically excludes both classic and AIDS-related KS [42,43]. Given the variable natural history of classic KS, one group of investigators used their experience with 300 classic KS patients to derive a proposed staging system based on disease distribution and the clinical pace of progression [44]:
●Stage I (maculonodular stage) – Small macules and nodules primarily confined to the lower extremities.
●Stage II (infiltrative stage) – Plaques mainly involving the lower extremities, sometimes associated with a few nodules.
●Stage III (florid stage) – Multiple angiomatous plaques and nodules involving the lower extremities that are often ulcerated.
●Stage IV (disseminated stage) – Multiple angiomatous nodules and plaques extending beyond the lower extremities.
Stage I to III disease was further subdivided into slow (group A) or rapid disease progression (group B, defined as an increase in the total number of plaques/nodules or in the total area of plaques in the three months following an examination); all patients with stage IV disease were considered to have rapidly progressive disease.
In the original series of 300 patients, those classified as having stage I or II disease had a slower rate of progression, fewer complications, and a lower occurrence of gastrointestinal tract/visceral involvement. In contrast, patients with stage III or IV disease had more rapid disease progression and a greater likelihood of gastrointestinal tract/visceral involvement, local complications, and functional impairment. Rapid evolution was prevalent in the florid and disseminated stages (92 and 100 percent, respectively) and less frequent in the infiltrative and maculonodular stages (42 and 21 percent, respectively). Visceral involvement occurred only in patients with stage IIIB and IV disease (1.2 and 24 percent, respectively). Survival for the four groups was not reported.
The authors proposed using this classification scheme to select patients with the most aggressive natural history (ie, those with stages IIB, III, and IV disease) for systemic therapy. However, this staging system is not in widespread use. It is based on subjective rather than objective classification of the extent of disease, and its prognostic value has not been independently validated. Furthermore, its predictive value for response to systemic therapy has not been addressed.
TREATMENT
Overview of the general approach to treatment — Given the absence of treatments capable of eradicating latent human herpes virus 8 (HHV-8) infection, one can question whether any form of KS, including classic KS, can be considered "curable." Nonetheless, a number of strategies have been used to manage classic KS, with the major therapeutic goals of achieving symptom palliation, alleviating lymphedema, improving function, decreasing the size of cutaneous or visceral lesions, and delaying or preventing disease progression.
With relatively few exceptions, the published literature on treatment of classic KS consists of retrospective series and case reports. Prospectively designed phase II trials are scarce, usually include relatively few patients, and do not use standardized objective methods to document response. Furthermore, with a single exception [45], there are no prospectively randomized trials that compare different treatments for classic KS, making it impossible to identify the "best" approach. This is not surprising given the relative scarcity of the disease, the advanced age of many affected individuals, and the frequent presence of comorbidities that may limit treatment options and the ability to participate in clinical trials.
As an example, one retrospective review of 160 adult patients diagnosed with either classic (131 patients) or endemic (African; 29 patients) KS was conducted at a single dermato-oncology center [46]. At median follow-up of approximately five years, no treatment was required in 14 percent of patients, whereas local or systemic treatments were administered in 45 and 41 percent, respectively. Risk factors that were significantly associated with initiation of systemic therapy included endemic versus classic KS (hazard ratio [HR] 3.29), greater than 10 skin lesions (HR 3.64), visceral KS (HR 2.11), head or neck lesions (HR 2.21), presence of edema (HR 2.18), and delayed diagnosis (ie, time between first symptoms and diagnosis >1 year; HR 2.70). Similar response rates and durations were seen between patients with classic or endemic KS and between those who received systemic chemotherapy or interferon alfa. It should be noted, however, that precise criteria for initiation of systemic therapy, and the choice of therapeutic modality, were not described.
Despite the limitations described above, some general principles have emerged about classic KS treatment based on empirical evidence; the following represents our general approach to treatment:
●Observation without specific treatment is an option for patients who have a limited number of asymptomatic lesions that do not impair function, although disease progression eventually occurs in most patients. In a study of 39 patients with asymptomatic lesions who were observed without specific treatment, only 34 percent remained progression free at two years [35].
