Ophthalmologic Manifestations of Kaposi Sarcoma

Kaposi sarcoma (KS) is a low-grade vascular neoplasm associated with human herpesvirus 8 infection. Ophthalmic presentations of Kaposi sarcoma most frequently involve the eyelid and conjunctiva.

The four clinicoepidemiological forms of Kaposi sarcoma include classic, African (endemic), AIDS-associated (epidemic), and iatrogenic (or transplant-associated) Kaposi sarcoma.

In 1872, Moritz Kaposi was the first to report an idiopathic, multiple-pigmented sarcoma of the skin that predominantly affected elderly men of Mediterranean or Ashkenazi ancestry.[1]

Transplant-related  Kaposi sarcoma has been reported in patients with solid organ transplants on immunosuppressive therapy.

Epidemic  Kaposi sarcoma, better known as AIDS-related Kaposi sarcoma, commonly affects homosexual males with AIDS.[2, 3, 4, 5] Aids-related Kaposi sarcoma is more aggressive than the other forms of Kaposi sarcoma.

Whether the 4 variants of Kaposi sarcoma represent the same disease process or different processes that manifest the same end-stage lesion is unclear.

Although the etiology has not been elucidated, the human herpesvirus 8 (HHV-8) or Kaposi sarcoma–associated herpesvirus (KSHV) has been implicated.[6] Chang et al identified this virus in more than 90% of patients with AIDS-related Kaposi sarcoma.[7] KSHV is also the etiological agent of 3 other AIDS-related lymphoproliferative disorders: (1) primary effusion lymphoma, (2) the plasma-cell variant of multicentric Castleman disease, and (3) the vascular tumor recurrent angiolymphoid hyperplasia with eosinophilia.[8]

The life cycle of KSHV consists of a latent and a lytic replication phase. During latent infection, only a limited number of KSHV genes are expressed. The switch between the latent form and lytic replication is regulated by epigenetic factors. Reactive oxygen species hydrogen peroxide also mediates KSHV reactivation from latency.[9] However, induction of lytic replication by environmental stimuli or chemical agents is important for the spread of KSHV, the persistence of infection, the evasion of host immune response, and induction of KSHV-related malignancies (by modification of the host genome).[7]

Kaposi sarcoma is most likely caused by multiple factors, including deregulated expression of oncogenes and oncosuppressor genes by KSHV/HHV-8 combined with decreased immune surveillance and the release of cytokines (viral interleukin [vIL]–6) and growth factors, by HIV acting on infected cells.[10]

vIL-6 is a product of KSHV expressed in latently infected cells and to a higher degree during viral replication. Secretion of vIL-6 is generally poor, but vIL-6 has the potential to induce a wide range of biological effects, such as inducing vascular endothelial growth factor.[10]

KSHV/HHV-8 mediates oncogenesis, although the exact mechanisms by which this happens has not yet been fully elucidated; numerous KSHV/HHV-8 viral oncogenes may contribute to neoplasia formation.[11, 12]

Frequency

United States

Prior to 1981, fewer than 25 reported cases of ophthalmic Kaposi sarcoma existed in the literature. Currently, the overwhelming majority of ophthalmic Kaposi sarcoma is AIDS related. In 1986, the Centers for Disease Control and Prevention (CDC) reported that Kaposi sarcoma occurs in approximately 24% of patients with AIDS and in 35% of all homosexual men with AIDS.[13] The CDC reported that during the period from 1992-1997, Kaposi sarcoma occurred in 23.8% of males with AIDS and in 27.4% of all homosexual men with AIDS. During the same period, only 2.3% of women with AIDS developed Kaposi sarcoma.[2]

Ophthalmic involvement occurs in 20-24% of patients with AIDS-related Kaposi sarcoma. Ophthalmic presentation was the initial manifestation of AIDS-related Kaposi sarcoma in 4-12% of patients. Eye lesions are neither an early nor a late manifestation of Kaposi sarcoma. A review of the literature reports that most eye lesions involve the conjunctivae or eyelids; 10-75% of patients have conjunctival lesions, and 25-80% of patients have eyelid lesions.

