Spotlight on ocular Kaposi’s sarcoma: an update on the presentation, diagnosis, and management options

Abstract

Introduction:

Kaposi’s sarcoma (KS) is a multifocal low-grade vascular neoplasm that can affect the skin, mucus membranes, visceral organs, and lymph nodes. KS can also affect the ocular surface and adnexa and can masquerade as other entities, delaying prompt diagnosis.

Areas covered:

In this review, the manifestations of ocular KS are discussed along with theories for pathogenesis, common risk factors, and management options.

Expert opinion:

KS is caused by the oncogenic human herpesvirus 8 (HHV8). Immunosuppression in patients with HIV and AIDS contributes to the development of KS but conjunctival and ocular adnexal KS lesions are now uncommon in the era of anti-retroviral therapy. A high index of suspicion is required to diagnose ocular KS as these lesions can be mistaken for alternative entities. Prompt diagnosis can reduce significant morbidity and mortality by prompting a multidisciplinary systemic evaluation, particularly in immunosuppressed individuals. While surgical excision, cryotherapy, intralesional or systemic chemotherapy, and radiation are all viable treatment options, ongoing research to identify novel therapies and molecular treatment targets will help expand the armamentarium of therapeutics available for this disease.

1. Introduction

Kaposi’s sarcoma (KS) is a low-grade vascular neoplasm that is predominantly found on the skin [1], and is often also found in mucocutaneous areas, such as the nasal, conjunctival, buccal, and anal mucosa. KS lesions can additionally be multifocal with lymphatic and visceral organ involvement [2].

KS was first described by the Hungarian physician, Moritz Kaposi in 1872 [3]. KS lesions were originally described in immunocompetent Eastern European men. In the 1980s, KS was established as an AIDS defining illness, occurring in patients with CD4 + T cell counts <200, with 20% of patients having ocular adnexal and conjunctival KS lesions at the height of the AIDS epidemic [4-6]. Currently, KS is still one of the most common cancers associated with HIV occurring in patients with CD4 + T cell counts >200 [7-9]. KS is also considered an endemic disease in sub-Saharan Africa, affecting both children and older adults, and is associated with the high incidence of human herpesvirus 8 (HHV8) as well as HIV and AIDS in this region [10,11].

When affecting the eye, KS can manifest as red, pink, or violaceous lesions on the eyelids and/or the conjunctiva, with infrequent extension onto the cornea [12,13] or orbit [14]. In some cases, ocular KS can be the initial manifestation of the HIV or AIDS [15] but ocular KS lesions are now overall uncommon with the advent of anti-retroviral therapy (ART). Ocular KS lesions can also masquerade as other entities, delaying prompt diagnosis.

Since eye care providers can in certain cases be the first to identify KS lesions, it is critical for them to know the ocular manifestations of KS as well as understand the condition’s pathogenesis and various available treatment options. Expedient diagnosis of ocular KS can reduce significant morbidity and mortality and prompt multidisciplinary, collaborative care to ensure that affected patients receive appropriate ocular as well as systemic treatment.

2. Methods

A search of all articles published in the English language from 1872 to 2020 on the causes and treatment of KS was performed on the PubMed search engine. Search terms included: ‘sarcoma, Kaposi’ ‘Kaposi sarcoma on the eye,’ ‘Kaposi sarcoma on the conjunctiva,’ ‘conjunctival Kaposi sarcoma,’ ‘Kaposi sarcoma and human herpesvirus 8,’ ‘Kaposi sarcoma as opportunistic infection,’ ‘Kaposi sarcoma and AIDS,’ ‘Kaposi sarcoma and acquired immunodeficiency syndrome.’ These terms were used to find articles that were pertinent to this review article.

3. Pathogenesis

KS is a low-grade tumor of the vascular or lymphatic endothelial cells that is caused by the oncogenic virus HHV8 [16]. HHV8, also known as the KS associated herpesvirus (KSHV), has an estimated prevalence of 1–5% in the United States, more commonly in men who have sex with men, but is more widespread globally, with a prevalence of 10–20% in certain Mediterranean countries and 30–50% in parts of sub-Saharan Africa [17-19]. In 1994, Drs. Yuan Chang and Patrick S. Moore discovered that HHV8 caused KS lesions using representational difference analysis, a subtraction technique for identifying differences between genomes that is highly useful for researching the genetics of cancers such as KS [16,20].

Oncogenic viruses cause cancer by initiating a sequence of cellular events, which lead to the dysregulation of cell cycle checkpoints [21,22]. As a result, the infected cells become immortalized and proliferate in an uncontrolled fashion. Specifically, when considering the role of HHV8 in inducing KS, viral proteins arising from human gene homologues, such as v-cyclin and vFLIP, can lead to uncontrolled cellular proliferation, suppression of apoptosis, and blockage of cellular senescence [23-25]. HHV8 infection also induces expression of tyrosine-protein kinase Kit (cKit) leading to proliferation of tumor spindle cells [26]. Other important HHV8 genes involved in the pathogenesis of KS include latency-associated nuclear antigen (LANA-1), viral interleukin 6 (vIL-6), and viral G-protein coupled receptor (VGPCR) [27]. In addition, HHV8 infection may reprogram the host’s blood endothelial cells so that they resemble lymphatic endothelium, upregulating vascular endothelial growth factor receptor 3 (VEGFR3), platelet-derived growth factor receptor alpha (PDGFR-A), lymphatic vessel endothelial receptor 1 (LYVE1), and podoplanin [12,28].

