Kaposi sarcoma: review and medical management update Mahnaz Fatahzadeh, DMD, MSD, Newark, NJ

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MEDICAL MANAGEMENT AND PHARMACOLOGY UPDATE

Kaposi sarcoma: review and medical management update

Mahnaz Fatahzadeh, DMD, MSD, Newark, NJ

NEW JERSEY DENTAL SCHOOL-UMDNJ

Despite recent advances in our understanding of pathogenic mechanisms involved, the true nature of Kaposi sarcoma remains an enigma. Four clinical variants have been described for the disease, differing in natural history, site of predilection, and prognosis. All forms of Kaposi sarcoma may manifest in the oral cavity and Kaposi sarcoma–associated virus appears essential to development of all clinical variants. The spectrum of therapeutic strategies is broad and selection of appropriate intervention mandates a thorough understanding of disease spread and the patient’s symptomatology, as well as risks and benefits of therapy. This article provides an overview of epidemiology, subtypes, clinical course, pathogenesis, and management strategies for Kaposi sarcoma. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:2-16)

Kaposi sarcoma (KS) is a multifocal angioproliferative disorder of vascular endothelium, primarily affecting mucocutaneous tissues with the potential to involve viscera.

¹

Four clinical variants of classic, endemic, iatrogenic, and epidemic KS

^2,3

are described for the disease, each with its own natural history, site of pre- dilection, and prognosis.

^4,5

In the absence of therapy, the clinical course of KS varies from innocuous lesions seen in the classic variant to rapidly progressive and fatal lesions of epidemic KS.

^6,7

Classic KS is a rare and mild form of the disease first described by the Hungarian dermatologist Moritz Ka- posi in the 19th century as a vascular tumor affecting the lower extremities of elderly men from the Mediter- ranean region.

^8,9

Although primarily detected in the Eastern European and Mediterranean basin,

^10,11

pock- ets of this variant in other geographic regions have also been reported.

^5,12

The male-to-female ratio for classic KS is 17:1

¹³

and lesions primarily present as multiple purplish-red pigmented plaques on the skin of arms, legs, and trunk of men older than 50 years in the endemic areas.

^5,11,14

Lesions tend to start on the ex- tremities, progressively enlarge, and spread to more proximal sites.

¹⁴

Classic KS has an indolent course, often spares viscera, and does not require aggressive therapy.

^11,15

There is evidence that some patients with classic KS may be at a greater risk for development of solid or hematopoeitic neoplasms.

¹⁰

Iatrogenic KS refers to the form associated with the use of steroids, immunosuppressive agents, and drugs

with antitumor necrosis factor (TNF) activity in pa- tients with autoimmune disorders, inflammatory condi- tions, or solid organ transplantation.

^16-20

Interestingly, the incidence of KS following bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation is low with only a few cases reported in the literature.

^21-23

Iatrogenic KS has a 3:1 male predilection

¹³

; may involve mucocutaneous tissues, lymph nodes, or vis- cera

^2,24

; and tends to affect liver transplant patients more often than recipients of kidney or heart allo- grafts.

²⁵

Although no clear association between dose or duration of immunosuppressive therapy and de- velopment of iatrogenic KS has been reported,

¹⁹

discontinuation of therapy appears to improve iatro- genic KS.

^2,3,4,19

African or endemic KS is a variant of disease affecting human immunodeficiency virus (HIV)-se- ronegative children and young adults in sub-Saharan Africa.

^9,26

Following the HIV epidemic, the inci- dence of this variant has increased significantly, par- ticularly in the pediatric population, in the African subcontinent.

^13,27-30

The clinical course of endemic KS is variable and includes indolent skin disease, locally infiltrative lesions of extremities, and aggres- sive visceral involvement with potentially fatal se- quela.

^5,9,11,31

Generalized lymphadenopathy is a common feature of endemic KS,

^9,32

and oral mucosa is infrequently affected.

³³

Epidemic or acquired immunodeficiency syn- drome (AIDS)-associated KS (AIDS-KS) is the most common variant and a more aggressive form of this disorder.

^9,11

It is also the second-most frequent tu- mor affecting HIV patients worldwide,

³⁴

known to have an unfavorable prognosis in the absence of therapy.

^9,31,35

The incidence of epidemic KS is cor- related with the mode of HIV acquisition

^36-38

and in the western hemisphere, HIV-seropositive male ho-

Associate Professor, Division of Oral Medicine, Department of Di- agnostic Sciences, New Jersey Dental School-UMDNJ.

Received for publication Feb 15, 2011; returned for revision May 11, 2011; accepted for publication May 15, 2011.

2212-4403/$ - see front matter doi:10.1016/j.tripleo.2011.05.011

2

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mosexuals are 5 to 10 times more at risk for KS compared with other groups with high-risk behav- iors.

³⁴

This is in stark contrast with Africa, where AIDS-KS affects younger age groups and both gen- ders, albeit unequally.

³⁹

Although epidemic KS may develop throughout the entire spectrum of HIV disease, it is more likely to occur in the context of advanced immunosuppression,

⁶

and could represent the first manifestation of HIV in- fection in some patients.

¹⁵

Lesions of AIDS-KS tend to enlarge, multiply in number, become more nodular, or coalesce in association with immune deterioration and drop in CD4 count.