●Symptoms related to limited lower extremity edema can be alleviated in many patients with elastic compression stockings [47,48].
●When treatment is indicated, there are a variety of local and systemic tumor-directed therapy options, the choice of which depends on the extent, location, and pace of disease. Because many active treatments have been described, therapeutic choices are often made based on the experience and medical discipline of the treating clinician, but they also include consideration of patient preferences and comorbid conditions.
●The presence of regional nodal disease does not necessarily influence the choice of local versus systemic treatment. Unless the nodal disease is large and symptomatic (an uncommon scenario), we treat these patients based on the volume and extent of their local skin disease.
●There is no consensus as to the indications for systemic therapy. We consider this approach in (but not limited to) the following situations:
•Symptomatic visceral or mucosal involvement (although rare).
•Diffuse symptomatic lesions on multiple body parts that are not easily encompassed in a single or a limited number of radiation fields.
•Extensive nodular disease or diffuse involvement of a large portion of an extremity.
•Bulky disease in a localized area of one limb that cannot be encompassed within a single radiation therapy (RT) port.
•Moderate to severe associated lymphedema beyond what can be controlled with elastic stockings.
●For patients with an indication for chemotherapy and without cardiac contraindications, we suggest initial therapy with pegylated liposomal doxorubicin (PLD). (See 'Pegylated liposomal doxorubicin' below.)
•For those with an indication for chemotherapy and a cardiac contraindication to PLD, we offer initial therapy with paclitaxel as an alternative to PLD, extrapolating from data supporting the use of paclitaxel in AIDS-related Kaposi sarcoma. (See 'Paclitaxel' below.)
•For those with more limited disease, pomalidomide is an alternative option to chemotherapy. (See 'Initial therapy' below.)
●For patients with disease progression on initial therapy with either PLD or pomalidomide and who retain adequate performance status, options for subsequent-line chemotherapy include a single-agent taxane (eg, paclitaxel), oral etoposide, vinblastine or vincristine (alone or in combination with bleomycin), vinorelbine, or gemcitabine. For patients with indolent disease progression after initial treatment with chemotherapy, pomalidomide is an alternative for subsequent-line therapy. (See 'Subsequent therapy' below.)
●Individual patients may also be suitable candidates for investigational approaches such as HIV protease inhibitors, mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitors, molecularly targeted antiangiogenic agents (eg, pazopanib), and immune checkpoint inhibitor immunotherapy. In our view, these approaches are best considered in the context of a clinical trial. (See 'Investigational therapies' below.)
There is a need for prospectively defined studies that use well-defined response criteria to better define optimal treatment(s) for classic KS.
Options for local control — There are several options for local control directed at specific lesions or groups of lesions. There is no consensus on the optimal tumor-directed therapy for different classic KS manifestations. Because many active treatments have been described, therapeutic choices are often made based on the experience and medical discipline of the treating clinician, but they also include consideration of patient preferences and comorbid conditions.
Surgery — In some cases, if there is a single symptomatic lesion (eg, bleeding or chafing against clothing), excision alone may provide sustained local tumor control [35,36,49], but new lesions commonly develop at other sites. Curettage of single KS nodules followed by topical application of hydrogen peroxide (to achieve hemostasis) is a safe, effective, and simple method for lesion control [50].
Radiation therapy — All forms of KS, including classic KS, are very sensitive to RT. However, because of the multifocal nature of the disease, the persistence of HHV-8 even with successful local lesion control, and the tendency for new lesions to develop in nonirradiated areas, there is no consensus as to the place of RT in the therapeutic armamentarium (particularly when to choose RT over systemic therapy) or as to the optimal RT technique. One scenario in which RT might be chosen is if there were multiple lesions in a confined anatomic area, whereas one might be less inclined to use RT if there were one or a few lesions or if they were widely scattered.
