A variety of tumors, including hamartomas and neoplastic tumors of the choroid, may lead to serous and less often to hemorrhagic detachment of the macula. Examples used in this text are presented to illustrate how these choroidal tumors may cause a clinical picture that can be confused with degenerative or inflammatory diseases of the choroid and retina affecting the macular area.
Choroidal Nevi
Choroidal nevi are developmental tumors composed of benign melanocytes. These tumors are usually not evident at birth. Their maximum period of growth occurs before puberty. However, up to 6.5% of the adult white population may have choroidal nevi. Although most do not achieve a size greater than one disc diameter, some reach a size that may simulate that of a medium-size or even large malignant melanoma. It is estimated that the risk of malignant transformation of a choroidal nevus is about 1 in 10 000. Over a period of many years these pigmented or nonpigmented choroidal nevi may cause degenerative changes in Bruch’s membrane, drusen deposition ( Figures 14.01 D and 14.02 ), serous detachment of the retinal pigment epithelium (RPE) and retina ( Figure 14.01 A), choroidal neovascularization ( Figure 14.01 D, G, and J), circinate retinopathy ( Figure 14.01 J), hemorrhagic detachment of the macula ( Figure 14.01 J), vitreous hemorrhage, and RPE hyperplasia ( Figure 14.03 A–C). Clumps or patches of orange pigment may overlie choroidal nevi, although they are more frequently observed in greater numbers overlying choroidal melanomas. Zones of atrophy of the RPE and a bone corpuscular pattern of pigment migration into the retina may occur at the inferior margin of these nevi, particularly those that are elevated and greater than two disc diameters in size ( Figure 14.01 G–I and 14.04 F–L). These areas are caused by prolonged detachment of the retina that previously existed in that area, probably during the growth phase of the tumor in childhood. Similar zones occur inferior to choroidal hemangiomas (see Figure 14.16 ) and choroidal osteomas and in patients with chronic idiopathic central serous chorioretinopathy (see Figure 3.05) and traumatic chorioretinopathy (see Figure 8.02F).
When not associated with alterations in the overlying RPE, choroidal nevi appear hypofluorescent throughout the course of angiography when they occupy either the inner portion or the entire thickness of the choroid. Angiography is helpful in detecting any abnormality involving change in the degree of pigmentation or permeability of the RPE overlying nevi ( Figure 14.01 ). Drusen overlying choroidal nevi usually show fluorescence during the first minute of the angiogram and evidence of staining but little or no change in the size of the area of fluorescence during the later stages of the study. Angiography is also of value in detecting the presence of choroidal neovascularization ( Figure 14.01 E, H, and L). Fine details of these capillary membranes may be partly or completely obscured because of the relative opacity of the exudate or reactive fibrous metaplasia of the RPE overlying the membrane: when causing subretinal exudation, neovascular membranes usually stain intensely during the course of angiography. Angiography is also helpful in detecting zones of RPE atrophy surrounding these tumors ( Figure 14.01 I). The extrinsic effects of the nevus on the surrounding retina and RPE can be readily assessed by optical coherence tomography (OCT) and fundus autofluorescence ( Figure 14.05 ).
Histologically, choroidal nevi are composed of any one of several benign cell types: spindle cells, fusiform or round cells, and branched melanocytes. They may be pigmented or nonpigmented. They may partly replace the choriocapillaris and cause drusen and choroidal neovascularization ( Figure 14.02 ).
Patients with macular detachments caused by small pigmented choroidal lesions, and those with larger more elevated lesions of uncertain growth potential, should be observed carefully with serial photographs and ultrasonography to exclude the possibility of a malignant melanoma. If the lesion is a nevus, particularly in a teenager or young patient, the detachment may resolve spontaneously. In some cases, however, with persistence of the detachment, laser treatment may be necessary ( Figure 14.01 A–C). The presence of multiple drusen on the surface of a pigmented choroidal tumor, dependent zones of pigment epithelial atrophy adjacent to the tumor, and overlying choroidal neovascularization is highly suggestive that the tumor is a choroidal nevus. While serous retinal detachment may occur overlying a nevus, it is more often a sign of growth potential, particularly if associated with fluorescein angiographic evidence of multiple pinpoint areas of leakage. (See subsection on melanoma for discussion of signs suggesting growth potential of small melanocytic tumors.) Since some choroidal nevi and melanocytomas (one of the cytologic variants of choroidal nevi) may continue to grow beyond adolescence, demonstrable growth, particularly in children or young adults, is not an unequivocal sign of malignancy. It is important to differentiate an increase in size of a nevus caused by an expanding reactive pigment epithelial proliferative and fibrous metaplastic disciform process on the surface of the nevus from growth of the melanocytic tumor itself ( Figures 14.03A–C and 14.06 ).