⁴⁰

Epidemic KS often affects mu- cocutaneous tissues as multifocal plaques, patches, and nodules with a predilection for the face and lower extremities (Figs. 1 and 2).

^1,6,41,42

More than half of patients with AIDS-KS may have visceral involvement.

³⁴

Manifestation of AIDS- KS in the gastrointestinal tract may occur indepen- dent of skin disease and lead to abdominal pain, diarrhea, weight loss, bleeding, and vomiting when symptomatic.

^1,34

Pulmonary KS, the second-most common site of extracutaneous KS, is a late and poten- tially fatal complication presenting with cough, dyspnea, and hemoptysis in symptomatic patients.

^1,43,44

Asymp- tomatic pulmonary KS may manifest with abnormal radiographic findings on chest x-ray, which could be differentiated from opportunistic infections by gal- lium and thallium scans.

^34,45

Lymphedema, a com- plication resulting from obstruction of lymphatics, frequently affects the lower extremities and perior- bital region of HIV patients.

^15,41

It may develop before or concurrent with diagnosis or progression of KS

²⁶

and, in the context of AIDS-KS, indicates ad- vanced disease and poor prognosis.

^6,32,46,47

MANIFESTATION OF KS IN THE ORAL CAVITY

All forms of KS may present in the oral cavity; how- ever, oral lesions are more likely to occur with the epidemic variant of the disease.

5,9,11,36,48,49

The oral cavity is the first clinical site of disease in 22% of patients with KS,

^5,36,50-52

and up to 71% of HIV pa- tients may develop oral KS concurrent with cutaneous and visceral involvement.

^5,36

Oral KS may also be the initial indication of undiagnosed HIV infection.

^9,15,36

The most frequently affected oral sites include hard palate, gingival, and dorsal tongue (Figs. 3 and 4).

^7,15,36

Oral KS may present as solitary, mutifocal, or multi- centric macules, plaques, or nodules of different sizes, varying in color from deep red to bluish-purple. Mul- tifocal lesions may gradually coalesce into confluent, exophytic masses affecting oral mucosa.

^36,53

Resorp- tion of alveolar bone underlying KS and tooth mobil- ity,

^54,55

primary intraosseous KS of the jaw bones,

⁵²

and involvement of major salivary glands have also been documented.

^54,56

Oral KS may cause local tissue destruction, pain, bleeding, difficulty with mastication, or interference with wearing of oral prosthesis.

^5,7

De- velopment of KS in the oral cavity also has prognostic implications for untreated HIV patients,

^15,57

who are found to have higher death rates than patients affected only by cutaneous disease.

^57,58

ROLE OF KSHV IN KS PATHOGENESIS The pathogenesis of KS involves infection with human herpes virus type 8 (HHV-8), also known as Kaposi sarcoma–associated herpes virus (KSHV).

³¹

KSHV is a DNA virus first isolated by Chang et al.

⁵⁹

from the KS lesion of an AIDS patient in 1994. It is believed to be the infectious agent necessary for devel- opment of all clinical subtypes of KS irrespective of

Fig. 1. Clinical presentation of an irregular pink patch at the

tip of the nose of an HIV-positive male.

Fig. 2. Clinical presentation of an irregular light purple patch on the upper thigh of an HIV-positive male.

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differences in presentation, natural history, or progno- sis.

^4,9,31,46

The finding that KSHV induces angiogenic and inflammatory cytokines, as well as gene products implicated in angiogenesis, may suggest a direct role for this virus in KS pathogenesis.

⁶⁰

Also, viral load of KSHV in lesions positively correlates with clinical progression of KS from patch/plaque to the nodular stage.

⁴⁶

The etiologic role for KSHV is further sup- ported by higher risk of KS development in KSHV- infected solid organ transplant recipients and HIV- seropositive patients.

^10,49

In addition, the rarity of KS occurrence following stem cell transplantation (SCT) has been attributed to elimination of latent KSHV res- ervoir from the body by total body irradiation before transplantation.

²³

Of interest is also the rare development of nonmalignant illness, including fever, cutaneous rash, splenomegally, hepatitis, bone marrow failure, and plas- macytosis coincident with primary infection or reactiva-

tion of KSHV in solid organ or peripheral blood stem cell (PBSC)/BM transplant recipients,

^61,62

development of which appears related to the patient’s immunosuppressed state.

²³

Some investigators recommend pretransplant screening of donors and recipients for KSHV, as well as prophylactic measures and close follow-up for KSHV-seropositive patients in highly endemic re- gions.

²³

Although necessary, KSHV may not be sufficient for initiation and progression of KS.

^4,7,31,36

This may ex- plain why despite high prevalence of KSHV in the endemic regions and in high-risk populations, KSHV infection is frequently asymptomatic and does not lead to KS.

15,46,63,64

Regression of iatrogenic KS with the cessation of immunosuppressive therapy also indicates KSHV may be an essential but insufficient cofactor in KS pathogenesis.

⁶⁵

In HIV-seropositive patients, detection of KSHV DNA in peripheral blood and in mononuclear cells of peripheral blood is shown to predict onset of KS.

^66,67

In men coinfected with both HIV and KSHV, the KS hazards appear to increase by 60% for each year of infection with HIV

⁶⁸

and KS pathogenesis probably involves a synergistic action between these viruses.

⁴⁶

It is postulated that HIV-mediated immune suppres- sion/dysregulation promotes T-helper type-1 cyto- kines, such as TNF-alpha, interleukin-1b (IL-1b), and IL-6.