Several successful strategies have been described [35,51-61]. High rates of tumor regression are reported using different energy sources (cobalt-60, low-energy electrons, superficial X-rays) to deliver local (or, occasionally, extended-field) RT. There is marked variation in total RT doses (6 to 60 Gy) and in fractionation regimens, which range from doses of 6 to 12 Gy in a single fraction to larger total doses administered in smaller fractions over several weeks [35,51,52,54-58,61]. One of the most commonly prescribed regimens is 30 Gy in 15 daily 2 Gy fractions [59,60].
Although durable local lesion control and symptom relief can be achieved in over 90 percent of cases, most publications do not clearly address the frequency of out-of-field recurrences and the eventual need for additional local or systemic therapy. Treatment of solitary lesions as they arise may require irradiation of numerous adjacent fields and can lead to dosimetric problems at junction points. For this reason, although overall response rates are similar, some authors prefer a strategy of subtotal-skin electron beam therapy over local involved-field RT because of the lower out-of-field recurrence rates [53]. One other frequently employed technique is treatment of the involved portion(s) of the feet and lower extremities (when extensively involved) using a water bath technique, which allows homogeneous radiation of a complex target. In one series using a split-course technique delivering 30 Gy in 10 fractions, disappearance of lesions was seen in 89 percent of patients, although limb edema only regressed in 57 percent [62].
Cryotherapy and laser therapy — As with acquired immunodeficiency syndrome (AIDS)-related KS [63], liquid nitrogen cryotherapy is sometimes used (mainly by dermatologists) for local control of small classic KS lesions [64,65]. However, the effect is mainly cosmetic, and there is no information on the impact of this form of local therapy on long-term disease control. Laser therapy may also be useful for selected cases [66-68].
Intralesional therapy — In our experience, intralesional injections, while capable of eradicating injected tumors, can be painful and lead to local scarring; we generally do not use this for treatment of classic KS. However, others have described the associated pain as tolerable, and some authors consider the best candidates for intralesional therapy to be patients with nodular classic KS without visceral involvement and with fewer than 10 lesions on acral sites [69]. The role of electrochemotherapy is unclear.
Intralesional injection of chemotherapy (most often vinblastine, but sometimes bleomycin or other agents) leads to local regression of cutaneous KS lesions [69-71]. Case reports have also described a high response rate in single nodular classic KS lesions treated with intralesional vincristine [71] or doxorubicin [72].
Although the characteristics of patients most likely to benefit from intralesional therapy have not been systematically studied, some authors consider the best candidates for intralesional chemotherapy to be patients affected by nodular classic KS without visceral involvement and with fewer than 10 lesions on acral sites [69].
Intralesional injection of interferon alfa-2a has also been reported to induce regression of classic KS lesions [73]. However, this treatment is unlikely to be practical for individuals with multiple cutaneous lesions as it requires multiple weekly injections over several months.
Electrochemotherapy uses a small electric current (electroporation, a form of electromotive drug administration) to increase drug delivery into the tumor; this approach has been used primarily with bleomycin. In one series of 23 patients with classic KS treated with this approach, all patients showed tumor regression, which was complete in 65 percent [74]. It should be noted, however, that general or spinal anaesthesia was required to administer the treatment. A similar response rate was noted in a series of 19 patients with stage I or II KS (according to the staging system described by Brambilla et al [44]) [75], and in another series of 18 patients, it was reportedly accompanied by a reduction of the HHV-8 viral load [76]. In the latter study, however, two patients with rapidly progressive disease failed to respond to electrochemotherapy.
Topical therapy — The literature is very limited on the benefits of topical therapy for classic KS. While there are no comparator trials, this approach could potentially be considered for patients with a limited number of lesions confined to a relatively small anatomic site who place a high value on avoiding the side effects of more conventional therapy, such as systemic chemotherapy or RT, or for whom other treatment approaches are contraindicated. The optimal agent is not established.
●Cis-retinoic acid – Alitretinoin (9-cis-retinoic acid) gel 0.1% is a US Food and Drug Administration (FDA)-approved topical treatment for cutaneous AIDS-associated KS, but published experience in classic KS is limited. (See "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Local symptomatic therapy'.)