Epidemiologic studies suggest that exchange of saliva or blood are the primary routes of HHV8 transmission [29-31]. Not all individuals infected with HHV8 develop KS as the body’s natural immune response is usually capable of suppressing HHV8 expression and eliminating HHV8 induced cancerous cells [32]. While often indolent in immunocompetent individuals, KS can become aggressive in those with underlying immunodeficiencies [33].

HIV and resultant AIDS can cause a decrease in T cell function leading to immunosuppression. Affected patients can suffer from opportunistic infections secondary neoplasia and viral-related cancers. In patients with HIV, the lack of an immune response to HHV8 infected cancerous cells contributes to the development of malignant/aggressive KS [34].

KS is the most common neoplasm in patients with HIV and AIDS. Several case reports have described ocular KS as the initial manifestation of HIV infection [15,35-37] or AIDS without any other AIDS-defining illness [6,15,38-41]. In these cases, patients presented with ocular lesions without significant histories indicative of HIV infection or AIDS-related illnesses. Histopathological examination of the lesions revealed they were KS, and subsequent serologic testing confirmed HIV infection and low CD4 + T cell counts. In one case by Kurumety et al. [39], a patient was known to be HIV-positive but had no prior history of AIDS-associated illness. In their original 1994 discovery of HHV8, Chang et al. found HHV8 DNA in over 90% of KS samples obtained from individuals with AIDS. In patients with AIDS-related KS, HHV8 has been identified in 95% of all tissue samples and 88% had antibodies to HHV8 [42,43]. Further studies have since found that over 95% of KS lesions of any type or origin contain HHV8 [16,44].

While certainly a strong risk factor for the development of KS, HHV8 infection alone is not sufficiently causative. The global prevalence of HHV8 infection supersedes the incidence of KS. This indicates that other factors are necessary for the occurrence of KS [43,45].

4. KS subtypes and cutaneous features

KS skin tumors can manifest across the entire body, presenting as macules, papules, or nodules that are red, purple, or dark brown in color. They can be flat patches or raised lesions, small or large in diameter, and may have associated ulceration and bleeding [4]. KS lesions can also involve the gastrointestinal tract, lungs, and lymph nodes. KS occurs more commonly in males and varies from asymptomatic disease to widespread multiorgan cancerous infiltration with high morbidity and mortality.

There are four separate, recognized types of KS: classical, AIDS-associated, iatrogenic or drug-induced, and African. All four types of KS are characterized by development of tumors in mucocutaneous areas as well as visceral and lymphatic lesions. However, the epidemiology and behavior of KS differ within these categories [46].

Classical KS is an indolent disease typically seen in immunocompetent males of Mediterranean and Jewish descent between the ages of 40–70 years. AIDS-associated KS is common among intravenous drug users and men who have sex with men aged 20–50 years; due to the weakened immune system in these individuals, AIDS-associated KS is much more aggressive than its classical counterpart. Prior to the advent of ART, AIDS-associated KS was one of the most fatal AIDS-associated cancers. Similar to AIDS-associated KS, iatrogenic KS also appears in individuals with weakened immune systems secondary to immunosuppressive drug therapies for autoimmune diseases or for the prevention of graft rejection after organ transplantation. The behavior of KS in this group varies but typically regresses after the immunosuppressive therapy is de-escalated or terminated. In contrast, African KS has near equal incidence in men and women and is primarily seen in children and middle-aged adults of African descent. There is a high seroprevalence of both HHV8 and HIV in this population and African KS tends to be more aggressive than classical KS. African KS can present with indolent nodular skin lesions, florid exophytic lesions that are locally aggressive, infiltrative lesions with deep bone involvement and widespread and aggressive lymphadenopathy, which is often seen in children [10,11,47].

5. Ocular KS clinical features

Conjunctival and ocular adnexal KS lesions can present either as flat lesions or elevated, fleshy, mobile masses that are bright red, dark brown, or violaceous in color with or without associated hemorrhage. Ocular KS lesions can manifest on the bulbar, tarsal, or palpebral conjunctiva including the plica semilunaris and caruncle and also develop on the eyelids and lacrimal sac. They rarely extend onto the cornea [13], invade into the orbit or involve the lacrimal gland [14]. When affecting the conjunctiva, KS most commonly involves the lower forniceal conjunctiva (Figures 1A and 2A) followed by the bulbar (Figures 2B and 3A) and upper forniceal conjunctiva [4]. With ocular surface and adnexal KS lesions, patients will often complain of foreign body sensation, irritation, or epiphora and can also report decreased vision if the lesions obstruct the visual axis.

Figure 1.

<This is a 51-year-old Hispanic male who is HIV-positive with CD4 + T cell count of 200 who presented with a large Kaposi’s sarcoma (KS) lesion in the right eye. A. Highly vascular tumor is noted in the inferior fornix of the right eye. This was surgically excised, and pathology confirmed KS. B. High resolution anterior segment optical coherence tomography (HR-OCT) of the KS lesion revealed a large hyperreflective, highly cellular, sub-epithelial mass. Note the significant shadowing due to the thickness of the lesion. Inset shows scan location.