^15,46,69

Production and release of HIV-Tat protein from HIV-infected cells further contribute to release of proinflammatory cytokines, vascular endo- thelial growth factors (VEGFs), and matrix metallo- proteinases (MMPs), facilitating proliferation of endothelial cells and development of KS.

^15,46,70

HIV-Tat protein and chronic state of inflammation also mediate reactivation and replication of latent KSHV, promoting expression of viral gene products implicated in angiogenesis.

^15,36,70

In this postulate, coinfection with HIV and KSHV in the presence of a chronic inflammatory state is conducive to initiation and progression of KS.

⁴⁶

This model is, however, incomplete, as KS also develops in HIV-seronegative patients, indicating that contribution of HIV gene products is not critical in all variants of KS.

^36,63

KSHV SEROPREVALENCE AND MODE OF TRANSMISSION

Seroprevalence of KSHV among the general popu- lation varies geographically and its precise mode of transmission is not clearly understood.

¹³

KSHV has been detected in a variety of body fluids and potential routes of transmission include vertical, horizontal through sex or oral shedding, blood transfusion, and injection drug use, as well as solid organ or BM transplantation.

^71-74

The pathogenesis of iatrogenic

Fig. 3. Clinical presentation of a bluish-purple mass affecting

the palatal aspect of maxilla in an HIV-positive male.

Fig. 4. Clinical presentation of purplish-blue gingival enlargement affecting anterior and right buccal maxillary arch in an HIV-positive male.

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KS may involve transmission of KSHV from the infected graft or reactivation of KSHV in seroposi- tive recipients in the context of immunosuppres- sion.

^49,72

In regions where KSHV infection is endemic, in- fection is probably acquired in childhood from sero- positive family members and seroprevalence rates increase with age reaching as high as 80%.

^71,75-77

The drop in the mean age of onset and loss of male predilection for AIDS-KS in the African subcontinent have been attributed to high KSHV seroprevalence among HIV-seronegative residents of sub-Saharan Af- rica and superimposition of AIDS-KS on the preexist- ing risk of endemic KS in these regions.

13,34,38,77,78

In view of both spread of the HIV epidemic in Africa and poor access to highly active antiretroviral therapy (HAART), infected patients often develop rapidly pro- gressive KS with life expectancy of fewer than 6 months.

^34,79

Several studies suggest mode of transmission may affect risk of KSHV infection.

^80,81

In a cohort of HIV-seronegative males from Brazil, KSHV sero- prevalence was higher among men who have sex with men (MSM) compared with males with an in- travenous drug use habit, suggesting a sexual route for KSHV transmission.

⁸²

Smith and coworkers

⁸¹

identified homosexual/bisexual but not heterosexual behavior as the independent risk factor for KSHV seropositivity among 2718 patients attending a sex- ually transmitted diseases clinic. Distribution pattern of KSHV seropositivity also mirrors that of sexually transmitted pathogens and HIV-infected homosexu- als have higher prevalence of KSHV antibodies com- pared with HIV-seronegative MSM.

^38,82,83

Despite the evidence in support of a sexual route of transmission for HHV-8,

^80,81

a number of studies sup- port a role for saliva and saliva-contaminated objects for transmission of KSHV between immunocompetent MSM.

^84,85

For instance, KSHV has been detected more frequently and at a higher viral load in saliva compared with genital and anal specimens collected from a group of homosexual males.

⁸⁴

Also, higher copy numbers of KSHV in saliva compared with semen have been found in patients with and without KS and independent of HIV status.

⁸⁶

Moreover, saliva samples from HIV- infected Kenyan women more often tested positive for KSHV DNA than plasma or vaginal swabs.

⁸⁷

It is possible that oropharyngeal epithelial cells harbor KSHV and facilitate its replication and shedding into saliva, contributing to viral transmission.

^84,88,89

KS HISTOLOGY AND DIAGNOSIS

KS lesions clinically resemble vascular entities and vary in color from pink to reddish-purple.

³²

Although

mucocutaneous discoloration is a classic feature of KS, isolated nonpigmented oral lesions have been docu- mented.

^90,91

Differential diagnosis of clinical mucocu- taneous lesions includes nevi, pyogenic granuloma, bacillary angiomatosis, hemangioma, angiosarcoma, and, when affecting bone-bearing oral tissues, also mel- anoma, leukemia, and lymphoma, as well as inflamma- tory or fibrotic gingival enlargements,

^5,7,92-95

necessi- tating histopathological tissue evaluation for definitive diagnosis.

^4,5

Microscopic features of KS are diagnostic and shared by all variants of the disease (Fig. 5).

⁹⁶

They include an abundance of proliferating mononuclear inflammatory and spindle cells, ill-defined vascular channels, hemor- rhage, and edema.

^9,60

Hemorrhage may result from the absence of smooth muscle cells known as pericytes in the newly formed blood vessels, causing leakage and erythrocyte extravasation.

⁶⁰

Histopathological features of KS become more prominent with clinical progres- sion from the early patch to plaque and more advanced nodular form of the disease.

^7,33

Microscopically, this is manifested as a transition from focally proliferative miniature vessels to tumorlike fascicles mainly com- posed of spindle cells and vascular network, as well as atypical and extravasated erythrocytes.