In recent years, the incidence of Kaposi sarcoma among HIV patients has significantly declined, from 60.6% in 1992 to 19.7% in 1997. The exact cause for this decline is unclear, but the introduction of protease inhibitors, combination HIV therapy, and safer sexual practices may have played significant roles.

Mortality/Morbidity

Kaposi sarcoma is linked to significant morbidity and mortality; it can disseminate to visceral organs (ie, lungs, liver, adrenal glands, kidneys, bone marrow, GI tract) and possibly cause bowel obstruction, lower extremity edema, shortness of breath, hemorrhage, and pain. Visceral and lung involvement usually portends a poor prognosis.

Generally, ophthalmic Kaposi sarcoma is indolent. Ocular tumor growth can result in severe damage to the ocular adnexa, the ocular surface, and even the orbit and choroid.[14]

Involvement of the eyelids can cause significant disfigurement and lid dysfunction. Trichiasis can develop from mechanical ectropion or entropion. Lagophthalmos and trichiasis can result in profound irritation and dryness, infections, and corneal scarring. Large lid tumors can induce irregular corneal astigmatism. Conjunctival involvement may result in recurrent subconjunctival hemorrhages and may even be associated with squamous cell carcinoma in patients with HIV infection. Ultimately, vision could be lost from lid dysfunction, corneal surface changes, or visual obstruction.

Race

Classic Kaposi sarcoma usually involves elderly men with Mediterranean or Ashkenazi ancestry. Endemic Kaposi sarcoma usually involves young black males from central Africa.[15] Transplant-related or AIDS-related Kaposi sarcoma has no racial predilection.

Sex

Classic Kaposi sarcoma usually involves elderly men. Endemic Kaposi sarcoma usually involves young males. AIDS-related Kaposi sarcoma predominantly involves homosexual males.

Age

Classic Kaposi sarcoma affects the older population. Endemic Kaposi sarcoma affects children with a male-to-female ratio of 1:1; after puberty, males are predominantly affected. AIDS-related Kaposi sarcoma usually affects males aged 20-49 years.

Identify risk factors for Kaposi sarcoma. The clinician should ask about the following:

• Demographics

• Immune status

• Previous skin lesions

• Previous treatment for Kaposi sarcoma

• History of opportunistic infections

• Current medication use

Symptoms of Kaposi sarcoma include the following:

• Pain

• Photophobia

• Recurrent red or bloody eyes

• Irritation and foreign body sensation

• Epiphora

• Dry eyes

• Mucopurulent discharge

• Heavy or swollen eyelids

• Cosmetic disfigurement of the eyelids

• Eyelashes rubbing against the eyes

• Inability to close the eyes

• Visual obstruction

• Blurred vision

Full ocular examination should include the following:

• Inspect and evert the eyelids and lashes

• Perform slit lamp biomicroscopy

• Examine palpebral and bulbar conjunctivae and fornices in detail

• Palpate the lacrimal gland, and examine for masses

• Examine both eyes for proptosis in the rare likelihood of orbital involvement; fortunately, intraocular Kaposi sarcoma has never been reported

The lesions are purplish-red to bright-red and highly vascular with surrounding telangiectatic vessels. They may be macular, plaquelike, or nodular. Ophthalmic Kaposi sarcoma lesions are found on the eyelids, conjunctiva, caruncle, and lacrimal sac. They rarely are found inside the orbit (1 case of choroidal involvement).[16]

See the image below.

Dugel et al described 3 clinical stages that may help direct therapy. Stage I and II tumors are patchy and flat. These lesions have a thickness of less than 3 mm in vertical height and are younger than 4 months. Stage III tumors are nodular and elevated with a vertical height of greater than 3 mm. They tend to be older than 4 months.[17]

Of ophthalmic Kaposi sarcoma cases, 6-16% are eyelid lesions, and the superior and inferior eyelids tend to be involved equally. Of ophthalmic Kaposi sarcoma cases, 7-18% are conjunctival lesions. Many conjunctival lesions tend to involve the inferior conjunctiva (as is shown in the image below) and fornix.