Figure 2.

<This is a 99-year-old Iranian woman with chronic lymphocytic leukemia who presented with bilateral conjunctival KS lesions as well as skin lesions. A. Small KS noted in the inferior tarsal conjunctiva (black arrow) of the left eye. B. Large, highly vascular KS lesion seen in the interior fornix and medial canthus of the right eye. C. HR-OCT of the lesion revealed a large hyperreflective, highly cellular, sub-epithelial mass. Note vascular channels in the mass and significant shadowing due to the thickness of the lesion. Inset shows scan location. D. The patient had multiple purple skin lesions primarily on her chest.

Figure 3.

<A. This is a a 44-year-old Hispanic man with AIDS with a CD4 + T cell count of 147 who presented with a red mass on the inferior bulbar conjunctiva in addition to purple skin lesions. A. Red raised mass noted on the inferior bulbar conjunctiva. B. HR-OCT revealed normal thickness epithelium containing large luminal structures (white asterisk) with hyper-reflective walls located within the substantia propria.

Eyelid lesions can present as elevated, purpuric masses [36]. Lymphatic obstruction can occur with or without the presence of KS lesions causing marked eyelid thickening and edema (Figure 4). Larger eyelid lesions can cause lid margin deformities leading to secondary ptosis, entropion, or ectropion, lagophthalmos, or trichiasis that can lead to keratopathy, corneal erosions, or infectious keratitis [4,48]. Figure 5 highlights most common locations of ocular KS lesions.

Figure 4.

<This is a 31-year-old HIV positive Haitian man with KS lesions on the upper and lower eyelids with associated lymphatic obstruction causing eyelid fullness and edema on the right eye. Bulbar conjunctival lesions were also noted in this patient in both eyes.

Figure 5.

Illustration depicting common locations of KS lesions on the ocular adnexa and ocular surface.

High resolution anterior segment optical coherence tomography (HR-OCT) can be utilized to further characterize KS lesions on the conjunctiva. HR-OCT will reveal large, hyperreflective and hypercellular lesions in the sub-epithelial space (Figure 1B). Vascular channels can also be visualized within the lesions (Figures 2C and 3B). Posterior shadowing is common given the generally large size and thickness of these lesions (Figure 1B). Ocular lesions can also be accompanied by systemic lesions on the skin (Figure 2D) and in internal organs.

6. Histopathology and immunohistochemistry

Histopathological analysis of KS is performed after incisional or excisional biopsies of suspected lesions. Lesions can be obtained from conjunctival or periocular lesions but can also be performed from cutaneous or internal lesions if needed.

Dugel et al. proposed a histopathologic classification system comprised three types – Types I, II, and III – to better characterize KS lesions [49]. Type I lesions are characterized by thin, dilated vascular channels filled with erythrocytes and lined by flat endothelial cells with fusiform nuclei and scanty cytoplasm. Type II lesions are characterized by dilated, empty vascular channels surrounded by larger, fusiform endothelial cells with hyperchromatic nuclei. Type III lesions are characterized by large densely packed spindle cells with hyperchromatic nuclei and occasional mitotic cells surrounding slit-like vascular channels with. Type I and II lesions are often associated with a surrounding inflammatory infiltrate comprised macrophages, plasma cells, and lymphocytes [49,50]. The three types of lesions are part of a continuum with the progressive involution of granulation and vascular tissue into dense, compact spindle cells. At times, all three types can be present within the same lesion [49,51]. The pathologic subtype of a KS lesion is thought to correlate to its clinical appearance. Type I lesions are often flat and patchy in appearance while type II and III lesions tend to be more discrete, raised, nodular, and vascular in nature [49].

Immunohistochemical staining can show positivity for CD31, CD34, and podoplanin (D2-40) of the endothelial cells, confirming the vascular origin of these tumors [12,15,37,52]. Cells in KS lesions can also stain for factor VII, a clotting protein produced by endothelial cells [50]. Lastly, HHV8 DNA in KS lesions can be detected by reverse-transcriptase polymerase chain reaction [15,53] and HHV8 latent-associated nuclear antigen-1 (LANA-1) can also be detected via immunohistochemistry to help distinguish KS from other masquerading lesions [54,55].

7. Differential diagnosis of ocular KS lesions

The differential diagnosis of ocular KS lesions can be broad. Smaller and less discrete conjunctival lesions can be mistaken for a subconjunctival hemorrhage, pyogenic granuloma, conjunctival cyst, inflamed pinguecula, or a conjunctival foreign body [5,11,56]. Larger lesions can be misdiagnosed as a cavernous hemangioma, hemangiopericytoma, conjunctival lymphangioma, lymphoma, malignant melanoma, squamous cell carcinoma, or even metastasis [15,37]. Eyelid KS lesions can mimic cellulitis, eyelid ecchymoses or edema, recalcitrant hordeola or even squamous cell tumors of the eyelid [4,36,38,45].

Incisional and/or excisional biopsies of these lesions are needed to confirm the diagnosis via histopathologic and immunohistochemical studies as discussed above. Once the diagnosis has been established, prompt referrals are needed to dermatology, hematology/oncology, and infectious disease specialists to evaluate for systemic lesions and a conduct infectious disease work-up.