A single case report of an older adult patient with classic KS noted a good local response, with partial or complete resolution of multiple treated cutaneous lesions, although the patient continued to develop new lesions in untreated skin [77]. Of note, another case report described the failure of alitretinoin gel in a patient with classic KS [78].
●Imiquimod – A prospective clinical trial of topical imiquimod demonstrated an objective response (complete or partial) in 47 percent of 17 patients with non-AIDS-related KS [79]. Response was assessed at only one point (36 weeks), and the duration of disease control was not reported. There was an inverse association between lesion area and response. A single case report described complete regression of extensive classic KS using topical imiquimod with occlusive dressings [80].
●Timolol – A few small case series note regression of classic KS lesions treated with topical timolol, a nonselective beta-adrenergic antagonist [81-83]. The use of such agents in KS is of interest given the clinical efficacy of oral and topical propranolol, another beta blocker, in the treatment of infantile hemangioma, a benign condition that, similar to KS, is characterized by abnormal angiogenesis. (See "Infantile hemangiomas: Management".)
Propranolol's clinical efficacy in infantile hemangioma, together with the proangiogenic effects of catecholamine signaling [84], prompted investigation of its potential anti-KS activity in an in vitro model of KS and led to the demonstration that propranolol treatment diminished the proliferative advantage conferred on endothelial cells by infection with Kaposi sarcoma-associated herpes virus (KSHV) [85], an effect that may be mediated via downregulation of vascular endothelial growth factor (VEGF) [86], an important driver of endothelial cell proliferation.
●Topical silver nitrate – A report described local control of 10 of 11 soft, fungating, and/or oozing classic KS tumors after cauterization with silver nitrate sticks [87].
●Nicotine patches – Based on the observation that smoking was associated with a reduced risk of classic KS, and the potential effects of nicotine both on immune function and vasoconstriction, a randomized, placebo-controlled trial of dermal nicotine patches was conducted in classic KS [88]. Treatment was well tolerated, but there were no significant effects on classic KS lesions, or on HHV-8 antibody titers or DNA levels in peripheral blood mononuclear cells [88]. (See "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis", section on 'Smoking'.)
●Rapamycin – A single case report described KS regression after 16 weeks of topical treatment with rapamycin (sirolimus) [89]
Advanced disease
Initial therapy — No cytotoxic chemotherapeutic agents have been approved in the United States or elsewhere specifically for treatment of classic KS, although a number of drugs approved for treatment of AIDS-associated KS or other neoplasms have activity against classic KS, either as initial chemotherapy or, in some cases, after failure of prior therapy. These include PLD, paclitaxel, vinblastine or vincristine (alone or in combination with bleomycin), oral etoposide, vinorelbine, and gemcitabine [35,37,45,90-105].
Pomalidomide does have regulatory approval in the United States for the treatment of both classic KS and AIDS-related KS. (See 'Pomalidomide' below and "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Indolent disease (pomalidomide)'.)
Pegylated liposomal doxorubicin — In patients with an indication for chemotherapy (ie, general, widespread, bulky, or rapidly progressive classic KS, particularly when it interferes with function or is associated with moderate to severe symptomatic edema or visceral organ involvement) and without cardiac contraindications, we suggest initial therapy with PLD, a drug approved in the United States for AIDS-related KS. (See "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Liposomal doxorubicin (preferred)'.)
We usually treat with one or two courses of chemotherapy beyond a stable maximal response and gradually stretch out the intervals between treatments. If there is no evidence of progression, we attempt to discontinue therapy and closely monitor, offering retreatment with the same regimen at the time of progression. Although systemic therapy has the potential to cause regression at all disease sites, the optimal duration of chemotherapy has not been systematically studied.
The benefit of initial treatment with PLD (20 mg/m2 every three weeks) was addressed in a retrospective multi-institutional series of 55 patients with classic KS [37]. A complete (absence of detectable lesions for at least eight weeks) or major response (≥50 percent decrease in the number of measurable lesions, and absence of new cutaneous lesions for at least eight weeks) was noted in 71 percent. The median time to response was four months, and the median response duration was 25 months.