Lesions tend to be indolent, but, as the tumor grows, it can alter ocular adnexal structures[14] and the ocular surface. The mass effect of the tumor on the eyelids can cause mechanical ectropion or entropion with trichiasis and lagophthalmos and irregular astigmatism. Ectropion or entropion can result in poor lid apposition, trichiasis, and lagophthalmos. Consequently, the patient may experience epiphora, poor tear clearance and drainage, recurrent corneal abrasions, pain and discomfort, foreign body sensation, dry eyes, and photophobia. Long-standing trichiasis and exposure can result in corneal infection, scarring, and opacification.

Rarely, tumor bulk may block the visual axis by ptosis or direct obstruction. Tumor bulk may even prevent the complete closure of the eyelid.

Conjunctival involvement may present with subconjunctival hemorrhage, injection, and chemosis.

Human herpesvirus-8 (HHV-8) DNA or Kaposi sarcoma–associated herpesvirus (KSHV) has been implicated with patients who are HIV-negative or HIV-positive.[18]

Homosexual males with HIV infection are at an increased risk. This risk is markedly increased with the number of partners.

Patients who have had organ transplants and use immunosuppressive agents and steroids are at an increased risk.

Elderly males of Mediterranean or Ashkenazi ancestry are at an increased risk.

The following studies are indicated in patients with Kaposi sarcoma:

• HIV enzyme-linked immunosorbent assay

• HIV Western blot

• CD4 T-lymphocyte count[19]

Imaging studies are generally not necessary, unless orbital or disseminated Kaposi sarcoma is suspected.

Cutaneous or conjunctival biopsy of the lesion may be necessary for a definitive diagnosis.

All 4 variants of Kaposi sarcoma demonstrate similar histologic findings of tissue, containing endothelium-lined vascular channels and proliferation of spindle-shaped cells surrounded by inflammatory cells. Examples of histologic findings are shown in the images below.

Often, an increased angiogenesis with erythrocyte extravasation is present. Dugel et al described 3 histologic types of Kaposi sarcoma, which probably represents different stages along a continuum.[17]

Type I

Thin, dilated vascular channels are lined by flat endothelial cells with lumen-containing erythrocytes. The cells have flat endothelial fusiform nuclei and scanty cytoplasm. Moderate mononuclear cell infiltrate surround these abnormal vessels. No spindle cells or slit spaces are observed.

Type II

Plump, fusiform endothelial cells line thin, dilated empty vascular channels. Many of these cells have hyperchromatic nuclei. The inflammatory infiltrate of macrophages, plasma cells, and lymphocytes is sparse. Foci of a few immature spindle cells and early slit vessels are present.

Type III

Large aggregates of densely packed spindle cells with hyperchromatic nuclei, occasional mitotic figures, and abundant slit spaces often contain erythrocytes. Inflammatory cells are scant.

The goal of therapy in patients with Kaposi sarcoma is to relieve ocular irritation, mass effect, and disfigurement. Therapy is not curative. If the patient has no ophthalmic complaints, the tumor is usually observed. For AIDS-related Kaposi sarcoma, consider immune reconstitution with triple antiviral medication.[20, 21]

Kaposi sarcoma tends to respond to chemotherapy. Ophthalmologists may want to delegate the use of chemotherapy to a chemotherapist or an oncologist familiar with the use of the agents. If the patient has systemic involvement that requires chemotherapy, the eye lesion often resolves or is reduced markedly after starting this therapy. However, recurrence commonly follows after discontinuation of chemotherapy. If local treatment is indicated, defer for at least 4 weeks after systemic chemotherapy to allow for regression of the lesions.