^64,92

In early lesions, the spindle cell component may be

sparse, leading to misdiagnosis of KS as a benign

vascular lesion.

⁵

In addition, bacillary angiomatosis

(BA) caused by Bartonella henselae, shares similar

clinical and microscopic features with early KS.

^1,4

Demonstration of the etiologic agent by Warthin-Starry

silver stain or a positive therapeutic response to doxy-

cycline, however, help exclude this infectious en-

tity.

^1,97

Identification of KSHV DNA by polymerase

Fig. 5. Histopathological photomicrograph of an oral KS lesion illustrating fascicles of pleomorphic spindle cells com- pressing extravasated erythrocytes with release of hemosid- erin seen as black-brown granules (hematoxylin and eosin, magnification⫻400).

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chain reaction (PCR) or immunohistochemistry and detection of KSHV latency-associated nuclear antigen (LANA) have been proposed for differentiation of KS from clinically similar lesions.

^7,98

Diagnosis of KS in a patient with unknown HIV status mandates evaluation for the presence of coexist- ing HIV infection.

^9,11

HIV-seropositive patients with lesions suggestive of KS should receive a diagnostic biopsy for confirmation.

⁶

Initial workup for staging AIDS-KS involves a complete physical examination that includes evaluation of skin, oral cavity, and rec- tum, as well as a chest x-ray.

⁶

When pulmonary or gastrointestinal disease is suspected, lesions may be visualized by bronchoscopy or endoscopy, respec- tively.

⁶

Presence of additional symptoms or physical and laboratory findings may necessitate other diagnos- tic workup.

⁶

Clinical features of lesions, such as color, surface features, and, in particular, presence of nodu- larity and KS-associated edema should also be docu- mented at each visit.

⁶

PATHOGENESIS OF KS

Lesions of KS are composed of a heterogeneous pop- ulation of cells expressing a variety of antigenic pro- files.

7,24,26,31,99

For example, the endothelial cells of KS express both lymphatic and vascular immunophe- notypes.

⁷

KS lesions test positive for CD-34, a glyco- protein expressed on blood vascular endothelium,

¹⁰⁰

and C-kit, expressed on both vascular and lymphatic endothelium.

¹⁰¹

The evidence for lymphatic expres- sion of endothelial cells includes positivity for D2- 40,

^102-104

a highly sensitive and specific marker of podoplanin glycoprotein that is not expressed on vascular endothelium.

¹⁰⁵

The current opinion sug- gests that infection of endothelial cell precursors by KSHV may lead to a cascade of intracellular events conducive to a hyperinflammatory state, angiogene- sis, and lymphatic differentiation.

^35,102

The patho- genesis of lymphedema in AIDS-KS may involve cytokine-driven local inflammation, KSHV-induced proliferation of lymphatic endothelial cells, obstruc- tion of lymphatic channels, and enlargement of af- fected lymph nodes.

¹⁰⁶

There is no consensus on whether KS represents a true malignant neoplasm derived from monoclonal expansion of a single neoplastic progenitor cell; a multicentric, reactive, polyclonal, angioproliferative disorder; or both.

^10,33,107

Although the monoclonal nature of advanced nodular lesions arising in differ- ent body parts has been demonstrated by several investigators,

^108,109

a number of questions remain unresolved. These include variable course of KS lesions, the absence of classic features of malig- nancy,

⁷

rarity of metastasis or anaplastic transforma-

tion, absence of cytogenetic abnormalities even with established monoclonality,

^110,111

and the potential for spontaneous regression,

^15,32

particularly with the start of HAART,

^112-114

all of which point to a reac- tive virus-induced angioproliferative pathogene- sis.

¹¹⁵

Proponents of this concept argue that disseminated KS probably results from multicentric proliferation of KSHV-infected endothelial cells at different sites rather than true metastatic spread as expected from a malig- nant process.

^15,108

Although early lesions may result from reactive polyclonal hyperplasia driven by inflam- matory mediators,

31,46,60,63

persistent cellular prolifer- ation also increases the risk of mutations leading to dysregulated growth.

⁶⁹

Clinically aggressive KS could potentially represent malignant transformation of a sub- set of monoclonal cells within advanced lesions.

^31,46,109

Future studies will help clarify whether KS represents a malignant neoplasia or an inflammatory hyperplasia.

⁹⁹

MANAGEMENT STRATEGIES

Selection of therapeutic interventions for KS depends on the location and variant of KS; the rate of progres- sion and distribution of lesions; the presence, absence, or severity of symptoms; the efficacy and potential side effects of therapy; the presence or absence of HIV infection and comorbidities; the degree of host immune competence; and the prognosis and preference of the patient.

2,3,4,6,34,116

Therapy for KS aims to palliate symptoms, reduce tumor-associated edema, and im- prove esthetics and function.

32,36,41,42,106

Therapeutic approaches for classic KS range from no treatment to surgical excision, local interventions, and radiother- apy.

^11,33

Management of iatrogenic KS often involves reduction or elimination of immunosuppressive therapy with or without local measures,

^3,4,32,117

whereas en- demic KS is frequently responsive to systemic chemo- therapy.

^3,32

Management of epidemic KS, in contrast, is not aimed at a cure but palliation and control of KS progression with HAART is considered an essential component of this process.

6,34,106,116

AIDS-KS AND HAART

There is evidence that epidemic KS often regresses with HAART

112-114,118

and that HIV patients under-

going antiretroviral therapy have a less severe form

of the disease compared with those naive to HAART

at the time of KS diagnosis.

