Chapter 183 – Ocular Neoplasms Related to Human Immunodeficiency Virus
PRAVIN U. DUGEL
ALLEN B. THACH
• A number of neoplastic disorders that take on an aggressive course in the setting of immunosuppression induced by the human immunodeficiency virus.
• A well-localized or diffuse mass that involves ocular adnexa, orbit, or intraocular structures.
• A constellation of ocular, adnexal, intraocular, intraorbital, and intracranial signs and symptoms dependent on the site and nature of the neoplasm.
The most common ocular neoplasm in individuals infected by the human immunodeficiency virus (HIV) is Kaposi’s sarcoma. Other tumors in such patients include lymphoma and squamous cell carcinomas. Ocular manifestation of Kaposi’s sarcoma and lymphoma may be the first sign of systemic dissemination of the neoplasm. Therefore, a thorough systemic evaluation is essential. Kaposi’s sarcoma and squamous cell carcinoma develop in the conjunctiva and ocular adnexa. Lymphomas develop at these sites, in the orbit, and intraocularly.
OCULAR ADNEXAL KAPOSI’S SARCOMA
EPIDEMIOLOGY AND PATHOGENESIS
Since the original description of Kaposi’s sarcoma in 1872, two aggressive variants of this tumor have been described. The first is an endemic variety found in Africa, especially Kenya and Nigeria, where it accounts for nearly 20% of all malignancies. The second variant, epidemic Kaposi’s sarcoma, occurs in about 30% of all patients who have AIDS. Kaposi’s sarcoma associated with AIDS is particularly aggressive and disseminates to visceral organs (gastrointestinal tract, lung, and liver) in 20–50% of patients.
The pathogenesis of AIDS-related Kaposi’s sarcoma is not known. Recent developments suggest that this tumor may be caused by human herpes virus 8 (HHV-8).  Transgenic mice that bear the HIV-1 transactivator (tat) gene under control of the virus regulatory region (HIV-LTR) produce a protein that has been shown to be a potent mitogen for human Kaposi’s sarcoma–derived cell lines. Interestingly, in mice as in humans, Kaposi’s
Figure 183-1 Kaposi’s sarcoma, stage III lesions. These are nodular, raised (>3?mm) lesions of more than 4 months’ duration.
sarcoma occurs predominantly in males, which suggests that the development may be hormonally controlled.
Typically, AIDS-associated adnexal Kaposi’s sarcoma occurs in the eyelids or conjunctiva late in the course of disease.    However, rarely ocular adnexal Kaposi’s sarcoma may be the initial manifestation of AIDS. The clinical features include a vascular lesion that may be flat or raised. In the conjunctiva it is bright red in color and is surrounded by tortuous and dilated vessels. No evidence of necrosis or discharge is seen. Three clinical stages have been described. Clinically, stage I and stage II tumors (clinically indistinguishable, differentiated only by their pathologic features) are patchy and flat (<3?mm in vertical height) and of less than 4 months’ duration. Stage III tumors are nodular and elevated (>3?mm in height; Fig. 183-1 ) and of more than 4 months’ duration.
The diagnosis of Kaposi’s sarcoma may be based on the clinical findings in a patient who has a history of HIV infection. Tortuous and dilated vessels around the mass and the presence of subconjunctival hemorrhages help to make the correct diagnosis. The hemorrhages may be recent or old, and the blood pigment is usually present. Tissue diagnosis may be obtained by local excision of the tumor.
The differential diagnosis of ocular adnexal Kaposi’s sarcoma includes subconjunctival hemorrhage, hemangioma, foreign body,
allergic reaction, infection, and orbital cellulites. Slit-lamp evaluation, with lid eversion and a thorough examination of the entire conjunctival surface, discloses the typical, densely vascular nature of the tumor. Therefore, such an evaluation is undertaken in all patients, especially those known to have AIDS.