8. Treatment options for ocular KS

Treatment of ocular KS is often multi-pronged and is dependent on the number and location of lesions affecting the ocular surface and/or adnexa, systemic involvement, and the patient’s immune status. The goal of treatment in patients with KS involving the eye is to preserve vision, alleviate symptoms, and to improve cosmesis. Therapeutic options include surgical excision, cryotherapy, use of ART in patients with HIV/AIDS, chemotherapy, radiation, immunomodulatory agents, or molecular targeted therapies. A multidisciplinary approach with ophthalmology, hematology/oncology, radiology, and infectious diseases is required to treat patients.

8.1. Surgical excision

Primary surgical excision remains a common modality of treatment for localized KS lesions [57,58] but may be associated with recurrence as it is not curative of the underlying disease process [59]. There are limited case series that study the use of surgical excision in treating ocular KS with documented follow-up of only up to 4 to 6 months.

In a study by Dugel et al., 14 AIDS positive patients with bulbar KS lesions underwent total excisional biopsy of conjunctival lesions with 1–2 mm wide margins. While all 14 tumors were excised with negative margins, 2 tumors recurred at the 4 to 6 week follow-up time point, and were histopathologically classified as stage III tumors [51]. Due to the recurrences seen after excision of stage III tumors, four additional patients with stage III bulbar KS lesions underwent fluorescein angiography (FA)-based surgical excision to help better detect all vessels emanating from or leading to the lesion to ensure complete excision of these lesions. FA-based excision proved to be more successful than surgical excision alone with no KS recurrences at a median of 5 months of follow-up [51]. Shuler et al. also described surgical excision as the primary modality of therapy in two male patients with conjunctival KS, both of whom developed recurrences within 1 month [4].

Following surgical excision, amniotic membrane can be used to reconstruct the conjunctival defect to facilitate re-epithelialization [13,60]. In cases with deep scleral or corneal involvement, a sclerectomy may be required along with a scleral patch graft [13]. Wide margin excisions for large, multifocal ocular surface KS tumors may pose risks of delayed epithelial healing or secondary limbal stem cell deficiency.

KS lesions can arise at sites of previous local injury, in both cutaneous and mucocutaneous locations, a characteristic known as the Koebner phenomenon. Given this known phenomenon, careful observation for recurrent lesions at a site of previous surgical excision of an ocular lesion is important in the post-operative period [61].

8.2. Cryotherapy

Cryotherapy can also be applied to the base of the KS lesions after surgical excision; however, this treatment option has limited data. It has only been demonstrated in solo case reports with up to 2 years of follow-up. In a 62-year-old HIV-negative Hispanic male with a pedunculated KS lesion involving the lower eyelid margin and tarsal conjunctiva, cryotherapy was applied to the base of the lesion on the tarsal conjunctiva after surgical excision with no recurrence after 8 months of follow-up [62]. Similarly, in a case of a 32-year-old HIV-positive black male with a growing lesion on the bulbar conjunctiva, surgical excision with cryotherapy in a double-freeze thaw technique to the conjunctival edges resulted in regression of the lesions with no recurrence 4 months after treatment [39]. Surgical excision with cryotherapy in combination with systemic ART also facilitated regression of a bulbar conjunctival lesion in a 43-year-old HIV-positive male with no recurrence after 2 years [63]. Lastly, surgical excision with cryotherapy in a 28-year-old HIV-negative female with a conjunctival KS lesion in the setting of iatrogenic immunosuppression also proved to be successful with no recurrences after 14 months [64].

Primary cryotherapy may be a viable treatment option for KS lesions; however, there are only two reported cases in the literature with limited long-term data. In one case, an 83-year-old HIV-negative white male with nodular bulbar and palpebral conjunctival KS lesions underwent primary cryotherapy to the lesions once weekly for 4 weeks with significant regression and no recurrence of lesions after 2 years [65]. Yet another patient with ocular KS in a larger series was noted to have an inadequate response to cryotherapy alone with recurrence within 3 weeks [4].

8.3. Chemotherapeutic and biological agents

Topical and intralesional chemotherapeutic agents are often used in the treatment of various ocular surface tumors, such as ocular surface squamous neoplasia [8]. There are five reports of the use of these agents in HIV-associated ocular KS.

8.3.1. Interferon alpha (IFN-α)

IFN-α is part of a group of low molecular weight glycoproteins that have anti-viral and anti-neoplastic properties. For KS lesions specifically, IFN-α has been shown to inhibit HIV and HHV8 replication, KS angiogenesis, and VEGF production [66]. IFN-α has been used intralesionally in the dermatologic literature to treat AIDS-related cutaneous KS lesions [67] as well as systemically for disseminated AIDS-related KS [66,68].

There are only three cases in the literature that suggest the utility of intralesional IFN for the treatment of ocular KS lesions with varied success. Qureshi et al. reported a case of a 31-year-old black male with AIDS who presented with bilateral upper and lower eyelid KS tumors and infiltrative bulbar and palpebral conjunctival KS lesions. Systemic treatment with ART, doxorubicin chemotherapy, and topical IFN-α-2b drops [3 million international units (MIU)] were started, but after 9 weeks of therapy, the eyelid lesions were noted to worsen and three intralesional injections of IFN-α-2b were then administered in the upper and lower eyelids over a 3-week period (first injection was 3 MIU but the subsequent 2 were 1.5 million MIU in concentration to mitigate flu-like syndrome side effects). A marked decrease in tumor burden was noted after the intralesional injections with no worsening at 1 year of follow-up and all repeat conjunctival biopsies were also negative for KS [48]. It is unclear if the lesions responded primarily to the intralesional IFN-α or if the combination of intralesional IFN and systemic ART had a synergistic effect.