Conventional Adriamycin, bleomycin sulfate, and vinblastine sulfate (ABV) combination therapy

Doxorubicin hydrochloride (Adriamycin) is administered at 40 mg/m2 every 4 weeks or 20 mg/m2 every 2-3 weeks.

Bleomycin sulfate is administered at 10 U/m2 every 2 weeks.

Vinblastine sulfate 1.4 mg/m2 with 2 mg maximum dose every 2 weeks has been recommended with ABV combination therapy. See Medication.

Single-agent therapies

Liposomal daunorubicin (DaunoXome) is administered 40 mg/m2 intravenously (IV) every 2 weeks until complete response; the response is comparable to ABV but with less resultant neutropenia.[22]

Pegylated liposomal doxorubicin (Doxil) is administered at 20 mg/m2 every 3 weeks; the response is comparable to ABV or BV but with either lower or similar neutropenia risk.

Liposomal anthracyclines have a prolonged half-life when compared with their unencapsulated counterparts.

Alternative therapies

Paclitaxel (Taxol) is administered at 135 mg/m2 IV over 3 hours every 3 weeks or a total dose of 100 mg/m2 given IV over 3 hours every 2 weeks. All patients should be premedicated with the following 3 medications to prevent hypersensitivity reactions:

• Dexamethasone 10 mg orally (PO) 12 hours before treatment

• Diphenhydramine 50 mg IV 30 minutes prior to treatment

• Cimetidine or ranitidine IV 30 minutes before treatment

If the absolute neutrophil count is greater than 1,000 cells/mcL, then continue with treatments. Reduce the dose of subsequent treatments by 20% if the neutrophil count falls below 500 cells/mcL. See the Absolute Neutrophil Count calculator.

Other chemotherapeutic agents used in Kaposi sarcoma include etoposide (VePesid), dactinomycin (Cosmegen), cisplatin (Platinol), and interferon alfa-n3 (Alferon N).

Intralesional chemotherapy[23]

Interferon alfa-2a administered at 0.5 mL of 3 million IU in a subconjunctival injection adjacent to the tumor was reported to be efficacious in a 46-year-old man with AIDS- related conjunctival Kaposi sarcoma.[24]

A 31-year-old man on highly active antiretroviral therapy (HAART) and systemic doxorubicin who initially received topical 3 million IU/mL of interferon alpha-2b eyedrops with no improvement received 3 injections (3 million IU in 0.5mL, 1.5 million IU in 0.5mL, and 1.5 million IU in 0.5 mL) over a 4-week period, leading to a dramatic decrease in tumor mass.[25]

Investigational medications

Human chorionic gonadotropin–associated factors

Because males are at a higher risk for developing Kaposi sarcoma, some investigators believe that female hormones may play a protective role. Hermans et al experienced complete or partial regression of skin lesions in 38% of patients with AIDS-related Kaposi sarcoma after intralesional injections of human chorionic gonadotropin (hCG).[26]

Samaniego et al demonstrated that human chorionic gonadotropin–associated factors (HAF) can induce apoptosis of Kaposi sarcoma cells in vivo and in vitro.[27]

Iron chelators

Simonart et al is investigating the role of regulating iron concentration in tumor cells.[28] They demonstrated that the addition of iron salts strongly stimulates the growth of Kaposi sarcoma and that the use of iron chelators inhibits growth. Their findings are disclosing new therapeutics in tumor management with iron-chelating agents.

Hermans et al speculate that the lower risk for developing Kaposi sarcoma in females may be because women have lower iron stores.[29] The analysis concludes that patients with renal transplants are more susceptible to Kaposi sarcoma because they tend to have higher iron loads from repeated blood transfusions.

Other experimental medications include fumagillin analogues (AGM 1470), bacterial cell-wall peptidoglycan (SP-PG derivatives), interleukin 4, and L-glutamine-tryptophan.