The recognition of ocular adnexal Kaposi’s sarcoma by the ophthalmologist is important. Once this tumor has been recognized, a thorough evaluation must be undertaken to rule out systemic Kaposi’s sarcoma. Therefore, an immediate referral to a qualified internist or oncologist is necessary. Systemic lesions often precede ocular manifestation, but it is thought that approximately 20% of patients who have systemic Kaposi’s sarcoma have an ocular manifestation. Occasionally, patients present to the ophthalmologist with recurrent epithelial defects, irritation, red eyes, or entropion that result from ocular adnexal Kaposi’s sarcoma, which may be the first manifestation of a more widespread disease.
The pathological features of ocular adnexal Kaposi’s sarcoma are dependent on the size, and therefore duration, of the lesion. They can range from benign vascular changes to the malignant appearance of spindle cell formation. Three histological stages have been described and correspond to the clinical stages already discussed. Histologically, stage I tumors consist of thin, dilated vascular channels lined by flat endothelial cells that are often filled with erythrocytes. Abnormal mitotic figures are usually not seen. A moderate amount of mononuclear cells infiltrate the abnormal vessels, but no spindle cells or slit spaces are seen. Stage II lesions feature plump, fusiform cells that line thin, dilated, empty vascular channels. Many of these cells have hyperchromatic nuclei. Usually, no mitotic cells are noted. A sparse, inflammatory infiltrate, which consists mostly of macrophages, plasma cells, and lymphocytes, is seen. Foci of immature spindle cells and early slit vessels occur. Stage III lesions are characterized by large aggregates of densely packed spindle cells that have hyperchromatic nuclei and occasional mitotic figures. Between these spindle cells are slit spaces, many of which contain erythrocytes ( Fig. 183-2 ). Inflammatory cells are scant. On the basis that recurrences are of an earlier stage than the primary tumor and that all three stages can be present within the same lesion, it is believed that these three stages are part of a continuum.
Figure 183-2 Kaposi’s sarcoma, histopathology. Stage III lesions show densely packed spindle cells with hyperchromatic nucleus.
The treatment of ocular adnexal Kaposi’s sarcoma depends on the ocular complaints of the patient as well as on the possible systemic manifestations of the tumor. If the patient has no ocular symptoms, no local treatment is required. After systemic evaluation, if the patient is found to have systemic Kaposi’s sarcoma that requires chemotherapy, the ocular lesions often regress significantly after systemic chemotherapy. Only if ocular symptoms continue after a full course of systemic chemotherapy or only if significant ocular symptoms occur in a patient who does not have systemic Kaposi’s sarcoma should local treatment be considered. Radiotherapy is an effective local treatment, but the expense and complications are significant. Complications specifically reported after irradiation of ocular adnexal Kaposi’s sarcoma include skin erythema, hair loss, and possible radiation-induced optic neuropathy. A safer and more effective treatment regimen, based on the clinical and histopathological stage of the tumor and its location, involves surgical excision and cryotherapy. If the tumor is confined to the bulbar conjunctiva and is clinical stage I or stage II, excisional biopsy with 1–2?mm of tumor-free margins is considered. Clinical stage III Kaposi’s sarcoma of the bulbar conjunctiva is excised surgically, preferably after delineation by fluorescein angiography, which may allow better visualization of tumor-associated vessels. Stage I and stage II Kaposi’s sarcoma that involve the eyelid may be treated with cryotherapy. However, stage III Kaposi’s sarcoma of the eyelid may require radiotherapy. Injection of intralesional interferon may be effective in some cases.
COURSE AND OUTCOME
Untreated Kaposi’s sarcoma may grow and damage the ocular adnexa and ocular surface. Frequent subconjunctival hemorrhage may occur. With surgical intervention, most tumors are excised totally. Ocular morbidity may be prevented by early diagnosis and treatment with either surgical excision, cryotherapy, or intralesional interferon injection. Radiation treatment may result in ocular sicca.