Similarly, a bulbar conjunctival KS lesion in a 46-year-old HIV-positive patient described by Hummer et al. underwent a subconjunctival injection of IFN-α-2a 3 MIU with resolution of the tumor within 1 month and no recurrence after 5 months of follow-up. This patient did not receive any systemic therapies in conjunction with the intralesional IFN injection [69]. In contrast, another report described the use of IFN-α-n3 to treat a palpebral conjunctival lesion in a 71-year-old HIV-negative male with only transient regression of the lesion [70].

8.3.2. Mitomycin-C (MMC)

MMC is a cell-cycle alkylating agent derived from Streptomyces caespitosus that has anti-proliferative and cytotoxic properties. MMC has not been used systemically or intralesionally in cutaneous or other mucocutaneous KS lesions. There are two cases in the literature of the use of MMC in the treatment of ocular KS, one where MMC was administered subconjunctivally and the other topically.

Korn et al. describe a case of a 38-year-old Asian male with AIDS on ART who developed a bulbar conjunctival lesion in the right eye that was biopsy proven KS. Two subconjunctival injections of 0.2% MMC were administered in the inferior and nasal aspects of the lesion with progressive resolution of the lesion over a 5 month period with no recurrence at 36 months of follow-up [71]. Similar to the case by Qureshi et al. with the use of intralesional IFN, it is challenging to determine if the lesions regressed solely from the intralesional injection of MMC or if the combination of ART and MMC played a role.

Topical MMC can also be applied intra-operatively during surgical excision of KS lesions. In a case by Yang et al., 0.2 mg/ml of MMC was placed over the sclera and medial rectus muscle for 5 minutes after removal of an extensive conjunctival and cornea KS tumor in a 13-year-old Asian male. When using MMC intra-operatively, it is important to monitor the patient for development of scleromalacia and scleral perforation [13].

8.4. Anti-retroviral therapy (ART)

Ocular adnexal and conjunctival KS lesions can occur, although uncommonly, in patients with HIV and AIDS. As such, many patients with KS and co-morbid HIV or AIDS are started on ART for immune reconstitution. Reduction of viral load and immune reconstitution with ART can also help stabilize and regress KS lesions [5,72,73].

In a cohort of 163 patients treated only with ART for systemic stage T0 KS lesions (lesions confined to skin, lymph nodes and oral mucosa), overall 5-year survival was 91% with only 1 KS-related death [74] Similarly, a study of 39 patients with mild to severe forms of AIDS-related KS treated with ART showed that 74% of patients had a partial/complete response of KS lesions at 24 months of follow-up with associated rises in CD4 + T cell counts [72]. Many times, ART is employed in conjunction with systemic chemotherapy to treat systemic KS tumors. In a randomized controlled trial comparing ART alone versus combination ART with systemic chemotherapy in HIV-associated KS in a South African population, KS response rate at 1 year was higher in the combination arm (66%) vs ART alone (39%), yet ART alone provided similar survival rates and HIV viral loads in comparison to combination therapy [73].

Interestingly, in rare cases, ART has been shown to worsen cutaneous KS lesions. Loke et al. described two cases of cutaneous KS in HIV-positive individuals (a 29-year-old female and a 38-year-old male) that worsened significantly after initiation of ART, likely secondary to immune reconstitution syndrome. In both patients, addition of systemic chemotherapy (liposomal doxorubicin) and use of radiotherapy in one patient, improved the clinical course of KS [75].

For ocular KS lesions, ART therapy, in most cases, can also serve as a sole treatment option for KS. Conjunctival [76] and eyelid [77] KS lesions in HIV-positive patients have resolved completely after 4 to 6 months of sole ART therapy. ART can also be used in combination with interferon injections for ocular KS lesions, as reported by Shields et al. [78]. Multiple case reports of ocular KS lesions treated with ART and chemotherapeutic agents such as docetaxel or doxorubicin have been reported to allow for partial [79,80] or complete resolution of these lesions [6,40,81]. These data, while limited, suggest a role for systemic ART in patients with HIV or AIDS-associated ocular KS.

8.5. Chemotherapy

Systemic chemotherapy is used in patients with ocular KS who also have progressive or extensive disease, visceral lesions causing life-threatening complications (i.e. airway obstruction or gastrointestinal bleeding), as well as lymphedema. Chemotherapy is often necessary to control these grave sequelae.

Commonly used chemotherapeutic agents include liposomal doxorubicin, paclitaxel, daunorubicin, vinblastine, vincristine, bleomycin, and etoposide, and can be used as single agents or in combination therapy. Adverse effects related to chemotherapy can include neutropenia, alopecia, as well as an increased risk of opportunistic infections in severely immunocompromised patients [4,5,82,83].

In a study by Shuler et al., six patients with ocular KS were treated with chemotherapy alone, of which only one showed continued progression of the lesions; the remaining five patients showed regression in the KS lesions without recurrence at a median of 5 months [4]. As described above, chemotherapy, when used in conjunction with ART, can also increase response rates of KS lesions [73].