Paclitaxel — Extrapolating from data supporting the use of paclitaxel in AIDS-related KS, we offer paclitaxel as an alternative to PLD in patients with an indication for chemotherapy and a cardiac contraindication to PLD. Although the optimal dose and schedule of paclitaxel administration has not been systematically studied, randomized trial data supporting the use of paclitaxel in AIDS-related KS suggested better tolerability for an every-three-week dosing schedule of paclitaxel when compared with an every-two-week dosing schedule historically reported in other trials [106,107]. These data are discussed separately. (See "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Paclitaxel' and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity".)
Pomalidomide — Pomalidomide is an acceptable alternative for patients with moderately extensive classic KS confined to the skin or oral cavity, or those with peripheral lymphedema. Pomalidomide has a tolerable toxicity profile and can be given orally [108]. However, some experts may still reasonably offer chemotherapy as initial treatment in these patients, as pomalidomide has only been evaluated in limited numbers of patients and has not been directly compared with chemotherapy in randomized trials. (See 'Pegylated liposomal doxorubicin' above.)
We do not offer pomalidomide to those with symptomatic pulmonary or visceral disease, or those with very bulky, ulcerated skin lesions, as pomalidomide has not been evaluated in such patients and further studies are needed to evaluate its clinical efficacy. These patients should be treated initially with chemotherapy in order to achieve immediate and rapid disease response. Additionally, we do not offer pomalidomide to patients with symptomatic peripheral neuropathy, which is a potential side effect. (See 'Pegylated liposomal doxorubicin' above and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Pomalidomide'.)
Pomalidomide is administered at 5 mg by mouth daily on days 1 through 21 of a 28-day cycle until disease progression or unacceptable toxicity. We suggest the following management strategies:
●Pomalidomide is associated with teratogenic risk and can only be prescribed through a Risk Evaluation and Mitigation Strategy (REMS) program.
●We concurrently administer low-dose aspirin daily for venous thromboembolism prophylaxis, using a similar approach to patients treated with this agent for multiple myeloma. (See "Multiple myeloma: Prevention of venous thromboembolism", section on 'During maintenance therapy'.)
●Specific issues regarding the use of pomalidomide in those with baseline kidney impairment and liver disease are discussed separately.
•(See "Nephrotoxicity of chemotherapy and other cytotoxic agents", section on 'Pomalidomide'.)
Pomalidomide was investigated in an open-label, single-arm phase I/II trial (12-C-0047) of 28 patients with KS, a majority of whom (75 percent) had previously received chemotherapy [109]. Among the cohort of 10 HIV-negative patients, overall responses were seen in 8 patients (80 percent), including one complete response (10 percent); median duration of response was 10.5 months. Grade ≥3 toxicities included neutropenia (50 percent), decreased phosphate (25 percent), elevated glucose (7 percent), elevated creatinine, rash, diarrhea, and peripheral edema (4 percent each). Neurologic toxicities of pomalidomide are discussed separately. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Pomalidomide'.)
Based on these results, the FDA granted accelerated approval for pomalidomide in HIV-negative patients with classic KS [110]. Pomalidomide has not been directly compared with other available systemic therapies, and further studies are needed in larger groups of patients to evaluate long-term survival and identify patient subgroups most likely to benefit from this agent.
The use of pomalidomide in patients with AIDS-related KS is discussed separately. (See "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Indolent disease (pomalidomide)'.)
Other agents — Other available options for initial therapy in classic KS include vinblastine or vincristine (alone or in combination with bleomycin), oral etoposide, vinorelbine, and gemcitabine.
Overall response rates for all of these drugs or drug combinations have been quite high (60 to over 90 percent), and the treatments are generally well tolerated, even in the older adult population at greatest risk for classic KS. Median response durations range from four months to over two years. One retrospective analysis of 32 patients with classic KS treated at a single institution showed that the presence of nodular lesions (versus macular lesions only) was associated with lower progression-free survival after chemotherapy [111].