Intralesional cidofovir (an antiherpetic medication) injections have demonstrated poor results. Bailey et al have reported that all-trans -retinoic acid has not demonstrated optimistic results.[30]

Irradiation

Most patients respond immediately to radiation therapy, but recurrence is common. Consequently, irradiation is primarily used as a palliative measure. A typical treatment includes 2,000-3,000 cGy with the total dose given in fractions of 200-300 cGy per session over 3 weeks.

Ocular complications of radiation include lid atrophy, skin necrosis, ectropion, telangiectasia, tearing, eyelash loss, keratitis, cataract formation, conjunctival keratinization, skin erythema, keratoconjunctivitis sicca, alopecia, optic neuropathy, and lid notching.

Cryotherapy protocol

Subcutaneous injection of 2% lidocaine with epinephrine applied directly under the lesion is administered.

Cryoprobe with circulating liquid nitrogen is set at -30°C. Cryoprobe is applied to the tumor and extended out to 1-2 mm of clear margin until the lesion becomes bright white.

Antibiotic ointment is applied to the treated site.

Follow-up care is arranged for the following day.

Ocular complications of cryotherapy include depigmentation and erythema, lid notching, and epilation.

Surgical excision

Indications for local excision include cosmetically disturbing lesions, discomfort, and obstruction of vision from tumor bulk. Consider treating a lesion to prevent entropion formation with trichiasis and exposure keratopathy and corneal ulcer.

Protocol for local excision is as follows:

• A cotton swab is soaked in 0.5% tetracaine hydrochloride, then applied directly over the tumor

• Lidocaine 2% with epinephrine is injected subconjunctivally with a 25-gauge needle

• Westcott scissors are used for blunt and sharp dissection to free the tumor. Clear margins of 1-2 mm are excised

• The specimen is marked for orientation

• Antibiotic ointment is applied, and the eye is patched

• Patient should receive follow-up care the next day.

Protocol for fluorescein angiography demarcation of conjunctival lesions is as follows:

• A 5 mL bolus of fluorescein dye is injected intravenously and photographed using a Zeiss SE-40 blue exciter filter.

• The fluorescein angiography is used to mark tumor vessels with heat cautery.

Recurrence usually occurs within 4 weeks after surgical excision.

Conjunctival tumors

Dugel et al recommended an effective treatment regimen based on the clinical and histopathologic stage of the tumor.[31]

If the lesion is stage I or II and confined to the bulbar conjunctiva, excisional biopsy with 1-2 mm of clear margins is suggested.

For stage III tumors involving the bulbar conjunctiva, surgical excision guided by fluorescein angiography delineation of tumor margins resulted in no lesion recurrence during 4-8 months of follow-up care.

Alternative treatment can include intralesional mitomycin[32] or intralesional injections of interferon alfa-2b[25]

Recurrence usually occurs within 4 weeks after surgical excision.

Eyelid tumors[33]

Stage I and II lesions may be treated with cryotherapy. Stage II lesions may require radiation therapy.

If an eye lesion is identified, a thorough workup is necessary to rule out systemic involvement and HIV/AIDS infection.

After a thorough ophthalmologic examination, refer to an internist or oncologist/chemotherapist.

Disseminated Kaposi sarcoma may necessitate bronchoscopy, sigmoidoscopy, or lymph node biopsy for a definitive diagnosis and systemic chemotherapy.[34]

Most ophthalmologists defer the administration of systemic chemotherapeutic agents to chemotherapists or oncologists. The medical therapy for disseminated Kaposi sarcoma consists of either Adriamycin, bleomycin sulfate, and vinblastine sulfate (ABV) combination or liposomal daunorubicin alone.[35] Liposomal doxorubicin is usually reserved for those patients who fail ABV combination or who are intolerant to ABV therapy.[36] Other second-line therapies include the use of paclitaxel[37] and interferon alfa-n3.

Class Summary

These agents inhibit cell growth and proliferation.