8.6. Radiation therapy

KS is considered a highly radiosensitive tumor and cutaneous, oral as well as genital KS tumors have proven to be highly sensitive to radiation therapy [84,85]. In a series of 149 patients with cutaneous KS lesions treated with localized or extended radiation therapy, 93% of patients achieved remission [86]. In the largest series of 643 patients with cutaneous, oral cavity, genital, eyelid, or conjunctival KS lesions treated with radiotherapy by Kirova et al., 92% of patients with cutaneous KS, 100% of patients with oral cavity lesions and 89% of patients with genital, eyelid, or conjunctival lesions exhibited partial or complete remission [85]. Several studies have demonstrated the utility of various radiation protocols for the treatment of ocular KS lesions. Cooper and Fried initially described the use of radiation therapy at a dose of 3000 cGy in 10 fractions over 2 weeks for a rapidly growing KS tumor on the superior palpebral conjunctiva of a 52-year-old male with AIDS that completely resolved without recurrence with radiation therapy at 4 months follow-up [87]. In the study by Kirova et al., 362 sites of ocular KS lesions were irradiated with 20 Gy administered in fractions of 10 Gy per week. This dosage of treatment permitted shrinkage of a large series ocular KS tumors and palliation of symptoms in patients [85]. In a recent study of 49 ocular KS tumor sites treated with two different regimens of radiation therapy (1 group with a single dose of 800 cGy and the other group with a multiple fraction regimen of 1500 to 3600 cGy), KS tumor response rates and recurrence rates were similar between both groups, with an overall response rate of 98%, complete response rate of 29% and partial response rate of 71%. Similarly, Shuler et al. reported 12 patients with ocular KS lesions who underwent a radiation protocol of 2000 to 3000 cGy administered in fractions of 200 to 300 cGy per session over 3 weeks. All patients exhibited either a complete or partial response to radiation therapy, but there were two recurrences of KS lesions noted 4 and 6 months after completion of treatment.

Radiation therapy is associated with acute and chronic side effects including local skin changes such as hyperpigmentation and erythema, eyelash loss, hair loss, and conjunctivitis. Optimal radiation treatment doses for a particular patient will depend on his/her immune status, size of the KS lesion(s), and response to prior therapy.

8.7. Immunomodulating agents

KS is often a complication in post-transplant patients and studies have shown that discontinuation or reduction of immunosuppressive therapy can generally lead to regression of KS lesions as demonstrated in 93.9% of organ transplant patients with KS lesions studied by Brambilla et al. [88]. Post renal transplant patients with cutaneous KS who were switched to an mTOR inhibitor (i.e. everolimus or sirolimus) from alternative immunosuppressive agents (i.e. calcineurin inhibitors, cyclosporine, or azathioprine) were noted to have regression of their lesions [47,89]. mTOR inhibitors through their effects on VEGF signaling can be successful in treating KS lesions [90]. This has been shown in one case of ocular KS in a young patient post renal transplant who after surgical excision, cryotherapy, and transition to everolimus from tacrolimus had full KS tumor regression with no recurrence [64]. However, adverse effects of everolimus, namely pneumonitis, limited the ability to use this medication long term to aid with tumor regression [64]. More recently, other immunomodulatory drugs including lenalidomide and pomalidomide, which are oral derivatives of thalidomide, have shown promise in stabilizing KS lesions in clinical trials. Pomalidomide recently obtained accelerated approval by the FDA to treat KS after ART failure and in adult patients who are HIV-negative [91].

8.8. Other biological agents under clinical investigation

Proteasome inhibitors are anti-neoplastic drugs that have clinical activity against various malignancies and are currently approved for the treatment of multiple myeloma. Bortezomib, a drug that targets NF-κB activity and induces HHV8 lytic expression, was recently tested in patients with relapsed/refractory KS [92]; a partial response was observed in 60% of patients. A new phase 2 trial of ixazomib, an oral proteasome inhibitor, is currently being conducted by the AIDS Malignancy Consortium (AMC). The AMC is also conducting a phase 2 trial of recombinant EphB4-HSA fusion protein (EphB4-HSA) in patients with KS. KS is a vessel-derived angioproliferative tumor that expresses pro-angiogenic ligand Ephrin B2 and its receptor ephrin B4 (EphB4) [93]; as such, a drug that blocks the interaction between Ephrin B2 and ephrin B4 can also block the VEGF-Notch-EphrinB2 angiogenic pathway.

8.9. Anti-viral therapies

Although KS is associated with HHV8 infection, effective anti-viral treatments for KS are lacking as the virus is typically latent. Common anti-herpetic viral agents, such as acyclovir, show no activity against HHV8 while agents such as ganciclovir and foscarnet exhibit some anti-HHV8 activity but are not often used [94].

Recently, an FDA-approved drug library was used to identify 15 new compounds that effectively inhibited HHV8 virion production [17]. Three of the identified compounds all exhibited overlapping inhibitory effects on histamine receptors and work in this study showed that inhibition of most histamine receptors by antagonists reduced HHV8 virion lytic replication. Downstream activation of the MAPK/PI3K/Akt signaling pathways triggered by histamine and other agonists has also been found to promote HHV8 virion lytic replication. This is another potential targetable pathway that can be blocked to reduce the development of KS [17].