^57,58,119

Potent antiretro-

viral medications have, in fact, led to a dramatic

decline in the incidence of KS among patients in-

fected with HIV.

^6,120

The criteria for staging epi-

demic KS, with the advent of HAART, have also

been modified.

¹

The current prognostic indicators for

staging of AIDS-KS, proposed by Nasti et al.,

¹²¹

(6)

include tumor extension (T) and HIV-related sys- temic illness (S) resulting in good and poor survival risk categories depending on the combination of prognostic markers (Table I). In this modified clas- sification, severity of immunosuppression reflected in CD4 count is not an independent prognostic indi- cator for staging AIDS-KS as initially put forth by the AIDS Clinical Trials Group (ACTG) Oncology Committee.

^121,122

In the post-HAART study by Nasti et al.,

¹²¹

treated HIV-positive patients with the com- bination of poor tumor stage (e.g., tumor-associated edema) and constitutional symptoms (T

₁

S

₁

) were found to have an unfavorable prognosis with a 3-year survival rate of 53%. In contrast, HIV patients on HAART with none or only 1 prognostic criteria (T

₀

S

₀

, T

₀

S

₁

, T

₁

S

₀

) were found to have a good prog- nosis with 3-year survival rates of 88%, 80%, and 81%, respectively.

¹²¹

In addition, within the T

₁

risk category, pulmonary involvement was predictive of poorest survival.

¹²¹

Suppression of viral replication and restoration of immunity by HAART has proven efficacious in control of disease in most patients considered to have good prognosis (T

₀

S

₀

, T

₀

S

₁

, T

₁

S

₀

).

1,34,78,112,123

Based on review of 9 prospective studies, Krown

¹²⁴

found that institution of antiretroviral therapy alone led to resolu- tion of early lesions of epidemic KS in 80% of patients.

Initiation of HAART in newly diagnosed patients or intensification of medical therapy in those resistant to or incompliant with antiretroviral therapy is, therefore, indispensable to treatment of HIV-KS.

^6,34,106

Never- theless, some clinicians advocate watchful waiting or consideration of CD4 cell count, viral load, and

active opportunistic infections prior to HAART ini- tiation for asympromatic KS (T

₀

S

₀

, T

₁

S

₀

).

^1,124,125

Despite these observations, HAART alone is not sufficient for advanced epidemic KS with poor prog- nostic index (T

₁

S

₁

), which requires additional interven- tions.

1,34,124,126-128

When tolerable, AIDS-KS with unfa- vorable prognosis (e.g., pulmonary involvement or rapidly progressive disease) is best managed with a combination of HAART and systemic chemother- apy.

34,35,41,106,113,129

Although protease inhibitors are thought to have specific antiangiogenic effects, the choice of HAART regimen does not appear to influence protection against epidemic KS.

6,35,126,130,131

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME—ASSOCIATED KS

In contrast to the general drop in the incidence and severity of AIDS-KS with HAART, some HIV-infected patients are at risk of developing KS within a few weeks of HAART initiation.

^15,34,132

This paradoxical exacerbation of opportunistic infections, such as KS, despite immunologic recovery and favorable virologi- cal response with HAART is known as immune recon- stitution inflammatory syndrome (IRIS).

³⁴

This phe- nomenon typically affects younger individuals who are profoundly immunosuppressed (CD4 ⬍ 100 cells/mm

³

) at the time of HAART introduction.

^133,134

IRIS may represent a pathogen-specific immune reconstitution in the presence of a dysregulated hy- perinflammatory state and high antigenic burden.

¹⁵

Although acute IRIS occurs in response to a subclin- ical infection within the first 3 months of HAART initiation, delayed IRIS often develops against anti- genic components of dead pathogens anytime after the first 3 months of therapy.

^15,132

To reduce the risk of IRIS, severely immunosuppressed patients naive to therapy should be screened for preexisting oppor- tunistic infections, educated about the potential risk of IRIS with HAART initiation, and monitored closely.

^15,134

The potential risk of IRIS with HAART initiation in patients with advanced immunosuppres- sion supports early institution of antiretroviral ther- apy to improve CD4 count and reduce viral load.

^135,136

Management of IRIS-associated KS gen- erally does not involve interruption of HAART but may necessitate additional modes of therapy.

¹⁵

Ta- bles II and III, respectively, provide an overview of the management strategies and the spectrum of ther- apeutic modalities for epidemic Kaposi sarcoma. The 5 drugs currently approved by the Food and Drug Administration (FDA) for treatment of HIV-KS in- clude 0.1% alitretinoin gel for topical therapy and daunorubicin citrate liposome (DNX), pegylated li- Table I. Post-HAART prognostic criteria in staging

epidemic Kaposi sarcoma

Prognostic indicators^a Definition^b

Tumor extension (T) T₀⫽ restriction of lesions to skin and/or lymph nodes and/or minimal oral disease^c

T₁⫽ presence of tumor associated edema or ulceration, extensive oral disease, or visceral involvement

Systemic disease (S) S₀⫽ no history of opportunistic infections, “B” symptoms,^dKarnofsky Performance Statusⱖ70

S1⫽ history of opportunistic infections,

“B” symptoms,^dother HIV-related illnesses, Karnofsky Performance Status⬍70

Based on references 1, 34, 42, 121, 122.

a and bInitially described by ACTG Oncology Committee for staging AIDS-KS.

cNon-nodular solitary Kaposi restricted to palate.

dUnexplained fever, night sweats,⬎10% involuntary weight loss or diarrhea⬎2 weeks.