Patients presenting with choroidal neovascularization should be managed using the same guidelines for treatment of neovascularization associated with presumed ocular histoplasmosis and age-related macular degeneration. Those presenting with serous retinal detachment without evidence of neovascularization and with no clear signs of a growth potential can be followed for up to 4 months after onset of symptoms, for evidence of spontaneous resolution of the detachment or growth of the tumor. If no growth occurs after that period and the area of fluorescein leakage is outside the center of the fovea, the author recommends photocoagulation to the area of leakage only, while continuing to monitor the patient for evidence of tumor growth ( Figure 14.01 A–C). Whereas some of these patients will show evidence of tumor breakthrough Bruch’s membrane at the site of photocoagulation, usually many months or several years after treatment, there is no evidence to suggest that this affects the likelihood of extraocular spread of the tumor ( Figure 14.04 ). The development of a localized nodule of tumor breakthrough on the surface of these tumors after treatment, particularly if it occurs many months after the treatment, may not necessarily indicate a change in the tumor’s growth potential ( Figure 14.04 ). In some cases this extension appears to occur more as mechanical displacement of pliable tissue, rather than growth of tumor, through a focus of laser-damaged Bruch’s membrane. Other treatment options include photodynamic therapy, transpupillary thermotherapy, and intravitreal antivascular endothelial growth factor agents.
Melanocytoma
Melanocytoma ( Figure 14.06 A) and magnocellular nevus are histopathologic names used to describe highly pigmented uveal nevi that are composed of large, round, polygonal, or fusiform melanocytes with small nuclei and occasionally abundant nucleoli. These same cells are the predominant cell type found in eyes with diffuse uveal melanocytosis. Occasionally, melanocytosis of the optic disc without tumefaction can be seen (Figure 14.06B and C). Clinical differentiation of uveal melanocytomas from other highly pigmented nevi composed of spindle and dendritic melanocytes is not possible, except when the tumor involves the optic nerve head. Benign melanocytic tumors that are intrinsic to the optic nerve head and may extend into the surrounding choroid and nerve fiber layer of the retina, histologically are invariably melanocytomas. Features, other than their intense black or greenish-black pigmentation, that to some degree differentiate melanocytomas from other uveal nevi include an apparent greater propensity to exhibit some local growth potential beyond puberty; a greater predilection for undergoing spontaneous necrosis; a greater likelihood of involving adjacent structures, including the sclera as well as the optic nerve head and retina; and perhaps a lower propensity for malignant transformation ( Figure 14.06 ). The incidence of melanocytoma is equal in all ethnic groups, unlike uveal melanomas that are more common in lightly pigmented individuals. Spontaneous necrosis of a melanocytoma, particularly when it involves the optic nerve head or ciliary body, may cause pigment debris in the vitreous that may be mistaken for vitreous seeding of a melanoma. Necrosis of an iris melanocytoma may cause similar confusion because of a macrophage response to necrotic tumor in the aqueous humor and trabecular meshwork. The reason for their predilection for spontaneous necrosis is unknown. It may be that these cells are more responsive than usual to hormonal and immunologic changes. (See discussion of bilateral diffuse uveal melanocytic proliferation associated with systemic carcinoma, below.) Slow local growth can be documented over years of observation; malignant transformation is rare but known. Complications secondary to compression of the optic nerve fibers resulting in a visual field defect, rarely severe enough to lose light perception, central or branch retinal artery ( Figure 14.06 H–J) and vein occlusions and choroidal neovascularization, can occur ( Figure 14.06 D–G).
Diffuse Sclerochoroidal Melanocytic Nevus
Diffuse choroidal hyperpigmentation and thickening may be observed either as an isolated finding ( Figure 14.08 ) or in association with episcleral pigmentation (ocular melanocytosis) that may extend to involve ipisilateral skin in the distribution of branches of the trigeminal nerve (oculodermal melanocytosis: nevus of Ota). The lifetime risk of developing uveal melanoma in a Caucasian with ocular melanocytosis is estimated to be about 1 in 400 ( Figure 14.09 ). The risk in nonwhites may also be higher but has not been quantified.
Diffuse Posterior Choroidoscleral Melanotic Schwannoma
Dr. Gass had observed one girl and reviewed fundus photographs and fluorescein angiograms of a boy with an identical, peculiar, diffuse plaquelike thickening and hyperpigmentation of the posterior and inferior choroid in one eye associated with ultrasonographic and histopathologic evidence of posterior bowing and marked thickening of the choroid and sclera in the macular region ( Figure 14.07 ). The boy’s condition, observed for several years, showed no evidence of growth but he did develop retinal detachment. The optic disc in the affected eye appeared swollen. The fundus of the affected eye was more pigmented than the fellow eye, but there was no clinical evidence of melanosis oculi in the anterior segment ( Figure 14.07 A and B). Fluorescein angiography revealed irregular early hyperfluorescence and evidence of some staining over the inferior portion of the tumor. The eye was enucleated and histopathologic examination revealed a diffuse thickening of the choroid and sclera posteriorly and inferiorly by a spindle cell nevus ( Figure 14.07 C–E). In the macular region the thickest part of the tumor was associated with prominent posterior bowing of the sclera. There was evidence of serous retinal detachment and papilledema. The girl was 14 years old when first examined by Dr. Gass in January 1985 because of recent worsening of vision in the right eye that had been amblyopic since birth. The fundus findings in her right eye were identical to those in the other patient, except for the presence of a small subretinal parafoveal neovascular membrane and minimal evidence of retinal detachment ( Figure 14.07 F and G). There was irregular thickening of the slightly elevated darkened choroid in the macula and inferior fundus. The optic disc was swollen. Ultrasonography revealed a diffuse posterior medium-reflective choroidal tumor that was thickest in the macular region, where there was posterior bowing of the sclera. Ultrasonography suggested that the configuration of the tumor was similar to that previously found histopathologically in the boy ( Figure 14.07 H). The clinical diagnosis was choroidoscleral melanocytic hamartoma.