A recent study has also shown that curcumin, the main bioactive compound in turmeric, is an APE1 redox inhibitor that is able to block HHV8 virion production and replication, thereby inhibiting subsequent angiogenesis and cell invasion implicated with KS [95]. At this time, none of the drugs affected HHV8 virion production have been approved for the treatment of KS, but their use may warrant further investigation.

8.10. Summary of treatment algorithm for ocular KS

The presence of a KS lesion on the conjunctiva or ocular adnexa should lead to a systemic workup for immunodeficiency and the presence of other KS lesions. ART should be initiated for patients with underlying HIV or AIDS to aid in immune reconstitution and to decrease viral loads and stabilize KS lesions, which may often regress. Smaller, slowly progressive ocular KS lesions that are asymptomatic can usually be observed. However, in KS lesions causing symptomatic and visual disturbances, treatment is necessary. Localized therapy, such as surgical excision, cryotherapy, or intralesional chemotherapeutic agents, can often be successful first-line treatment options with limited adverse effects. However, recurrences may occur in patients with more aggressive KS subtypes (i.e. African or AIDS-associated) and the patients should be accordingly counseled. Radiation therapy can be employed as either first-line or second-line therapy for larger, multifocal, or rapidly growing ocular KS lesions, but can pose risks such as hair loss, skin changes, or ocular irritation. Chemotherapy or immunomodulatory agents can be used for suitable patients with systemic and widespread disease. Novel therapies targeting inhibition of HHV8 to treat KS lesions may warrant further investigation. Ultimately, a robust multi-disciplinary approach with internal medicine, hematology, oncology, radiology, and infectious disease is critical to help patients with KS receive a targeted treatment plan to treat their disease.

9. Conclusion

In summary, KS is a multifocal vascular tumor that is thought to typically involve the skin, mucus membranes, internal organs, and lymph nodes and is often associated with HIV, AIDS, and other immunosuppressive states. This neoplasm can rarely manifest on the ocular surface and ocular adnexa and can sometimes be the first presenting sign of systemic disease. As an ophthalmologist, a high index of suspicion for these lesions can expedite the diagnosis not only of KS but also the diagnosis of underlying infection (i.e. HIV/AIDS), secondary immunosuppression (from neoplasia or organ transplantation), or widespread multifocal lesions that can pose significant morbidity and mortality. Treatment for ocular KS lesions depends on the location of the lesion, underlying comorbid infections or neoplasia, as well as presence of widespread lesions with life-threatening complications. Localized lesions can be treated with surgical excision, cryotherapy, radiation, or intralesional or topical chemotherapeutic agents. Patients with diffuse disease and/or HIV may warrant ART, radiation, systemic chemotherapy, or use of new immunomodulatory and targeted biological agents. Discontinuation or reduction of immunosuppressive therapy and/or switching to alternative mTOR agents is often required in cases of iatrogenic KS. Active research to identify novel anti-viral therapies as well as molecular treatment targets for the treatment of KS will help expand the armamentarium of therapeutics available for this disease.

10. Expert opinion

Significant headway has been made in the understanding of the presentation, risk factors, and pathogenesis of KS since its initial discovery. The association of KS with HHV8 was exciting and novel.

Aside from chemotherapy drugs used as first-line treatment, such as liposomal doxorubicin and paclitaxel, some new biological agents have potential in stabilizing KS lesions in clinical trials. Immunomodulatory drugs such lenalidomide and pomalidomide, have shown promising activity in KS [91]. Pomalidomide was recently approved by the FDA for the treatment of KS. Bortezomib, a drug that targets NF-κB activity and induces HHV8 lytic expression, has also shown activity in patients with KS [92]. A new phase 2 trial of ixazomib, an oral proteasome inhibitor, is currently ongoing. Another ongoing phase 2 trial is using recombinant EphB4-HSA fusion protein (EphB4-HSA) in patients with KS, which expresses pro-angiogenic ligand Ephrin B2 and its receptor ephrin B4 (EphB4) [93]; such drugs block the interaction between Ephrin B2 and ephrin B4 and block the VEGF-Notch-EphrinB2 angiogenic pathway. A summary of the currently approved and investigational immunodulating and biological agents for the treatment of KS are summarized in Table 1.

Table 1.

<FDA approved and investigational immunomodulatory and biological agents for the treatment of Kaposi’s Sarcoma.

Compound	Mechanism	FDA approval status for KS
Everolimus	mTOR inhibitor with anti-VEGF activity	Approved
Pomalidomide	Anti-angiogenic properties; upregulation of interferon gamma, IL-2, IL-10; down regulation of IL-6	Approved
Sirolimus	mTOR inhibitor with anti-VEGF activity	Approved
Bortezomib	Targets NF-kB activity; induces HHV8 lytic expression	Investigational
Ixazomib	Binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome	Investigational
Lenalidomide	Tumor cell apoptosis; anti-angiogenic and anti-osteoclastogenic activities	Investigational
Recombinant EphB4-HSA fusion protein (EphB4-HSA)	Blocks the interaction between Ephrin B2 and ephrin B4l; blocks the VEGF-Notch-EphrinB2 angiogenic pathway	Investigational

Work is currently being conducted to identify other targeted molecular therapies that can improve KS. Studies of ocular KS lesions have shown upregulation of VEGF, PDGFR-A, c-Kit, and PD-1 in ocular KS lesions, highlighting potential targetable pathways for the treatment of ocular KS [12]. Treatments such as intravenous bevacizumab (an anti-VEGF agent) [96], oral sorafenib (an agent with anti-VEGF, anti PDGFR-A, and anti-Raf family kinase activity) [97], and nivolumab (PD-1 blocker) [98] have all been tried in small cohorts of patients with systemic KS with success in some cases. Similarly, in-vitro studies have found regression of KS spindle cell formation with pharmacologic inhibition of c-Kit [26].