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posomal doxorubicin (PLD), taxane paclitaxel, and interferon alpha-2b for systemic therapy.

^33,176,177

LOCAL THERAPY

Local therapy is safe, easy to administer, and effica- cious for limited, asymptomatic mucocutaneous lesions of AIDS-KS.

^1,34,126

It may also be considered when HAART is unavailable, response to HAART is less

than optimal, or as a palliative measure in patients with rapidly progressive mucocutaneous lesions causing pain, esthetic concerns, or interference with oral func- tion.

^34,36

In addition, local therapy may prevent pain, ulceration, and bleeding in indolent lesions of classic KS.

¹³⁷

Local delivery of chemotherapeutics to a large, solitary nodular lesion of classic KS may also provide additional benefit to ongoing systemic therapy.

^34,126,137

In spite of these benefits, the local approach is often costly and frequently unsuccessful in controlling the onset of new lesions.

¹

Radiotherapy is highly effective for management of local or regional KS causing pain, bleeding, or edema and remission rates in excess of more than 90% for AIDS-KS have been documented.

1,34,116,138

Radiotherapy has also been effectively used to treat solitary or widespread lesions of classic KS, achiev- ing response rates higher than 80%.

^5,11,139

Although generally well-tolerated,

¹²⁶

potential drawbacks of ra- diotherapy include risk of radiodermatitis with repeated cutaneous exposure, disease relapse because of radiation- induced fibrosis, and hyperpigmentation.

34,137,178,179

Although oral KS is highly responsive to radiother- apy,

^126,179

adverse effects, such as severe mucositis, hyposalivation, and dysguesia have been reported with total doses as low as 7.5 Gy delivered in mul- tiple fractions.

116,178-181

Oral toxicities are often transient and develop early in the course of therapy, necessitating close patient follow-up and institution of palliative measures as needed.

140,179,180

Effective doses range from 8 Gy as a single fraction to 30 Gy delivered over 10 fractions, and it is appropriate to individualize radiotherapy based on a patient’s needs.

125,179,181

Intracavitary contact irradiation—a technique similar to brachytherapy— delivered in 1 or 2 weekly fractions of 5 Gy each through a source intro- duced into the oral cavity has been reported as effec- tive, well-tolerated, and associated with only minimal mucosal sensitivity.

¹⁴¹

The potential for oral toxicity with external beam radiotherapy together with the Table II. Potential management strategies for epidemic Kaposi sarcoma based on disease severity

Severity of AIDS-KS Management approach

● T₀S₀(focal disease in the absence of systemic illness)^1,34

● T₀S₁(early but mildly symptomatic KS, e.g., minimal cutaneous disease)^1,34 HAART⫾ local therapy^1,34

● T₁S₀(slowly progressive AIDS-KS)³⁴ HAART³⁴

● Extensive disfiguring skin lesions¹

● Widespread, symptomatic cutaneous AIDS-KS⫹ edema¹

● Rapidly progressive AIDS-KS^1,34

● Symptomatic visceral involvement^1,34

● Obstructive or painful oropharyngeal AIDS-KS¹

● Inadequate response to HAART alone¹

● IRIS-associated KS³⁴

Based on reference 34. AIDS, acquired immunodeficiency syndrome; HAART, highly active antiretroviral therapy; IRIS, immune reconstitution inflammatory syndrome; KS, Kaposi sarcoma.

Table III. Spectrum of therapeutic modalities for epi- demic Kaposi sarcoma

Local/regional therapy

● surgical excision^11,15,137

● cryotherapy¹⁴⁸

● sclerotherapy^149,150

● intralesional vinca-alkaloids,137,144,145,149bleomycin,¹⁴⁶ interferon-alpha¹⁴⁷

● topical 0.1% alitretinoin,^151,152,* imiquimod 5% cream¹⁵³

● radiotherapy^138-141

● laser therapy^142,143 Systemic therapy

HAART

● NNRT-based therapy¹³⁰

● PI-based therapy^130,131 Chemotherapy

● Liposomal anthracyclins^154,155,*

● Paclitaxel^156,*

● Oral etoposide^157-159,*

● Combination agent ABV154,155,160or ABVb¹⁵⁹

● Single agent vincristine,¹⁶¹vinblastine,¹⁶²vinorebline,¹⁶³ bleomycin¹⁶⁴

Immune modulators

● Interferon-alpha 2b^165-167,* Experimental & targeted therapies

● Antiherpes therapy^168-170

● Angiogenic inhibitors (e.g., thalidomide)^171,172

● VEGF inhibitors¹⁷³

● Tyrosine kinase inhibitors¹⁷⁴

● Matrix metalloproteinases¹⁷⁵

ABV, doxorubicin, bleomycin, vincristine; ABVb, doxorubicin, bleo- mycin, vinblastine; HAART, highly active antiretroviral therapy;

NNRT, non-nucleoside reverse transcriptase; PI, protease inhibitor;

VEGF, vascular endothelial growth factor.

*Drugs approved by the US Food and Drug Administration for epidemic Kaposi sarcoma.