In March 1991 she returned because of further loss of vision in the right eye. Her visual acuity was hand movements only and this was limited to the inferior visual field. She had a bullous retinal detachment with shifting subretinal fluid. The tumor dimensions were unchanged except for some increase in its central elevation that appeared to result from extensive fibrous metaplastic changes of the pigment epithelium on its anterior surface. A few prominent blood vessels were visible near the tumor surface. Angiography revealed extensive staining in the area of fibrous metaplasia. This portion of the tumor was treated with intense, long-duration, 500-mm applications of argon green laser. The detachment persisted and the visual acuity was light perception only in August 1991. Because of the thick fibrovascular plaque on the tumor surface and the marked vascularity of the tumor, xenon photocoagulation was advised but refused. In 1992 she was examined at the Wills Eye Hospital, at which time the clinical findings were unchanged except for progression to no light perception in the right eye. Enucleation was advised. Histopathologic examination revealed a melanocytic hamartoma interpreted as a melanotic schwannoma with a prominent angiomatous component ( Figure 14.07 I and J).
Awareness of these diffuse hamartomatous nevoid melanocytic malformations is important because their large size and their potential for limited growth during childhood are likely to cause visual symptoms in childhood, and the tumors may be mistaken for a choroidal melanoma with intrascleral extension. Intense and extensive laser treatment and in some cases irradiation may be necessary to prevent total retinal detachment and blindness.
Multiple Choroidal Nevi and Melanoma Associated with Neurofibromatosis 1
Approximately 35% of patients with neurofibromatosis will have multiple choroidal nevi that in some patients are hypopigmented. If discovered in children, the size of the lesions and the intensity of their pigmentation may increase with age. The increased risk for development of a uveal melanoma in patients with neurofibromatosis may be related to their predilection for having not only multiple nevi, but in some cases a diffuse melanocytic hyperplasia of the entire uveal tract resembling café-au-lait lesions of the skin may be present ( Figure 14.10 ). Given the high prevalence of neurofibromatosis 1, the association of uveal melanoma and neurofibromatosis 1 may be regarded as coincidental ( Figure 14.11 ).
Choroidal nevi in patients with neurofibromatosis should not be mistaken for RPE nevi (congenital hypertrophy of the RPE and combined RPE and retinal hamartomas), which may be associated with neurofibromatosis (see Figure 12.11).
Choroidal Malignant Melanoma
A melanoma in its earlier stages of development is most likely to be observed clinically when it arises in or near the macular area. There it may cause a scotoma and photopsia produced by invasion of the retina or loss of vision caused by serous retinal detachment. The clinician who discovers a small pigmented choroidal lesion associated with a macular detachment should not, however, conclude that the lesion is a malignant melanoma, since, as mentioned previously, macular detachment may occur overlying a choroidal nevus. The most helpful signs that distinguish a small choroidal melanoma from a nevus are: (1) globular elevation of the lesion of 3 mm or more; (2) multiple areas of orange pigment deposition over the tumor surface ( Figure 14.12 D); (3) serous retinal detachment in the absence of drusen or evidence of choroidal neovascularization; (4) evidence of tumor breaking through Bruch’s membrane; and (5) fluorescein angiographic evidence of multiple pinpoint leaks that increase in size during the course of angiography on the surface of the tumor ( Figure 14.12 B, C, and F).
Analysis of Collaborative Ocular Melanoma Study (COMS) data suggests that the majority of tumors enrolled in the observational small-melanoma study were choroidal nevi rather than true melanoma, as more than 60% of such tumors did not grow (without treatment) over a period of 5 years. It is preferable to classify small choroidal melanoma (COMS size definition of 5–16 mm in basal diameter and less than 2.5 mm in height) as indeterminate melanocytic tumor rather than small melanoma, large nevus, suspicious nevus, or dormant melanoma. It can be assumed that the size category of indeterminate lesions (IML) includes an as-yet undetermined proportion of large choroidal nevus, small choroidal melanoma, or even true intermediate lesions. Several authors have tried to identify qualitative surface features that predict the likelihood of growth suggestive of melanoma. Reappraisal of the published COMS data has revealed that the presence of orange pigmentation significantly predicts risk of growth. Abnormal intrinsic choroidal vasculature, as observed by indo cyanine green, may also be predictive of growth risk.