In the absence of uniform, prospectively defined, objective criteria for inclusion or for response and progression, and in the absence of randomized trials, it is difficult to make recommendations for preferred treatments on the basis of response rates, duration of benefit, or adverse effects [112]. Only one randomized trial has been conducted in which two different systemic therapies were compared [45]. Sixty-five patients with classic KS were randomly assigned to oral etoposide (60 mg/m2 daily for three days for the first cycle, four days for the second cycle, and five days for the third cycle, as tolerated, with courses repeated every three weeks) or intravenous vinblastine (3 mg/m2 weekly for three weeks, then 6 mg/m2 every three weeks). There were no significant differences between the two treatments with regard to response rate (74 and 58 percent with etoposide and vinblastine, respectively), duration of response, or survival (median not reached in either group with a median follow-up of 38 months). Side effects were infrequent and mild in both groups, although alopecia, nausea, and vomiting (all grade 1 or 2) were more prominent with etoposide, and myelosuppression was more evident with vinblastine (grade 1 in seven, grade 3 in two).
Subsequent therapy
Chemotherapy — For patients with initial disease progression on PLD and/or pomalidomide, we offer paclitaxel as subsequent therapy. In a randomized trial of patients with AIDS-related KS, paclitaxel demonstrated a progression-free survival benefit compared with either oral etoposide or the combination of bleomycin plus vincristine and was well tolerated [106]. Further details of this study are discussed separately. (See "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Paclitaxel'.)
Alternative subsequent-line chemotherapy agents also include vinblastine or vincristine (alone or in combination with bleomycin); oral etoposide; or gemcitabine. The choice between these agents must be individualized, taking into account age, comorbidity, and personal preference.
Pomalidomide — Pomalidomide is an acceptable alternative for patients with indolent progression after initial chemotherapy. In phase I/II studies of patients with classic KS previous treated with chemotherapy, pomalidomide demonstrated overall response rates of approximately 80 percent [108,109]. Further details regarding pomalidomide are discussed separately. (See 'Pomalidomide' above.)
Other immunomodulators — Other immunomodulators have been studied in KS, but are not approved by the FDA for patients with classic KS.
●Thalidomide – Thalidomide, a prototypic member of a class of medications called immunomodulatory imide drugs, has antiangiogenic, anti-inflammatory, and immunomodulatory effects, similar to IFNa, and the drug is active in AIDS-related KS [113]. Experience with thalidomide is limited in classic KS [114,115]. One report noted activity in three patients with classic KS who received thalidomide 100 mg daily [114]. Two of the three had a complete clinical response after 12 months of treatment. In a second series, 3 of 11 patients with classic KS had a partial response to the same dose of thalidomide [115]. Three patients discontinued drug therapy prematurely due to sensory neuropathy or vertigo. Thalidomide is not an FDA-approved treatment for any form of KS.
●Interferon alfa-2b – Interferon alfa-2b is approved for treatment of AIDS-associated KS in the United States, but has limited availability as the manufacturer has decreased production. While the mechanism of antitumor action of this agent in KS is not known, it may involve direct antiproliferative effects, antiviral effects, inhibition of angiogenesis, and modulation of host cellular and humoral immune responses [116]. (See "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Subsequent therapy'.)
There is limited experience with interferon alfa-2b in classic KS. In a prospectively designed phase II clinical trial, 16 patients (13 with classic KS, 3 with endemic African KS), 9 of whom were refractory to chemotherapy and/or RT, were treated with interferon alfa-2b (5 million units subcutaneously three times a week) for a minimum of six months [117]. Major (complete or partial) tumor regressions were observed in 10 patients, and four other patients showed a minor response or stable disease. However, side effects, especially fatigue, low-grade fever, myalgias, and depression, can be prominent
Investigational therapies — For patients with KS, investigational approaches include HIV protease inhibitors, mTOR inhibitors, molecularly targeted antiangiogenic agents (eg, pazopanib), and checkpoint inhibitor immunotherapy. Patients with either HIV related or non-HIV related KS are encouraged to enroll in clinical trials, where available. If proven successful, it is likely that these approaches (with the exception of those specifically targeting HIV infection), would also apply to treatment of classic KS.