New anti-viral therapies may be on the horizon and could be explored for the treatment of KS; however, their efficacies against latent HHV8 infection could be limited theoretically. As mentioned previously, multiple compounds have been recently identified through an FDA-approved drug library that effectively inhibit HHV8 virion production [17]. Three of the identified compounds exhibited inhibitory effects on histamine receptors and blockage of histamine receptors by antagonists can inhibit HHV8 virion lytic replication. Other agents identified in this database such as monobenzone (an agent used for vitiligo treatment), oxibendazole (an agent used for intestinal helminth infections), oxaliplatin (a chemotherapy drug for colon and rectal cancers), and hycanthone (topoisomerase II inhibitor) all inhibit HHV8 lytic reactivation. Identified compounds targeting neurotransmitters, such as dopamine, adrenergic, serotonin, and muscarinic receptors, also exhibit a potential role in the regulation of HHV8 reactivation [17]. These new therapies targeting HHV8 are summarized in Table 2.

Table 2.

<Potential new upcoming treatment options with anti-HHV-8 activity for Kaposi’s sarcoma.

Compound	Mechanism	Administration
Acrisorcin	Tyrosyl-DNA phosphodiesterase 1 inhibitor	2 mg/gm topical cream
Arecoline	Muscarinic and nicotinic acetylcholine receptor agonist	Subcutaneous injection
Arsenic trioxide	Thioredoxin reductase inhibitor	Injection; multiple doses
Cyproheptadine	H1, 5-H2, 5-HT1C receptor agonist	Tablet, syrup; multiple doses
Fulvestrant	Estrogen receptor antagonist	Intramuscular injection; multiple doses
Hycanthone	DNA topoisomerase inhibitor	Intramuscular injection; multiple doses
Manidipine	Calcium and aldosterone antagonist	Tablet
Mefloquine	Cholinesterase inhibitor	250 mg tablet
Monobenzone	Tyrosinase inhibitor	20% topical cream
Oxaliplatin	Disrupts DNA synthesis	Injection; multiple doses
Oxibendazole	Polymerase inhibitor	Tablet and cream
Paroxetine	Selective serotonin reuptake inhibitor (SSRI)	Tablet; multiple doses
Phenothiazine	Histamine 1, dopamine D2, adrenergic α, serotonergic 2 C, and muscarinic receptors antagonist	Not found (does have approved derivatives)
Protriptyline	Histamine 1, muscarinic, and adrenergic α1 receptor inhibitor; inhibits reuptake of serotonin and norepinephrine	Tablet; multiple doses
Spironolactone	Aldosterone receptor antagonist	Tablet; multiple doses

Ultimately, further clinical studies are required to determine the utility of targeted pharmacologic therapies for ocular KS lesions. As more treatment modalities are discovered, the treatment algorithm for ocular and systemic KS lesions can evolve. Targeted molecular therapies may be used first-line prior to local excision or injection of agents. Safe and effective treatments for this can significantly reduce the morbidity and mortality associated with KS.

Improved diagnostic imaging modalities for ocular KS can also serve as an area for further research. Optical coherence tomography angiography (OCT-A) has been utilized in previous studies to characterize and quantify vessel structure and density in ocular surface squamous neoplasia lesions [99]. For conjunctival KS lesions, OCT-A may prove to be a powerful imaging tool to permit detailed visualization and characterization of the intrinsic vasculature of these lesions. Understanding vessel density and patterns in and around KS lesions may allow surgeons to better delineate the borders of these lesions and may permit surgeons to better map conjunctival KS tumor borders, hopefully reducing risks of tumor recurrence [100]. Further research is ultimately needed in this area to assess the utility of this technology for this disease.

Article highlights.

• Kaposi’s sarcoma (KS) is a multifocal low-grade vascular neoplasm that can be found on the skin, mucocutaneous areas, as well as lymphatic and visceral organs.

• When affecting the eye, KS lesions can manifest on the eyelids, conjunctiva, and uncommonly extend onto the cornea and into the orbit.

• KS is caused by the oncogenic human herpesvirus 8 (HHV8). Immunosuppression in patients with HIV and AIDS can contribute to the development of KS but conjunctival and ocular adnexal KS lesions are now uncommon in the era of anti-retroviral therapy.

• KS can be found in both immunocompetent and immunosuppressed individuals with varying manifestations.

• Histopathology coupled with immunohistochemistry can confirm the diagnosis of KS after incisional or excisional biopsies.

• Treatment modalities for ocular KS depend on the location of the lesions, systemic involvement, and co-morbid infections. Common therapeutic options include immune reconstitution with anti-retroviral therapy in the setting of HIV, surgical excision, cryotherapy, intralesional injections of chemotherapeutic agents, radiation, or systemic chemotherapy.