At present, the management of IML (small choroidal melanoma) remains controversial in the absence of data from a randomized clinical trial. It must be emphasized that one can only attribute an estimated risk to a given IML depending upon the presence of “risk factors” predictive of growth. Therefore, caution should be exercised in making a diagnosis of a small choroidal melanoma in the absence of documented growth. The treatment options of prompt treatment versus observation to document growth prior to treatment should be clearly discussed with the patient. With few exceptions, the growth rate of a melanoma is constant but the growth rate of different melanomas varies widely. Some will demonstrate growth within a few months ( Figure 14.12 A), but 3 years or longer may be required to detect the growth of some melanomas. As mentioned in the previous section, the demonstration of growth, although the single most reliable sign of malignancy, may occasionally occur in a benign choroidal nevus in children and young adults. If the macular detachment persists and the choroidal lesion remains unchanged, low- to moderate-intensity argon photocoagulation applied to the area of fluorescein leakage usually causes resolution of the subretinal fluid. Only the leaking area should be treated; no attempt should be made to destroy the tumor. (See previous discussion concerning treatment of choroidal nevi with retinal detachment.) During pregnancy there is some evidence that benign nevi or low-grade melanomas may be stimulated to grow ( Figure 14.13 E–J). Large nevi, like choroidal hemangiomas and osteomas, may be first detected during the course of pregnancy because of development of an overlying serous retinal detachment (see Figures 14.15 J–L, and 14.20 J–L). Figure 14.13 (E–K) illustrates a patient who during the third trimester of pregnancy developed blurred vision caused by a localized serous macular detachment caused by 10×10×6 mm partly pigmented choroidal tumor that was associated with a focal area suggesting extension of the tumor through Bruch’s membrane. The ultrasound was atypical in that the lesion appeared moderately reflective with evidence of prominent vascularity ( Figure 14.13 H). The presence of a large zone of RPE atrophy and bone corpuscular intraretinal migration of RPE that extended from the inferior edge of the tumor to the ora serrata inferiorly suggested that the tumor had been previously associated with a long-standing retinal detachment that had spontaneously resolved. In spite of these atypical features for a melanoma, the eye was enucleated. The tumor contained many large dilated blood vessels and was composed of benign-appearing melanocytes showing no evidence of mitotic activity ( Figure 14.13 I and J).
Histopathologically the retina inferior to the tumor was markedly degenerated and showed migration of RPE into the retina around blood vessels ( Figure 14.13 K). Presumably the pregnancy played a role in causing increased tumor vascular engorgement and macular detachment. If it had not been enucleated, it is likely that the retina would have spontaneously reattached after delivery of the infant. This case and two other cases illustrated in Figure 14.04 demonstrate that biomicroscopic evidence of tumor extension through Bruch’s membrane alone is not necessarily a sign of high growth potential or malignancy. In this case it is probable that the extension through Bruch’s membrane occurred many years previously during the active growth phase of the tumor.
Choroidal melanomas will occasionally undergo spontaneous necrosis and regression. This may occur rapidly and be associated with apparent vitreous seeding or more slowly over a period of years. In some patients spontaneous necrosis may be associated with pain, anterior-chamber and vitreous inflammation, and exudative retinal detachment. The management of a patient presenting with evidence of recent spontaneous necrosis of a melanocytic tumor is difficult because of the distinct possibility that the tumor may be a melanocytoma rather than a melanoma. (See previous discussion of melanocytoma.) Because the pigmented material that often sheds into the vitreous is necrotic, vitreous biopsy or fine-needle biopsy is unlikely to provide a definitive diagnosis. If the tumor is relatively small and there is good visual function, observation may be advisable. Some of the reported cases of spontaneous resolution of melanomas may have been the result of misdiagnosis. Bleeding into the subretinal space or into the vitreous caused by erosion of the choriocapillaris by a small melanoma in the macular area may result in a misdiagnosis of a benign disciform disorder. Patients with peripherally located melanomas may occasionally present because of a retinal detachment that appears to be confined to the central macular area or because of cystoid macular edema.
Lesions other than nevi that may simulate a malignant melanoma include: hemorrhagic disciform detachment of the RPE and retina (see Figure 3.24 and 3.26), spontaneous suprachoroidal hemorrhage, combined retinal and RPE hamartomas (see Figures 12.8–12.10), hypertrophy of the RPE (see Figure 12.01), hyperplasia of the RPE (see Figures 12.07 and 12.14A–C and H–L), subretinal iron, foreign-body granuloma (see Figure 8.11C–E), varix of the ampulla, and partly organized disciform detachments of the RPE and retina secondary to a variety of causes (see Figure 3.50). Changes in permeability of the blood vessels within disciform lesions may occasionally cause these disciform masses to enlarge and simulate a melanoma (see Figure 3.50). Small amelanotic melanomas arising in the posterior fundus are often mistaken for focal choroiditis, choroidal neovascularization with overlying exudative detachment, juxtapapillary exophytic capillary hemangiomas of the retina, choroidal hemangiomas (see Figures 14.15 and 14.16 ), osteomas (see Figures 14.20 and 14.21 ), or metastatic carcinoma (see Figure 14.30 G–I). Fluorescein angiography is of limited value in the differential diagnosis of nonpigmented lesions simulating malignant melanomas. In those eyes with a mildly elevated pigmented lesion with overlying serous fluid, fluorescein angiography is most helpful in differentiating a neovascular membrane from early growth of the tumor. Several pinpoint hyperfluorescent dots of fluorescein leakage occurs due to breakdown in the RPE from growth of the lesion (Figure 14.2 A–C), while early lacy hyperfluorescence is indicative of an overlying CNVM. Echography for tumors 3 mm or thicker is perhaps the most helpful ancillary test in the differential diagnosis of choroidal tumors. It is not of help in differentiating melanocytic nevi from melanomas. Radioactive 32 P is unreliable in the differential diagnosis of melanomas. Computed tomography, magnetic resonance, and color Doppler imaging are of limited value in the differential diagnosis of lesions simulating melanomas. The COMS has recently reported the lowest incidence (0.48%) of incorrect clinical diagnosis of tumors in eyes enucleated because of suspected melanomas. The author believes that this low incidence of incorrect diagnosis is more the result of greater awareness of the clinical appearance of lesions previously mistaken for melanomas than the availability of more ancillary tests that for the most part play a limited role in physicians’ decision-making.