CONJUNCTIVAL INTRAEPITHELIAL NEOPLASIA
In immunocompetent individuals, conjunctival intraepithelial neoplasia (CIN) is the most common neoplasm of the ocular surface. It is a known precursor of squamous cell carcinoma, the most common conjunctival malignant neoplasm. Traditional risk factors for this disease include ultraviolet light exposure, petroleum products, heavy cigarette smoking, light hair and ocular pigmentation, and family history.  The most significant risk factor, however, is human papillomavirus infection. Although CIN typically affects men in the sixth and seventh decades of life, this ocular tumor has been observed in young AIDS patients. Cervical intraepithelial neoplasia, increasingly common in women who have AIDS, shares some characteristics with CIN—both involve nonkeratinized epithelium, occur at transitional zones of surface epithelium, and have been associated with human papillomavirus infection.
SQUAMOUS CELL CARCINOMA
EPIDEMIOLOGY AND PATHOGENESIS
In patients who have AIDS, several studies describe an aggressive form of squamous cell carcinoma in the conjunctiva and/or eyelids.     The pathogenesis of CIN and squamous cell carcinoma in AIDS patients is not clear. Two hypotheses exist. First, a generalized depression of immune surveillance may be present with severe immunosuppression. Second, immunosuppression by
HIV may enable coinfection with the human papillomavirus, which is a known causative agent for CIN as well as squamous cell carcinoma.
The clinical features include a hyperemic nodular mass with well-defined borders in the conjunctiva or eyelid ( Fig. 183-3 , A). This mass is often more than 2?mm in vertical height and may contain areas of necrosis. The overlying epithelium is of a grayish color, which distinguishes it from the surrounding normal epithelium.
Several epithelial as well as stromal neoplasms may mimic squamous cell carcinomas of the ocular adnexa and conjunctiva. Excisional biopsy in small tumors or incisional biopsy of the larger tumors establishes the tissue diagnosis.
The differential diagnosis of squamous cell carcinoma includes basal cell carcinoma, Kaposi’s sarcoma, lymphoma, sebaceous carcinoma, and amelanotic melanoma. Squamous cell carcinoma may be differentiated by a lack of the vascularity that occurs with Kaposi’s sarcoma, the lack of significant overlying necrosis that occurs with basal cell carcinoma, and the lack of a salmon or a pink color that occurs with lymphoma. A rough, grayish, amorphous, raised epithelial lesion characterizes squamous cell carcinoma. Histological examination of the tumor is essential to rule out other neoplasms.
Extensive squamous cell proliferation is the most prominent histological manifestation. The epithelium shows acanthosis and dyskeratosis ( Fig. 183-3 , B). Stromal invasion is present, with a concentric collection of epithelial and spindle cells that have prominent nuclei and nucleoli. Abnormal mitotic figures are abundant within neoplastic cells. Immunohistologic staining of the spindle cells and other infiltrating carcinoma cells shows positive staining with antibodies to cytokeratin. Polymerase chain reaction studies are often positive for the human papillomavirus.
TREATMENT, COURSE, AND OUTCOME
The only known systemic association of CIN is cervical intraepithelial neoplasia. Both are thought to be caused by the human papillomavirus. Ophthalmologists must be aware of suspicious lesions in the ocular adnexa in AIDS patients. Treatment consists of total excision of the tumor with clear surgical margins documented histologically. The patient is checked frequently thereafter for early detection of any recurrence or invasion into adjacent tissue, or both. One patient who had CIN was treated effectively with topical interferon. Early diagnosis and total excision of the tumor carry a good prognosis against recurrence.
INTRAOCULAR, INTRAORBITAL, AND CENTRAL NERVOUS SYSTEM LYMPHOMA
EPIDEMIOLOGY AND PATHOGENESIS
Non-Hodgkin’s lymphoma associated with HIV infection is now recognized more frequently as survival increases in patients who have AIDS. Approximately 20% of patients who are affected with both AIDS and non-Hodgkin’s lymphoma have extranodular involvement,
Figure 183-3 Squamous cell carcinoma. A, Raised nodular, hyperemic mass with grayish overlying epithelium. B, Extensive squamous cell proliferation with acanthosis, dyskeratosis, and infiltration into the stroma (hematoxylin and eosin). (With permission from Muccioli C, Belfort R, Burnier M, Rao N. Squamous cell carcinoma of the conjunctiva in a patient with the acquired immune deficiency syndrome. Am J Ophthalmol. 1996;121:94–6.)
especially of the central nervous system (CNS), compared with less than 1% of patients who do not have AIDS but who have non-Hodgkin’s lymphoma. The risk for the development of ocular and CNS non-Hodgkin’s lymphoma in patients who have AIDS has been estimated to be approximately 100 times that of immunocompetent patients. In AIDS-affected patients, the disease is more likely to be a high-grade B-cell malignancy that can develop in the ocular adnexa or orbit. Nevertheless, intraocular lymphoma in AIDS patients is quite rare.