●HIV protease inhibitors – One study attempted to exploit the finding that HIV protease inhibitors exert antiangiogenic and antitumor properties that are distinct from their antiretroviral effects [118]. Sixteen of 28 patients with classic KS who were treated with indinavir were described as having benefits that included a complete response (n = 1), a partial response (n = 2), "improved disease" (n = 5), and stabilization of progressive disease (n = 8). The authors described an association between a favorable clinical course and higher plasma indinavir levels, reduced levels of basic fibroblast growth factor, lower numbers of circulating endothelial cells (a cell type reported to be increased in classic KS [119]), and a reduction in HHV-8 antibody titers.
●mTOR inhibitors – Case reports describing regression of classic KS in patients treated with the mTOR inhibitor rapamycin (sirolimus) [120,121] suggest that this approach, which has proven effective in some cases of transplant-associated KS, may be more generally applicable. Another member of this class of drugs, everolimus, has been used successfully to treat KS in transplant recipients; the reported experience with this agent in classic KS has been scant and mixed [122].
●Targeted therapies – Viral genes expressed during the lytic phase of HHV-8 infection may be particularly important in increased expression of growth factors such as VEGF and KIT, which stimulate angiogenesis and activate growth regulatory pathways, such as the phosphoinositide 3-kinase (PI3K) pathway, that lead to dysregulated cell growth. Overexpression of these factors may be exploited as treatment targets. (See "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis", section on 'Molecular pathogenesis'.)
As an example, pazopanib is a multitargeted receptor tyrosine kinase inhibitor that inhibits angiogenic pathways through inhibition of various receptor tyrosine kinases, including VEGF receptors 1 and 2; it is approved in the United States for treatment of advanced soft tissue sarcoma and renal cell carcinoma. A single case report describes a patient with classic KS who had an excellent response to low-dose (400 to 800 mg once daily), single-agent pazopanib after failing multiple lines of prior systemic chemotherapy and RT [123]. Although pazopanib is approved in the United States for treatment of advanced soft tissue sarcoma, we still consider its use investigational for classic KS, given the paucity of information on clinical benefit in this patient group. (See "Second and later lines of therapy for metastatic soft tissue sarcoma", section on 'Pazopanib'.)
●Checkpoint inhibitor immunotherapy – The use of checkpoint inhibitor immunotherapy remains investigational in KS, where tumors can express programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1), or high tumor mutational burden (TMB). Further prospective clinical trials, especially in those with classic KS, are necessary to determine the optimal immunotherapy regimen as well as predictive markers for treatment response [124-126]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)
•Pembrolizumab – Pembrolizumab, a PD-1 inhibitor, has promising clinical efficacy in patents with KS [127]. As an example, in a single-arm phase II trial of 17 patients with KS (eight with classic and nine with endemic disease) treated with pembrolizumab, the objective response rate was 71 percent, including complete responses in two patients (12 percent) [128].
•Other agents – Other immunotherapy agents that have been described in observational studies include single-agent nivolumab [129-131] and nivolumab plus ipilimumab [132,133].
Prevention of infection in sexual partners — A common question is the ability of patients with non-HIV HHV-8 KS to transmit the virus and whether there should be any specific precautions taken by patients with non-HIV KS with spouses, significant others, etc. There are no rigorously examined interventions for prevention of HHV-8 infection in the sexual partners of individuals with HHV-8 infection. Saliva is the body fluid that most commonly harbors HHV-8 [134]. It has been suggested that the use of saliva as a sexual lubricant may explain the high rate of HHV-8 infection among men who have sex with men [135]. It is not known whether this has implications for the prevention of HHV-8 transmission among heterosexual adults.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Kaposi sarcoma (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – Classic Kaposi sarcoma (KS) is a neoplasm characterized by abnormal angiogenesis that requires infection with human herpes virus 8 (HHV-8), along with other cofactors. (See 'Introduction' above.)