Histopathologically, melanomas have a variable predilection for causing damage to the overlying RPE and retina ( Figure 14.13 A and B). This is dependent on many factors, particularly their cytologic composition and growth rate.
Therapeutic considerations for choroidal melanoma depend upon tumor size (small, medium, large: COMS criteria), location (macular, juxtapapillary, peripheral), visual acuity, potential for visual acuity, status of the other eye, systemic status of the patients (comorbidity, metastasis), and patient preference. In general, small choroidal melanoma can be observed to document growth prior to treatment or treated with transpupillary thermotherapy or radiotherapy (episcleral plaque or proton beam irradiation). For medium-sized tumors radiotherapy is the preferred treatment. Enucleation is the treatment of choice for large-sized tumors and for tumors with neovascular glaucoma, opaque media, or extraocular extension. In exceptional circumstances, large tumors can also be treated by radiotherapy (one-eyed, patient preference). Enucleation is also considered for medium-sized tumors with poor vision (less than 20/400) or low potential for improved vision (macular location, optic nerve invasion). Surgical resection (transscleral) or endoresection either as sole treatment or in combination with radiotherapy is an alternative option for those medium-sized tumors which carry a high likelihood of visual loss from radiation retinopathy/optic neuropathy. Additional details about the management of patients with choroidal melanoma are available elsewhere.
Despite improvements in diagnosis and local tumor control using eye-sparing techniques, improvement in uveal melanoma survival has not been observed. This current situation underlines the need for effective methods to predict and address microscopic metastatic disease. The cytologic classification of Callender has undergone considerable modification and amplification during the past decade in an effort to provide better prognostic information regarding these tumors. More recently, prognostication of uveal melanoma based upon tumor cytogenetic and molecular assays has become feasible. Karyotype abnormalities, including loss of chromosome 3 (monosomy 3), loss of 6q, and gain of chromosome 8q, have a statistically significant association with increased risk of metastatic death. Gene expression profiling by microarray can also be used to sort tumors into one of two subgroups: less aggressive class 1 tumors and class 2 tumors with a higher risk of metastasis. Such techniques are applicable to tumor sample obtained after enucleation or resection and even after fine-needle aspiration biopsy. The ultimate goal is to develop targeted adjuvant therapies for patients at high risk of metastasis.
Rapid resolution of melanomas following either brachytherapy or ionizing irradiation usually indicates a more rapidly growing melanoma and is associated with a higher mortality. Similarly, a tumor that shows minimal decrease in size after irradiation is more likely to have been a slow-growing melanoma and is associated with a more favorable prognosis.
Bilateral Diffuse Uveal Melanocytic Proliferation Associated with Systemic Carcinoma
Bilateral diffuse uveal melanocytic proliferation (BDUMP) is an unusual syndrome occurring in predominantly elderly patients who have diffuse uveal thickening that has been attributed to proliferating, predominantly spindle-type benign melanocytes in both eyes associated with a carcinoma elsewhere in the body. The onset of visual symptoms may antedate or follow those caused by the systemic carcinoma. Visual loss is associated with either or both rapidly progressing cataract and loss of retinal function. This latter may be caused either by direct nutritional or toxic damage to the overlying retina and RPE or by bilateral secondary retinal detachment. The diffuse usually mild uveal thickening may be overlooked and may be difficult to detect with ultrasonography. There may be multiple faint orange spots or patches scattered throughout the posterior fundus ( Figure 14.14 B, M, and N). At the time of presentation or soon afterward these patients develop the sine qua non of the syndrome: multiple, slightly elevated, pigmented choroidal tumors suggesting multiple nevi or metastatic melanomas scattered throughout the fundus ( Figure 14.14 A, K, L–N). Focal pigmented and nonpigmented tumors may develop on the iris. Signs of iridocyclitis may be present.