Vinblastine sulfate (Velban)

Alkaloid extract of Catharanthus roseus. FDA indications for use of vinblastine are Kaposi sarcoma, choriocarcinoma, histiocytosis X, lymphocytic lymphoma, mycosis fungoides, breast carcinoma, and testicular carcinoma. Mechanism of action is to arrest growing cells in metaphase by inhibiting formation of microtubule assembly during spindle formation. For treatment of Kaposi sarcoma, ABV is conventional combination treatment used. Major route of elimination is through excretion. A small portion is eliminated through urine. Main route of administration is IV.

Bleomycin sulfate (Blenoxane)

Cytotoxic glycopeptide extracted from a strain of Streptomyces verticillus. Commonly used in combination with Adriamycin and vinblastine. Inhibits DNA, RNA, and protein synthesis. Major route of elimination is through urine. Serum concentrations may increase in patients with poor creatinine clearance.

Doxorubicin hydrochloride (Adriamycin, Doxil)

Cytotoxic anthracycline extracted from Streptomyces peucetius. Not FDA approved for the treatment of Kaposi sarcoma but often used in combination with bleomycin and vinblastine.

Mechanism of action is by intercalation of anthracycline with DNA. Subsequently, this blocks DNA and RNA polymerases, resulting in the inhibition of cell growth and proliferation. Major route of elimination is via biliary excretion.

Daunorubicin citrate liposome (DaunoXome)

Anthracycline antibiotic extracted from S peucetius. Indicated for treatment of Kaposi sarcoma. Liposomal version of daunorubicin greatly enhances functional characteristics of the treatment by decreasing plasma clearance and a smaller volume of distribution. Characteristics translate into longer drug exposure. Daunorubicin is a first-line drug for advanced HIV-Kaposi sarcoma. Not recommended for mild involvement.

Paclitaxel (Taxol)

Extract of Taxus baccata. Indicated for second-line treatment of AIDS-related Kaposi sarcoma. Mechanism of action is to promote polymerization of microtubules and to inhibit depolymerization. Prevention of microtubule dynamics results in the inability of the cell to undergo mitosis. Major route of elimination is through hepatic clearance. All patients should be premedicated with dexamethasone 10 mg PO 12 h before treatment, diphenhydramine 50 mg IV 30 min prior to treatment, and cimetidine or ranitidine IV 30 min before treatment.

Class Summary

These agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alfa, beta, and gamma interferons may be given topically, systemically, and intralesionally.

Interferon alfa-2a (Roferon A), alfa-2b (Intron A), alfa-n3 (Alferon N)

Derived from pooled units of human leukocytes induced by Sendai virus. Human sources of leukocytes are screened carefully for infectious agents (Sendai virus, HIV-1, HTLV-I, HBV, HSV-1, CMV, and EBV).

FDA indication is for condyloma acuminata. Off-label uses include bladder carcinoma, ovarian epithelial carcinoma, renal carcinoma, chronic active hepatitis, AIDS-related Kaposi sarcoma, chronic myelocytic leukemia, hairy cell leukemia, non-Hodgkin lymphoma, malignant melanoma, multiple myeloma, mycosis fungoides, laryngeal papillomatosis, essential thrombocytosis, and carcinoid tumors.

Interferons are secreted normally by cells in response to viral infections. Binding of interferon to receptors initiates of cascade of events that ultimately involves inhibition of viral replication, suppression of mitosis, and other enhancements to the immune system.

Dose of interferon alfa will vary depending on type and brand chosen. SC route is recommended in those with coagulopathies.

Patients with Kaposi sarcoma should have routine ophthalmic examinations; the frequency depends on the severity of eye involvement.

Most eye lesions can be observed. Severe eye discomfort, disfigurement, and dysfunction indicate a need for local treatment.

Most eye lesions are simply observed.

See Mortality/Morbidity.

Ophthalmic Kaposi sarcoma has an indolent course. Most lesions are observed.

Instruct patients about the risk of HIV because Kaposi sarcoma may be the initial manifestation of AIDS.

Educate patients about the importance of routine ophthalmologic examinations.