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availability of newer therapeutic alternatives support reserving this modality for limited but symptomatic or obstructive lesions of the aerodigestive tract.

^52,179

The focal, superficial mucocutaneous KS is ame- nable to surgical excision. Potential drawbacks in- clude functional impairment with repeat procedures in anatomical areas where tissue is sparse,

^11,138

as well as local recurrence of KS.

^11,126,137

In addition, oral KS is often diffuse or multifocal

³³

and not suitable for surgical excision.

^32,116

The laser ablation procedure has also proven effective in treating mac- ular KS affecting the face and oral cavity.

^142,143

Laser may also be used to treat the surgical bed of exophytic oral KS after excision to achieve postop- erative hemostasis.

⁷

Elastic stockings offer another form of local therapy for KS-associated edema af- fecting the lower exterimities.

³³

Intralesional injection with vinca alkaloids, such as vincristine and vinblastine, known to disrupt microtu- bular function, has been efficacious for local treatment of mucocutaneous lesions of classic and epidemic KS.

137,144,145

The procedure is painful, there is poten- tial for necrosis if healthy tissue is injected, and thera- peutic effects last about 4 months.

¹

Therapeutic effi- cacy for intralesional bleomycin and interferon-alpha (INF-alpha) in treatment of epidemic and classic KS, respectively, have also been demonstrated.

^146,147

Cryo- therapy with liquid nitrogen for focal skin lesions of AIDS-KS have been tried, yielding full resolution in 80% of cases, although the procedure may be associ- ated with local blistering and pain.

^32,148

Regression of oral KS with local administration of sodium tetradecyl sulfate has also been documented.

^149,150

Retinoid products appear to have an inhibitory effect on IL-6, a cytokine implicated in KS patho- genesis, and an antiproliferative effect on KS le- sions.

⁶

Application of 0.1% alitretinoin gel, the only self-administered FDA-approved topical agent for cutaneous AIDS-KS, has shown efficacy for skin lesions of both classic and HIV-KS.

1,34,151,152

Alit- retinoin gel needs to be applied 2 to 5 times daily as tolerated and therapeutic response may be delayed by 3 months.

^1,34

It is also expensive and may be asso- ciated with skin reactions.

^1,34

In a study of cutaneous KS in HIV-seronegative patients, the overall re- sponse rate to topical 5% imiquimod cream was 47%, although 53% of subjects experienced local erythema and pruritis.

¹⁵³

Compared with topical medicaments, such as alitretinoin or imiquimod, intralesional in- jections are more efficacious because of faster, more precise delivery of therapeutic agents;

¹³⁷

however, the need for the clinician to perform the injections renders these to be less attractive options.

¹³⁷

SYSTEMIC CHEMOTHERAPY

Although early lesions of epidemic KS (T

₀

S

₀

) are highly responsive to antiretroviral therapy, systemic chemotherapy is generally indicated for advanced disease with poor prognostic index.

1,34,124,126-128

The current first-line systemic therapy for advanced, pro- gressive AIDS-KS includes liposomal anthracy- clines, including PLD and DNX.

^1,34,106

PLD has been equally efficacious as a single agent compared with multiple agent systemic chemotherapy in man- agement of AIDS-KS.

^154,155

In patients with moder- ate to severe AIDS-KS, the addition of PLD to HAART led to a significantly better response rate (76%) compared with HAART alone (20%).

¹²⁷

Li- posomal formulations have improved the half- life and toxicity profile relative to anthracyclines alone.

^6,35,126

Nevertheless, the response to therapy is delayed by 3 to 6 months,

¹

and the main adverse affects include myelosuppression and opportunistic infections.

^1,6,34

Although the potential for these ad- verse effects is reduced by subcutaneous administra- tion of granulocyte colony-stimulating factor,

^34,114

development of anemia and neutropenia after multi- ple cycles of liposmal agents may necessitate reduc- tion of dose or cessation of therapy.

¹

Toxicity rele- vant to DNX includes stomatitis and infusion reactions.

³⁴

The second-line systemic drug approved by the

FDA for AIDS-KS in patients refractory to or intol-

erant of liposomal anthracycline, is paclitaxel.

^1,34,156

Similar to vinca alkaloids, paclitaxel polymerizes

microtubules and interferes with cell division.

^34,126

The response rate of advanced AIDS-KS to pacli-

taxel in different studies varies, but is reported as

high as 71%.

^1,156

Although well tolerated, the intra-

venous mode of administration and the potential for

bone marrow suppression, peripheral neuropathy, re-

nal dysfunction, alopecia, and arthralgia renders pac-

litaxel a less favorable agent than liposomal anthra-

cyclines in the management of widespread KS.

^34,177

Another second-line drug for progressive AIDS-

KS with incomplete response to liposomal anthracy-

clines is oral etoposide.

¹

Oral etoposide has been

effective in treatment of both severe classic KS and

advanced AIDS-KS.

^157-159

Although ideal for self-

administration and less myelosuppressive than vin-

blastine, the risk of alopecia and gastrointestinal

toxicity, as well as the potential for myelosuppres-

sion in up to 60% of those treated, necessitates close

follow-up and limits its application in therapy.

^1,6,126

Cytotoxic regimens with single or multiple chemother-

apeutic agents for AIDS-KS may be considered when

first- and second-line therapies (liposomal anthracycline

and paclitaxel) are unavailable or failed to resolve the

(9)

disease.