In areas of the posterior fundus that may appear ophthalmoscopically relatively normal, early-phase fluorescein angiography may show a striking, rather widespread pattern of multiple irregularly round areas of hyperfluorescence that correspond with the orange spots seen biomicroscopically, as well as pinpoint and patchy areas of fluorescein staining later during the study ( Figure 14.14 C, P–R). This dramatic angiographic picture is apparently caused by the patchy depigmentation and destructive changes of the RPE overlying the relatively intact choriocapillaris and diffuse uveal melanocytic infiltration ( Figure 14.14 F). Autofluorescence shows decreased autofluorescence corresponding to the RPE destruction and increased autofluorescence in the intervening areas ( Figure 14.14 U and V). The presence of subretinal fluid can be confirmed by OCT ( Figure 14.14 O). Electroretinography may show severe abnormalities. Ultrasonography may show evidence of diffuse, usually mild thickening of the uveal tract. Histopathologically the melanocytic cells responsible for the diffuse uveal thickening are relatively hypopigmented plump spindle cells with a benign appearance. Mitotic figures are rare. Relative sparing of the choriocapillaris and extensive patchy areas of destruction and degeneration of the pigment epithelium and retinal receptor cells are characteristic features ( Figure 14.14 F). The multifocal more elevated and pigmented choroidal lesions are composed of large round or polygonal melanocytes, small nuclei, and abundant cytoplasm packed with melanin ( Figure 14.14 D and E). Necrosis is present in most of these lesions. The ciliary body, including the ciliary processes, is thickened by infiltration of melanocytic cells and the lens shows cataractous changes. Although some authors have classified this uveal infiltration as a melanoma, most have favored a benign classification.
These patients usually die because of metastatic carcinoma within 2 years of the onset of visual symptoms. The longest survival to date is 6.5 years for a woman whose primary carcinoma was ovarian and who had bilateral enucleations because of uncontrolled melanocytic proliferation, retinal detachment, and postirradiation complications. Another patient who had bilateral enucleations has survived 5 years without developing evidence of a primary cancer. The primary tumor in women is usually carcinoma of the uterus or ovary and in men is carcinoma of the lungs or a retroperitoneal carcinoma of uncertain origin. None of the patients to date have had evidence of metastatic melanoma. It is not known whether the intraocular proliferation is a response to substances released by the systemic carcinoma or whether they both arise from a common oncogenic stimulus. The cytologic structure of the melanocytes composing the uveal thickening and the relative sparing of the choriocapillaris suggest that diffuse congenital uveal melanocytosis may be a pre-existing requirement for the development of this syndrome. The concept that hormonal substances released by certain carcinomas are responsible for stimulating proliferation, focal melanin production, and necrosis in the uveal melanocytes, as well as causing immune-induced destruction of the RPE and retina, is an attractive but as yet unproven theory. This cancer-associated melanocytopathy may be associated with severe loss of visual function and severe electroretinographic changes before the development of retinal detachment. This suggests that these patients may share some pathogenetic features in common with those who develop acute loss of retinal receptor elements in the presence of a systemic carcinoma, the so-called cancer-associated retinopathy syndrome (see discussion in Chapter 13). Stimulation of production of melanin by melanocytes in the skin and mucous membranes of the mouth and genitalia may also occur occasionally in these patients and produce a clinical picture simulating the Peutz–Jeghers syndrome ( Figure 14.14 G–L).
The term BDUMP does not fully describe extraocular paraneoplastic manifestations of the disease, and given that extraocular manifestations may occur in about 20% of cases, the author has suggested paraneoplastic melanocytic proliferation be used to describe this unique paraneoplastic disease.
The differential diagnosis includes Harada’s disease, idiopathic uveal effusion, metastatic carcinoma, metastatic melanoma, reactive lymphoid hyperplasia of the uveal tract, and bilateral multicentric or diffuse primary uveal melanomas.
The retinal detachment in these patients is nonresponsive to corticosteroids, antimetabolites, and irradiation treatment. Plasmapheresis may be useful if steroids and antimetabolites do not help. In desperate cases use of pars plana vitrectomy and fluid–silicone exchange to tamponade the retina in place may be successful in restoring ambulatory vision.
Circumscribed Choroidal Hemangioma
Cavernous hemangioma of the choroid is a benign developmental tumor that typically occurs either as a localized tumefaction, usually in patients without other vascular malformation, or as a diffuse thickening of the choroid in patients with Sturge–Weber syndrome (see next subsection). Localized cavernous hemangiomas of the choroid are rarely detected before the third decade of life. They occur nearly always as a solitary tumor in one eye, although bilateral involvement occasionally occurs. Their rate of growth is probably maximal during the normal growth period of the individual. By adulthood the hemangioma may cause secondary degenerative and proliferative changes in the overlying pigment epithelium and cystic edema and degeneration of the retina. These changes as well as the development of some varicosity and congestion of the large vascular channels are probably responsible for the minor enlargement of choroidal hemangiomas demonstrated in later life. Unless the tumor is large and is located directly in the macular area, patients are usually asymptomatic until middle or later life (average age approximately 50 years), when they develop serous retinal detachment that spreads from the edge of the tumor into the macular area ( Figure 14.15 ). Less often, these tumors may be discovered as an incidental finding by the physician or by the patient, who on covering the eye, notices a slight distortion of central vision caused by the tumor’s presence in the macula before it causes any significant alteration in the overlying RPE and retina.