The pathogenic mechanism of AIDS-associated B-cell lymphoma is not known. Possible hypotheses include the synergistic association between the Epstein-Barr virus and HIV. Immunosuppression induced by HIV may enable the clonal expansion of B cells immortalized by Epstein-Barr virus. With clonal expansion, a small population of B cells may undergo genetic alteration (c-myc rearrangement), which transforms these cells into truly monoclonal malignant lymphoma. Interleukins, which are involved in differentiation and maturation of white blood cells, may modulate this process. Another hypothesis proposes the proliferation of B cells because of chronic antigenic stimulation, which may occur by stimulation via retroviral products and which results in a lymphomatous transformation.
Intraocular involvement of non-Hodgkin’s lymphoma in patients who have AIDS is similar to that in patients who do not have AIDS. Patients often present with poor vision, which may be unilateral or bilateral. Minimal to moderate anterior segment inflammation may occur. The primary site of inflammation, however, is the posterior segment. A significant vitritis may be seen with peripapillary infiltrates and often with a marked swelling of the optic disc. Yellow-white, subretinal pigment epithelium lesions ( Fig. 183-4 ) are most characteristic. Most of the lesions represent localized and multiple areas of retinal pigment epithelial detachment that results from tumor infiltration. The
Figure 183-4 Intraocular lymphoma. Peripapillary hemorrhage and subretinal infiltrates.
aggressive nature of this tumor may cause infiltration into retinal vessels, which produces vascular sheathing, vein occlusion, and artery occlusion. Patients who have orbital or sinus involvement may present with facial numbness, proptosis, poor vision, diplopia, and ptosis.
Patients with primary CNS involvement may present with a history of diplopia, ocular motor paresis, and signs and symptoms of increased intracranial pressure. Neuroimaging studies show a typical periventricular, aqueductal position of these lymphomas. However, the diagnosis requires cerebrospinal fluid cytology. Ocular manifestations may be the first and only sign of primary CNS lymphoma. Alternatively, ocular manifestations may occur as a result of metastasis late in the course of systemic lymphoma. However, a full systemic evaluation with particular attention to the CNS must be carried out in patients who have ocular lymphoma.
The clinical features of lymphoma depend on the location. The diagnosis is best made by a vitrectomy followed by cytologic examination of the specimen.  The diagnosis of adnexal or intraorbital lymphoma is made on the basis of fine-needle aspiration or an incisional biopsy. Intracranial lymphoma is diagnosed by neuroimaging studies followed by lumbar puncture and/or craniotomy with a biopsy of the brain.
The differential diagnosis of intraocular lymphoma includes infectious multifocal choroiditis, retinal necrosis induced by varicella-zoster virus, ocular toxoplasmosis, ocular histoplasmosis, and cytomegalovirus (CMV) retinitis. The differential diagnosis of orbital lymphoma includes all forms of bacterial and fungal infections. Intraorbital lymphoma tends to be more indolent and slowly progressive than an intraorbital infection. The differential diagnosis of intracranial lymphoma includes toxoplasmosis, AIDS-associated infectious or noninfectious dementia, cryptococcosis, and CMV.
Histopathological studies reveal that the tumor cells are usually large B cells that exhibit prominent nucleoli or multiple nucleoli in a large nucleus. The neoplastic cells may show an eosinophilic cytoplasm and altered nuclear/cytoplasmic ratio. Necrotic foci may be observed. Abnormal mitotic figures are found frequently. 
TREATMENT, COURSE, AND OUTCOME
Treatment involves radiation and chemotherapy (see Chapter 184 ). Despite treatment, patients usually die within 12–18 months.
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