●Epidemiology – Classic KS arises most commonly in older adult males of Mediterranean and Central/Eastern European descent, but it can also occur in younger individuals, in females, and in other geographic areas. (See "Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis", section on 'Epidemiology'.)
●Clinical presentation – The most common presentation is that of purplish, reddish blue, or dark brown/black skin lesions (macules, nodules, plaques) on the lower extremities, often with lymphedema. (See 'Clinical features' above.)
Classic KS is frequently described as slow growing, localized, and indolent, but it can become disseminated and/or grow rapidly, and it can cause significant morbidity and mortality. (See 'Natural history' above.)
●Diagnosis – The diagnosis of classic KS requires a biopsy. Involvement of mucous membranes, lymph nodes, and visceral organs is relatively infrequent; radiographic staging evaluation and endoscopic screening are not routinely indicated in asymptomatic patients. (See 'Extracutaneous involvement' above and 'Radiographic evaluation' above.)
●Management of asymptomatic or limited disease – There is no consensus on the optimal tumor-directed therapy for different classic KS manifestations. Because many active treatments have been described, therapeutic choices are often made based on the experience and medical discipline of the treating clinician, but they also include consideration of patient preferences and comorbid conditions.
The following represents our general approach:
•We suggest observation rather than specific treatment for patients who have a limited number of asymptomatic lesions that do not impair function (Grade 2C). Symptoms related to limited lower extremity edema can be alleviated in many patients with elastic compression stockings. (See 'Treatment' above.)
•For patients who have limited-volume disease causing symptoms (eg, bleeding or chafing against clothes) or cosmetic disfigurement, we suggest local treatment rather than observation or systemic chemotherapy (Grade 2C). The choice of modality (radiation therapy [RT], excision, cryotherapy, laser ablation, intralesional or topical therapy) depends on a number of factors, including the site and extent of disease involvement, as well as clinician and patient preference. (See 'Options for local control' above.)
●Management of symptomatic or diffuse disease – There is no consensus as to the indications for systemic therapy. We consider this approach in (but not limited to) the following situations:
•Symptomatic visceral or mucosal involvement (although rare).
•Diffuse symptomatic lesions on multiple body parts that are not easily encompassed in a single or a limited number of radiation fields.
•Extensive nodular disease or diffuse involvement of a large portion of an extremity.
•Bulky disease in a localized area of one limb that cannot be encompassed within a single RT port.
•Moderate to severe associated lymphedema beyond what can be controlled with elastic stockings.
●Initial therapy – For patients with an indication for chemotherapy and without cardiac contraindications, we suggest pegylated liposomal doxorubicin (PLD) as initial therapy over other available agents (Grade 2C). (See 'Pegylated liposomal doxorubicin' above.)
For patients with indication for chemotherapy and a cardiac contraindication to PLD, we offer paclitaxel as an alternative to PLD, extrapolating from data supporting the use of paclitaxel in AIDS-related Kaposi sarcoma. (See 'Paclitaxel' above.)
For those with more limited disease, pomalidomide is an alternative option to chemotherapy. (See 'Pomalidomide' above.)
●Subsequent therapy – For patients with disease progression, there are several options for subsequent-line therapy in those who retain an adequate performance status. Available options include a single-agent taxane (eg, paclitaxel), oral etoposide, vinblastine or vincristine (with or without bleomycin), vinorelbine, or gemcitabine. Pomalidomide is an alternative for patients with indolent progression. The decision must be individualized, taking into consideration patient age, accompanying comorbidity, and clinician and patient preference. (See 'Subsequent therapy' above.)
●Investigational approaches – Investigational approaches include HIV protease inhibitors, mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitors, molecularly targeted antiangiogenic agents (eg, pazopanib), and checkpoint inhibitor immunotherapy. Patients are encouraged to enroll in clinical trials, where available. (See 'Investigational therapies' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas F DeLaney, MD, who contributed to an earlier version of this topic review.
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