Many of these patients are referred with the incorrect diagnosis of central serous chorioretinopathy, choroiditis, disciform degeneration, metastatic carcinoma, malignant melanoma, or rhegmatogenous detachment. The hemangiomas are typically round or oval, slightly elevated, orange-red tumors with an indistinct border ( Figure 14.15 A, F, H, and J). They are most easily detected with binocular indirect ophthalmoscopy. They usually measure 2–10 disc diameters in size. Most of the tumors are centered in the paramacular area, but may extend into the edge of the central macular area. Some are juxtapapillary in location. Others may be located on the nasal side of the optic disc. In most cases the retinal detachment extends away from the margins of the tumor. The retina overlying the tumor is usually thickened by cystic degeneration. Complete separation of the tumor from the overlying retina by a serous detachment occurs infrequently. Varying amounts of splotchy yellowish material lie between the tumor and within the cystic spaces of the overlying retina ( Figure 14.15 A, F, and H). Hyperpigmentation caused by RPE hyperplasia is relatively uncommon but, when prominent, may cause a misdiagnosis of a melanoma or disciform scar. Some patients develop a bullous detachment of the retina inferior to the tumor at the time of presentation. Others will show large flask-shaped areas of atrophy of the RPE with a bone corpuscular pattern of pigmentation in the overlying retina extending inferiorly from the margins of the tumor ( Figure 14.16 B and C). These areas are indicative of previous long-standing retinal detachment with atrophy of the outer retinal layers permitting migration of pigment epithelial cells into the overlying retina. When the hemangioma is small, the subtle elevation and hyperfluorescence may be missed and a misdiagnosis of chronic idiopathic central serous chorioretinopathy may be made. Stereoscopic imaging helps to detect the elevation of the hemangioma. In addition to retinal detachment, other causes for loss of central vision in these patients include cystoid macular edema, lamellar macular hole formation, and epiretinal membrane changes. Choroidal neovascularization is an uncommon complication in these patients. The maintenance of a high oxygen tension in the vicinity of the hemangiomas may be part of the explanation, if ischemia is important in the pathogenesis of choroidal neovascularization. Retinal and optic disc neovascularization occasionally develops in patients with choroidal hemangiomas. Two patients presented to the Bascom Palmer Eye Institute because of rubeosis iridis and long-standing bullous retinal detachment caused by previously unrecognized solitary choroidal hemangiomas.
Patients with choroidal hemangiomas associated with overlying cystic changes and serous detachment demonstrate field defects corresponding with the site of the tumor and the surrounding detachment. Nerve fiber bundle defects have been reported but are unusual.
The characteristic angiographic findings in choroidal hemangiomas are: (1) a pattern of fluorescence indicative of large vascular channels corresponding to the location of the tumor in the prearterial and arterial phase of angiography ( Figure 14.15 K); (2) widespread and irregular areas of fluorescence secondary to diffuse leakage of dye from the surface of the tumor; and (3) a diffuse multiloculated pattern of fluorescein accumulation in the outer retina characteristic of polycystic degeneration and edema during the later stages of angiography ( Figure 14.15 I). A circular zone of hypofluorescence corresponding to the peripheral part of the hemangioma is often present during the early and middle stages of angiography. In some cases this corresponds with an area seen ophthalmoscopically in these tumors that may suggest slight pigmentation of the peripheral portion of the tumor. The reasons for this color and angiographic change are unclear. Evidence of cystoid macular edema may be present remote from the area of the tumor. In patients with choroidal hemangiomas without extensive secondary degenerative changes in the overlying RPE and retina, angiography may reveal only an exaggerated background choroidal fluorescence in the area of the tumor during the first few minutes of the study and no abnormalities during the later stages of angiography.
Indocyanine angiography reveals a diagnostic pattern of early diffuse hyperfluorescence (within 1 minute) with late hypofluorescence (5 minutes) and delayed washout phenomenon (beyond 10 minutes) due to exit of the dye from the tumor ( Figure 14.17 ).
Histopathologically a cavernous hemangioma of the choroid is composed of predominantly large, dilated, thin-walled vessels with minimal stroma. These tumors blend almost imperceptibly into the surrounding normal choroidal tissue ( Figure 14.16 G and H). Extensive cystic degeneration of the overlying retina is usually present and in some cases may be associated with extensive fibrous metaplasia of the RPE and, less often, RPE hyperplasia.
Although not pathognomonic for cavernous hemangioma of the choroid, the early pattern of fluorescence caused by the large vascular spaces in the tumor and the late pattern of dye staining caused by the cystic degeneration of the overlying retina are infrequently found in association with other similarly sized tumors. The 32 P uptake is usually, but not always, negative in cavernous hemangioma. Ultrasonography gives a characteristic pattern of high reflectivity that is helpful in differentiating a choroidal hemangioma from a melanoma ( Figure 14.16 E and F). In the last analysis, however, the reddish-orange color of choroidal hemangiomas as viewed with a binocular indirect ophthalmoscope is the most important diagnostic sign that differentiates choroidal hemangiomas from white or cream-colored metastatic carcinomas and amelanotic melanomas. Other orange fundus tumors that must be considered in the differential diagnosis include serous or partly organized detachment of the RPE (see Figure 3.21 and 3.23), osteoma of the choroid (see Figure 14.21 A), nodular scleritis (see Figure 11.35A), and exophytic retinal capillary hemangioma (see Figure 13.18).