6,32,42,106

The first- and second-line agents are expensive and often not readily available in devel- oping countries burdened by the HIV epidemic.

⁶

The combination regimens, including doxorubicin, bleo- mycin, and either vincristine or vinblastine (ABV or ABVb) have been widely studied in AIDS-KS

⁶

with response rate varying from 25% to 88%.

154,155,159,160

The response rate and duration of response in AIDS- KS, as well as reported toxicities to single-agent cytotoxic therapy, such as bleomycin or vinca alka- loids, have also been variable.

^6,106

Single-agent vincristine is efficacious for AIDS-KS,

¹⁶¹

has a favorable hematological profile, and is generally safe for anemic and neutropenic patients.

¹

The potential risk for neurotoxicity, however, requires exclusion of patients concomitantly treated with specific antiretroviral drugs, as well as those with preexisting neuropathy.

¹

In addition, patients should be screened for neuropathy at each visit.

¹

Systemic vinblastine alone was found effec- tive in 25% of AIDS-KS cases treated, providing remission for nearly 4 months.

¹⁶²

Although less neu- rotoxic than vincristine,

¹⁸²

the risk of myelosuppres- sion is a concern with systemic administration of vin- blastine.

¹²⁶

In a study by Nasti et al.,

¹⁶³

efficacy in treatment of AIDS-KS was also achieved with vinore- bline, also a vinca alkaloid. Vinorebline has mild and reversible adverse effects and is effective in treating AIDS-KS refractory to regimens containing either vin- blastine or vincristine.

^126,163

The response rate of AIDS-KS to single-agent chemotherapy with bleomy- cin is also variable depending on dosing and route of administration.

^42,126,164

INF-alpha, an immunomodulatory agent with antivi- ral and antiangiogenic properties, has dose-dependent efficacy in treatment of AIDS-KS when administered systemically.

^1,165,171

This is particularly evident in pa- tients with relatively preserved immune function, lack- ing lymphomalike “B” symptoms and those with exclusively skin lesions.

106,165,166,171

Drawbacks, how- ever, include hepatotoxicity, flulike symptoms, myelo- suppression, and predisposition to opportunistic infec- tions.

1,34,167,183

Concurrent antiretroviral therapy with a lower dose of INF-alpha appear to provide similar therapeutic outcome for AIDS-KS with less toxic- ity.

^34,106,167

The delayed therapeutic response renders INF-alpha inappropriate for treatment of rapidly pro- gressive or symptomatic visceral KS.

^1,34,106

PATHOGENESIS-BASED THERAPEUTIC APPROACHES

In general, available systemic agents may be used for all forms of KS, although therapeutic efficacy, response duration, and severity of adverse effects may vary for different variants.

¹²⁶

To improve efficacy and overcome chemotherapy- associated toxicity, new therapeutic approaches have focused on direct control of KSHV for prevention and treatment of KS.

¹

Anti-herpes medications were shown to reduce plasma viral load of KSHV and prevent KS in KSHV-seropositive transplant recepients.

⁴

Anti-herpes drugs ganciclovir and foscarnet were found to reduce the risk of KS by up to 62% among HIV-positive subjects.

^168,169

Moreover, a decrease in mucosal repli- cation of KSHV with valganciclovir has been demon- strated.

¹⁷⁰

Although limited efficacy does not support the use of anti-herpes drugs alone,

¹

the combination of anti-herpes medications with HAART offers the prom- ise to diminish replication of both viruses, prevent new lesions, and help regress lesions already present.

⁷

Other efforts have focused on developing novel inhibitors to target angiogenesis,

^171,172

VEGF,

¹⁷³

tyrosine kinase,

^60,174

and matrix metalloproteinases,

^60,175

all of which appear to play a role in KS pathogenesis.

ROLE OF THE ORAL HEALTH CARE PROVIDER

All forms of KS may manifest in the oral cavity, and

KSHV appears essential to development of all clinical

variants. Although not clearly understood, oropharyn-

geal epithelial cells may harbor KSHV, facilitating its

replication and transmission through saliva. Oral health

care practitioners should be familiar with orofacial

manifestations of KS, contribute to prevention of KS by

educating patients about risk factors, and question those

engaged in risk behaviors about the presence of muco-

cutaneous lesions. Manifestation of KS in the oral

cavity may indicate further deterioration of the immune

system or signal development of IRIS following the

start of antiretroviral therapy. In an untreated HIV

patient, diagnosis of oral KS is also considered a sig-

nificant prognostic marker of survival. In addition, the

onset of oral KS may be the first sign of undiagnosed

HIV infection. Therefore, oral lesions clinically sug-

gestive of KS should be biopsied and patients with

biopsy-proven KS should be tested for HIV. Develop-

ment of KS in the oral cavity may cause local tissue

damage, pain, bleeding, or interference with oral func-

tions and prosthesis wear, all of which may negatively

affect a patient’s nutritional status, adherence to med-

ical therapy, and quality of life. Close communication

between an oral health care provider and the patient’s

infectious disease specialist facilitates a mutual under-

standing of the extent of KS spread, severity of symp-

toms, available therapeutic strategies, and potential ad-

verse effects of therapy. Oral health care providers may

contribute to interdisciplinary management of oral KS

by using a variety of local measures, such as surgical

excision, laser ablation, and intralesional injections to

(10)

help accessible oral lesions regress in size, and to provide palliation.

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