Localized cavernous hemangiomas of the choroid located in the extrafoveal area and associated with serous detachment of the retina may be treated successfully with xenon or intense argon photocoagulation directed to that portion of the tumor surface where the fluorescein angiography shows evidence of diffusion of dye from the surface of the tumor ( Figure 14.15 D; see p. 1206). Photocoagulation should be sufficiently intense to create prominent whitening of the outer retinal layers. It is successful in collapsing the cystic retina on to the surface of the tumor and causing complete resolution of all subretinal fluid in most cases. It does not alter the size of the tumor. Photodynamic therapy offers the advantage of selective ablation of the tumors while sparing the overlying retina. Using standard full-fluence protocol (TAP study) we have been able to achieve excellent tumor response of more than 90% with a single treatment application ( Figure 14.17 A, D). Repeat treatment may be necessary but it is recommended to wait for about 6 weeks to 3 months to assess full response before embarking on additional treatment. Overall, excellent visual results can be expected over the long term following photodynamic therapy. It is preferable to use a single large spot rather than multiple overlapping spots to avoid damage to overlying RPE that may lead to delayed visual loss.
Transscleral cryopexy, microwave thermotherapy, and external-beam and episcleral irradiation have been used to treat choroidal hemangiomas. Because of the morbidity associated with these latter techniques they should be reserved for use either in those patients for whom photocoagulation or photodynamic therapy is not successful or for patients in whom, because of the large size and central location of the tumor, photocoagulation is unlikely to be successful in restoring or preserving visual function. Treatment is optional in patients with the incidental finding of cavernous hemangioma unassociated with retinal detachment or evidence of previous detachment. These patients, however, should be cautioned to monitor their visual acuity frequently and to be examined at yearly intervals. Treatment of patients with localized detachment and evidence of severe permanent macular damage is optional. Photocoagulation might be considered to prevent further spread of retinal damage caused by further extension of the retinal detachment.
The onset of symptoms in patients with hemangiomas usually is unrelated to any recognized precipitating cause. The first manifestation, however, of a choroidal hemangioma, as well as choroidal osteoma or a large choroidal melanocytic nevus, may be visual loss caused by development of serous retinal detachment in the macula during the latter half of pregnancy. The author has seen this occur in four women, two with choroidal hemangiomas, one each with a choroidal osteoma and large choroidal nevus. In three patients the detachment resolved spontaneously soon after delivery of the infant. The added hemodynamic stress, and perhaps other endocrine changes, occurring during pregnancy are probably responsible for transient decompensation of the altered choriocapillaris and RPE overlying the hamartomas. A similar decompensation may occur during pregnancy in some patients who develop idiopathic central serous chorioretinopathy in the absence of any other choroidal abnormality (see p. 82).
Other less common and rare choroidal tumors of vascular origin include capillary angiomas (see following discussion), hemangioendotheliomas, hemangioendotheliosarcomas, leiomyomas, and hemangiopericytomas.
Sturge–Weber Syndrome
Sturge–Weber syndrome is a nonfamilial hamartomatous disease characterized by ipsilateral angiomatous malformation involving the brain, face (nevus flammeus), and uveal tract in a patient who often has seizures, evidence of intracranial calcification, and ipsilateral development of glaucoma ( Figure 14.18 ). Most patients have diffuse hypertrophy of the choroid, eye, and face on the same side of the nevus flammeus and intracranial vascular malformation. In a few cases both eyes may be affected. The choroidal hypertrophy (diffuse angioma) gives the fundus a reddish glow compared to the opposite eye ( Figure 14.18 A and B). Elevation of the intraocular pressure and glaucomatous cupping of the optic disc may be present. Some patients with Sturge–Weber syndrome have a focal area of angiomatous thickening of the choroid in addition to the diffuse thickening ( Figure 14.18 C–H). In the author’s experience it is these patients who are most likely to develop secondary retinal detachment with shifting of the subretinal fluid, either spontaneously or after filtering operations for glaucoma. In most cases the localized highly elevated portion of the tumor is located somewhere in the posterior fundus in the paramacular area. The retina, which is usually attached to the dome of this localized thickening, shows marked cystic degeneration and some yellowish and gray tissue lying between the retina and the tumor surface. Angiographically, this area in the fundus is usually the only one that shows evidence of staining. Intense xenon or argon photocoagulation to this area may be successful in reattaching the retina ( Figure 14.18 C–H). Retinal and ciliochoroidal detachment occurring immediately after filtering surgery may reattach without treatment. When elevation of the hemangioma is so abrupt that adequate treatment cannot be applied by the transpupillary route, intravitreal photocoagulation may prove successful. In the absence of evidence of a localized choroidal tumefaction or pigmentary retinal degenerative changes, the use of prophylactic scatter laser treatment to prevent retinal detachment is probably unnecessary. Scatter treatment, however, may prove to be useful in preventing recurrent detachment in patients after successful reattachment of the retina.
